Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion
Phase: PHASE3
Conditions: SMA - Spinal Muscular Atrophy, Gene Therapy
Sponsor: Novartis Gene Therapies

Protocol Number:  AVXS-101-CL-303 
 
Official Title:      
 Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients 
with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering AVXS-101 by 
Intravenous Infusion  
 
NCT Number:  NCT03306277 
 
Document Date:  4 October 2018 

TITLE PAGE 
AVXS-101 
AVXS-101-CL-303 
IND Number: 
15699 
Protocol Title: 
Phase 3, Open-Label, Single-Arm, Single-Dose Gene 
Replacement Therapy Clinical Trial for Patients with Spinal 
Muscular Atrophy Type 1 with One or Two SMN2 Copies 
Delivering AVXS-101 by Intravenous Infusion 
Indication Studied: 
Spinal Muscular Atrophy Type 1 
Sponsor Address: 
AveXis, Inc. 
2275 Half Day Road 
Bannockburn, IL 60015 
Protocol Version/Date: 
4.0 / 4 October 2018 
The study will be completed according to the guidelines of Good Clinical Practice.  Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are protected, 
consistent with the principles that have their origin in the Declaration of Helsinki. 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or 
confidential and may not be disclosed unless such disclosure is required by federal or state law or 
regulations.  In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them.  These restrictions on 
disclosure will apply equally to all future information supplied to you which is indicated as privileged or 
confidential. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 2 of 136 
1. 
ADMINISTRATIVE INFORMATION 
1.1. 
Approval 
REPRESENTATIVES FROM AVEXIS: 
This trial will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical trial protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki 
• 
International Council for Harmonization and the Harmonized Tripartite Guideline for Good 
Clinical Practice E6 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations 
SIGNATURES (may be applied electronically and will therefore be maintained in the 
electronic system): 
 
 
 
 
 
Vice President Clinical Development 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Executive Director Clinical Development 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Senior Vice President Regulatory Affairs, AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Vice President Clinical Operations 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Sr. Director, Head of Biostatistics 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 3 of 136 
1.2. 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for AVXS-101.  I have read the 
AVXS-101-CL-303 protocol and agree to conduct the study in accordance with the relevant 
current protocol(s).  I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  I agree to personally conduct or supervise the 
investigation(s).  I also agree to promptly report to the Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC) all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others.  Additionally, I will not make any changes 
in the research without IRB/IEC approval, except where necessary to eliminate apparent 
immediate hazards to human subjects.  I agree to protect the safety, rights, privacy, and well-
being of study participants.  I agree to comply with: 
•
The ethical principles that have their origin in the Declaration of Helsinki
•
International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline
•
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations including but not limited to Informed Consent 21 CFR Part 56, Institutional
Review Board Review in 21 CRF Part 56, Adverse Event Reporting as defined in
Section 13.4 and in 21 CFR 312.64, Adequate/accurate and accessible records in accordance
with 21CFR 312.62 and 312.68.
•
Terms outlined in the study site agreement
•
Responsibilities of the Investigator (per regulatory guidelines and applicable regulations) I
further authorize that my personal information may be processed and transferred in
accordance with the uses contemplated in this protocol.
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator or 
Consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.  Your acceptance of this document constitutes agreement 
that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 
 _________________________________________________ 
Printed Name of Investigator 
 _________________________________________________ 
Signature of Investigator 
 _________________________________________________ 
Date (ddMmmyyyy) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 4 of 136 
1.3. 
Contact Information 
Table 1: 
Important Study Contact Information 
Role in Study 
Name/Address and Telephone Number 
Clinical Study Leader 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Responsible Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Drug Safety Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Serious Adverse Event 
Reporting 
Please see Project Management Plan in TMF or Study Contact list 
in ISF 
24-Hour Emergency Contact 
Please see Study Contact List in ISF 
 
Table 2: 
Study Vendor Listing 
Role in Study 
Name/Address 
Clinical Research 
Organization 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Investigational Product 
Shipment 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Video 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Independent Video Review 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Holter Monitor and  
12-lead Electrocardiogram 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
immunoassays 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
viral shedding studies 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Autopsy 
Please see Project Management Plan in TMF or Study Contact list in ISF 
ISF = Investigator site file; TMF = trial master file 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 5 of 136 
2. 
SYNOPSIS 
Name of Sponsor/Company: AveXis, Inc. 
Name of Investigational Product: AVXS-101 
Name of Active Ingredient: Survival Motor Neuron Gene by Self‐Complementary Adeno-Associated 
Virus Serotype 9 (AAV9) 
Title of Study: Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical 
Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering 
AVXS-101 by Intravenous Infusion 
Study Center(s): 10 to 20 United States (US) Investigators 
Studied Period (years): 
Estimated date first patient enrolled: 2Q 2017 
Estimated date last patient completed: 4Q 2019 
Phase of Development: 3 
Objectives: 
Co-Primary 
• 
Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of 
functional independent sitting for at least 30 seconds at the 18 months of age study visit. 
• 
Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is defined by 
the avoidance of combined endpoint of either (a) death or (b) permanent ventilation, which is 
defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via 
non-invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible 
illness, excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
Co-Secondary 
• 
Determine effect of AVXS-101 on the ability to thrive defined as achieving all of the following at 
18 months of age: 
o Does not receive nutrition through mechanical support (e.g., feeding tube) or other non-oral 
method 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• 
Determine the effect of AVXS-101 on the ability to remain independent of ventilatory support, 
defined as requiring no daily ventilator support/usage at 18 months of age 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 6 of 136 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• 
Determine the safety of AVXS-101 based on the development of unacceptable toxicity defined as 
the occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 
higher, unanticipated, treatment-related toxicity 
Methodology: 
Phase 3, open-label, single-arm, single-dose, study of AVXS-101 (gene replacement therapy) in up to 
twenty (20) patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria, may be 
either symptomatic or pre-symptomatic and are genetically defined by no functional survival motor 
neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2) and who are 
< 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1).  Enrolling up to 
twenty (20) patients under the broader enrollment criteria is projected to enable enrollment of at least 
15 patients that meet the Intent-to-Treat Population (ITT) criteria.  The ITT population is identified as 
symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene 
modifier mutation (c.859G>C) who meet all other study enrollment criteria.  In addition, the first 
3 patients enrolled must meet the criteria for the Intent-to-Treat Population to enable a comparison of 
CHOP-INTEND scores at 1-month following gene replacement therapy to enable a comparison of 
patient response between AVXS-101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 7 of 136 
(AVXS-101-CL-101). 
The study includes a screening period, a gene replacement therapy period, and a follow-up period.  
During the screening period (Days –30 to –2), patients whose parent(s)/legal guardian(s) provide 
informed consent will undergo screening procedures to determine eligibility for study enrollment.  
Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day –1 to 
Day 3).  On Day –1, patients will be admitted to the hospital for pre-treatment baseline procedures.  On 
Day 1, patients will receive a 1-time intravenous (IV) infusion of AVXS-101 and will undergo 
in-patient safety monitoring over the next 48 hours.  Patients may be discharged 48 hours after the 
infusion, based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of 
Study at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 
assessments until the End of Study when the patient reaches 18 months of age.  After the End of Study 
visit, eligible patients will be asked to rollover into the long-term follow up study. 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, 
except for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
There will be at least a 4 -week dosing interval between dosing of the first 3 patients to allow review of 
the safety analysis from 6-time points (day 1, 2, 7, 14, 21, and 30 visits) as well as early signals of 
efficacy including CHOP-INTEND score prior to dosing of the next patient.  The first 3 patients 
enrolled must meet the criteria for the Intent-to-Treat Population.  AveXis will compare the 
CHOP-INTEND 1 month improvement for the AVXS-101-CL-303 patients that meet the ITT criteria to 
assess the clinical response to the dose 1.1 × 1014 vg/kg as being what was expected from the Cohort 2 
patients in the Phase 1 trial (AVXS-101-CL-101).  This comparison will be performed as a per patient 
assessment for the first 3 patients.  The individual patients who receive their gene therapy at 0-3 months 
of age will be compared to a value of 10 CI points, while patients who receive their gene therapy at >3 
but <6 months of age will be compared to a value of 5 CI points.  Furthermore, patients from either age 
group are expected to maintain the improvement in the absence of an acute illness or perioperatively.  If 
the expected CI improvements are observed for the first 3 ITT patients, AveXis will remove the 4-week 
interval between patients and proceed to dose at least 12 additional patients that meet the ITT criteria 
and perform safety and efficacy assessments as described elsewhere in the clinical protocol 
(AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  Study enrollment will stop as soon 
as practical following enrollment of the fifteenth patient that meets the ITT criteria.  If the expected CI 
improvements are not observed for the first 3 ITT patients, AveXis will discuss next steps with the FDA 
before continuing study enrollment. 
In an attempt to dampen the host immune response to the adeno-associated virus (AAV) derived 
therapy, all patients will receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 
24 hours prior to AVXS-101 infusion until at least 30 days post-infusion.  After 30 days of treatment, 
the dose of prednisolone can be tapered for patients whose alanine aminotransferase (ALT) values, 
aspartate aminotransferase (AST) values, and T-cell response are below the threshold of 2 X ULN for 
ALT and AST, and < 100 SFC/106 PBMCs in accordance with the following treatment guideline: 
1 mg/kg/day until at least 30 days post-infusion, 0.5 mg/kg/day at Weeks 5 and 6, 0.25 mg/kg/day at 
Weeks 7 and 8, and discontinued at Week 9. 
Efficacy will be assessed by achievement of the key developmental milestone of functional independent 
sitting for at least 30 seconds at the 18 months of age study visit and survival at 14 months of age.  The 
ability to thrive (as defined above) and the ability to remain independent of ventilatory support (as 
defined above) will also be assessed at 18 months of age.  Additional developmental milestones will be 
assessed using Bayley Scales of Infant and Toddler Development (Version 3).  Safety will be assessed 
through monitoring adverse events (AEs), concomitant medication usage, physical examinations, vital 
sign assessments, cardiac assessments, and laboratory evaluations.  A Data Safety Monitoring Board 
(DSMB) will review safety data on a quarterly basis and will also convene within 48 hours should any 
patient experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 8 of 136 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or requires 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the DSMB 
will review the safety information and provide its recommendation.  The DSMB can recommend early 
termination of the study for safety reasons. 
Number of Patients (planned): Up to twenty (20) patients that meet the study enrollment criteria to 
enable at least 15 patients that meet ITT criteria.  Study enrollment will stop as soon as practical 
following enrollment of the fifteenth patient that meets the ITT criteria. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
1. 
Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or 
point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier 
mutation (c.859G>C))2.   
2.    The first 3 patients enrolled must meet the criteria for the Intent-To-Treat Population. 
3. 
Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
4. 
Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
5. 
Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab prophylaxis 
(also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also 
recommended in accordance with American Academy of Pediatrics (26) 
6. 
Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply 
with study procedures and visit schedule 
 
Exclusion Criteria: 
1. 
Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. 
Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without any 
supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does 
not decrease by ≥ 4 percentage points 
3. 
Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the 
screening period or requiring ventilatory support while awake over the 7 days prior to screening or 
at any point during the screening period prior to dosing 
4.  Patients with signs of aspiration/inability to tolerate non-thickened- liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass the 
swallowing test will be allowed to enroll in the study 
5. 
Patients whose weight-for-age is below the third percentile based on World Health Organization 
(WHO) Child Growth Standards[25] 
6. 
Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for 
hepatitis B or C, or Zika virus) 
7. 
Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 9 of 136 
2 weeks prior to screening 
8. 
Upper or lower respiratory infection requiring medical attention, medical intervention, or increase 
in supportive care of any manner within 4 weeks prior to screening 
9. 
Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy such 
as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients 
11. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents 
used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, 
immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene 
replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) 
binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody titer > 1:50, he 
or she may receive retesting within 30 days of the screening period and will be eligible to 
participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values (gamma glutamyl- transpeptidase [GGT], ALT, 
and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or 
> 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy 
14.  Participation in recent SMA treatment clinical study (with the exception of observational 
Cohort studies or non-interventional studies) or receipt of an investigational or commercial 
compound, product, or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic 
acid) at any time prior to screening for this study.  Oral β-agonists must be discontinued at least 
30 days before gene therapy dosing.  Inhaled albuterol specifically prescribed for the purposes of 
respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior 
to screening for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal surgery or 
tracheostomy) 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to 
travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain 
from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 
19. Gestational age at birth < 35 weeks (245 days) 
Investigational Product, Dosage and Mode of Administration: 
Patients will receive a 1-time dose of AVXS-101 at 1.1 × 1014 vg/kg, a dose determined to be equivalent 
to the dose received by the Cohort 2 patients in the Phase 1 study (AVXS-101-CL-101) by direct testing 
using improved analytical methods. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 10 of 136 
Duration of Treatment: 
AVXS-101 will be administered as a 1-time IV infusion over approximately 30-60 minutes, dependent 
upon the volume required. 
Reference Therapy, Dosage and Mode of Administration: Not Applicable 
Criteria for Evaluation: 
Efficacy: 
Co-Primary 
• 
Proportion of patients that achieve functional independent sitting for at least 30 seconds at the 
18 months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler Development 
(Version 3), confirmed by video recording, as a patient who sits up straight with head erect for at 
least 30 seconds 
• 
Survival at 14 months of age.  Survival is defined by the avoidance of the combined endpoint of 
either (a) death or (b) permanent ventilation, which is defined by tracheostomy or by the 
requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive ventilatory support) 
for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative 
ventilation.  Permanent ventilation, so defined, is considered a surrogate for death 
Co-Secondary 
• 
The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate thin 
liquids (as demonstrated through a formal swallowing test) and to maintain weight (> third 
percentile based on World Health Organization [WHO] Child Growth Standards [25] for age and 
gender) without need of gastrostomy or other mechanical or non-oral nutritional support at 
18 months of age 
• 
The proportion of patients who are independent of ventilatory support, defined as requiring no daily 
ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative 
ventilation, as defined above through assessment of actual usage data captured from the device 
(Phillips Trilogy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 11 of 136 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• 
Incidence of elevated liver function tests (LFTs) and/or unresolved liver function enzymes (LFEs) 
• 
Incidence of CTCAE Grade 3 or higher toxicity, treatment emergent- adverse events 
• 
Clinically significant changes in laboratory values, physical exams, cardiac assessments or vital 
signs 
• 
Research Immunology Blood Labs including serum antibody to AAV9 and SMN as well as IFNγ 
Enzyme-linked ImmunoSpot (ELISpot) to detect -T-cell- responses to AAV9 and SMN 
Statistical Methods: 
This is a pivotal Phase 3, open-label, single-arm, single-dose, study assessing the efficacy and safety of 
AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal muscular atrophy 
(SMA) Type 1 who meet enrollment criteria, may be symptomatic or pre-symptomatic and are 
genetically defined by no functional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival 
motor neuron 2 gene (SMN2) and who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1).  Enrolling up to twenty (20) patients under the broader enrollment criteria 
is projected to enable enrollment of at least 15 patients that meet the Intent-to-Treat Population (ITT) 
criteria.  The ITT population is identified as symptomatic patients with bi-allelic SMN1 deletions and 
2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) and will comprise the primary 
population for evaluation of the primary and secondary endpoints.  Study power is based upon efficacy 
analysis of the ITT population.  Furthermore, the first 3 patients enrolled must meet criteria for the 
Intent-To-Treat Population to enable a comparison of CHOP-INTEND scores at 1-month following 
gene replacement therapy to enable a comparison of patient response between AVXS-101-CL-303 
patients and patient results from the Phase 1 trial (AVXS-101-CL-101).  Patients with 1 copy of SMN2, 
pre-symptomatic patients and patients with the SMN2 gene modifier mutation (c.859G>C) will be 
evaluated separately as part of additional subgroup analyses.  Details of all analyses will be contained 
within the Statistical Analysis Plan. 
Based upon widely cited natural history of the disease (Pediatric Neuromuscular Clinical Research 
Network [PNCR]) [21], it is expected that no patient meeting the study entrance criteria (SMN2 copy 
number of 2 without the SMN2 gene modifier mutation (c.859G>C)) would be expected to attain the 
ability to sit without support for at least 30 seconds at or before the 18 months of age study visit or other 
milestones (rolling over, standing, walking) assessed as part of the study. 
Assuming the true response rate for the primary endpoint is actually zero (or as low as 0.1%) in the 
population of interest of the historical control, the first co-primary efficacy endpoint hypothesis is 
whether the AVXS-101 treated patients achieve a response rate greater than 0.1%.  Based upon 
preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at least 40% of treated 
patients in the ITT population are expected to achieve the co-primary efficacy endpoint of functional 
independent sitting for at least 30 seconds at the 18 months of age visit.  With the assumption for the 
true response rate of AVXS-101 for the primary endpoint being in the range of 30% - 40%, a sample 
size of 15 patients that meet ITT criteria will be enrolled and assuming approximately 30% of patients 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 12 of 136 
are excluded from analysis, would yield an ITT population that would provide power of > 90% to detect 
a significant difference from 0.1% with α = 0.025 using a 1-sided exact test for a binomial proportion. 
The second co-primary efficacy endpoint of survival at 14 months of age will be evaluated by 
comparing the results observed in the ITT population with the results from the age and gender-matched 
control patients selected from existing natural history data sets (PNCR) [Neurol. 2014; 
83(9):810-817].  It is anticipated that 75% of patients in the PNCR population would not survive beyond 
13.6 months of age, and that these control patients will represent a 25% survival rate based upon the 
natural history of the disease.  Based upon preliminary results from the ongoing Phase 1 clinical study 
(AVXS-101-CL-101), at least 80% of patients in the ITT population are expected to survive, as defined, 
through 14 months of age.  With this efficacy, an enrolled sample size of 15 patients that meet ITT 
criteria (assuming 30% of patients are excluded from the analysis) would yield an ITT population that 
would provide power of > 80% to detect a significant difference from the historical control with 
α = 0.05 using a 2-sided Fisher’s Exact test. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 13 of 136 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
ADMINISTRATIVE INFORMATION .......................................................................2 
1.1. 
Approval .......................................................................................................................2 
1.2. 
Investigator’s Agreement ..............................................................................................3 
1.3. 
Contact Information ......................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background .................................................................................................................20 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients ................................................21 
5.3. 
Non-clinical Studies ....................................................................................................23 
5.4. 
Clinical Studies ...........................................................................................................26 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................28 
6.1. 
Primary Objectives .....................................................................................................28 
6.2. 
Secondary Objective ...................................................................................................28 
 
 
6.4. 
Safety Objectives ........................................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.2. 
Number of Patients .....................................................................................................32 
7.3. 
Criteria for Study Termination ...................................................................................32 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................33 
8.1. 
Patient Inclusion Criteria ............................................................................................33 
8.2. 
Patient Exclusion Criteria ...........................................................................................33 
8.3. 
Patient Withdrawal Criteria ........................................................................................35 
9. 
TREATMENT OF PATIENTS ..................................................................................36 
9.1. 
Description of Product ................................................................................................36 
9.2. 
Prior and Concomitant Medications ...........................................................................36 
9.2.1. 
Prophylactic Administration of Prednisolone .............................................................36 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 14 of 136 
9.2.2. 
Prohibited Medications ...............................................................................................37 
9.3. 
Treatment Compliance ................................................................................................37 
9.4. 
Randomization and Blinding ......................................................................................37 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT ....................................38 
10.1. 
Study Product ..............................................................................................................38 
10.2. 
Study Product Dose and Dose Justification ................................................................38 
10.3. 
Study Product Packaging and Labeling ......................................................................38 
10.4. 
Study Product Storage ................................................................................................38 
10.5. 
Study Product Preparation ..........................................................................................39 
10.6. 
Study Product Administration ....................................................................................39 
10.7. 
Dose Adjustment Criteria ...........................................................................................39 
10.8. 
Study Product Accountability .....................................................................................39 
10.9. 
Study Product Handling and Disposal ........................................................................39 
11. 
ASSESSMENT OF EFFICACY ................................................................................41 
11.1. 
Developmental Milestones .........................................................................................41 
11.2. 
Motor Function Tests ..................................................................................................42 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones ........42 
11.2.2. 
CHOP-INTEND .........................................................................................................42 
11.3. 
Video Evidence ...........................................................................................................43 
11.4. 
Compound Motor Action Potential ............................................................................43 
12. 
ASSESSMENT OF SAFETY .....................................................................................44 
12.1. 
Safety Parameters .......................................................................................................44 
12.1.1. 
Demographic/Medical History ...................................................................................44 
12.1.2. 
Physical Examinations ................................................................................................44 
12.1.3. 
Vital Signs/Weight and Length ..................................................................................45 
12.1.4. 
Electrocardiogram .......................................................................................................45 
12.1.5. 
12-Lead Holter Monitor ..............................................................................................45 
12.1.6. 
Echocardiogram ..........................................................................................................46 
12.1.7. 
Pulmonary Examinations ............................................................................................46 
12.1.8. 
Swallowing Test .........................................................................................................46 
12.1.9. 
Photographs of Infusion Site ......................................................................................47 
12.1.10. 
Laboratory Assessments .............................................................................................47 
12.1.10.1. Hematology .................................................................................................................48 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 15 of 136 
12.1.10.2. Blood Chemistry .........................................................................................................49 
12.1.10.3. Urinalysis ....................................................................................................................50 
12.1.10.4. Virus Serology ............................................................................................................50 
12.1.10.5. Capillary Blood Gas ...................................................................................................50 
12.1.10.6. Immunology Testing (ELISA and IFNγ- ELISpots) ..................................................51 
12.1.10.7. AAV9 Antibody Screen in Mother .............................................................................51 
12.1.10.8. Blood for Diagnostic Confirmation Testing ...............................................................51 
12.1.10.9. Saliva, Urine, and Stool Collection ............................................................................51 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................53 
13.1.1. 
Definition of Adverse Events .....................................................................................53 
13.1.1.1. 
Adverse Event .............................................................................................................53 
13.1.1.2. 
Serious Adverse Event ................................................................................................54 
13.1.1.3. 
Other Adverse Event ...................................................................................................54 
13.2. 
Relationship to Study Product ....................................................................................54 
13.3. 
Recording Adverse Events .........................................................................................55 
13.4. 
Reporting Adverse Events ..........................................................................................55 
14. 
STATISTICS ..............................................................................................................56 
14.1. 
Study Endpoints and Populations ...............................................................................56 
14.1.1. 
Study Endpoints ..........................................................................................................56 
14.1.1.1. 
Co-Primary Efficacy Endpoint ...................................................................................56 
14.1.1.2. 
Co-Secondary Efficacy Endpoint ...............................................................................57 
 
 
14.1.1.4. 
Safety Endpoints .........................................................................................................58 
14.1.2. 
Statistical Analysis Populations ..................................................................................58 
14.1.2.1. 
Intent-to-Treat Population (ITT) .................................................................................58 
14.1.2.2. 
Efficacy Completers Population .................................................................................58 
14.1.2.3. 
All Enrolled Population ..............................................................................................58 
14.1.2.4. 
Safety Population ........................................................................................................59 
14.2. 
Sample Size Calculation .............................................................................................59 
14.3. 
Efficacy Analysis ........................................................................................................60 
14.3.1. 
General Considerations ...............................................................................................60 
14.3.2. 
Primary and Secondary Efficacy Analysis .................................................................60 
14.4. 
CHOP-INTEND Comparison .....................................................................................61 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 16 of 136 
14.5. 
Safety Analysis ...........................................................................................................62 
15. 
DATA SAFETY MONITORING BOARD ...............................................................63 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................64 
16.1. 
Study Monitoring ........................................................................................................64 
16.2. 
Audits and Inspections ................................................................................................64 
16.3. 
Institutional Biosafety Committee ..............................................................................65 
16.4. 
Institutional Review Board/Institutional Ethics Committee .......................................65 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................66 
18. 
ETHICS ......................................................................................................................67 
18.1. 
Ethics Review .............................................................................................................67 
18.2. 
Ethical Conduct of the Study ......................................................................................67 
18.3. 
Written Informed Consent ..........................................................................................67 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................69 
19.1. 
Electronic Case Report Forms ....................................................................................69 
19.2. 
Inspection of Records .................................................................................................69 
19.3. 
Retention of Records ..................................................................................................69 
20. 
PUBLICATION POLICY ..........................................................................................70 
21. 
LIST OF REFERENCES ............................................................................................71 
22. 
APPENDICES ............................................................................................................73 
APPENDIX 1. AUTOPSY PLAN ..............................................................................................74 
APPENDIX 2. BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) .............................................................................................................75 
APPENDIX 3. PERFORMANCE CRITERIA FOR BAYLEY SCALES OF INFANT 
AND TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES .........................................................................................................120 
APPENDIX 4. CHOP-INTEND ...............................................................................................121 
APPENDIX 5. SCHEDULE OF ASSESSMENTS ..................................................................123 
APPENDIX 6. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS ...............................127 
APPENDIX 7. SUMMARY OF CHANGES ...........................................................................131 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 17 of 136 
LIST OF TABLES 
Table 1: 
Important Study Contact Information ...........................................................................4 
Table 2: 
Study Vendor Listing ....................................................................................................4 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 4: 
Spinal Muscular Atrophy Classification .....................................................................21 
Table 5: 
Investigational Product ...............................................................................................36 
Table 6: 
Total Blood Volume ...................................................................................................48 
Table 7: 
Common Terminology Criteria for Adverse Events ..................................................53 
Table 8: 
Tissue Sample for Analysis ........................................................................................74 
 
LIST OF FIGURES 
Figure 1: 
Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 
2, and 3 ........................................................................................................................22 
Figure 2: 
Study Results, Including Staining of Transduced Spinal Motor Neurons, 
SMN Expression Levels, Righting Ability, and Weight and Survival Curves ...........24 
Figure 3 
Body Mass of Treated and Control Mice Showed No Difference ..............................25 
Figure 4: 
Study Design ...............................................................................................................31 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 18 of 136 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AAV 
Adeno-associated virus 
AAV9 
Adeno-associated virus serotype 9 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASO 
Antisense oligonucleotide  
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CB 
Chicken-β-actin-hybrid 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CI 
CHOP-INTEND 
CHOP-INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders 
CK 
Creatine kinase 
CK-MB 
Creatine kinase isoenzyme 
CLIA 
Clinical Laboratory Improvement Amendment 
CMAP 
Compound motor action potential 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
First 24-hour interval after the start of gene replacement therapy infusion 
Day –1 
24-hour interval prior to the start of gene replacement therapy infusion  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISpot 
Enzyme-linked ImmunoSpot 
ET 
Early termination 
FVB 
Friend Virus B-Type 
GCP 
Good Clinical Practice 
GFP 
Green fluorescent protein 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HEENT 
Head, eyes, ears, nose, and throat 
HgB 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 19 of 136 
Abbreviation or Specialist Term 
Explanation 
ICD-10 code 
International Statistical Classification of Diseases and Related Health 
Problems 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon gamma 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITR 
Inverted terminal repeat 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFE 
Liver function enzymes 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHP 
Non-human primates 
NOAEL 
No Observable Adverse Effect Level 
OAE 
Other significant Adverse Event 
PBMC 
Peripheral blood mononuclear cells 
PICU 
Pediatric intensive care unit 
PNCR 
Pediatric Neuromuscular Clinical Research Network 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
Self-complementary 
scAAV 
Self-complimentary adeno-associated virus 
scAAV9.CB.SMN 
Self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SMN1 
Survival motor neuron 1 gene 
SMN2 
Survival motor neuron 2 gene 
SOC 
System Organ Class 
TMF 
Trial master file 
US 
United States 
vg/kg 
Vector genome per kilogram 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 20 of 136 
5. 
INTRODUCTION 
Study AVXS-101-CL-303 is a pivotal Phase 3, open-label, single-arm, single-dose, study of 
AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal muscular atrophy 
(SMA) Type 1 who meet enrollment criteria, may be either symptomatic or pre-symptomatic and 
are genetically defined by no functional survival motor neuron 1 gene (SMN1) as well as 1 or 
2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 months (< 180 days) of age at 
the time of gene replacement therapy (Day 1).  Enrolling up to twenty (20) patients under the 
broader enrollment criteria is projected to enable enrollment of at least 15 patients that meet the 
Intent-to-Treat Population (ITT) criteria.  The first 3 patients enrolled must meet the ITT criteria to 
enable a comparison of CHOP-INTEND scores at 1-month following gene replacement therapy to 
enable a comparison of patient response between AVXS-101-CL-303 patients and Cohort 2 patient 
results from the Phase 1 trial (AVXS-101-CL-101). 
In this study, the survival motor neuron (SMN) gene will be transferred using 
self-complementary adeno-associated virus (scAAV) Type 9 under control of the chicken-β-actin 
hybrid promoter.  Pre-clinical studies have demonstrated survival of the SMNΔ7 mouse model 
for SMA from a median of 15.5 days to over 1 year, following IV delivery to a facial vein.  
Additionally, preliminary results from an ongoing Phase 1 clinical study (AVXS-101-CL-101) of 
AVXS-101 in SMA Type 1 patients demonstrates broad improvements in survival, motor 
function, pulmonary function, and nutritional function (Section 5.4). 
5.1. 
Background 
Spinal muscular atrophy is a neurogenetic disorder caused by a loss or mutation in the survival 
motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN protein levels 
and a selective dysfunction of motor neurons.  Spinal muscular atrophy is an autosomal 
recessive, early childhood disease with an incidence of approximately 1: 10,000 live births [1].  
Spinal muscular atrophy is the leading cause of infant mortality due to genetic diseases.  Disease 
severity and clinical prognosis depends on the number of copies of survival motor neuron 2 gene 
(SMN2).  In its most common and severe form (Type 1), hypotonia and progressive weakness are 
recognized in the first few months of life, leading to diagnosis before 6 months of age and early 
death due to respiratory failure before 2 years of age.  Motor neuron loss in SMA Type 1 is 
profound in the early post-natal period (or may even start in the prenatal period), whereas motor 
neurons in SMA Type 2 and Type 3 patients adapt and compensate during development and 
persist into adult life.  The findings from various neurophysiological and animal studies have 
shown an early loss of motor neurons in the embryonic and early post-natal periods [2,3,4].  
From a clinical perspective, these findings emphasize the importance of first targeting the SMA 
Type 1 group for gene transfer of SMN1 in hopes of rescuing neurons at this critical stage.  The 
goal in continuing the development plan for AVXS-101 is to modify the SMA Type 1 
phenotype, which will hopefully lead to a milder disease course and prolonged survival as seen 
in SMA Type 2 and Type 3 patients. 
Therapeutic efforts in SMA have focused on the potential for small molecules to increase SMN 
levels.  These include deacetylase inhibitors, such as, valproic acid, sodium butyrate, 
phenylbutyrate, and trichostatin A.  These agents activate the SMN2 promoter, resulting in 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 21 of 136 
increased full-length SMN protein in SMA animal models [5,6], however, clinical studies 
employing several of these agents, most notably phenylbutyrate, valproic acid, and hydroxyurea, 
have not resulted in clinical benefit [7,8].  FDA recently approved Nusinersen, an antisense 
oligonucleotide (ASO) drug designed to increase the production of the SMN protein by 
modulating the splicing of the SMN2 gene, thereby compensating for the underlying genetic 
defect.  Clinical studies have shown some modest promise in improving motor function; 
however, the treatment must be administered indefinitely on a quarterly basis via intrathecal 
injection, requires a lengthy induction period prior to effectiveness, and has safety considerations 
which require clinical monitoring.  A single-dose IV administration study of AVXS-101 will 
provide information on the potential gene transfer has in treating SMA Type 1 patients and will 
hopefully show promise for success in modifying the disease prognosis. 
This is a single-dose study that will include up to 20 Type 1 patients with no functional SMN1 
gene as well as 1 or 2 copies of SMN2 and who are < 6 months (< 180 days) of age at the time 
of gene replacement therapy (Day 1).  The rationale for IV dosing is based upon the need for 
rapid, systemic impact given the severity of the disease in SMA Type 1 and its potential impact 
on systems outside of the central nervous system (CNS) such as the peripheral and autonomic 
nervous systems, heart, pancreas and gastrointestinal tract. 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients 
Patients with SMA Type 1 have been chosen as the target population for this gene therapy study 
based on studies of the natural history of this disease.  The classification of SMA is shown below 
(Table 4) in which SMA Types 0 to 4 are described.  Spinal muscular atrophy is conventionally 
classified into 4 phenotypes on the basis of age at onset and highest motor function achieved, 
with an additional phenotype (Type 0) to describe the severe forms of antenatal-onset SMA. 
Table 4: 
Spinal Muscular Atrophy Classification 
Type 
Age at Symptom Onset 
Maximum Motor Function 
Life Expectancy 
SMN2 Copy No. 
0 
Fetal 
Nil 
Days – Weeks 
1 
1 
< 6 months 
1A: B-2 Weeks 
1B: < 3 Months 
1C: > 3 Months 
Never sits 
< 2 years 
1, 2, 3 
2 
6 – 18 months 
Never walks 
20 – 40 years 
2, 3, 4 
3 
1.5 – 10 
Years 
3A: < 3 Years 
3B: > 3 Years 
Walks, regression 
Normal 
3, 4, 5 
4 
> 35 Years 
Slow decline 
Normal 
4, 5 
Source: Adapted from Kolb 2011 [10] 
SMN2 = survival motor neuron 2 gene 
 
Spinal muscular atrophy Type 1 patients, by definition, never attain independent sitting and have 
hypotonia within the first 6 months of life.  Spinal muscular atrophy Type 1 is the leading 
genetic cause of infant death with an onset at ≤ 6 month of age (Table 4).  In contrast, SMA 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 22 of 136 
Type 2 manifests within the first 18 months, and children afflicted with this condition are able to 
maintain sitting unassisted but never walk independently.  Spinal muscular atrophy Type 3 
patients attain the ability to walk unaided (Type 3a have onset 18 months to 3 years of age; 
Type 3b have onset > 3 years of age).  Spinal muscular atrophy Type 4 is an adult onset disease.  
The genetic cause for SMA is well established and is intimately involved with one’s prognosis.  
All forms of SMA are autosomal recessive in inheritance and are caused by deletions or 
mutations of the SMN1 gene. 
Humans also carry a second nearly identical copy of the SMN1 gene called SMN2 [11].  Both the 
SMN1 and SMN2 genes express SMN protein; however, the amount of functional full-length 
protein produced by SMN2 is only 10 to 15% of that produced by SMN1 [11,12,13].  Although 
SMN2 cannot completely compensate for the loss of the SMN1 gene, patients with milder forms 
of SMA generally have higher SMN2 copy numbers [14,15].  Quantitative analysis of SMN2 
copies in 375 patients with Type 1, 2, or 3 SMA showed a significant correlation between SMN2 
copy number and SMA Type, as well as, duration of survival.  In a large early study by 
Feldkotter et al 2002, 2 copies of SMN2 was 97% predictive for developing SMA Type 1, 
3 copies of SMN2 was 83% predictive for developing SMA Type 2, and 4 copies of SMN2 was 
84% predictive of SMA Type 3 [16].  As these percentages do not reflect the possible impact of 
modifier mutations such as that described by Prior et al 2009 [17], they may understate the 
relationship between copy number (in the absence of a genetic modifier) and clinical phenotype.  
Among 113 patients with Type 1 SMA, 9 with one SMN2 copy lived < 11 months, 88/94 with 
2 SMN2 copies lived < 21 months, and 8/10 with 3 SMN2 copies lived 33 to 66 months.  Even 
more refined data describing this relationship has been generated and has also influenced our 
choice of the study target group. 
The severity of SMA Type 1 is demonstrated by prognosis as illustrated in Kaplan-Meier 
survival curves shown in Figure 1. 
Figure 1: Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 2, 
and 3 
 
n = number of patients 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 23 of 136 
Source: Farrar 2013 [18] 
 
In Figure 1, the relative stability of the clinical course of SMA Type 2 and Type 3 is dramatically 
illustrated.  Perhaps most importantly, these findings show that outcome differences are related 
to the number of SMN2 copies that enable motor neurons to adapt and compensate during the 
growth of the child and persist into adult life.  This contrasts with SMA Type 1 where motor 
neuron loss is profound in the early post-natal period (or may even start in the prenatal period, 
especially for SMA Type 1 patients presenting in first 3 months of life).  The findings in Figure 1 
confirm other pieces of evidence from neurophysiological studies and animal studies that also 
show early loss of motor neurons in the embryonic and early post-natal periods [2,3,4]. 
There is reason to believe that there are few safety issues to be concerned about when targeting 
the SMA Type 1 group in this gene therapy clinical study.  Overexpression of SMN has been 
shown to be well tolerated in both mice and non-human primates, and in humans, a high copy 
number of SMN2 poses no risk (as seen in Type 2, 3, and 4 patients who have high SMN2 copy 
number), allowing for use of robust, ubiquitous expression systems (like the CB-promoter) to 
ensure sustained, high-level SMN expression.  Additionally, it is important to point out that 
recombinant scAAV can be employed for this study because of the small size of the SMN gene.  
This enables efficient packaging and allows for efficient gene transfer with lower viral titers (a 
safety consideration), compared with prototypical single-stranded adeno-associated virus (AAV) 
vectors. 
Recent studies using self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron (scAAV9.CB.SMN) show a robust post-natal rescue of SMNΔ7 
mice with correction of motor function, neuromuscular electrophysiology and survival after a 
1-time delivery of vector [19].  Intravenous scAAV9 is able to transduce neurons, muscle and 
vascular endothelium, all of which have been proposed as target cells for SMA treatment. 
5.3. 
Non-clinical Studies 
A mouse model was developed by the 
 after a generation of multiple 
variants.  It was found that the double transgenic, referred to as the SMNΔ7 mouse, provided the 
most suitable model to study gene transfer [20].  Studies performed in the 
 
have shown that injecting 5 × 1011 viral genomes of scAAV9.CB.SMN into the facial vein on 
Day 1 old mice rescues the SMNΔ7 mouse model [19].  Figure 2 shows the results of these 
studies, including staining of transduced spinal motor neurons, SMN expression levels, righting 
ability, and weight and survival curves.  Approximately 42 ± 2% of lumbar spinal motor neurons 
were transduced in scAAV9.CB.GFP treated mice.  SMN transduction was shown by real time 
polymerase chain reaction (RT-PCR) in the mice.  GFP transduction was observed by 
microscopy.  Both constructs were in AAV9 and had transduction of motor neurons.  SMN 
levels were increased as well, in brain, spinal cord, and muscle of scAAV9.CB.SMN-treated 
animals, compared to untreated SMNΔ7 mice (although lower than wild type [WT] controls).  
SMNΔ7 animals treated with either scAAV9.CB.SMN or scAAV9.CB.GFP on post-natal Day 1 
were assessed for their righting ability and were compared to WT control mice and untreated 
mice.  Wild type controls could right themselves quickly, whereas the SMN- and green 
fluorescent protein (GFP)-treated SMA animals showed difficulty at P5, however, by P13, 
90% of SMN-treated animals could right themselves compared with 20% of GFP-treated 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 24 of 136 
controls and 0% of untreated SMA animals.  At P18, SMN-treated animals were larger than 
GFP-treated animals, but smaller than WT controls.  Locomotive ability of the SMN-treated 
mice was nearly identical to WT controls, as assayed by open field testing and wheel running. 
Survival of SMN-treated SMNΔ7 animals compared with GFP-treated SMNΔ7 animals was 
significantly improved.  No GFP-treated control animals survived past P22 and had a median life 
span of 15.5 days.  The weights of GFP mice peaked at P10 and then precipitously declined until 
death, while SMN mice showed a steady weight gain until around P40 with it stabilizing at 17 g 
(about half the weight of WT controls).  The smaller size of corrected animals is likely related to 
the tropism and incomplete transduction of scAAV9, resulting in a ‘chimeric’ animal in which 
some cells were not transduced.  Additionally, the smaller size suggests an embryonic role for 
SMN.  Most remarkably, SMN-treated mice survived well past 250 days of age. 
Figure 2: Study Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves 
 
Source: Foust 2010 [19] 
CNS = central nervous system; GFP = green fluorescent protein; SMN = survival motor neuron; WT = wild type 
a) Shows transduced motor neurons in lumbar spinal cord 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 25 of 136 
b) 
Western Blots of SMN expression in CNS and muscle 
c) Improved righting ability of SMN-treated- similar to WT controls by P13 
d) 
SMN-treated are larger than GFP-treated at P18 
e) Survival of SMN-treated markedly improved compared to GFP- treated 
f)  
Body weight increased in SMN-treated vs GFP 
 
Toxicology biodistribution studies were generated by the 
 [data on file].  In the 
non-Good Laboratory Practice (GLP) studies, 24 mice and 4 non-human primates (NHPs) were 
injected, by way of vascular delivery, with AVXS-101.  To assess toxicity and safety, 
AVXS-101 was injected into P1 wild type Friend Virus B-Type (FVB) mice with either vehicle 
(3 males/6 females) or 3.3 × 1014 vg/kg of scAAV9.CB.SMN (6 males/9 females) via the facial 
temporal vein.  This dose was previously shown to be most efficacious in the SMNΔ7 mouse 
model [19].  P1 mice were used in anticipation of simulating potential clinical studies in infants.  
All mice survived the injection procedure and the initial 24-hour observation period without any 
signs of distress or weight loss.  Body mass was measured and hands-on observations were 
performed weekly for the remainder of the study; neither revealed any difference between 
control and treated cohorts (Figure 3). 
Figure 3 
Body Mass of Treated and Control Mice Showed No Difference 
 
 
At 60, 90 and 180 days post-injection, blood from the mice was collected for hematology studies 
including complete blood counts with differentials.  At 90, 120 and 180 days post-injection, 
blood was collected for clinical chemistries assessment (alanine amino transferase [ALT], 
aspartate amino transferase [AST], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], 
electrolytes, and creatine kinase [CK]).  For histopathology, 13 mice were necropsied at 
120 days post-injection and 8 mice at 180 days.  There were no clinically significant results 
observed during from the hematology, clinical chemistry, and histopathology portions of the 
study and trends of both groups were comparable.  Of note, no significant lesions were present in 
any brain or spinal cord sections, although, the sections were frozen and thicker than 5 microns 
which made cellular morphology obscure and subtle changes may not have been identified. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 26 of 136 
In the safety study for the 4 male Cynomolgus Macaques, animals were injected at 90 days of 
age to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
AVXS-101 vector was administered 1 time by catheterization of the saphenous vein with a dose 
of 6.7 × 1013 vg/kg, which corresponds to the lowest dose tested for which SMNΔ7 mice showed 
a significant increase of survival.  Animals were followed for 6 months until they were sacrificed 
at approximately 9 months of age.  No adverse effects were seen, and all clinical chemistries 
were normal.  T-cell immune response was tested using Enzyme-linked ImmunoSpot (ELISpot) 
in peripheral blood mononuclear cells (PBMCs), and all were negative at 6 months 
post-injection. 
In these non-GLP studies, the serum chemistry and hematology studies were unremarkable as 
was the histopathology assessment.  The NHP patient animals mounted appropriate immune 
responses to capsid (but not to transgene), with very high transgene expression persisting at 
6 months post-injection.  In conclusion, these studies provide strong evidence that 
systemically-delivered scAAV9.CB.SMN is safe and well tolerated, even at the high doses 
required for penetration of the blood-brain barrier [data on file]. 
In pivotal GLP compliant 3-month mouse toxicology studies, the main target organs of toxicity 
were the heart and liver.  Following intravenous infusion in the mouse, vector and transgene 
were widely distributed with the highest expression generally observed in heart and liver, and 
substantial expression in the brain and spinal cord.  AVXS-101-related findings in the ventricles 
of the heart were comprised of dose-related inflammation, edema and fibrosis, and in the atrium, 
inflammation and thrombosis.  Liver findings were comprised on hepatocellular hypertrophy, 
Kupffer cell activation, and scattered hepatocellular necrosis.  A no observable adverse effect 
level (NOAEL) was not identified for AVXS-101-related heart and liver findings in the mouse, 
and the Maximum Tolerated Dose was defined as 1.5 × 1014 vg/kg, providing a safety margin of 
approximately 1.4-fold relative to the recommended therapeutic dose of 1.1 × 1014 vg/kg.  The 
translatability of the observed findings in mice to primates is not known at this time. 
5.4. 
Clinical Studies 
First-in-human study AVXS-101-CL-101 is an ongoing 2-year study evaluating the efficacy and 
safety of AVXS-101 in 15 SMA Type 1 patients with 2 copies of SMN2.  All patients have 
received a single IV dose of AVXS-101 in 2 cohorts: Cohort 1 (n = 3) received the low dose 
used in this study (equivalent to a dose that doubled mouse lifespan in the SMN∆7 Mouse 
potency assay) and Cohort 2 (n = 12) received the high dose used in this study (equivalent to a 
dose that restored mouse lifespan to greater than 200 days or “full life” in the SMN∆7 Mouse 
potency assay).  The dose received by Cohort 2 patients in AVXS-101-CL-101 (proposed 
therapeutic dose) has been demonstrated to be equivalent to the dose to be used in the 
AVXS-101-CL-303 study by direct testing using improved analytical methods. 
Preliminary data as of 15 September 2016 indicate that treatment with AVXS-101 results in 
broad improvements in survival, motor function, pulmonary function, and nutritional function.  
All patients in Cohort 2 (proposed therapeutic dose) showed improvements in survival, as 
defined by Finkel et al 2014 [21], with no deaths or requirements for permanent ventilation 
≥ 16 hours/day for ≥ 14 consecutive days through 15 September 2016.  The median age at last 
follow-up for Cohort 2 was 17.3 months, with the oldest patient at 27.4 months of age.  One 
patient in Cohort 1 (low dose−cohort) had a pulmonary event of increased use of bi-level 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 27 of 136 
positive airway pressure in advance of surgery related to hypersalivation, a condition 
experienced by some SMA patients.  The event was determined by independent review to 
represent progression of disease and not related to AVXS-101. 
As of September 15, 2016, improvements in motor function, as assessed by the CHOP-INTEND 
scores, were observed with mean increases of 9.0 points in Cohort 1 and 24.8 points in Cohort 2.  
The CHOP-INTEND scores in Cohort 2 were ≥ 40 points for 11/12 patients, ≥ 50 points for 
9/12 patients, and ≥ 60 points (normal) for 3/12 patients. 
As of September 15, 2016, patients in Cohort 2 consistently achieved and maintained key 
developmental motor milestones as summarized below: 
• 11/12 patients achieved head control, 7/12 patients could roll, 11/12 patients could sit with 
support, and 8/12 patients could sit unassisted, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016 
• 7 patients were able to feed themselves, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016, and 5 patients were speaking (1 bilingual) 
• 2 patients were walking independently, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016.  These 2 patients each achieved earlier 
and important developmental milestones such as crawling, standing with support, standing 
alone, and walking with support 
 
As of September 15, 2016, AVXS-101 appears to have a favorable safety profile and appears to 
be generally well-tolerated in this study.  A total of 118 treatment-related AEs were reported 
(34 serious adverse events [SAEs] and 84 non-serious- adverse events [AEs]).  Two SAEs were 
deemed treatment-related in 2 patients, and 3 AEs were deemed treatment-related in 2 patients.  
All treatment-related events consisted of clinically asymptomatic liver enzyme elevations that 
resolved with prednisolone treatment.  There were no clinically significant elevations of gamma 
glutamyl transferase (GGT), alkaline phosphatase or bilirubin, and as such, Hy’s Law was not 
met.  Other non-treatment-related AEs were expected and were associated with SMA. 
In summary, through September 15, 2016, the consistently positive clinical observations are 
remarkably different from that described in extensive natural history studies, clinical 
publications, the experience of seasoned clinicians, and concurrent SMA Type 1 studies with 
other therapies.  These significant and clinically meaningful responses in patients treated with 
AVXS-101 indicate preliminary clinical evidence of a treatment effect that addresses an unmet 
need in this devastating pediatric disease. 
A full understanding of all the risks associated with AVXS-101 is not known at this time.  
Elevated liver function tests have been observed in the ongoing AVXS-101-CL-101 study, which 
is believed to be a T-cell immune response to the AAV9 vector.  None of the liver enzyme 
abnormalities observed in the study were accompanied by clinical sequelae.  Patients could 
experience an allergic response to AVXS-101.  Patients could also develop an immune response 
to the AAV9 viral vector, which could prevent future use of gene transfers using this vector. 
Taken together, results from the clinical and non-clinical studies support further clinical 
investigation of the efficacy and safety of AVXS-101 in patients with SMA Type 1. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 28 of 136 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The co-primary objectives are to: 
• Determine the efficacy of AVXS-101 by demonstrating achievement of developmental 
milestone of functional independent sitting for at least 30 seconds at the 18 months of age 
study visit. 
• Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is 
defined by the avoidance of combined endpoint of either (a) death or (b) permanent 
ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of 
respiratory assistance per day (via non-invasive ventilatory support) for ≥ 14 consecutive 
days in the absence of an acute reversible illness, excluding perioperative ventilation.  
Permanent ventilation, so defined, is considered a surrogate for death. 
 
6.2. 
Secondary Objective 
The co-secondary objectives are to: 
• Determine the effect of AVXS-101 on the on the ability to thrive defined as achieving all of 
the following at 18 months of age 
o Does not receive nutrition through mechanical support (e.g., feeding tube) 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• Determine the effect of AVXS-101 on the ability to remain independent of ventilatory 
support, defined as requiring no daily ventilator support/usage at 18 months of age, excluding 
acute reversible illness and perioperative ventilation, as defined above through assessment of 
actual usage data captured from the device, for patients issued a Trilogy 100 BiPAP device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 29 of 136 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4. 
Safety Objectives 
The safety objectives are to: 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• Determine the safety of AVXS-101 based on the development of unacceptable toxicity 
defined as the occurrence of any Common Terminology Criteria for Adverse Events 
(CTCAE) [9] Grade 3 or higher, unanticipated, treatment-related toxicity. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 30 of 136 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, open-label, single-arm, single-dose study of AVXS-101 (gene replacement 
therapy) that will enroll up to twenty (20) patients with SMA Type 1who may be either 
symptomatic or pre-symptomatic with no functional SMN1 gene as well as 1 or 2 copies of 
SMN2 and who are < 6 months (< 180 days) of age at the time of gene replacement therapy 
(Day 1).  Enrolling up to twenty (20) patients under the broader enrollment criteria is projected 
to enable enrollment of at least 15 patients that meet the Intent-to-Treat Population (ITT) criteria.  
The ITT population is identified as symptomatic patients with bi-allelic SMN1 deletions and 
2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who meet all other 
study enrollment criteria.  In addition, the first 3 patients enrolled must meet the criteria for the 
Intent-to-Treat Population to enable a comparison of CHOP-INTEND scores at 1-month 
following gene replacement therapy to enable a comparison of patient response between 
AVXS-101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial 
(AVXS-101-CL-101). 
The study includes 3 study periods: screening, gene replacement therapy, and follow-up 
(Figure 4).  During the screening period (Days –30 to –2), patients whose parent(s)/legal 
guardian(s) provide informed consent will undergo screening procedures to determine eligibility 
for study enrollment.  Patients who meet the entry criteria will enter the in-patient gene 
replacement therapy period (Day –1 to Day 3).  On Day –1, patients will be admitted to the 
hospital for pre-treatment baseline procedures.  On Day 1, patients will receive a 1-time IV 
infusion of AVXS-101 at a dose equivalent to the dose received by the second dosing Cohort in 
the Phase 1 study over approximately 60 minutes and will undergo in-patient safety monitoring 
over the next 48 hours.  Patients may be discharged 48 hours after gene replacement therapy, 
based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of Study 
at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 
assessments until the patient reaches 18 months of age.  Any missed visit should be rescheduled 
as soon as possible, but within 7 days. 
All post-treatment visits will be relative to the date on which gene replacement therapy is 
administered, except for the 14 and 18 months of age visits, which will be relative to the 
patient’s date of birth.  For the 14 and 18 months of age visits, the patient will return within 0 to 
14 days after the date on which the patient reaches 14 and 18 months of age, respectively.  The 
18 months of age visit will also serve as the End of Study visit.  After the End of Study visit, 
eligible patients will be asked to roll over into the long-term follow-up study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 31 of 136 
Figure 4: Study Design 
 
Note: After the End of Study visit at 18 months of age, eligible patients will be asked to roll over into the 
long-term follow-up study. 
ET = early termination 
a 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, except 
for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
 
There will be at least a 4 -week dosing interval between dosing of the first 3 patients to allow 
review of the safety analysis from 6 time points (day 1, 2, 7, 14, 21, and 30 visits) as well as 
early signals of efficacy including CHOP-INTEND score prior to dosing of the next patient. 
The first 3 patients enrolled must meet the criteria for the Intent-to-Treat (ITT) Population.  
AveXis will compare the CHOP-INTEND 1-month improvement for the AVXS-101-CL-303 
patients that meet the ITT criteria to assess the clinical response to the dose 1.1 × 1014 vg/kg as 
being what was expected from the Cohort 2 patients in the Phase 1 trial (AVXS-101-CL-101).  
This comparison will be performed as a per patient assessment for the first 3 patients.  The 
individual patients who receive their gene therapy at 0-3 months of age will be compared to a 
value of 10 CI points, while patients who receive their gene therapy at >3 but <6 months of age 
will be compared to a value of 5 CI points.  Furthermore, patients from either age group are 
expected to maintain the improvement in the absence of an acute illness or perioperatively.  If 
the expected CI improvements are observed for the first 3 ITT patients, AveXis will remove the 
4-week interval between patients and proceed to dose at least 12 additional patients that meet the 
ITT criteria and perform safety and efficacy assessments as described elsewhere in the clinical 
protocol (AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  If the expected CI 
improvements are not observed for the first 3 ITT patients, AveXis will discuss next steps with 
the FDA before continuing study enrollment. 
In an attempt to dampen the host immune response to the AAV-derived therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion in accordance with the specified 
guidelines for tapering (Section 9.2.1). 
A schedule of study assessments is provided in Appendix 5.  Efficacy will be assessed by 
achievement of the key developmental milestone of functional independent sitting for at 
least 30 seconds at the 18 months of age study visit and survival at 14 months of age (as defined 
in Section 14.1.1.1).  The ability to thrive and the ability to remain independent of ventilatory 
support (as defined in Section 14.1.1.2) will also be assessed.  Additional developmental 
milestones will be assessed using Bayley Scales of Infant and Toddler Development© 
(Version 3) (Section 11).  Safety will be assessed through monitoring AEs, concomitant 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 32 of 136 
medication usage, physical examinations, vital sign assessments, cardiac assessments, and 
laboratory evaluations (Section 12).  Additionally, a Data Safety Monitoring Board (DSMB) will 
review safety data on a quarterly basis, and will also convene within 48 hours should any patient 
experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or 
requires medical treatment (Section 13.1.1.1 and Section 15).  This includes any patient death, 
important clinical laboratory finding, or any complication attributed to administration of gene 
replacement therapy.  In such instances, the DSMB will review the safety information and 
provide its recommendation.  The DSMB can recommend early termination of the study for 
safety reasons. 
7.2. 
Number of Patients 
Up to twenty (20) patients that meet the study entry criteria will be enrolled to enable enrollment 
of at least 15 patients that meet ITT criteria.  Study enrollment will stop as soon as practical 
following enrollment of the fifteenth patient that meets the ITT criteria. 
7.3. 
Criteria for Study Termination 
An independent DSMB will conduct quarterly and ad hoc reviews of the emerging safety data 
throughout the study as described in Section 15. 
The study will be completed as planned but may be terminated for the following reasons: 
• Development of unacceptable toxicity, defined as the occurrence of any unanticipated 
CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely related to gene 
replacement therapy, and is associated with clinical symptoms and/or requires medical 
treatment 
• DSMB can recommend early termination of the study for safety reasons 
• Study is terminated by Sponsor 
• Regulatory Authority recommendation 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 33 of 136 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients with SMA Type 1 who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1) with proven biallelic- mutations of the SMN1 gene and 1 or 
2 copies of the SMN2 will be enrolled in this study.  Patients may be of any racial, ethnic, or 
gender background. 
8.1. 
Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 
mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of 
the known SMN2 gene modifier mutation (c.859G>C)) 
2. The first 3 patients enrolled must meet the criteria for the Intent-To-Treat population 
3. Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
4. Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
5. Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab 
prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections 
are also recommended in accordance with American Academy of Pediatrics [26] 
6. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and 
comply with study procedures and visit schedule 
 
8.2. 
Patient Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
1. Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without 
any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation 
does not decrease by ≥ 4 percentage points 
3. Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours/day over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during 
the screening period or requiring ventilatory support while awake over the 7 days prior to 
screening or at any point during the screening period prior to dosing 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 34 of 136 
4. Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass 
the swallowing test will be allowed to enroll in the study 
5. Patients whose weight-for-age is below the third percentile based on World Health 
Organization (WHO) Child Growth Standards [25] 
6. Active viral infection (includes human immunodeficiency virus [HIV] or positive serology 
for hepatitis B or C, or Zika virus) 
7. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 weeks prior to screening 
8. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 weeks prior to screening 
9. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy 
such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
11. Concomitant use of any of the following: drugs for the treatment of myopathy or neuropathy, 
agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, 
plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 
3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, 
methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay 
(ELISA) binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody 
titer > 1:50, he or she may receive retesting within 30 days of the screening period and will 
be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values (GGT, ALT, and AST > 3 × ULN; bilirubin 
≥ 3.0 mg/dL; creatinine ≥ 1.0 mg/dL; hemoglobin < 8 or > 18 g/dL; white blood cells [WBC] 
> 20,000/cmm) prior to gene replacement therapy 
14. Participation in recent SMA treatment clinical study (with the exception of observational 
Cohort studies or non-interventional studies) or receipt of an investigational or commercial 
compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, 
valproic acid) at any time prior to screening for this study.  Oral β-agonists must be 
discontinued at least 30 days prior to gene therapy dosing.  Inhaled albuterol specifically 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 35 of 136 
prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not 
a contraindication at any time prior to screening for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal 
surgery or tracheostomy) 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability 
to travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to 
refrain from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 
19. Gestational age at birth < 35 weeks (< 245 days) 
8.3. 
Patient Withdrawal Criteria 
Patients may be discontinued from the study for the following reasons: 
• Death 
− An autopsy will be requested for any patient who expires following participation in a gene 
replacement study [25] (see Autopsy Plan in Appendix 1) 
• Failure to comply with protocol-required visits or study procedures for 3 or more consecutive 
visits that are not rescheduled, unless due to hospitalization 
• Parent(s)/legal guardian(s) withdraws consent 
• Investigator discretion 
 
Early termination procedures should be completed within 14 days for any patient who 
prematurely discontinues the study for any reason, as indicated in Appendix 5. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 36 of 136 
9. 
TREATMENT OF PATIENTS 
It is the responsibility of the Investigator to ensure the safe storage and administration of gene 
replacement therapy. 
9.1. 
Description of Product 
The biological product is a non-replicating recombinant AAV9 containing the complimentary 
deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the 
cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB).  The AAV inverted 
terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, 
thus forming a double-stranded transgene ready for transcription.  This modified ITR, termed a 
“self-complementary” (sc) ITR, has been shown to significantly increase the speed of which the 
transgene is transcribed, and the resulting protein is produced.  The biological product, called 
AVXS-101 (formerly scAAV9.CB.hSMN), expresses the human SMN protein in transduced 
cells. 
Table 5: 
Investigational Product 
 
Investigational Product 
Product Name: 
AVXS-101 
Dosage Form: 
Equivalent to the dose received by the second dosing Cohort in the Phase 1 study 
Unit Dose 
1.1 × 1014 vg/kg; Equivalent to the dose received by the Cohort 2 in the Phase 1 
study (AVXS-101-CL-101) as determined by direct product testing with improved 
analytical methods. 
Route of Administration 
Intravenous infusion 
Physical Description 
AVXS-101 is a clear, colorless liquid. 
 
9.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be captured in the electronic Case Report Form (eCRF) 
from 2 weeks prior to administration of gene replacement therapy through the last study visit. 
9.2.1. 
Prophylactic Administration of Prednisolone 
An antigen specific T-cell response to the AAV vector was observed in the ongoing Phase 1 
clinical study (AVXS-101-CL-101) investigating AVXS-101 treatment via IV infusion.  This is 
an expected response between 2 to 4 weeks following gene replacement therapy.  One possible 
consequence to such antigen specific T-cell response is clearance of the transduced cells and loss 
of transgene expression. 
In an attempt to dampen the host immune response to the AAV based- therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion.  After 30 days of treatment, the 
dose of prednisolone can be tapered for patients whose ALT values, AST values, and T-cell 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 37 of 136 
response are ≤ 2 X ULN for ALT and AST, and < 100 SFC/106 PBMCs in accordance with the 
following treatment guideline: 
• Until at least 30 days post-infusion: 1 mg/kg/day 
• Weeks 5 and 6: 0.5 mg/kg/day 
• Weeks 7 and 8: 0.25 mg/kg/day 
• Week 9: prednisolone discontinued 
 
If the AST or ALT values are > 2 X ULN, or if T-cell response is ≥ 100 SFC/106 PBMCs after 
30 days of treatment, the dose of prednisolone will be maintained until the AST and ALT values 
decrease below threshold.  If T-cell- response continues past Day 60, Investigator discretion 
should be used considering risk benefit for maintaining prednisolone.  Variance from these 
recommendations will be at the discretion of the Investigator based on potential safety issues for 
each patient. 
9.2.2. 
Prohibited Medications 
Concomitant use of any of the following medications is prohibited: 
• Drugs for treatment of diabetes, myopathy or neuropathy 
• Therapy received with the intent to treat SMA (e.g., nusinersen, valproic acid) 
o Oral β-agonists must be discontinued at least 30 days prior to gene therapy dosing. 
o Inhaled β-agonists may be used to treat respiratory complications of SMA provided 
such medications are dosed at clinically appropriate levels 
• Any investigational medication other than AVXS-101 is prohibited during the study 
• Ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as 
adalimumab, or immunosuppressive therapy within 3 months of starting the study 
(e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV 
immunoglobulin, rituximab) 
 
Corticosteroid usage following completion of the prednisolone taper is permissible as part of 
routine clinical management.  The use of corticosteroids in such circumstances should be 
documented appropriately as a concomitant medication, and the event precipitating its usage 
should be appropriately documented as an adverse event. 
Should the use of corticosteroids (aside from inhaled corticosteroids for bronchospasm) be 
considered as part of care during the course of the prednisolone taper, this medical management 
should be discussed with the medical monitor. 
9.3. 
Treatment Compliance 
AVXS-101 will be administered as a 1-time IV injection. 
9.4. 
Randomization and Blinding 
This is an open-label study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 38 of 136 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT 
AVXS-101 is manufactured in accordance with current Good Manufacturing Practices (cGMP).  
Investigational product accountability logs will be maintained by the clinical pharmacy. 
10.1. 
Study Product 
AVXS-101 
10.2. 
Study Product Dose and Dose Justification 
Patients will receive a 1-time dose of AVXS-101 at 1.1 × 1014 vg/kg, equivalent to the dose 
received by Cohort 2 in the Phase 1 study via IV infusion administered in the ongoing Phase 1 
clinical study (AVXS-101-CL-101). 
Two doses are being studied in the ongoing Phase 1 clinical study (AVXS-101-CL-101); the 
higher dose (dose received by the Cohort 2 patients) was chosen for the present study as 
preliminary data demonstrated both a dose response and significant clinical benefit thus 
identifying it as the proposed therapeutic dose.  In the Phase 1 study, AVXS-101 demonstrated a 
dose response, with efficacy greater as observed by motor milestone achievement and CHOP-
INTEND scores at the higher dose (received by Cohort 2) than the lower dose (received by 
Cohort 1).  Direct testing of the actual lot of Investigational Medicinal Product (IMP) used in the 
AVXS-101-CL-101 study by an improved and more fully qualified analytical method has 
assigned a value of 1.1 × 1014 vg/kg to the actual dose received by Cohort 2 in this Phase 1 
study.  The same method has been used to establish an equivalent dose for the Phase 3 IMP.  
This vg/kg value has been further verified in an improved and more fully qualified SMN∆7 
Mouse Biopotency assay to support a similar extension of mouse life time in direct comparative 
assessment between the Phase 1 and Phase 3 IMP. 
10.3. 
Study Product Packaging and Labeling 
AVXS-101 kits are labeled with a specific kit number and batch/lot number assigned at the 
cGMP facility.  The content of the labeling is in accordance with the local regulatory 
specifications and requirements. 
10.4. 
Study Product Storage 
AVXS-101 kits will be stored in an appropriate, locked room under the responsibility of the 
Investigator or other authorized persons (e.g., pharmacists) in accordance with local regulations, 
policies, and procedures.  Control of storage conditions, especially control of temperature (e.g., 
refrigerated/freezer storage) and information on in-use stability and instructions for handling 
prepared AVXS-101 should be managed in accordance with the Pharmacy Manual. 
The vessel used for delivery of the vector should be resealed in the procedure room and 
processed for destruction and/or return to AveXis in accord with the Pharmacy manual and 
applicable biohazardous waste guidelines for disposal. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 39 of 136 
10.5. 
Study Product Preparation 
Preparation of AVXS-101 will be done aseptically under sterile conditions by a pharmacist and 
will arrive at the clinical site ready for infusion. 
AVXS-101 will be received diluted with normal saline, as outlined in the Pharmacy Manual. 
The total vector genome dose will be calculated based on the patient’s body weight. 
The dose-delivery vessel will be delivered to the designated pediatric intensive care unit 
(PICU) patient room or other appropriate setting (e.g., interventional suite, operating room, 
dedicated procedure room) with immediate access to acute critical care management.  The 
vessel will be delivered in accord with the Pharmacy Manual. 
10.6. 
Study Product Administration 
AVXS-101 infusion will be administered under sterile conditions in a PICU or other appropriate 
setting (e.g., interventional suite, operating room, dedicated procedure room) with immediate 
access to acute critical care management.  AVXS-101 will be delivered 1-time through a venous 
catheter inserted into a peripheral limb vein (arm or leg) at a dose equivalent to the dose received 
by the second dosing Cohort in the Phase 1 study.  AVXS-101 should be slowly infused over 
approximately 30-60 minutes, dependent upon total volume in accord with the Pharmacy 
Manual, utilizing an infusion set and pump in accordance with the Pharmacy Manual. 
Following administration of gene replacement therapy, patients should return to an appropriate 
designated setting to ensure close monitoring of vital signs and adverse events.  Vital signs will 
be continuously monitored throughout the gene replacement therapy infusion as described in 
Section 12.1.3.  Patients should be maintained in the PICU or other appropriate setting for 
48 hours after the start of gene replacement therapy. 
10.7. 
Dose Adjustment Criteria 
The study investigates a 1-time IV infusion of AVXS-101; no dose adjustments are possible. 
10.8. 
Study Product Accountability 
The pharmacist or designee will maintain accurate records of the quantities of AVXS-101 
received, dispensed, destroyed, and/or returned to AveXis.  The pharmacist or designee will 
document the date and time of delivery of the dose vessel to the dose procedure room as well as 
the time the used vessel was returned to AveXis or destroyed as per the Pharmacy Manual. 
10.9. 
Study Product Handling and Disposal 
All materials used for injection, including sterile drapes, needles, and syringes in contact with the 
vector must be sealed in leak-proof containers.  All waste must be sealed in bags bearing the 
biohazard symbol and disposed of in a biohazard waste container. 
All transfers must be done in spill-proof containers.  Individuals manipulating the vector will be 
required to wear personal protective equipment, such as gloves. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 40 of 136 
Any quality issue noticed with the receipt or use of AVXS-101 (e.g., deficiency in condition, 
appearance, pertaining to documentation, labeling, expiration date, etc.) should be promptly 
reported to the Sponsor in accord with procedures outlined in the Pharmacy Manual. 
Under no circumstances will the Investigator supply AVXS-101 to a third party, allow 
AVXS-101 to be used other than as directed by this clinical trial protocol, or dispose of 
AVXS-101 in any other manner. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 41 of 136 
11. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed by achievement of the key developmental milestone of functional 
independent sitting for at least 30 seconds at the 18 months of age study visit and survival at 
14 months of age (as defined in Section 14.1.1.1).  The ability to thrive and the ability to remain 
independent of ventilatory support (as defined Section14.1.1.2) will also be assessed at 
18 months of age.  Additional developmental milestones will be assessed using the Bayley 
Scales of Infant and Toddler Development (version 3©).  Efficacy assessments will be performed 
at the times specified in the Table of Assessments (Appendix 5) and should be the first 
assessments performed at any scheduled visit.  All post-treatment visits will be relative to the 
date on which gene replacement therapy is administered except the 14 and 18 months of age 
visits, which will be relative to the patient’s date of birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
11.1. 
Developmental Milestones 
Developmental milestones will be assessed using relevant definitions obtained from the Bayley 
Scales of Infant and Toddler Development (version 3), and will be analyzed to assess efficacy 
(Appendix 2 and Appendix 3).  Achievement of each developmental milestone will be 
determined by the Physical Therapist and confirmed by the central reader (as may be necessary) 
based on an assessment of the submitted videos (Section 11.3).  Developmental milestones will 
be determined at each monthly visit as listed in Section 11.2.1. 
During the Screening visit, the physical therapist will complete an assessment of baseline 
milestone achievement in accordance with Appendix 5; this assessment must address all 
milestones/items noted on Appendix 5 that are at or below the child’s expected function for age, 
and be recorded on video.  The findings must be documented in the source.  Items that are below 
the expected function for age that are not successfully achieved during the baseline evaluation 
should be repeated at subsequent visits until successfully performed. 
The milestones of sitting independently (items 22 and 26) should be assessed at every subsequent 
visit, until attainment of milestone, regardless of starting point on the scale.  These milestones 
must also be assessed at the 18 months of age visit, regardless of previous attainment. 
As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each attained milestone be captured on video. 
A milestone will be considered achieved when demonstrated by a patient and observed with 
video capture confirmation during a physical therapy assessment or observed with video as 
provided by the patient’s family at the patient’s visit at 18 months of age. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 42 of 136 
11.2. 
Motor Function Tests 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones 
The Bayley Scales of Infant and Toddler Development (Version 3) (Appendix 2) is a 
standardized, norm-referenced infant assessment of developmental functioning across 5 domains 
of cognitive, language, motor, social-emotional, and adaptive behavior.  The Bayley Scales will 
be administered by a qualified Physical Therapist. 
The full Bayley Scales will be administered at screening, every 6 months starting at Month 6, 
and at End of Study when the patient reaches 18 months of age (or early termination), whereas 
the gross and fine motor subtests of the motor domain will be administered at each monthly visit.  
For patients in which English is not their first language, the language subtests (receptive 
communication and expressive communication) and cognitive scale portions of the Bayley will 
not be performed. 
Each Bayley Scales/developmental milestone assessment will be video recorded in accordance 
with the AVXS-101-CL-303 Video Manual and may be submitted to the vendor for review by a 
central reader (Section 11.3). 
The following developmental milestones will be assessed: 
• Ability to hold head erect without support 
• Ability to roll from back to both sides 
• Ability to sit with support 
• Ability to sit independently, > 10 seconds; WHO [22] 
• Ability to sit without support for at least 30 seconds 
• Ability to crawl 
• Ability to pull to stand 
• Ability to stand with assistance 
• Ability to stand alone 
• Ability to walk with assistance 
• Ability to walk alone 
 
11.2.2. 
CHOP-INTEND 
The CHOP-INTEND is a motor function scale developed and validated for use specifically to 
monitor motor function status and decline amongst children with SMA Type 1, and will be 
administered by a qualified Physical Therapist.[23,24]  The CHOP-INTEND scale examines 
several aspects of motor function, including head control, righting reactions, and trunk 
movements in supported sitting, supine, and prone positions (Appendix 4).  Anti-gravity 
movements in assisted rolling, ventral suspension, and supported standing will also be measured. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 43 of 136 
The CHOP-INTEND will be performed at screening, Day -1, and at each scheduled visit from 
Day 7 through the End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 5).  If Day -1 CHOP-INTEND assessment cannot be conducted, a CHOP-INTEND 
assessment must be completed on Day 1 prior to dose administration. 
Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not undergo any additional 
CHOP-INTEND examinations. 
Each CHOP-INTEND exam will be video recorded in accordance with the AVXS-101-CL-303 
Video Manual and submitted to the vendor for review by a central reader as may be necessary 
(Section 11.3). 
11.3. 
Video Evidence 
Physical therapy assessments (Bayley Scales and CHOP-INTEND) required at each study visit 
will be video recorded in an effort to produce compelling, demonstrable, documented evidence 
of efficacy, as determined by changes in functional abilities.  AveXis, Inc. (AveXis) will provide 
a secure and confidential upload process for transfer and storage of the videos from 
investigational sites to a contracted third-party vendor that will compile and arrange videos as 
per AveXis requirements.  Any/all videos received at AveXis or the contracted vendor will be 
treated as confidential study data and will be the sole property of AveXis.  AveXis and the 
contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families on the videos, which may be shared with regulatory 
agencies, the medical community, and/or in appropriate venues to discuss the results of this 
clinical study. 
Videos may be provided to an independent, centralized reviewer for unbiased assessment of 
developmental milestone achievement.  The independent reviewer will document whether the 
video displays evidence of having achieved each developmental milestone.  The date of 
developmental milestone achievement will be computed as the earliest date on which video 
evidence demonstrates the achievement of the specified milestone. 
Additionally, the Parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the study.  These videos will be 
handled in the same manner in which the study-derived videos are handled. 
11.4. 
Compound Motor Action Potential 
Peroneal nerve CMAP amplitude will be measured by a qualified electrophysiologist, at all 
clinical sites capable of performing this assessment, using the procedures as described in the 
CMAP Manual (Appendix 5).  CMAP will be measured at screening, every 6 months starting at 
Month 6, and End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 5). 
The CMAP data will be collected for centralized review and interpretation. 
Sites that do not have equipment or appropriately experienced personnel required to perform 
CMAP measurements will not be required to perform these assessments. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 44 of 136 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety parameters include physical examinations, pulmonary examinations, vital signs, capillary 
blood gas assessments, weight and length measurements, 12-lead electrocardiograms (ECGs), 
12-lead Holter monitor recordings, echocardiograms, swallowing tests, laboratory assessments, 
adverse event monitoring, and photographs of the infusion site.  In general, safety assessments 
will be performed at the times specified in the Table of Assessments (Appendix 5).  All post-
treatment visits are relative to the date on which gene replacement therapy is administered until 
the patient reaches 14 months of age, at which point all visits are relative to the patient’s date of 
birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
12.1.1. 
Demographic/Medical History 
Demographic/medical history information will be collected at screening and captured in the 
eCRF.  Information that will be collected includes: 
• Familial history of SMA including affected siblings or parent carriers 
• Gestational age at birth 
• Length/weight/head circumference at birth 
• Hospitalization information from time of birth including number, duration, and reason for 
hospitalizations including International Statistical Classification of Diseases and Related 
Health Problems (ICD-10 codes), if available 
• Historical ventilatory support, if any 
• Historical feeding support, if any 
 
Patients are encouraged to follow all routinely scheduled immunizations, as recommended by the 
Center for Disease Control (CDC), throughout the study.  Seasonal vaccinations that include 
palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) 
infections are also recommended in accordance with American Academy of Pediatrics [26]. 
12.1.2. 
Physical Examinations 
Physical examinations will be conducted by the Investigator or Sub-Investigator at each 
scheduled visit, except Day –1 (Appendix 5).  The Day 1 physical examination will be 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 45 of 136 
performed prior to the start of gene replacement therapy infusion.  Physical examinations include 
a review of the following systems: head, eyes, ears, nose and throat (HEENT), lungs/thorax, 
cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, lymphatic, and 
genitourinary. 
12.1.3. 
Vital Signs/Weight and Length 
Vital sign parameters include blood pressure, respiratory rate, pulse, axillary temperature, and 
pulse oximetry.  Vital signs will be obtained at each study visit (as specified in Appendix 5).  On 
Day 1, vital signs will be continuously monitored throughout the gene replacement therapy 
infusion and recorded pre-dose and every 15 (± 5) minutes for the first 4 hours after the start of 
infusion, and then every hour (± 15 minutes) until 24 hours after the start of infusion.  Axillary 
temperature will be recorded pre- and post-infusion. 
Weight and length will be measured at each study visit (as specified in Appendix 5).  On Day 1, 
weight and length will be measured pre-dose. 
12.1.4. 
Electrocardiogram 
A 12-lead ECG will be performed at screening, Day –1, pre-dose on Day 1, Day 2, Months 3, 6, 
9, and 12 visits and every 6 months thereafter.  A 12-lead ECG will also be performed at the End 
of Study visit when the patient reaches 18 months of age (or early termination) (Appendix 5).  
For patients enrolled in the study prior to amendment 3 and irrespective of the study schedule, 
after signing an updated informed consent form,  a 12-lead ECG will be conducted at the next 
scheduled visit and then in accordance with the Schedule of Assessments (Appendix 5).  
Additional ECG monitoring will be at the discretion of the Investigator as per local institutional 
guidelines. 
The ECG will be interpreted locally by a cardiologist.  The ECG tracings or ECG machine data 
will be collected for centralized review and interpretation by a cardiologist. 
12.1.5. 
12-Lead Holter Monitor 
A Holter monitor will continuously record the patient’s 12-lead ECG for a total of 72 hours from 
Day –1 (24 hours prior to the start of gene replacement therapy infusion) through 48 hours after 
the start of infusion.  On Days -1 to Day 3, serial ECG data will be pulled in triplicate from the 
Holter monitor at the following time points: 
• Pre-dose (within 24 hours prior to gene replacement therapy) 
• 2 hours 
• 4 hours 
• 6 hours 
• 8 hours 
• 12 hours 
• 24 hours 
• 36 hours 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 46 of 136 
• 48 hours 
 
Twenty-four-hour Holter monitoring will also be performed at the 3, 6, 9, and 12-month visits 
and every 6 months thereafter.  Twenty-four-hour Holter monitoring will also be performed at 
the End of Study visit when the patient reaches 18 months of age (or early termination).  For 
patients enrolled in the study prior to amendment 3 and irrespective of study schedule, after 
signing an updated informed consent form, a 24-hour Holter monitor will be performed at the 
next scheduled visit and then in accordance with the Schedule of Assessments (Appendix 5). 
Holter monitors will be provided to study sites along with a dedicated laptop for uploading the 
data from the memory cards for centralized review and analysis by a cardiologist within 24 hours 
of data upload.  The Sponsor physician or designee will be notified of any safety concerns from 
the centralized review, and the safety management plan will be followed for documenting and 
reporting of AEs/SAEs. 
12.1.6. 
Echocardiogram 
A standard transthoracic echocardiogram will be performed at screening, at 3, 6, 9, and 12-month 
visits and every 6 months thereafter.  An echocardiogram will also be performed at the End of 
Study visit when the patient reaches 18 months of age (or early termination) (Appendix 5).  For 
patients enrolled in the study prior to amendment 3 and irrespective of study schedule, after 
signing an updated informed consent form, an echocardiogram will be performed at the next 
scheduled visit and then in accordance with the Schedule of Assessments (Appendix 5). 
12.1.7. 
Pulmonary Examinations 
Pulmonary examinations will be performed by a pulmonologist or appropriate individual as per 
standard institutional practice at each scheduled visit except Day 1 (Appendix 5).  Prior to study 
entry, a pulmonologist or appropriate individual as per standard institutional practice will review 
and document ventilator usage in the 2 weeks prior to screening. 
Patients may be fitted with non-invasive ventilatory support at the discretion of the 
pulmonologist or appropriate individual as per standard institutional practice and/or Investigator.  
Non-invasive ventilatory support equipment will be provided by AveXis through a third-party 
vendor.  Should the patient require non-invasive ventilatory support at any time during the study, 
the equipment provided by AveXis must be used. 
Patients requiring non-invasive ventilatory support will be asked to bring their machine(s) to 
each study visit such that the study staff can remove an SD card which captures actual usage 
data.  The hours per day usage data for each day between visits will be extracted with software 
provided by the device manufacturer into a format that will be transferred/transcribed to the 
clinical database. 
12.1.8. 
Swallowing Test 
A swallowing test will be performed at screening (at the Investigator site), every 6 months 
starting at Month 6, and at End of Study when the patient reaches 18 months of age (or early 
termination) (Appendix 5) to determine if the patient has signs of aspiration.  If the test is 
positive for aspiration, there may be a recommendation for the patient to use an alternate method 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 47 of 136 
to oral feeding for the duration of the study at the determination of the Investigator and treating 
clinician. 
12.1.9. 
Photographs of Infusion Site 
Photographs will be taken of the infusion site at each scheduled visit from Day 1 (pre-dose) 
through Day 30 (Appendix 5) to monitor healing of the infusion site.  AveXis will provide a 
secure and confidential upload process for transfer and storage of the photographs from the 
investigative sites to a contracted third-party vendor that will compile and arrange photographs 
as per AveXis requirements.  Any/all photographs received at AveXis or the contracted vendor 
will be treated as confidential study data and will be the sole property of AveXis.  AveXis and 
the contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families in the photographs, which may be shared with 
regulatory agencies, the medical community, and/or in appropriate venues to discuss the results 
of this clinical study. 
12.1.10. 
Laboratory Assessments 
Blood samples will be collected at each scheduled visit, except Day 1 and Day 3 (as specified in 
Appendix 5).  On Day -1, blood and urine samples will be processed locally for receipt of results 
prior to the start of gene replacement therapy infusion.  Any clinically significant laboratory 
value will be repeated at the discretion of the Investigator. 
In most instances, blood samples will be collected and shipped to a central laboratory, however, 
at the discretion of the Investigator, samples may be processed locally for emergent safety 
monitoring or other logistical or technical reasons that warrant samples to be processed locally.  
Samples for laboratory tests required during the in-patient vector infusion period prior to dosing 
will be collected and processed by the investigative site’s Clinical Laboratory Improvement 
Amendment (CLIA) CLIA-certified local laboratory to ensure receipt of results prior to dosing. 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 48 of 136 
Table 6: 
Total Blood Volume 
Visit 
Tests 
Total Volume (mL) 
Screening 
Hematology, chemistry/CK-MB, virus serology,  
 immunology sample (AAV9 Ab only),   
diagnostic confirmation sample 
16.9 
Day –1 
Hematology, chemistry, capillary blood gas  
3.3 
Day 2 
Hematology, chemistry, capillary blood gas 
3.3 
Day 7 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.6b 
Day 14 
Hematology, chemistry, immunology sample  
(AAV9/SMN Ab only) 
3.3 
Day 21 
Hematology, chemistry, immunology sample 
 (AAV9/SMN Ab only) 
3.3 
Day 30 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.6b 
Day 60 
Hematology, chemistry/CK-MB, 
3.6 
Month 
3/4/5/7/8/10/11/13/14/16/17 
Hematology, chemistry 
25.3 
Month 6/9/12/15 
Hematology, chemistry/CK-MB 
14.4 
End of Study/ET 
Hematology, chemistry/CK-MB 
3.6 
Maximum Total Volume for Study a 
96.2 
ET = early termination 
a Patients will have different numbers of monthly visits, depending on their age at dosing.  Maximum total volume based on a 
maximum of 16 monthly visits, provided T-cell responses are not elevated at Day 30 requiring additional surveillance 
samples and virus serology is not positive at screening requiring additional testing 
b Immunology sample for IFNγ- ELISpots requires 4-6 mL whole blood.  Immunology sample for ELISA requires 1 mL whole 
blood.  When drawn at the same visit, 4-6 mL is sufficient for both assays. 
 
In a case where sufficient blood cannot be collected from a patient, blood will be used in the 
following priority order with the first having greatest priority and last having the least priority: 
1. Safety labs 
a. Chemistry 
b. Hematology 
c. CK-MB 
2. Interferon gamma (IFNγ) ELISpots to detect -T-cell responses 
3. Serum antibody to AAV9 and SMN 
4. Genetic reconfirmation testing 
 
If there is not sufficient blood volume to include the genetic reconfirmation testing sample at the 
screening visit, patient must return before Visit 2.  All patients must have genetic reconfirmation 
testing completed. 
12.1.10.1. Hematology 
Hematology analysis will include a complete blood count with differential and platelet count 
with smear.  Samples will be collected and shipped in accordance with the laboratory manual 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 49 of 136 
provided by the central laboratory.  Blood samples for hematology analysis will be collected at 
all scheduled visits except Day 1 and Day 3 (Appendix 5). 
Immediate/same-day hematology analyses required during in-patient dosing, as determined by 
the Investigator, will be performed as per investigational site standard procedures at the local 
laboratory.  Investigators will receive hematology results from all study visits from the central 
laboratory. 
12.1.10.2. Blood Chemistry 
Samples will be collected and shipped in accordance with the laboratory manual provided by the 
central laboratory.  Blood samples for chemistry analysis will be collected at all scheduled visits 
except Day 1 and Day 3 (Appendix 5). 
Immediate/same-day chemistry analyses required during in-patient dosing, as determined by the 
Investigator, will be performed as per investigational site standard procedures at the local 
laboratory. 
• Chemistry analysis will include the following at all study visits: 
• Serum GGT 
• AST/ALT 
• Serum total bilirubin 
• Direct bilirubin 
• Albumin 
• Glucose 
• Total creatine kinase 
• Creatinine 
• BUN 
• Electrolytes 
• Alkaline phosphatase 
 
Creatine kinase (CK-MB) will be collected at Screening, Day 7, Day 30, Day 60, Month 6, 9, 12, 
15 months of age, and at 18 months of age/End of Study. 
Investigators will receive chemistry results from all study visits from the central laboratory 
(except Day -1). 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 50 of 136 
12.1.10.3. Urinalysis 
Urine samples will be collected in accordance with the laboratory manual provided by the central 
laboratory at all study visits except Day 1 and Day 3 (Appendix 5).  Day -1 urinalysis will be 
performed as per investigational site standard procedures at the local laboratory.  Urinalysis will 
include the following parameters: 
• Color 
• Clarity/turbidity 
• pH 
• Specific gravity 
• Glucose 
• Ketones 
• Nitrites 
• Leukocyte esterase 
• Bilirubin 
• Blood 
• Protein 
• Red Blood Cell 
• White Blood Cell 
• Squamous epithelial cells 
• Casts 
• Crystals 
• Bacteria 
• Yeast 
 
12.1.10.4. Virus Serology 
The administration of an AAV vector has the risk of causing immune-mediated hepatitis.  For 
patients who have HIV or positive serology for hepatitis B or C or Zika virus, administration of 
AAV vector may represent an unreasonable risk; therefore, negative serology testing must be 
confirmed at screening, prior to treatment.  These samples will be collected at screening 
(Appendix 5) and shipped in accordance with the laboratory manual provided by the central 
laboratory. 
12.1.10.5. Capillary Blood Gas 
Capillary blood gas will be completed locally at Day –1 and Day 2 (Appendix 5).  A puncture or 
small incision will be made with a lancet or similar device into the cutaneous layer of the 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 51 of 136 
patient’s skin at a highly vascularized area (heel, finger, toe).  To accelerate blood flow and 
reduce the difference between the arterial and venous gas pressures, the area will be warmed 
prior to the puncture.  As the blood flows freely from the puncture site, the sample will be 
collected in a heparinized glass capillary tube. 
12.1.10.6. Immunology Testing (ELISA and IFNγ- ELISpots) 
Blood samples for immunology testing will be collected and shipped to the central laboratory in 
accordance with the laboratory manual to test for serum antibodies to AAV9 and SMN (ELISA), 
and to perform IFN-γ ELISpots to detect T-cell responses to AAV9 and SMN.  Blood samples 
will be collected at screening (ELISA anti-AAV9 only), Day 7, Day 14 (ELISA anti-
AAV9/SMN only), Day 21 (ELISA anti-AAV9/SMN only), and Day 30 (Appendix 5).  
Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to 
be elevated, based on further discussion with the Principal Investigator and Medical Monitor. 
12.1.10.7. AAV9 Antibody Screen in Mother 
There is potential that the biological mother of the patient may have pre-existing antibodies to 
AAV9 that may be transferred to the patient through breast milk or, theoretically, via placental 
transfer in utero.  Informed consent will be requested from the biological mother of the patient to 
screen the mother for circulating antibodies to AAV9.  Once informed consent has been 
obtained, the mother will have her blood drawn from a peripheral vein at screening and shipped 
to the central laboratory for screening of anti-AAV9 antibodies.  Mothers who test positive for 
antibodies to AAV9 will be asked to refrain from further feedings with breast milk. 
If AAV9 antibodies are identified, the patient must desist in consuming breast milk from the 
biological mother. 
Patients consuming banked breast milk from donor sources that cannot be test for anti-AAV9 
antibodies must be transitioned to formula prior to participation. 
12.1.10.8. Blood for Diagnostic Confirmation Testing 
A blood sample will be collected during the screening visit and shipped to the central laboratory 
in accordance with the laboratory manual for reconfirmation of SMN1 deletions/mutations, 
SMN2 copy number, and absence of exon 7 gene modifier mutation (c.859G>C).  This will be 
done to ensure consistency in diagnostic testing practices. 
12.1.10.9.   Saliva, Urine, and Stool Collection 
Studies have shown that some vector can be excreted from the body for up to a few weeks after 
injection; this is called “viral shedding.”  Vector shedding can be found in the blood, urine, 
saliva, and stool for up to 1 week following infusion.  The potential health risks associated with 
the shed vector are not fully known at this time; however, the health risk is thought to be low as 
the vector cannot replicate.  Regardless, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved instructions should be provided to the patient’s family and care 
giver(s) regarding use of protective gloves if/when they come into direct contact with the 
patient’s bodily fluids and/or waste, as well as good hand-hygiene for a minimum of 2 weeks 
(14 days) after gene replacement therapy.  Additionally, patients are prohibited from donating 
blood for 2 years following the vector infusion. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 52 of 136 
Saliva, urine, and stool samples will be collected for viral shedding studies at screening, 24 hours 
postdose-, 48 hours post-dose, Day 7, Day 14, Day 21, and Day 30 (Appendix 5).  Samples will 
be collected, prepared, and shipped as per the laboratory manual. 
A subset of patients at sites opting to participate in the viral shedding sub-study will have 24-
hour total volume urine and fecal samples collected through 24 hour post-dose and through 48 
hours-post dose. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 53 of 136 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1.1. 
Definition of Adverse Events 
13.1.1.1. Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product.  In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no study treatment has been administered. 
All adverse events that occur from the start of gene replacement therapy infusion through the last 
study visit will be collected and recorded in the eCRF. 
All adverse events will be classified in accordance with the CTCAE version 4.03 outlined in 
Table 7. 
 
Table 7: 
Common Terminology Criteria for Adverse Events 
Grade 
Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting selfcare -ADL. b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Source: Common Terminology Criteria for Adverse Events (version 4.03) [9] 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
Study enrollment will be interrupted should any patient experience an unanticipated CTCAE 
Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the 
gene replacement therapy.  The event will then be reviewed by the DSMB and an evaluation will 
be made as to whether the study should be terminated early following the discontinuation rules. 
Unanticipated CTCAE Grade 3 or higher adverse events that are possibly, probably, or definitely 
related to the gene replacement therapy must be reported within 24 hours to Sponsor and/or 
designee as per study safety management plan to ensure timely escalation to the DSMB. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 54 of 136 
13.1.1.2. Serious Adverse Event 
A SAE is an AE occurring during any study phase (e.g., baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, or comparator that fulfils 1 or more of the 
following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent 1 of the outcomes listed above. 
 
All SAEs that occur after signing of the informed consent through the last study visit, whether or 
not they are related to the study product, must be collected and recorded on forms provided by 
the Contract Research Organization. 
13.1.1.3. Other Adverse Event 
The following specific treatment-emergent AE of special interest, which may be searched using 
Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries, will be 
summarized: 
• Elevated liver enzymes 
 
Other adverse events (OAE) will be identified by the Drug Safety Physician and, if applicable, 
also by the Clinical Study Team Physician during the evaluation of safety data for the Clinical 
Study Report.  Significant adverse events of particular clinical importance, other than SAEs and 
those AEs leading to discontinuation of the patient from the study, will be classified as OAEs.  
For each OAE, a narrative may be written and included in the Clinical Study Report. 
13.2. 
Relationship to Study Product 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related, Probably Related, or 
Definitely Related).  The Investigator should decide whether, in his or her medical judgment, 
there is a reasonable possibility that the event may have been caused by the investigational 
product.  If no valid reason exists for suggesting a relationship, then the AE should be classified 
as “unrelated.”  If there is any valid reason, even if undetermined, for suspecting a possible 
cause-and-effect relationship between the investigational product and the occurrence of the AE, 
then the AE should be considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” then the event will be considered related to the investigational product 
for the purposes of expedited regulatory reporting. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 55 of 136 
13.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Information about AEs will be collected from the time of vector infusion 
until the end of the study.  Serious Adverse Event information will be collected from signing of 
consent form until the last study visit.  The AE term should be reported in standard medical 
terminology when possible.  For each AE, the Investigator will evaluate and report the onset 
(date (and time if during Visit 2)), resolution (date (and time if start date during Visit 2)), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the patient to discontinue the study. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 13.1.1.2.  An AE of severe intensity 
may not be considered serious. 
13.4. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of consent form until the last 
study visit.  Any SAEs considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All SAEs must be 
reported to AveXis or designee within 24 hours of the first awareness of the event.  The 
Investigator must complete, sign and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy by fax or 
e-mail to AveXis or designee. 
Additional follow-up information, if required or available, should all be faxed or e-mailed to 
AveXis or designee within 24 hours of receipt and this should be completed on a follow-up SAE 
form and placed with the original SAE information and kept with the appropriate section of the 
eCRF and/or study file. 
AveXis is responsible for notifying the relevant regulatory authorities of certain events.  It is the 
Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at his or 
her site.  Investigators will also be notified of all unexpected, serious, product-related events 
(7/15 Day Safety Reports) that occur during the clinical study.  Each site is responsible for 
notifying its IRB or IEC of these additional SAEs. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 56 of 136 
14. 
STATISTICS 
This section summarizes key aspects of the analysis plan including definitions of co-primary, 
co-secondary, and 
 and safety endpoints, and the methods to be 
used to test the primary effectiveness hypothesis.  Additional details regarding methods for the 
final data analysis will be provided in a separate Statistical Analysis Plan (SAP) which will be 
finalized and submitted to the Investigational New Drug application prior to the enrollment of 
the first patient.  The SAP will detail all analyses and data displays and will be executed 
according to Standard Operating Procedures in a controlled environment. 
14.1. 
Study Endpoints and Populations 
14.1.1. 
Study Endpoints 
The primary and efficacy endpoint will be compared to the null.  The survival co-primary 
efficacy variable will be evaluated relative to literature-based historical controls (such as the 
Pediatric Neuromuscular Clinical Research Network [PNCR] [21].  These were selected on the 
basis of comparability to the target population and similarity to the investigational device. 
14.1.1.1. Co-Primary Efficacy Endpoint 
The co-primary efficacy endpoints are: 
• The proportion of patients that achieve functional independent sitting for at least 30 seconds 
at the 18 months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler 
Development (Version 3) (Appendix 2), confirmed by video recording, as a patient who sits 
up straight with the head erect for at least 30 seconds. 
• The survival at 14 months of age.  Survival is defined by the avoidance of the combined 
endpoint of either (a) death or (b) permanent ventilation, which is defined by tracheostomy or 
by the requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive 
ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, 
excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
 
An “acute reversible illness” is defined as any condition other than SMA that results in increased 
medical intervention (e.g., increased requirement for respiratory support; use of other 
concomitant medications as rescue) requirements and is expected to be reversible or improved 
following definitive intervention (e.g., surgery, antibiotics) or introduction of escalated 
supportive care, such as hospitalization (e.g., for upper respiratory infection, spontaneous 
fracture).  The specific duration of the condition antecedent intervention shall not be considered 
in the definition of “acute.”  The date of “definitive intervention” shall be defined as the date of 
provision of a procedure (e.g., surgery, etc.) or medication (e.g., antibiotics) intended to cure or 
substantially improve the condition.  For conditions such as viral respiratory infections for which 
supportive care is provided, the date of “definitive intervention” shall be considered the date of 
hospitalization or substantial escalation of care. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 57 of 136 
“Perioperative” use reflects any alteration of ventilatory use related to a surgical or other medical 
procedure of any nature for which the patient received medications that could impair or interfere 
with respiratory function. 
For a patient who develops an acute reversible illness and/or requires perioperative ventilatory 
support, a recovery period not to exceed 21 days following the date of definitive intervention will 
be instituted.  Following this recovery period, the condition will be considered subacute and the 
patient will become evaluable with regards to the surrogate survival endpoint (requirement of 
ventilatory support of ≥ 16 hours/day for 14 or more days). 
14.1.1.2. Co-Secondary Efficacy Endpoint 
The co-secondary efficacy endpoints are: 
• The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate 
thin liquids (as demonstrated through a formal swallowing test) and to maintain weight 
(> third percentile based on World Health Organization [WHO] Child Growth Standards [25] 
for age and gender) without need of gastrostomy or other mechanical or non-oral nutritional 
support at 18 months of age. 
• The proportion of patients who are independent of ventilatory support, defined as requiring 
no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and 
perioperative ventilation, as defined above through assessment of actual usage data captured 
from the device (Phillips Trilogy). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 58 of 136 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.1.1.4. Safety Endpoints 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• Incidence of elevated LFTs and/or unresolved LFEs 
• Incidence of CTCAE Grade 3 or higher toxicity, treatment-emergent adverse events 
• Clinically significant changes in laboratory values, physical exams, cardiac assessments or 
vital signs 
• Research Immunology Blood Labs including serum antibody to AAV9 and SMN as well as 
IFN-γ ELISpot to detect T cell responses to AAV9 and SMN 
 
14.1.2. 
Statistical Analysis Populations 
14.1.2.1. Intent-to-Treat Population (ITT) 
The ITT population will consist of symptomatic patients with biallelic- deletion mutations of 
SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene 
modifier mutation (c.859G>C) who receive an IV infusion of AVXS-101 at < 180 days of age.  
The first 3 patients enrolled must meet the criteria for the Intent-to-Treat Population. 
14.1.2.2. Efficacy Completers Population 
The efficacy completers analysis population will consist of: 
• All treated patients who reach 14 months of age for the survival endpoint or 18 months of 
age for the endpoint of achievement of functional independent sitting, OR 
• All treated patients who meet discontinuation criteria, discontinue the study due to an AE or 
experience death 
 
14.1.2.3. All Enrolled Population 
The all enrolled population will consist of all patients who receive an IV infusion of AVXS-101.  
Analyses of endpoints in this population are considered descriptive. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 59 of 136 
14.1.2.4. Safety Population 
The safety analysis population will consist of all patients who receive an IV infusion of 
AVXS-101.  All safety analyses will be conducted on the safety analysis population. 
14.2. 
Sample Size Calculation 
This is a pivotal Phase 3, open-label, single-arm, single-dose, study assessing the efficacy and 
safety of AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal 
muscular atrophy (SMA) Type 1 who meet enrollment criteria, may be either symptomatic or 
pre-symptomatic and are genetically defined by no functional survival motor neuron 1 gene 
(SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 months 
(< 180 days) of age at the time of gene replacement therapy (Day 1).  Enrolling up to twenty 
(20) patients under the broader enrollment criteria is projected to enable enrollment of at least 
15 patients that meet the Intent-to-Treat Population (ITT) criteria. The ITT population is 
identified as symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without 
the SMN2 gene modifier mutation (c.859G>C) and will comprise the primary population for 
evaluation of the primary and secondary endpoints.  Study power is based upon efficacy analysis 
of the ITT population.  Furthermore, the first 3 patients enrolled must meet criteria for the Intent-
To-Treat Population to enable a comparison of CHOP-INTEND scores at 1-month following 
gene replacement therapy to enable a comparison of patient response between 
AVXS-101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial 
(AVXS-101-CL-101).  Patients with 1 copy of SMN2, pre-symptomatic patients and patients 
with the SMN2 gene modifier mutation (c.859G>C) and other permutations outside of those 
specified in the ITT population will be evaluated separately as part of additional subgroup 
analyses.  Details of all analyses will be contained within the Statistical Analysis Plan. 
The 2 co-primary efficacy endpoints will be assessed in sequence:  The endpoint of functional 
independent sitting will be assessed first and, only if this assessment meets statistical 
significance will the endpoint of survival be assessed. 
Based upon the widely cited natural history of the disease (Pediatric Neuromuscular Clinical 
Research Network [PNCR]) [Neurol. 2014; 83(9):810-817], it is expected that no patients in this 
population would be expected to attain the ability to sit without support or accomplish other 
milestones (rolling over, standing, walking) prior to 18 months of age.  Assuming that the true 
response rate for the primary endpoint is actually zero (or as low as 0.1%) in the population of 
interest of the historical control, the first co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 
18 months of age study visit. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 40% of treated symptomatic patients with bi-allelic deletions of SMN1 and 2 copies of 
SMN2 without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-
primary efficacy endpoint of functional independent sitting for at least 30 seconds at the 
18 months of age study visit.  With the assumption for the true response rate of AVXS-101 for 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 60 of 136 
the primary endpoint being in the range of 30% - 40%, a sample size of 15 patients that meet ITT 
criteria will be enrolled and assuming approximately 30% of patients are excluded from analysis, 
would yield an ITT population that would provide power of > 90% to detect a significant 
difference from 0.1% with α = 0.025 using a 1-sided exact test for a binomial proportion. 
The second co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹, 
where 𝑝𝑝 is the proportion of patients surviving at 14 months of age. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 80% of treated symptomatic patients with biallelic- SMN1 deletions and 2 copies of SMN2 
without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-primary 
efficacy endpoint of survival through 14 months of age.  It is anticipated that 75% of patients in 
the PNCR population would not survive beyond 13.6 months of age, and that these control 
patients will represent a 25% survival rate based upon the natural history of the disease.  With 
this efficacy, an enrolled sample size of  15 patients that meet ITT criteria (assuming 30% of 
patients are excluded from the analysis) would yield an ITT population that would provide power 
of > 80% to detect a significant difference from the historical control with α = 0.05 using a 2-
sided Fisher’s Exact test, comparing to the 26 age and gender matched patients from a published 
natural history observational study performed at 3 large, tertiary care centers in the United States 
(Harvard University, Columbia University, Children’s Hospital of Philadelphia; PNCR). 
14.3. 
Efficacy Analysis 
14.3.1. 
General Considerations 
This study will compare the activity of AVXS-101 administered IV versus the natural 
observational results from PNCR [21] in terms of functional independent sitting and survival 
rate.  The ability to thrive and the ability remain independent of ventilatory support will also be 
assessed. 
The analysis of the co-primary and co-secondary efficacy endpoints will be performed for the 
ITT and efficacy completers population.  The analysis based on the ITT population will be 
considered as the primary analysis.  In the case of missing data, observed data will be used for 
the analyses. 
Unless otherwise specified, the baseline measurement is defined as the last non-missing 
measurement collected prior to or on the day of gene replacement therapy infusion (e.g., on or 
before Day 1 visit). 
14.3.2. 
Primary and Secondary Efficacy Analysis 
Primary and secondary efficacy analyses will be based on the ITT population, those patients that 
are symptomatic with biallelic- deletion mutations of SMN1 and 2 copies of SMN2 without the 
SMN2 gene modifier mutation (c.859G>C).  These analyses are to test the superiority of 
AVXS-101 to the results from natural observation study (PNCR) [21]. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 61 of 136 
The first co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1% 
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 
18 months of age study visit. 
The second co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 , 
where 𝑝𝑝 is the proportion surviving at 14 months of age. 
Primary efficacy endpoints will be examined on the ITT population.  Testing for the first co-
primary endpoint, functional independent sitting will first be performed using 1-sided exact 
binomial test.  Only if the null hypothesis of equality in proportion of functional independent sitting 
is rejected at p<0.025, will the co-primary endpoint survival improvement be tested using 2-sided 
Fisher’s Exact test on the ITT population, comparing to matched patients from natural observational 
study (PNCR).  This hierarchy approach strongly protects the Type I error rate. 
The hypothesis for both co-secondary efficacy endpoints to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1% , 
where p is the proportion of patients maintaining the ability to thrive/are independent of 
ventilatory support. 
One-sided exact binomial tests will be executed for secondary efficacy analyses on the ITT 
population. 
A sensitivity analysis will be conducted by repeating the primary efficacy analysis on the 
efficacy completers analysis population. 
14.4. 
CHOP-INTEND Comparison 
A comparison will be performed of the first 3 patients CHOP-INTEND scores to the 
AVXS-101-CL-101 CHOP-INTEND scores.  The first 3 patients enrolled must meet the criteria 
for the Intent-to-Treat (ITT) Population.  AveXis will compare the CHOP-INTEND 1 month 
improvement for the AVXS-101-CL-303 patients that meet the ITT criteria to assess the clinical 
response to the dose 1.1 × 1014 vg/kg as being what was expected from the Cohort 2 patients in 
the Phase 1 trial (AVXS-101-CL-101).  This comparison will be performed as a per patient 
assessment for the first 3 patients.  The individual patients who receive their gene therapy at 0-3 
months of age will be compared to a value of 10 CI points, while patients who receive their gene 
therapy at >3 but <6 months of age will be compared to a value of 5 CI points.  Furthermore, 
patients from either age group are expected to maintain the improvement in the absence of an 
acute illness or perioperatively.  If the expected CI improvements are observed for the first 3 ITT 
patients, AveXis will remove the 4-week interval between patients and proceed to dose at least 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 62 of 136 
12 additional patients that meet the ITT criteria and perform safety and efficacy assessments as 
described elsewhere in the clinical protocol (AVXS-101-CL-303) and corresponding Statistical 
Analysis Plan.  If the expected CI improvements are not observed for the first 3 ITT patients, 
AveXis will discuss next steps with the FDA before continuing study enrollment. 
14.5. 
Safety Analysis 
Safety will be assessed through the incidence and severity of AEs, vital sign assessments, cardiac 
assessments, laboratory evaluations (chemistry, hematology, urinalysis, immunology), physical 
examinations, and use of concomitant medications.  Adverse events will be coded in accordance 
with the most current version of the MedDRA coding dictionary. 
Safety analyses will be conducted on safety population and summarized by subgroup and overall. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 63 of 136 
15. 
DATA SAFETY MONITORING BOARD 
The DSMB is an independent multidisciplinary group consisting of clinicians and a 
biostatistician that, collectively, have experience in the management of patients with SMA 
Type 1 and other diseases, and in the conduct and monitoring of randomized clinical studies with 
interim analyses.  The DSMB will be chartered to oversee the safety of patients during the 
conduct of the study and will act in an advisory capacity to AveXis.  A detailed description of 
the DSMB, its role in this study, and the timing of the scheduled reviews will be described in a 
DSMB Charter. 
The DSMB will routinely convene on a quarterly basis to review emerging safety data from the 
study.  All available safety data from all enrolled patients will be included in such reviews, 
which include, but are not limited to, screen failures, enrollment status, data from safety 
parameters, all SAEs, and other AEs.  Following each meeting, the DSMB will make a 
recommendation as to whether or not the accumulated safety data warrants a suspension or 
discontinuation of the study, a modification to the study, or any additional comments or 
recommendations related to safety.  The DSMB will prepare and provide minutes of their 
meetings to AveXis who will provide copies to the regulatory authorities as appropriate. 
The DSMB will also convene on an ad hoc basis within 48 hours should any patient experience 
an unanticipated CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely 
related to gene replacement therapy, and is associated with clinical symptoms and/or requires 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the 
DSMB will review the safety information and provide its recommendation. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 64 of 136 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of AveXis will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of AveXis or its representatives.  This will be 
documented in a Clinical Study Agreement between AveXis and the Investigator. 
During the study, a monitor from AveXis or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed 
• Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the study.  This will require direct access to all original records for each patient (e.g., clinic 
charts, electronic medical records) 
• Record and report any protocol deviations not previously sent to AveXis 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any SAEs 
have been forwarded to AveXis and those SAEs that met criteria for reporting have been 
forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of AveXis, a regulatory authority, an IEC or an IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of an AveXis 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP) 
guidelines of the International Council for Harmonization (ICH), and any applicable regulatory 
requirements.  The Investigator should contact AveXis immediately if contacted by a regulatory 
agency about an inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 65 of 136 
16.3. 
Institutional Biosafety Committee 
As this study involves gene therapy, the Principal Investigator must obtain approval/favorable 
opinion for the investigation from a designated institutional or independent biosafety committee 
in accordance with institutional requirements and/or guidelines. 
16.4. 
Institutional Review Board/Institutional Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation (Section 18.1).  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 66 of 136 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Qualified individuals designated by the Sponsor will monitor all aspects of the study according 
to GCP, standard operating procedures (SOPs), and for compliance with applicable government 
regulations.  Please see Section 16.1 for more details regarding the quality control and 
monitoring process.  AveXis may also conduct a quality assurance audit any time during or after 
the completion of the study.  Please see Section 16.2 for more details regarding the audit process. 
The Investigator agrees to allow these Sponsor representatives direct access to the clinical data 
and supplies, dispensing and storage areas and if requested, agrees to cooperate fully or assist the 
Sponsor representative.  The Investigator and staff are responsible for being present or available 
for consultation during routinely scheduled site visits conducted by the Sponsor or its designees. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
Investigator, site staff, or representatives of the Sponsor will lead to prompt action by the 
Sponsor to secure compliance.  Continued noncompliance may result in termination of the 
corresponding party’s involvement in the study.  The IRB/IEC and relevant regulatory authority 
will also be informed. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 67 of 136 
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval to AveXis before he or she can enroll any patient into 
the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  AveXis or designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (Appendix 6) and are consistent with ICH/GCP, applicable regulatory 
requirements and the AveXis’ policy on Bioethics. 
18.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the parent(s)/legal guardian(s) are 
given full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study.  The parent(s)/legal guardian(s) must also be notified that they are free to 
discontinue the patient from the study at any time.  The parent(s)/legal guardian(s) should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the parent(s)/legal guardian(s). 
There will be 3 informed consent forms: 
• Parent(s)/legal guardian(s) informed consent form 
• Biological mother baseline AAV9 antibody screening informed consent form 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 68 of 136 
• Autopsy informed consent form (Appendix 1; if the parent(s)/legal guardian(s) decline an 
autopsy, it will not prevent the patient from participating in the study) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 69 of 136 
19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Electronic Case Report Forms 
Adequate and accurate case records will be maintained, and all relevant observations and data 
related to the study will be recorded.  This will include medical history/ physical examination, 
hematology, clinical chemistry and serology results, a check list of inclusion and exclusion 
criteria, product administration, and a record of sample collection, hemodynamic measurements, 
clinical assessments, AEs, and final evaluation. 
Electronic CRFs will be used in this study.  The eCRF will be electronically signed and dated by 
the Principal Investigator or designee after his/her review.  After the completion of the study, 
completed eCRFs will be retained in the archives. 
Completed eCRFs will be reviewed by the study monitor against the source documentation for 
accuracy and completeness.  Once signed by the Investigator, the monitor will transmit the 
completed eCRFs to data management for data validation and database analysis. 
19.2. 
Inspection of Records 
AveXis or designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the product storage area, study product stocks, product accountability records, patient 
charts and study source documents, and other records relative to study conduct. 
19.3. 
Retention of Records 
All primary data that are a result of the original observations and activities of the study and that 
are necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period not < 2 years after the last approval of a marketing 
application in an ICH region, and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have lapsed since the formal 
discontinuation of the clinical development of the investigational product.  All country/region 
specific requirements that may be more stringent than the 2 years included in ICH shall be 
followed. 
The site will maintain a Clinical Study Document Binder, which will be maintained at the study 
site.  In this binder, there will be tabbed sections for study documents including the following: 
study personnel identification and signature list, patient / subject screening records, patient / 
subject roster (names omitted), protocol and amendments or administrative changes, FDA Form 
1572 (if required), study staff Curricula Vitae, IRB/IEC documentation, an approved sample 
ICF, drug / product accountability records, correspondence, site monitoring reports, blank Data 
Documentation form, and lab accreditations and normal values. The site must keep this binder 
current and available for review by the Sponsor, IRB/IEC, and/or regulatory bodies. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 70 of 136 
20. 
PUBLICATION POLICY 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study.  During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation.  Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and 
information generated by the Investigator) without the consent of the Investigator.  Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document.  All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement.  In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
If the study is being conducted as part of a multicenter clinical study, data from all sites 
participating in the study will be pooled and analyzed by the Sponsor or the Sponsor’s designee.  
The first publication of the study results shall be made in conjunction with the results from other 
study sites as a multicenter publication.  If a multicenter publication is not forthcoming within 
24 months of completion of the study at all sites, the Investigator may publish or present the 
results generated at his or her site. 
The Investigator will provide the Sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication.  The Sponsor shall inform the Investigator in writing of any changes or deletions 
in such presentation or publication required to protect the Sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results.  At the expiration of such 60-day period, the 
Investigator may proceed with the presentation or submission for publication unless the Sponsor 
has notified the institution or the Investigator in writing that such proposed publication or 
presentation discloses the Sponsor’s confidential and proprietary technical information.  Further, 
upon the request of the Sponsor, the Investigator will delay the publication or presentation for an 
additional 90 days to permit the Sponsor to take necessary actions to protect its intellectual 
property interests. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 71 of 136 
21. 
LIST OF REFERENCES 
1. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for 
spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum 
Genet. 2012;20(1):27-32. 
2. Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to 
age, SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-712. 
3. Le TT, McGovern VL, Alwine IE, et al. Temporal requirement for high SMN expression in 
SMA mice. Hum Mol Genet. 2011;20(18):3578-3591. 
4. Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and 
adaptation in spinal muscular atrophy. Arch Neurol. 2012b;69(4):467-473. 
5. Riessland M, Ackermann B, Forster A, et al. SAHA ameliorates the SMA phenotype in two 
mouse models for spinal muscular atrophy. Hum Mol Genet. 2010;19(8):1492-1506. 
6. Dayangac-Erden D, Bora-Tatar G, Dalkara S, Demir AS, Erdem-Yurter H. Carboxylic acid 
derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: a promising 
target for spinal muscular atrophy therapeutics. Arch Med Sci. 2011;7(2):230-234. 
7. www.ClinicalTrials.gov 
8. Darbar IA, Plaggert PG, Resende MB, Zanoteli E, Reed UC. Evaluation of muscle strength 
and motor abilities in children with Type II and III spinal muscle atrophy treated with 
valproic acid. BMC Neurol. 2011;11:36. 
9. US Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events (v4.03). Published May 2009 (Revised June 2010). 
10. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 
2011;68(8):979-984. 
11. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and 
characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-164. 
12. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene 
regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 
1999;96(11):6307-6311. 
13. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH et al. A single 
nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from 
the copy gene SMN2. Hum Mol Genet. 1999;8(7):1177-1183. 
14. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity & SMN protein level in 
spinal muscular atrophy. Nat Genet. 1997;16(3):264-269. 
15. Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights from 
model mice. Curr Neurol Neurosci Rep. 2010;10(2):108-117. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 72 of 136 
16. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 
and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and 
prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-368. 
17. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the 
SMN2 gene. Am J Hum Genet. 2009;85:408-413. 
18. Farrar MA, Vucic S, Johnston HM, et al. Pathophysiological insights derived by natural 
history and motor function of spinal muscular atrophy. J Pediatr. 2013;162(1):155-159. 
19. Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype 
in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010;28(3):271-274. 
20. Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the SMNDelta7 
mouse model of spinal muscular atrophy. Neurobiol Dis. 2007;27(2):207-219. 
21. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular 
atrophy Type I and implications for clinical trials. Neurol. 2014;83(9):810-817. 
22. Wijnhoven TMA, De Onis M, Oyango AW, Wang T, Bjoerneboe GA, Bhandari N, Lartey A, 
Al Rashidi B; WHO Multicentre Growth Reference Study Group. Assessment of gross motor 
development in the WHO multicenter growth reference study. Food Nutr Bull. 
2004;25(1 Supple 1):S37S45. 
23. Glanzman AM, McDermott MP, Montes J, et al.  Validation of the Children's Hospital of 
Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).  Pediatr Phys Ther. 
2011;23(4):322-326. 
24. Glanzman AM, Mazzone E, Main M, et al.  The Children’s Hospital of Philadelphia Infant 
Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability.  
Neuromusc Disord.  2010;20(3):155-161. 
25. Onis, M. "WHO Child Growth Standards based on length/height, weight and age." Acta 
paediatrica 95.S450 (2006): 76-85. 
26. American Academy of Pediatrics: Policy statements--Modified recommendations for use of 
palivizumab for prevention of respiratory syncytial virus infections. Committee on Infectious 
Diseases. Pediatrics. 2009 Dec;124(6):1694-701. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 73 of 136 
22. 
APPENDICES 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 74 of 136 
APPENDIX 1. AUTOPSY PLAN 
An autopsy will be requested for any patient who receives gene replacement therapy and expires.  
The autopsy and tissue collection will be performed by a contracted vendor who will deploy a 
pathology assistant to the funeral home of the deceased to perform the autopsy and tissue 
collection.  Standard autopsy incisions will be used to perform the autopsy and pathology 
necessary to determine the cause of death. 
During the procedure, multiple tissues along with the entire spinal cord will be collected for 
research purposes, including up to 7 sections or pieces from each organ and each region of the 
spinal cord.  Upon collection, these tissue samples will be provided to AveXis for analysis.  
Tissue analysis will be done to determine whether the vector transduced the expected motor 
neurons and if the SMN gene was expressed.  These results will demonstrate whether the vector 
delivered the therapeutic gene as expected.  Tissue samples collected will also be available for 
histology and immunohistochemistry, allowing the state of the motor neurons and muscles to be 
examined. 
Specifically, tissue samples from the spinal cord, muscles, and organs will be collected as 
indicated in Table 8.  Tissue samples will be frozen or fixed (e.g., 2% paraformaldehyde) for 
appropriate analysis. 
Families will be asked to consent to the autopsy and authorize tissue collection prior to any sign 
of moribund or death by the clinical team conducting the study.  There are distinct forms for the 
formal autopsy and for the research tissue collection.  This will allow families the flexibility to 
participate in one or both of the research activities.  Declining an autopsy will not prevent 
patients from participating in the study. 
Table 8: 
Tissue Sample for Analysis 
Brain 
Spinal Cord 
Muscles 
Organs 
Motor cortex 
Cervical spinal cord 
Diaphragm 
Spleen 
Layer 5 motor cortex 
Thoracic spinal cord 
#6/#7 Rib with intercostal 
muscle and nerve 
Kidney 
Brain stem 
Lumbar spinal cord 
Psoas muscle 
Small intestine 
 
Sacral spinal cord 
 
Large intestine 
 
Dorsal root 
 
Pancreas 
 
Cervical level 
 
Stomach 
 
Ventral root 
 
Lung 
 
Cervical level 
 
Heart 
 
DRG root 
 
Liver 
 
Cervical level 
 
Inguinal lymph node 
 
Cerebrospinal fluid 
 
Gonads 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 75 of 136 
APPENDIX 2. BAYLEY SCALES OF INFANT AND TODDLER 
DEVELOPMENT (VERSION 3) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 76 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 77 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 78 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 79 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 80 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 81 of 136 
  
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 82 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 83 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 84 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 85 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 86 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 87 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 88 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 89 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 90 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 91 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 92 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 93 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 94 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 95 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 96 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 97 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 98 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 99 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 100 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 101 of 136 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 102 of 136 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 103 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 104 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 105 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 106 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 107 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 108 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 109 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 110 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 111 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 112 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 113 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 114 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 115 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 116 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 117 of 136 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 118 of 136 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 119 of 136 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 120 of 136 
APPENDIX 3. PERFORMANCE CRITERIA FOR BAYLEY SCALES OF 
INFANT AND TODDLER DEVELOPMENT (VERSION 3) 
DEVELOPMENTAL MILESTONES 
Developmental Milestone 
Head Control – Gross Motor Subtest 
Item #4  
Rolls from Back to Sides – Gross 
Motor Subtest Item #20 
Sits Without Support – Gross Motor 
Subtest Item #26 
Stands With Assistance - Gross Motor 
Subtest Item #33 
Crawls – Gross Motor Subtest 
Item #34 
Pulls to Stand – Gross Motor Subtest 
Item #35 
Walks With Assistance – Gross Motor 
Subtest Item #37 
Stands Alone – Gross Motor Subtest 
Item #40 
Walks Alone – Gross Motor Subtest 
Item #43 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 121 of 136 
APPENDIX 4. CHOP-INTEND 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 122 of 136 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 123 of 136 
APPENDIX 5. SCHEDULE OF ASSESSMENTS 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Study a 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthly c 
18 months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Prophylactic Prednisolone 
 
Xq 
X 
X 
X 
X 
X 
X 
Xq 
 
 
AVXS-101 Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Bayley Scales/ Developmental 
Milestones d (with video) e 
X 
 
 
 
 
 
 
 
Xf 
Xf 
X 
CHOP-INTEND g (with video) e 
X 
Xs 
 
 
 
X 
X 
X 
X 
X 
X 
CMAP 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Demographic/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs h/Weight & Length 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
 
 
 
 
Xj, t 
X 
12-Lead Holter Monitoring k 
 
X 
X 
X 
X 
 
 
 
 
Xj, t 
X 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
Xj, t 
X 
Pulmonary Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Photograph of Infusion Site 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology/Chemistry/Urinalysis 
X 
Xo 
 
X 
 
X 
X 
X 
X 
X 
X 
CK-MB 
X 
 
 
 
 
X 
 
 
X 
Xr 
X 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
Capillary Blood Gas 
 
X 
 
X 
 
 
 
 
 
 
 
ELISA anti-AAV9/SMN Ab 
X 
 
 
 
 
X 
X 
X 
Xl 
 
 
Immunology Testing (ELISpot) 
 
 
X 
 
Xl 
 
 
Anti-AAV9 Ab Screen in Mother 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Diagnostic Confirmation 
Testing 
X 
 
 
 
 
 
 
 
 
 
 
Saliva, Urine, and Stool Samples 
(for viral shedding) p 
X 
 
 
Xm 
Xm 
X 
X 
X 
X 
 
 
Adverse Events n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
Collected from 2 weeks before gene replacement therapy until End of Study visit 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; 
CMAP = compound motor action potential; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; 
ELISpot = Enzyme-linked ImmunoSpot; ET = early termination; WHO = World Health Organization 
a The End of Study visit must occur within 0 to 14 days after the date on which the patient reaches 18 months of age (or ET). 
b Day 1 assessments will be performed prior to the start of gene replacement therapy infusion. 
c The 14 months of age visit must occur within 0 to 14 days after the date on which the patient reaches 14 months of age. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 124 of 136 
d Developmental milestones will be assessed as defined by Bayley Scales of Infant and Toddler Development, version 3 
(independent sitting will be assessed also by WHO Multicentre Growth Reference Study). 
e Videos may be submitted for review by a central reader. 
f The full Bayley test will be administered every 6 months, starting at Month 6, whereas the Bayley fine and gross motor 
subtests will be administered at each monthly visit. 
g Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not continue CHOP-INTEND assessments.  
h Vital signs include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry 
i Vital signs will be continuously monitored throughout the infusion of gene replacement therapy and recorded every 
15 minutes for the first 4 hours (+/- 5 minutes) after the start of infusion, then every hour (+/- 15 minutes) until 24 hours after 
the start of infusion.  Axillary temperature will be recorded pre- and post-infusion. 
j Completed at Months 3, 6, 9, and 12 and every 6 months thereafter. 
k On Days -1 to Day 3, serial ECG data will be pulled in triplicate from the Holter monitor at the following time points: 
pre-dose (within 24h), 2h, 4h, 6h, 8h, 12h, 24h, 36h, and 48h post-dose. 
l Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to be elevated, based on 
further discussion with the Principal Investigator and Medical Monitor. 
m Collected at 24 and 48 hours post-dose. 
n Serious adverse events are collected from signing of the informed consent through the last study visit.  All adverse events that 
occur from the start of gene replacement therapy through the last study visit are collected. 
o Laboratory samples collected on Day -1 to be processed locally, prior to dosing. 
p Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces at 24 and 48 
hours.  All other sites will collect singular urine and feces samples within 24 hours and 48 hours of dosing. 
q Prednisolone to be given 24 hours prior to scheduled AVXS-101 dosing and continued as per protocol Section 9.2.1. 
r CK-MB to be performed at Day 60, and Month 6, 9, 12, 15 months of age, 18 months of age/EOT). 
s If a Day -1 CHOP-INTEND assessment is not completed, a CHOP-INTEND assessment should be completed on Day 1 prior 
to dose administration. 
t For patients enrolled in the study prior to amendment 3 and irrespective of study schedule, after signing an updated informed 
consent form, an echocardiogram, 24-hour Holter monitoring, and 12-lead ECG will be performed at the next scheduled visit 
and then in accordance with the Schedule of Assessments Compound Motor Action Potential Manual 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 125 of 136 
 
Phase 3 Gene Transfer Clinical Study for Spinal Muscular Atrophy Type 1  
Delivering AVXS-101 
 
 
 
CMAP Manual 
Compound Motor Action Potential (CMAP) 
 
 
 
Materials Needed for the Process 
• Carefusion Disposable Ring Electrode with Leads (order number 019‐439300)  
(4 per visit) 
• Carefusion Tab Electrodes 1.0 meter leads (order number 019‐406600) (1 or 2 per visit) 
• CMAP case report form 
• Infrared temperature probe 
• Electrode gel 
• Warming packs or some other warming source 
• Transpore adhesive tape 
• Alcohol skin prep pads 
• EMG machine 
 
Temperature and Warming 
As only the peroneal motor study will be performed, only lower extremity temperatures will 
need to be assessed.  The temperature should be measured on the surface of the anterior calf 
distal to the recording electrodes and proximal to the ankle.  As the protocol only refers to 
measurement of upper extremity temperatures, by convention a temperature threshold that is 2 
degrees lower, i.e., ≥ 31 degrees Centigrade, should be sufficient. When the temperature is 
measured to be below 31 degrees, a warming procedure should be performed, either with heated 
towels or other authorized devices.  Care must be taken not to apply towels or other devices at 
temperatures that would put the infants at risk of burns, the examiner must test the temperature 
of the warming device against his/her own skin and/or the skin of a parent prior to application.  
As a general rule, the warming device should feel lukewarm, not hot, against an adult’s skin, and 
it should be expected that the warming procedure will take 3−5 minutes.  Scheduling of this 
procedure should allow for both temperature recording and warming procedures. 
Preparation of Skin 
The skin should be cleaned with alcohol (or equivalent) as needed to improve contact with the 
electrodes. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 126 of 136 
EMG machine settings 
For the peroneal CMAP measures the filter settings should be 10 Hz to 10 kHz. 
Tibialis Anterior (TA) CMAP Electrode Placement 
For the TA CMAP, the G1 electrode should be placed below the fibular head on the bulk of the 
Tibialis Anterior (TA) muscle belly.  The G2 reference electrode should be placed over the 
tendon above the ankle in a standard “belly-tendon” arrangement.  An adhesive ground electrode 
(Carefusion Tab Electrodes 1.0 meter leads (DIN Style) order number 019‐406600) is placed 
between the stimulating electrodes and the G1 electrode.  Adhesive tape may be used to secure 
any loose electrodes in place. Adhesive tape should not touch other electrodes or other pieces of 
adhesive tape. 
Supramaximal Nerve Stimulation for TA CMAP 
The stimulator should be a pediatric sized bipolar probe.  The stimulation site should be at or 
proximal to the fibular head.  A maximal response should be obtained (CMAP), using a stimulus 
120% of that producing the maximal response and a stimulus duration of 0.2 msec.  Maximum 
CMAP amplitude and area should be recorded on the Source Document and a printout of the 
CMAP tracing made.  Area is measured only for the initial negative peak.  Subsequent negative 
peaks are not included. 
Alternate G1 Electrode Placements and Repetition of Motor Study 
As the motor point of the tibialis anterior does not have precise landmarks, there is a possibility 
that the G1 electrode will not be placed exactly over the motor point without testing multiple 
sites.  Thus, as tolerated by the patient, the CMAP should be recorded at least 3 times, with a 
different placement of the G1 electrode each time.  The CMAP with the highest amplitude 
among the trials should be reported. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 127 of 136 
APPENDIX 6. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES 
FOR MEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving Human subjects, including research on identifiable 
human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians.  The 
WMA encourages others who are involved in medical research involving Human subjects to adopt 
these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research.  The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving Human subjects. 
6. The primary purpose of medical research involving Human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments).  Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all Human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research patients. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
patients.  The responsibility for the protection of research patients must always rest with the physician 
or other health care professionals and never with the research patients, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
Human subjects in their own countries as well as applicable international norms and standards.  No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research patients set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the environment. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 128 of 136 
12. Medical research involving Human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications.  Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research patients. 
15. Appropriate compensation and treatment for patients who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving Human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research patients. 
17. All medical research involving Human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving Human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group.  In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving Human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation.  The welfare of animals used for 
research must be respected. 
22. The design and performance of each research study involving Human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed.  The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
patients and information regarding provisions for treating and/or compensating patients who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 129 of 136 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins.  This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified.  It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards, but these must not be allowed to reduce or eliminate any of the protections for research 
patients set forth in this Declaration. 
The committee must have the right to monitor ongoing studies.  The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events.  
No amendment to the protocol may be made without consideration and approval by the committee.  
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research patients and the confidentiality of 
their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as patients in medical research must 
be voluntary.  Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving Human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study.  The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal.  Special attention should be given to the 
specific information needs of individual potential patients as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing.  If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
All medical research patients should be given the option of being informed about the general outcome 
and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress.  In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorized representative.  These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative.  The potential subject’s dissent should be 
respected. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 130 of 136 
30. Research involving patients who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group.  In such circumstances the 
physician must seek informed consent from the legally authorized representative.  If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving patients with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee.  Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research.  
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse.  There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research.  In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or where 
for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  Extreme care must be 
taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all patients who still need an intervention identified as beneficial in 
the trial.  This information must also be disclosed to patients during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving Human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research.  Researchers have a duty to make publicly 
available the results of their research on Human subjects and are accountable for the completeness 
and accuracy of their reports.  All parties should adhere to accepted guidelines for ethical reporting.  
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available.  Sources of funding, institutional affiliations and conflicts of interest must be declared in 
the publication.  Reports of research not in accordance with the principles of this Declaration should 
not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist, or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering.  
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy.  In all cases, new information must be recorded and, where appropriate, made publicly 
available. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 131 of 136 
APPENDIX 7. SUMMARY OF CHANGES 
The section below highlights content changes represented in this version of the protocol.  
Language deleted from Protocol version 3.0 appears in red strike through.  Language added to 
Protocol version 4.0 appears in bold. 
The Amendment 3 version of the protocol (Protocol version 4.0) is updated to included updated 
and recent GLP toxicology data, to provide additional cardiac monitoring for patient safety, 
standardize infusion times within protocol, and to exclude patients from Bayley scales where 
English is not their first language to preserve the validity of the Bayley scales.  Additionally, 
minor editorial edits were included where applicable. 
Section 1.1 
Approval 
 
 
 
Chief Medical Officer 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
Senior Vice President, Chief Regulatory and Quality Officer 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
Rationale for Change 
Administrative change. 
Section 2 
Synopsis, Duration of Treatment 
AVXS-101 will be administered as a 1-time IV infusion over approximately 30-60 minutes, 
dependent upon the volume required. 
Section 5.3 
Non-clinical Studies 
These mouse and monkey studies can be summarized as follows.  In these non-GLP studies, 
Tthe serum chemistry and hematology studies were unremarkable as was the histopathology 
assessment.   
Rationale for Change 
Updated to include GLP toxicology data. 
Section 5.3 
Non-clinical Studies 
In pivotal GLP compliant 3-month mouse toxicology studies, the main target organs of 
toxicity were the heart and liver.  Following intravenous infusion in the mouse, vector and 
transgene were widely distributed with the highest expression generally observed in heart 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 132 of 136 
and liver, and substantial expression in the brain and spinal cord.  AVXS-101-related 
findings in the ventricles of the heart were comprised of dose-related inflammation, edema 
and fibrosis, and in the atrium, inflammation and thrombosis.  Liver findings were 
comprised on hepatocellular hypertrophy, Kupffer cell activation, and scattered 
hepatocellular necrosis.  A no observable adverse effect level (NOAEL) was not identified 
for AVXS-101-related heart and liver findings in the mouse, and the Maximum Tolerated 
Dose was defined as 1.5 × 1014 vg/kg, providing a safety margin of approximately 1.4-fold 
relative to the recommended therapeutic dose of 1.1 × 1014 vg/kg.  The translatability of the 
observed findings in mice to primates is not known at this time. 
Rationale for Change 
Updated to include GLP toxicology data. 
Section 5.3 
Non-clinical Studies 
When newborn FVB mice were given a single IV injection of AVXS-101 at levels up to 
3.3 × 1014 vg/kg on Day 1, there was neither test article-related mortality nor evidence of toxicity 
seen at time points up to 24 weeks after administration.  Treatment-related decreases in mean 
body weight and mean body weight gain, as well as lower activated partial thromboplastin time 
(APTT) values, were mild effects of treatment, but did not result in toxicity.  Activity of 
AVXS-101 was demonstrated by the biodistribution and the presence of a specific transgene 
ribonucleic acid (RNA) expression in brain and spinal cord, the main targeted therapeutic tissues.  
Low levels of antibodies to the AAV9 capsid were found after 12 and 24 weeks in males and 
females given 3.3 × 1014 vg/kg (Group 3).  No alteration was observed in clinical pathology and 
histopathology analyses.  Based on these results, the no observable adverse effect level 
(NOAEL) of AVXS-101 in newborn male and female mice is considered to be 3.3 × 1014 vg/kg. 
Intravenous administration of AAV9 has been shown to be safe and well tolerated when 
administered to mice and monkeys.  The vector has also demonstrated the ability to cross the 
blood brain barrier in both species following IV administration.  Body weight increased, righting 
behavior improved, survival was extended and cardiac deficits returned toward normal in treated 
SMNΔ7 mice when compared to untreated SMNΔ7 mice.  Toxicology studies determined the 
NOAEL of AVXS-101 was 3.3 × 1014 vg/kg and there was no test article mortality or toxicity 
observed up to 24 weeks following IV administration in mice.  Biodistribution to the brain and 
spinal cord was reconfirmed and low levels of antibodies to the AAV9 capsid were observed at 
12 and 24 weeks following the 3.3 × 1014 vg/kg dose.  No alteration was observed in clinical 
pathology and histopathology analyses. 
Rationale for Change 
Updated to reflect recent GLP toxicology data. 
Section 10.6 
Study Product Administration 
AVXS-101 should be slowly infused over approximately 30-60 minutes, dependent upon total 
volume in accord with the Pharmacy Manual, utilizing an infusion set and pump in accordance 
with the Pharmacy Manual. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 133 of 136 
Rationale for Change 
Standardization of infusion time within the study. 
Section 11.2.1 
Bayley Scales of Infant and Toddler Development/Developmental 
Milestones 
The full Bayley Scales will be administered at screening, every 6 months starting at Month 6, 
and at End of Study when the patient reaches 18 months of age (or early termination), whereas 
the gross and fine motor subtests of the motor domain will be administered at each monthly visit.  
For patients which English is not their first language, the language subtests (receptive 
communication and expressive communication) and cognitive scale portions of the Bayley 
will not be performed. 
Rationale for Change 
For the purposes of this study, the Bayley Scales are only conducted in English.  Administering 
in a second or non-native language would jeopardize the validity of these portions of the Bayley 
Scales. 
Section 12.1.4 
Electrocardiogram 
A 12-lead ECG will be performed at screening, Day –1, pre-dose on Day 1, Day 2, Months 3, 6, 
9, and 12 visits and every 6 months thereafter.  A 12-lead ECG will also be 
performedstarting at Month 6, and the End of Study visit when the patient reaches 18 months of 
age (or early termination) (Appendix 5).  For patients enrolled in the study prior to 
amendment 3 in the study and irrespective of the study schedule, after signing an updated 
informed consent, all patients should have a 12-lead ECG at their next scheduled visit and 
then in conformity with the Schedule of Assessments (Appendix 5).  Additional ECG 
monitoring will be at the discretion of the Investigator as per local institutional guidelines. 
Rationale for Change 
Added to provide additional cardiac monitoring to assure patient safety. 
Section 12.1.5 
12-Lead Holter Monitor 
On Days -1 to Day 3, sSerial ECG data will be pulled in triplicate from the Holter monitor at the 
following time points: 
• Pre-dose (within 24 hours prior to gene replacement therapy) 
• 2 hours 
• 4 hours 
• 6 hours 
• 8 hours 
• 12 hours 
• 24 hours 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 134 of 136 
• 36 hours 
• 48 hours 
Twenty-four hour Holter monitoring will also be performed at the 3, 6, 9, and 12 month 
visits and every 6 months thereafter.  For patients enrolled in the study prior to 
amendment 3 and irrespective of study schedule, after signing an updated informed 
consent, all patients should have a 24-hour Holter monitor at their next scheduled visit and 
then in conformity with the Schedule of Assessments (Appendix 5). 
Rationale for Change 
Added to provide additional cardiac monitoring to assure patient safety. 
Section 12.1.6 
Echocardiogram 
A standard transthoracic echocardiogram will be performed at screening, at 3, 6, 9, and 12 
month visits and every 6 months thereafter.  An echocardiogram will also be performed 
starting at Month 6, and at the End of Study visit when the patient reaches 18 months of age (or 
early termination) (Appendix 5).  For patients enrolled in the study prior to amendment 3 
and irrespective of study schedule, after signing an updated informed consent, all patients 
should have an echocardiogram performed at their next scheduled visit and then in 
conformity with the Schedule of Assessments (Appendix 5). 
Rationale for Change 
Added to provide additional cardiac monitoring to assure patient safety. 
Section 12.1.10 
Laboratory Assessments 
In most instances, Bblood samples will be collected and shipped to a central laboratory, 
however, at the discretion of the Investigator, samples may be processed locally for 
emergent safety monitoring or other logistical or technical reasons that warrant samples to 
be processed locally.  Samples for laboratory tests required during the in-patient vector infusion 
period prior to dosing will be collected and processed by the investigative site’s Clinical 
Laboratory Improvement Amendment (CLIA) CLIA-certified local laboratory to ensure receipt 
of results prior to dosing. 
Rationale for Change 
Allowance for samples to be processed locally provides additional options and flexibility for 
safety monitoring. 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 135 of 136 
Appendix 5 
Schedule of Assessments 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Prophylactic Prednisolone 
 
Xq 
X 
X 
X 
X 
X 
X 
Xq 
 
 
AVXS-101 Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Bayley Scales/ Developmental 
Milestonesd (with video)e 
X 
 
 
 
 
 
 
 
Xf 
Xf 
X 
CHOP-INTENDg (with video)e 
X 
Xs 
 
 
 
X 
X 
X 
X 
X 
X 
CMAP 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Demographic/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsh/Weight & Length 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
 
 
 
 
Xj, t 
X 
12-Lead Holter Monitoringk 
 
X 
X 
X 
X 
 
 
 
 
Xj, t 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
Xj, t 
X 
Pulmonary Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Photograph of Infusion Site 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology/Chemistry/ 
Urinalysis 
X 
Xo 
 
X 
 
X 
X 
X 
X 
X 
X 
CK-MB 
X 
 
 
 
 
X 
 
 
X 
Xr 
X 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
Capillary Blood Gas 
 
X 
 
X 
 
 
 
 
 
 
 
ELISA anti-AAV9/SMN Ab 
X 
 
 
 
 
X 
X 
X 
Xl 
 
 
Immunology Testing 
(ELISpot) 
 
 
 
 
 
X 
 
 
Xl 
 
 
Anti-AAV9 Ab Screen in 
Mother 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Diagnostic 
Confirmation Testing 
X 
 
 
 
 
 
 
 
 
 
 
Saliva, Urine, and Stool 
Samples (for viral shedding)p 
X 
 
 
Xm Xm 
X 
X 
X 
X 
 
 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
Collected from 2 weeks before gene replacement therapy until End of Study visit 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v4.0 / October 4, 2018 
Confidential | Proprietary 
Page 136 of 136 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; 
CMAP = compound motor action potential; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; 
ELISpot = Enzyme-linked ImmunoSpot; ET = early termination; WHO = World Health Organization 
a The End of Study visit must occur within 0 to 14 days after the date on which the patient reaches 18 months of age (or ET). 
b Day 1 assessments will be performed prior to the start of gene replacement therapy infusion. 
c The 14 months of age visit must occur within 0 to 14 days after the date on which the patient reaches 14 months of age. 
d Developmental milestones will be assessed as defined by Bayley Scales of Infant and Toddler Development, version 3 
(independent sitting will be assessed also by WHO Multicentre Growth Reference Study). 
e Videos may be submitted for review by a central reader. 
f The full Bayley test will be administered every 6 months, starting at Month 6, whereas the Bayley fine and gross motor 
subtests will be administered at each monthly visit. 
g Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not continue CHOP-INTEND assessments.  
h Vital signs include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry 
i Vital signs will be continuously monitored throughout the infusion of gene replacement therapy and recorded every 
15 minutes for the first 4 hours (+/- 5 minutes) after the start of infusion, then every hour (+/- 15 minutes) until 24 hours after 
the start of infusion.  Axillary temperature will be recorded pre- and post-infusion. 
j Completed at Months 3, 6, 9, and 12 and every 6 months thereafter, starting at Month 6. 
k On Days -1 to Day 3, Sserial ECG data will be pulled in triplicate from the Holter monitor at the following time points: 
pre-dose (within 24h), 2h, 4h, 6h, 8h, 12h, 24h, 36h, and 48h post-dose. 
l Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to be elevated, based on 
further discussion with the Principal Investigator and Medical Monitor. 
m Collected at 24 and 48 hours post-dose. 
n Serious adverse events are collected from signing of the informed consent through the last study visit.  All adverse events that 
occur from the start of gene replacement therapy through the last study visit are collected. 
o Laboratory samples collected on Day -1 to be processed locally, prior to dosing. 
p Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces at 24 and 48 
hours.  All other sites will collect singular urine and feces samples within 24 hours and 48 hours of dosing. 
q Prednisolone to be given 24 hours prior to scheduled AVXS-101 dosing, and continued as per protocol Section 9.2.1. 
r CK-MB to be performed at Day 60, and Month 6, 9, 12, 15 months of age, 18 months of age/EOT). 
s If a Day -1 CHOP-INTEND assessment is not completed, a CHOP-INTEND assessment should be completed on Day 1 prior 
to dose administration. 
t Irrespective of study schedule, after signing the updated informed consent, all enrolled patients should have 12-lead ECG, 
24-hour Holter monitoring, and echocardiogram done at the next scheduled visit and then in conformity with the study 
Schedule of Assessments. 
Rationale for Change 
Added to provide additional cardiac monitoring to assure patient safety. 

1.
TITLE PAGE
AVXS-101
AVXS-101-CL-303 
IND Number: 
15699 
Protocol Title: 
Phase 3, Open-Label, Single-Arm, Single-Dose Gene 
Replacement Therapy Clinical Trial for Patients with Spinal 
Muscular Atrophy Type 1 with One or Two SMN2 Copies 
Delivering AVXS-101 by Intravenous Infusion 
Indication Studied: 
Spinal Muscular Atrophy Type 1 
Sponsor Address: 
AveXis, Inc. 
2275 Half Day Road 
Bannockburn, IL 60015 
Protocol Version/Date: 
3.0 / 21 December 2017 
The study will be completed according to the guidelines of Good Clinical Practice.  Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki. 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or confidential and 
may not be disclosed unless such disclosure is required by federal or state law or regulations.  In any event, persons 
to whom the information is disclosed must be informed that the information is privileged or confidential and may 
not be further disclosed by them.  These restrictions on disclosure will apply equally to all future information 
supplied to you which is indicated as privileged or confidential. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 2 of 143 
1. 
ADMINISTRATIVE INFORMATION 
1.1. 
Approval 
REPRESENTATIVES FROM AVEXIS: 
This trial will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical trial protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki 
• 
International Council for Harmonization and the Harmonized Tripartite Guideline for Good 
Clinical Practice E6 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations 
SIGNATURES (may be applied electronically and will therefore be maintained in the 
electronic system): 
 
 
 
 
 
Vice President Clinical Development 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Chief Medical Officer 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Senior Vice President, Chief Regulatory and Quality Officer 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Vice President Clinical Operations 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Sr. Director, Head of Biostatistics 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 3 of 143 
1.2. 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for AVXS-101.  I have read the AVXS-101-
CL-303 protocol and agree to conduct the study in accordance with the relevant current 
protocol(s).  I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.  I agree to personally conduct or supervise the investigation(s).  I 
also agree to promptly report to the Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others.  Additionally, I will not make any changes in the research 
without IRB/IEC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects.  I agree to protect the safety, rights, privacy, and well-being of study 
participants.  I agree to comply with:  
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations including but not limited to Informed Consent 21 CFR Part 56, Institutional 
Review Board Review in 21 CRF Part 56, Adverse Event Reporting as defined in 
Section 13.4 and in 21 CFR 312.64, Adequate/accurate and accessible records in accordance 
with 21CFR 312.62 and 312.68. 
• Terms outlined in the study site agreement  
• Responsibilities of the Investigator (per regulatory guidelines and applicable regulations) I 
further authorize that my personal information may be processed and transferred in 
accordance with the uses contemplated in this protocol. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator or 
Consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.  Your acceptance of this document constitutes agreement 
that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 
 _________________________________________________ 
Printed Name of Investigator 
 _________________________________________________ 
Signature of Investigator 
 _________________________________________________ 
Date (ddMmmyyyy) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 4 of 143 
1.3. 
Contact Information 
Table 1: 
Important Study Contact Information 
Role in Study 
Name/Address and Telephone Number 
Clinical Study Leader 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Responsible Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Drug Safety Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Serious Adverse Event 
Reporting 
Please see Project Management Plan in TMF or Study Contact list 
in ISF 
24-Hour Emergency Contact 
Please see Study Contact List in ISF 
 
Table 2: 
Study Vendor Listing 
Role in Study 
Name/Address 
Clinical Research 
Organization 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Investigational Product 
Shipment 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Video 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Independent Video Review 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Holter Monitor and  
12-lead Electrocardiogram 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
immunoassays 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
viral shedding studies 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Autopsy 
Please see Project Management Plan in TMF or Study Contact list in ISF 
ISF = Investigator site file; TMF = trial master file 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 5 of 143 
2. 
SYNOPSIS 
Name of Sponsor/Company: AveXis, Inc. 
Name of Investigational Product: AVXS-101 
Name of Active Ingredient: Survival Motor Neuron Gene by Self‐Complementary Adeno-Associated 
Virus Serotype 9 (AAV9) 
Title of Study: Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical 
Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering 
AVXS-101 by Intravenous Infusion 
Study Center(s): 10 to 20 United States (US) Investigators 
Studied Period (years): 
Estimated date first patient enrolled: 2Q 2017 
Estimated date last patient completed: 4Q 2019 
Phase of Development: 3 
Objectives: 
Co-Primary 
• 
Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of 
functional independent sitting for at least 30 seconds at the 18 months of age study visit. 
• 
Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is defined by 
the avoidance of combined endpoint of either (a) death or (b) permanent ventilation, which is 
defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via 
non-invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible 
illness, excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
Co-Secondary 
• 
Determine effect of AVXS-101 on the ability to thrive defined as achieving all of the following at 
18 months of age: 
o Does not receive nutrition through mechanical support (e.g., feeding tube) or other non-oral 
method 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• 
Determine the effect of AVXS-101 on the ability to remain independent of ventilatory support, 
defined as requiring no daily ventilator support/usage at 18 months of age 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 6 of 143 
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• 
Determine the safety of AVXS-101 based on the development of unacceptable toxicity defined as 
the occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 
higher, unanticipated, treatment-related toxicity 
Methodology: 
Phase 3, open-label, single-arm, single-dose, study of AVXS-101 (gene replacement therapy) in up to 
twenty (20) patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria, may be 
either symptomatic or pre-symptomatic and are genetically defined by no functional survival motor 
neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 
months (< 180 days) of age at the time of gene replacement therapy (Day 1).  Enrolling up to twenty 
(20) patients under the broader enrollment criteria is projected to enable enrollment of at least fifteen 
(15) patients that meet the Intent-to-Treat Population (ITT) criteria.  The ITT population is identified as 
symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene 
modifier mutation (c.859G>C) who meet all other study enrollment criteria.  In addition, the first three 
patients enrolled must meet the criteria for the Intent-to-Treat Population to enable a comparison of 
CHOP-INTEND scores at one-month following gene replacement therapy to enable a comparison of 
patient response between AVXS-101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial 
(AVXS-101-CL-101). 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 7 of 143 
The study includes a screening period, a gene replacement therapy period, and a follow-up period.  
During the screening period (Days –30 to –2), patients whose parent(s)/legal guardian(s) provide 
informed consent will undergo screening procedures to determine eligibility for study enrollment.  
Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day –1 to 
Day 3).  On Day –1, patients will be admitted to the hospital for pre-treatment baseline procedures.  On 
Day 1, patients will receive a one-time intravenous (IV) infusion of AVXS-101, and will undergo 
in-patient safety monitoring over the next 48 hours.  Patients may be discharged 48 hours after the 
infusion, based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of 
Study at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 
assessments until the End of Study when the patient reaches 18 months of age.  After the End of Study 
visit, eligible patients will be asked to rollover into the long-term follow up study. 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, 
except for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
There will be at least a 4 -week dosing interval between dosing of the first three patients to allow review 
of the safety analysis from six time points (day 1, 2, 7, 14, 21, and 30 visits) as well as early signals of 
efficacy including CHOP-INTEND score prior to dosing of the next patient.  The first three patients 
enrolled must meet the criteria for the Intent-to-Treat Population.  AveXis will compare the CHOP-
INTEND one month improvement for the AVXS-101-CL-303 patients that meet the ITT criteria to 
assess the clinical response to the dose 1.1 x 1014 vg/kg as being what was expected from the Cohort 2 
patients in the Phase 1 trial (AVXS-101-CL-101).  This comparison will be performed as a per patient 
assessment for the first three patients.  The individual patients who receive their gene therapy at 0-3 
months of age will be compared to a value of 10 CI points, while patients who receive their gene 
therapy at >3 but <6 months of age will be compared to a value of 5 CI points.  Furthermore, patients 
from either age group are expected to maintain the improvement in the absence of an acute illness or 
perioperatively.  If the expected CI improvements are observed for the first three ITT patients, AveXis 
will remove the 4-week interval between patients and proceed to dose at least 12 additional patients that 
meet the ITT criteria and perform safety and efficacy assessments as described elsewhere in the clinical 
protocol (AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  Study enrollment will stop 
as soon as practical following enrollment of the fifteenth patient that meets the ITT criteria.  If the 
expected CI improvements are not observed for the first three ITT patients, AveXis will discuss next 
steps with the FDA before continuing study enrollment. 
In an attempt to dampen the host immune response to the adeno-associated virus (AAV) derived 
therapy, all patients will receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 
24 hours prior to AVXS-101 infusion until at least 30 days post-infusion.  After 30 days of treatment, 
the dose of prednisolone can be tapered for patients whose alanine aminotransferase (ALT) values, 
aspartate aminotransferase (AST) values, and T-cell response are below the threshold of 2 X ULN for 
ALT and AST, and < 100 SFC/106 PBMCs in accordance with the following treatment guideline: 
1 mg/kg/day until at least 30 days post-infusion, 0.5 mg/kg/day at Weeks 5 and 6, 0.25 mg/kg/day at 
Weeks 7 and 8, and discontinued at Week 9. 
Efficacy will be assessed by achievement of the key developmental milestone of functional independent 
sitting for at least 30 seconds at the 18 months of age study visit and survival at 14 months of age.  The 
ability to thrive (as defined above) and the ability to remain independent of ventilatory support (as 
defined above) will also be assessed at 18 months of age.  Additional developmental milestones will be 
assessed using Bayley Scales of Infant and Toddler Development (Version 3).  Safety will be assessed 
through monitoring adverse events (AEs), concomitant medication usage, physical examinations, vital 
sign assessments, cardiac assessments, and laboratory evaluations.  A Data Safety Monitoring Board 
(DSMB) will review safety data on a quarterly basis, and will also convene within 48 hours should any 
patient experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or requires 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 8 of 143 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the DSMB 
will review the safety information and provide its recommendation.  The DSMB can recommend early 
termination of the study for safety reasons. 
Number of Patients (planned): Up to twenty (20) patients that meet the study enrollment criteria to 
enable at least fifteen (15) patients that meet ITT criteria.  Study enrollment will stop as soon as 
practical following enrollment of the fifteenth patient that meets the ITT criteria. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
1. 
Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or 
point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier 
mutation (c.859G>C))2.   
2.    The first three patients enrolled must meet the criteria for the Intent-To-Treat Population. 
3. 
Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
4. 
Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
5. 
Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab prophylaxis 
(also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also 
recommended in accordance with American Academy of Pediatrics (26) 
6. 
Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply 
with study procedures and visit schedule 
 
Exclusion Criteria: 
1. 
Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. 
Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without any 
supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does 
not decrease by ≥ 4 percentage points 
3. 
Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the 
screening period or requiring ventilatory support while awake over the 7 days prior to screening or 
at any point during the screening period prior to dosing 
4.  Patients with signs of aspiration/inability to tolerate nonthickened- liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass the 
swallowing test will be allowed to enroll in the study 
5. 
Patients whose weight-for-age is below the third percentile based on World Health Organization 
(WHO) Child Growth Standards[25] 
6. 
Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for 
hepatitis B or C, or Zika virus) 
7. 
Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 
2 weeks prior to screening 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 9 of 143 
8. 
Upper or lower respiratory infection requiring medical attention, medical intervention, or increase 
in supportive care of any manner within 4 weeks prior to screening 
9. 
Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy such 
as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients 
11. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents 
used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, 
immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene 
replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) 
binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody titer > 1:50, he 
or she may receive retesting within 30 days of the screening period and will be eligible to 
participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values ( gammaglutamyl- transpeptidase [GGT], ALT, 
and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or 
> 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy 
14.  Participation in recent SMA treatment clinical study (with the exception of observational cohort 
studies or non-interventional studies) or receipt of an investigational or commercial compound, 
product, or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any 
time prior to screening for this study.  Oral β-agonists must be discontinued at least 30 days before 
gene therapy dosing.  Inhaled albuterol specifically prescribed for the purposes of respiratory 
(bronchodilator) management is acceptable and not a contraindication at any time prior to screening 
for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal surgery or 
tracheostomy) 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to 
travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain 
from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 
19. Gestational age at birth < 35 weeks (245 days) 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 10 of 143 
Investigational Product, Dosage and Mode of Administration: 
Patients will receive a one-time dose of AVXS-101 at 1.1 X 1014 vg/kg, a dose determined to be 
equivalent to the dose received by the Cohort 2 patients in the Phase 1 study (AVXS-101-CL-101) by 
direct testing using improved analytical methods. 
Duration of Treatment: 
AVXS-101 will be administered as a one-time IV infusion over approximately 30-60 minutes, 
dependent upon the volume required. 
Reference Therapy, Dosage and Mode of Administration: Not Applicable 
Criteria for Evaluation: 
Efficacy: 
Co-Primary 
• 
Proportion of patients that achieve functional independent sitting for at least 30 seconds at the 18 
months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler Development 
(Version 3), confirmed by video recording, as a patient who sits up straight with head erect for at 
least 30 seconds 
• 
Survival at 14 months of age.  Survival is defined by the avoidance of the combined endpoint of 
either (a) death or (b) permanent ventilation, which is defined by tracheostomy or by the 
requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive ventilatory support) 
for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative 
ventilation.  Permanent ventilation, so defined, is considered a surrogate for death 
Co-Secondary 
• 
The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate thin 
liquids (as demonstrated through a formal swallowing test) and to maintain weight (> third 
percentile based on World Health Organization [WHO] Child Growth Standards [25] for age and 
gender) without need of gastrostomy or other mechanical or non-oral nutritional support at 
18 months of age 
• 
The proportion of patients who are independent of ventilatory support, defined as requiring no daily 
ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative 
ventilation, as defined above through assessment of actual usage data captured from the device 
(Phillips Trilogy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 11 of 143 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• 
Incidence of elevated liver function tests (LFTs) and/or unresolved liver function enzymes (LFEs) 
• 
Incidence of CTCAE Grade 3 or higher toxicity, treatment emergent- adverse events 
• 
Clinically significant changes in laboratory values, physical exams, cardiac assessments or vital 
signs 
• 
Research Immunology Blood Labs including serum antibody to AAV9 and SMN, as well as IFNγ 
Enzyme-linked ImmunoSpot (ELISpot) to detect T-cell responses to AAV9 and SMN 
Statistical Methods: 
This is a pivotal Phase 3, open-label, single-arm, single-dose, study assessing the efficacy and safety of 
AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal muscular atrophy 
(SMA) Type 1 who meet enrollment criteria, may be symptomatic or pre-symptomatic and are 
genetically defined by no functional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival 
motor neuron 2 gene (SMN2) and who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1).  Enrolling up to twenty (20) patients under the broader enrollment criteria 
is projected to enable enrollment of at least fifteen (15) patients that meet the Intent-to-Treat Population 
(ITT) criteria.  The ITT population is identified as symptomatic patients with bi-allelic SMN1 deletions 
and 2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) and will comprise the 
primary population for evaluation of the primary and secondary endpoints.  Study power is based upon 
efficacy analysis of the ITT population.  Furthermore, the first three patients enrolled must meet criteria 
for the Intent-To-Treat Population to enable a comparison of CHOP-INTEND scores at one-month 
following gene replacement therapy to enable a comparison of patient response between AVXS-101-
CL-303 patients and patient results from the Phase 1 trial (AVXS-101-CL-101).  Patients with 1 copy of 
SMN2, pre-symptomatic patients and patients with the SMN2 gene modifier mutation (c.859G>C) will 
be evaluated separately as part of additional subgroup analyses.  Details of all analyses will be contained 
within the Statistical Analysis Plan. 
Based upon widely cited natural history of the disease (Pediatric Neuromuscular Clinical Research 
Network [PNCR]) [Neurol. 2014; 83(9):810-817], it is expected that no patient meeting the study 
entrance criteria (SMN2 copy number of 2 without the SMN2 gene modifier mutation (c.859G>C)) 
would be expected to attain the ability to sit without support for at least 30 seconds at or before the 18 
months of age study visit or other milestones (rolling over, standing, walking) assessed as part of the 
study. 
Assuming that the true response rate for the primary endpoint is actually zero (or as low as 0.1%) in the 
population of interest of the historical control, the first co-primary efficacy endpoint hypothesis is 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 12 of 143 
whether the AVXS-101 treated patients achieve a response rate greater than 0.1%.  Based upon 
preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at least 40% of treated 
patients in the ITT population are expected to achieve the co-primary efficacy endpoint of functional 
independent sitting for at least 30 seconds at the 18 months of age visit.  With the assumption for the 
true response rate of AVXS-101 for the primary endpoint being in the range of 30% - 40%, a sample 
size of 15 patients that meet ITT criteria will be enrolled and assuming approximately 30% of patients 
are excluded from analysis, would yield an ITT population that would provide power of > 90% to detect 
a significant difference from 0.1% with α = 0.025 using a 1-sided exact test for a binomial proportion. 
The second co-primary efficacy endpoint of survival at 14 months of age will be evaluated by 
comparing the results observed in the ITT population with the results from the age and gender-matched 
control patients selected from existing natural history data sets (PNCR) [Neurol. 2014; 83(9):810-
817].  It is anticipated that 75% of patients in the PNCR population would not survive beyond 
13.6 months of age, and that these control patients will represent a 25% survival rate based upon the 
natural history of the disease.  Based upon preliminary results from the ongoing Phase 1 clinical study 
(AVXS-101-CL-101), at least 80% of patients in the ITT population are expected to survive, as defined, 
through 14 months of age.  With this efficacy, an enrolled sample size of 15 patients that meet ITT 
criteria (assuming 30% of patients are excluded from the analysis) would yield an ITT population that 
would provide power of > 80% to detect a significant difference from the historical control with α 
= 0.05 using a 2-sided Fisher’s Exact test. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 13 of 143 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
1. 
ADMINISTRATIVE INFORMATION .......................................................................2 
1.1. 
Approval .......................................................................................................................2 
1.2. 
Investigator’s Agreement ..............................................................................................3 
1.3. 
Contact Information ......................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background .................................................................................................................20 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients ................................................21 
5.3. 
Non-clinical Studies ....................................................................................................23 
5.4. 
Clinical Studies ...........................................................................................................26 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................29 
6.1. 
Primary Objectives .....................................................................................................29 
6.2. 
Secondary Objective ...................................................................................................29 
 
 
6.4. 
Safety Objectives ........................................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 
7.1. 
Overall Study Design ..................................................................................................31 
7.2. 
Number of Patients .....................................................................................................33 
7.3. 
Criteria for Study Termination ...................................................................................33 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................34 
8.1. 
Patient Inclusion Criteria ............................................................................................34 
8.2. 
Patient Exclusion Criteria ...........................................................................................34 
8.3. 
Patient Withdrawal Criteria ........................................................................................36 
9. 
TREATMENT OF PATIENTS ..................................................................................37 
9.1. 
Description of Product ................................................................................................37 
9.2. 
Prior and Concomitant Medications ...........................................................................37 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 14 of 143 
9.2.1. 
Prophylactic Administration of Prednisolone .............................................................37 
9.2.2. 
Prohibited Medications ...............................................................................................38 
9.3. 
Treatment Compliance ................................................................................................38 
9.4. 
Randomization and Blinding ......................................................................................38 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT ....................................39 
10.1. 
Study Product..............................................................................................................39 
10.2. 
Study Product Dose and Dose Justification ................................................................39 
10.3. 
Study Product Packaging and Labeling ......................................................................39 
10.4. 
Study Product Storage ................................................................................................39 
10.5. 
Study Product Preparation ..........................................................................................40 
10.6. 
Study Product Administration ....................................................................................40 
10.7. 
Dose Adjustment Criteria ...........................................................................................40 
10.8. 
Study Product Accountability .....................................................................................40 
10.9. 
Study Product Handling and Disposal ........................................................................40 
11. 
ASSESSMENT OF EFFICACY ................................................................................42 
11.1. 
Developmental Milestones .........................................................................................42 
11.2. 
Motor Function Tests ..................................................................................................43 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones ........43 
11.2.2. 
CHOP-INTEND .........................................................................................................43 
11.3. 
Video Evidence ...........................................................................................................44 
11.4. 
Compound Motor Action Potential ............................................................................44 
12. 
ASSESSMENT OF SAFETY .....................................................................................45 
12.1. 
Safety Parameters .......................................................................................................45 
12.1.1. 
Demographic/Medical History ...................................................................................45 
12.1.2. 
Physical Examinations ................................................................................................45 
12.1.3. 
Vital Signs/Weight and Length ..................................................................................46 
12.1.4. 
Electrocardiogram .......................................................................................................46 
12.1.5. 
12-Lead Holter Monitor ..............................................................................................46 
12.1.6. 
Echocardiogram ..........................................................................................................47 
12.1.7. 
Pulmonary Examinations ............................................................................................47 
12.1.8. 
Swallowing Test .........................................................................................................47 
12.1.9. 
Photographs of Infusion Site ......................................................................................47 
12.1.10. 
Laboratory Assessments .............................................................................................48 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 15 of 143 
12.1.10.1. Hematology .................................................................................................................49 
12.1.10.2. Blood Chemistry .........................................................................................................49 
12.1.10.3. Urinalysis ....................................................................................................................50 
12.1.10.4. Virus Serology ............................................................................................................51 
12.1.10.5. Capillary Blood Gas ...................................................................................................51 
12.1.10.6. Immunology Testing (ELISA and IFNγ- ELISpots) ..................................................51 
12.1.10.7. AAV9 Antibody Screen in Mother .............................................................................51 
12.1.10.8. Blood for Diagnostic Confirmation Testing ...............................................................51 
12.1.10.9. Saliva, Urine, and Stool Collection ............................................................................52 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................53 
13.1.1. 
Definition of Adverse Events .....................................................................................53 
13.1.1.1. 
Adverse Event .............................................................................................................53 
13.1.1.2. 
Serious Adverse Event ................................................................................................54 
13.1.1.3. 
Other Adverse Event ...................................................................................................54 
13.2. 
Relationship to Study Product ....................................................................................54 
13.3. 
Recording Adverse Events .........................................................................................55 
13.4. 
Reporting Adverse Events ..........................................................................................55 
14. 
STATISTICS ..............................................................................................................56 
14.1. 
Study Endpoints and Populations ...............................................................................56 
14.1.1. 
Study Endpoints ..........................................................................................................56 
14.1.1.1. 
Co-Primary Efficacy Endpoint ...................................................................................56 
14.1.1.2. 
Co-Secondary Efficacy Endpoint ...............................................................................57 
 
 
14.1.1.4. 
Safety Endpoints .........................................................................................................58 
14.1.2. 
Statistical Analysis Populations ..................................................................................58 
14.1.2.1. 
Intent-to-Treat Population (ITT) .................................................................................58 
14.1.2.2. 
Efficacy Completers Population .................................................................................58 
14.1.2.3. 
All Enrolled Population ..............................................................................................58 
14.1.2.4. 
Safety Population ........................................................................................................59 
14.2. 
Sample Size Calculation .............................................................................................59 
14.3. 
Efficacy Analysis ........................................................................................................60 
14.3.1. 
General Considerations ...............................................................................................60 
14.3.2. 
Primary and Secondary Efficacy Analysis .................................................................60 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 16 of 143 
14.4. 
CHOP-INTEND Comparison .....................................................................................61 
14.5. 
Safety Analysis ...........................................................................................................62 
15. 
DATA SAFETY MONITORING BOARD ...............................................................63 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................64 
16.1. 
Study Monitoring ........................................................................................................64 
16.2. 
Audits and Inspections ................................................................................................64 
16.3. 
Institutional Biosafety Committee ..............................................................................65 
16.4. 
Institutional Review Board/Institutional Ethics Committee .......................................65 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................66 
18. 
ETHICS ......................................................................................................................67 
18.1. 
Ethics Review .............................................................................................................67 
18.2. 
Ethical Conduct of the Study ......................................................................................67 
18.3. 
Written Informed Consent ..........................................................................................67 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
19.1. 
Electronic Case Report Forms ....................................................................................68 
19.2. 
Inspection of Records .................................................................................................68 
19.3. 
Retention of Records ..................................................................................................68 
20. 
PUBLICATION POLICY ..........................................................................................69 
21. 
LIST OF REFERENCES ............................................................................................70 
22. 
APPENDICES ............................................................................................................72 
APPENDIX 1. AUTOPSY PLAN ..............................................................................................73 
APPENDIX 2. BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) .............................................................................................................74 
APPENDIX 3. PERFORMANCE CRITERIA FOR BAYLEY SCALES OF INFANT 
AND TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES .........................................................................................................121 
APPENDIX 4. CHOP-INTEND ...............................................................................................122 
APPENDIX 5. SCHEDULE OF ASSESSMENTS ..................................................................124 
APPENDIX 6. COMPOUND MOTOR ACTION POTENTIAL MANUAL ..........................126 
APPENDIX 7. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS...............................129 
APPENDIX 8. SUMMARY OF CHANGES ...........................................................................133 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 17 of 143 
LIST OF TABLES 
Table 1: 
Important Study Contact Information ...........................................................................4 
Table 2: 
Study Vendor Listing ....................................................................................................4 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 4: 
Spinal Muscular Atrophy Classification .....................................................................21 
Table 5: 
Investigational Product ...............................................................................................37 
Table 6: 
Total Blood Volume ...................................................................................................48 
Table 7: 
Common Terminology Criteria for Adverse Events ..................................................53 
Table 8: 
Tissue Sample for Analysis ........................................................................................73 
 
LIST OF FIGURES 
Figure 1: 
Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 
2, and 3 ........................................................................................................................22 
Figure 2: 
Study Results, Including Staining of Transduced Spinal Motor Neurons, 
SMN Expression Levels, Righting Ability, and Weight and Survival Curves ...........24 
Figure 3 
Body Mass of Treated and Control Mice Showed No Difference ..............................25 
Figure 4: 
Study Design ...............................................................................................................32 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 18 of 143 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AAV 
Adenoassociated- virus 
AAV9 
Adeno-associated virus serotype 9 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASO 
Antisense oligonucleotide  
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CB 
Chicken-β-actin-hybrid 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CI 
CHOP-INTEND 
CHOP-INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders 
CK 
Creatine kinase 
CK-MB 
Creatine kinase isoenzyme 
CLIA 
Clinical Laboratory Improvement Amendment 
CMAP 
Compound motor action potential 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
First 24-hour interval after the start of gene replacement therapy infusion 
Day –1 
24-hour interval prior to the start of gene replacement therapy infusion  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISpot 
Enzyme-linked ImmunoSpot 
ET 
Early termination 
FVB 
Friend Virus B-Type 
GCP 
Good Clinical Practice 
GFP 
Green fluorescent protein 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HEENT 
Head, eyes, ears, nose, and throat 
HgB 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 19 of 143 
Abbreviation or Specialist Term 
Explanation 
ICD-10 code 
International Statistical Classification of Diseases and Related Health 
Problems 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon gamma 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITR 
Inverted terminal repeat 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFE 
Liver function enzymes 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHP 
Non-human primates 
NOAEL 
No Observable Adverse Effect Level 
OAE 
Other significant Adverse Event 
PBMC 
Peripheral blood mononuclear cells 
PICU 
Pediatric intensive care unit 
PNCR 
Pediatric Neuromuscular Clinical Research Network 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
Self-complementary 
scAAV 
Self-complimentary adeno-associated virus 
scAAV9.CB.SMN 
Self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SMN1 
Survival motor neuron 1 gene 
SMN2 
Survival motor neuron 2 gene 
SOC 
System Organ Class 
TMF 
Trial master file 
US 
United States 
vg/kg 
Vector genome per kilogram 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 20 of 143 
5. 
INTRODUCTION 
Study AVXS-101-CL-303 is a pivotal Phase 3, open-label, single-arm, single-dose, study of 
AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal muscular atrophy 
(SMA) Type 1 who meet enrollment criteria, may be either symptomatic or pre-symptomatic and 
are genetically defined by no functional survival motor neuron 1 gene (SMN1) as well as 1 or 
2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 months (< 180 days) of age at 
the time of gene replacement therapy (Day 1).  Enrolling up to twenty (20) patients under the 
broader enrollment criteria is projected to enable enrollment of at least fifteen (15) patients that 
meet the Intent-to-Treat Population (ITT) criteria.  The first three patients enrolled must meet the 
ITT criteria to enable a comparison of CHOP-INTEND scores at one-month following gene 
replacement therapy to enable a comparison of patient response between AVXS-101-CL-303 
patients and Cohort 2 patient results from the Phase 1 trial (AVXS-101-CL-101). 
In this study, the survival motor neuron (SMN) gene will be transferred using self-
complementary adeno-associated virus (scAAV) Type 9 under control of the chicken-β-actin 
hybrid promoter.  Pre-clinical studies have demonstrated survival of the SMNΔ7 mouse model 
for SMA from a median of 15.5 days to over 1 year, following IV delivery to a facial vein.  
Additionally, preliminary results from an ongoing Phase 1 clinical study (AVXS-101-CL-101) of 
AVXS-101 in SMA Type 1 patients demonstrates broad improvements in survival, motor 
function, pulmonary function, and nutritional function (Section 5.4). 
5.1. 
Background 
Spinal muscular atrophy is a neurogenetic disorder caused by a loss or mutation in the survival 
motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN protein levels 
and a selective dysfunction of motor neurons.  Spinal muscular atrophy is an autosomal 
recessive, early childhood disease with an incidence of approximately 1:10,000 live births [1].  
Spinal muscular atrophy is the leading cause of infant mortality due to genetic diseases.  Disease 
severity and clinical prognosis depends on the number of copies of survival motor neuron 2 gene 
(SMN2).  In its most common and severe form (Type 1), hypotonia and progressive weakness are 
recognized in the first few months of life, leading to diagnosis before 6 months of age and early 
death due to respiratory failure before 2 years of age.  Motor neuron loss in SMA Type 1 is 
profound in the early post-natal period (or may even start in the prenatal period), whereas motor 
neurons in SMA Type 2 and Type 3 patients adapt and compensate during development and 
persist into adult life.  The findings from various neurophysiological and animal studies have 
shown an early loss of motor neurons in the embryonic and early post-natal periods [2,3,4].  
From a clinical perspective, these findings emphasize the importance of first targeting the SMA 
Type 1 group for gene transfer of SMN1 in hopes of rescuing neurons at this critical stage.  The 
goal in continuing the development plan for AVXS-101 is to modify the SMA Type 1 
phenotype, which will hopefully lead to a milder disease course and prolonged survival as seen 
in SMA Type 2 and Type 3 patients. 
Therapeutic efforts in SMA have focused on the potential for small molecules to increase SMN 
levels.  These include deacetylase inhibitors, such as, valproic acid, sodium butyrate, 
phenylbutyrate, and trichostatin A.  These agents activate the SMN2 promoter, resulting in 
increased full-length SMN protein in SMA animal models [5,6].  However, clinical studies 
employing several of these agents, most notably phenylbutyrate, valproic acid, and hydroxyurea, 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 21 of 143 
have not resulted in clinical benefit [7,8].  FDA recently approved Nusinersen, an antisense 
oligonucleotide (ASO) drug designed to increase the production of the SMN protein by 
modulating the splicing of the SMN2 gene, thereby compensating for the underlying genetic 
defect.  Clinical studies have shown some modest promise in improving motor function; however 
the treatment must be administered indefinitely on a quarterly basis via intrathecal injection, 
requires a lengthy induction period prior to effectiveness, and has safety considerations which 
require clinical monitoring.  A single-dose IV administration study of AVXS-101 will provide 
information on the potential gene transfer has in treating SMA Type 1 patients, and will 
hopefully show promise for success in modifying the disease prognosis. 
This is a single-dose study that will include up to 20 Type 1 patients with no functional SMN1 
gene as well as 1 or 2 copies of SMN2 and who are < 6 months (< 180 days) of age at the time 
of gene replacement therapy (Day 1).  The rationale for IV dosing is based upon the need for 
rapid, systemic impact given the severity of the disease in SMA Type 1 and its potential impact 
on systems outside of the central nervous system (CNS) such as the peripheral and autonomic 
nervous systems, heart, pancreas and gastrointestinal tract. 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients 
Patients with SMA Type 1 have been chosen as the target population for this gene therapy study 
based on studies of the natural history of this disease.  The classification of SMA is shown below 
(Table 4) in which SMA Types 0 to 4 are described.  Spinal muscular atrophy is conventionally 
classified into 4 phenotypes on the basis of age at onset and highest motor function achieved, 
with an additional phenotype (Type 0) to describe the severe forms of antenatal-onset SMA. 
Table 4: Spinal Muscular Atrophy Classification 
Type 
Age at Symptom Onset 
Maximum Motor Function 
Life Expectancy 
SMN2 Copy No. 
0 
Fetal 
Nil 
Days – Weeks 
1 
1 
< 6 Months 
1A: B-2 Weeks 
1B: < 3 Months 
1C: > 3 Months 
Never sits 
< 2 years 
1, 2, 3 
2 
6 – 18 Months 
Never walks 
20 – 40 years 
2, 3, 4 
3 
1.5 – 10 
Years 
3A: < 3 Years 
3B: > 3 Years 
Walks, regression 
Normal 
3, 4, 5 
4 
> 35 Years 
Slow decline 
Normal 
4, 5 
Source: Adapted from Kolb 2011 [10] 
SMN2 = survival motor neuron 2 gene 
 
Spinal muscular atrophy Type 1 patients, by definition, never attain independent sitting and have 
hypotonia within the first 6 months of life.  Spinal muscular atrophy Type 1 is the leading 
genetic cause of infant death with an onset at ≤ 6 months of age (Table 4).  In contrast, SMA 
Type 2 manifests within the first 18 months, and children afflicted with this condition are able to 
maintain sitting unassisted but never walk independently.  Spinal muscular atrophy Type 3 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 22 of 143 
patients attain the ability to walk unaided (Type 3a have onset 18 months to 3 years of age; 
Type 3b have onset > 3 years of age).  Spinal muscular atrophy Type 4 is an adult onset disease.  
The genetic cause for SMA is well established and is intimately involved with one’s prognosis.  
All forms of SMA are autosomal recessive in inheritance and are caused by deletions or 
mutations of the SMN1 gene. 
Humans also carry a second nearly identical copy of the SMN1 gene called SMN2 [11].  Both the 
SMN1 and SMN2 genes express SMN protein; however, the amount of functional full-length 
protein produced by SMN2 is only 10 to 15% of that produced by SMN1 [11,12,13].  Although 
SMN2 cannot completely compensate for the loss of the SMN1 gene, patients with milder forms 
of SMA generally have higher SMN2 copy numbers [14,15].  Quantitative analysis of SMN2 
copies in 375 patients with Type 1, 2, or 3 SMA showed a significant correlation between SMN2 
copy number and SMA Type, as well as, duration of survival.  In a large early study by 
Feldkotter et al 2002, 2 copies of SMN2 was 97% predictive for developing SMA Type 1, 
3 copies of SMN2 was 83% predictive for developing SMA Type 2, and 4 copies of SMN2 was 
84% predictive of SMA Type 3 [16].  As these percentages do not reflect the possible impact of 
modifier mutations such as that described by Prior et al 2009 [17], they may understate the 
relationship between copy number (in the absence of a genetic modifier) and clinical phenotype.  
Among 113 patients with Type 1 SMA, 9 with one SMN2 copy lived < 11 months, 88/94 with 
two SMN2 copies lived < 21 months, and 8/10 with three SMN2 copies lived 33 to 66 months.  
Even more refined data describing this relationship has been generated, and has also influenced 
our choice of the study target group. 
The severity of SMA Type 1 is demonstrated by prognosis as illustrated in Kaplan-Meier 
survival curves shown in Figure 1. 
Figure 1: Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 2, 
and 3 
 
n = number of patients 
Source: Farrar 2013 [18] 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 23 of 143 
In Figure 1, the relative stability of the clinical course of SMA Type 2 and Type 3 is dramatically 
illustrated.  Perhaps most importantly, these findings show that outcome differences are related 
to the number of SMN2 copies that enable motor neurons to adapt and compensate during the 
growth of the child and persist into adult life.  This contrasts with SMA Type 1 where motor 
neuron loss is profound in the early post-natal period (or may even start in the prenatal period, 
especially for SMA Type 1 patients presenting in first 3 months of life).  The findings in Figure 1 
confirm other pieces of evidence from neurophysiological studies and animal studies that also 
show early loss of motor neurons in the embryonic and early post-natal periods [2,3,4]. 
There is reason to believe that there are few safety issues to be concerned about when targeting 
the SMA Type 1 group in this gene therapy clinical study.  Overexpression of SMN has been 
shown to be well tolerated in both mice and non-human primates, and in humans, a high copy 
number of SMN2 poses no risk (as seen in Type 2, 3, and 4 patients who have high SMN2 copy 
number), allowing for use of robust, ubiquitous expression systems (like the CB-promoter) to 
ensure sustained, high-level SMN expression.  Additionally, it is important to point out that 
recombinant scAAV can be employed for this study because of the small size of the SMN gene.  
This enables efficient packaging and allows for efficient gene transfer with lower viral titers (a 
safety consideration), compared with prototypical single-stranded adeno-associated virus (AAV) 
vectors. 
Recent studies using self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron (scAAV9.CB.SMN) show a robust post-natal rescue of SMNΔ7 
mice with correction of motor function, neuromuscular electrophysiology and survival after a 
one-time delivery of vector [19].  Intravenous scAAV9 is able to transduce neurons, muscle and 
vascular endothelium, all of which have been proposed as target cells for SMA treatment. 
5.3. 
Non-clinical Studies 
A mouse model was developed by the 
 after a generation of multiple 
variants.  It was found that the double transgenic, referred to as the SMNΔ7 mouse, provided the 
most suitable model to study gene transfer [20].  Studies performed in the 
 
have shown that injecting 5 × 1011 viral genomes of scAAV9.CB.SMN into the facial vein on 
Day 1 old mice rescues the SMNΔ7 mouse model [19].  Figure 2 shows the results of these 
studies, including staining of transduced spinal motor neurons, SMN expression levels, righting 
ability, and weight and survival curves.  Approximately 42 ± 2% of lumbar spinal motor neurons 
were transduced in scAAV9.CB.GFP treated mice.  SMN transduction was shown by real time 
polymerase chain reaction (RT-PCR) in the mice.  GFP transduction was observed by 
microscopy.  Both constructs were in AAV9 and had transduction of motor neurons.  SMN 
levels were increased as well, in brain, spinal cord, and muscle of scAAV9.CB.SMN-treated 
animals, compared to untreated SMNΔ7 mice (although lower than wild type [WT] controls).  
SMNΔ7 animals treated with either scAAV9.CB.SMN or scAAV9.CB.GFP on post-natal Day 1 
were assessed for their righting ability and were compared to WT control mice and untreated 
mice.  Wild type controls could right themselves quickly, whereas the SMN- and green 
fluorescent protein (GFP)-treated SMA animals showed difficulty at P5.  However, by P13, 
90% of SMN-treated animals could right themselves compared with 20% of GFP-treated 
controls and 0% of untreated SMA animals.  At P18, SMN-treated animals were larger than 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 24 of 143 
GFP-treated animals, but smaller than WT controls.  Locomotive ability of the SMN-treated 
mice was nearly identical to WT controls, as assayed by open field testing and wheel running. 
Survival of SMN-treated SMNΔ7 animals compared with GFP-treated SMNΔ7 animals was 
significantly improved.  No GFP-treated control animals survived past P22 and had a median life 
span of 15.5 days.  The weights of GFP mice peaked at P10 and then precipitously declined until 
death, while SMN mice showed a steady weight gain until around P40 with it stabilizing at 17 g 
(about half the weight of WT controls).  The smaller size of corrected animals is likely related to 
the tropism and incomplete transduction of scAAV9, resulting in a ‘chimeric’ animal in which 
some cells were not transduced.  Additionally, the smaller size suggests an embryonic role for 
SMN.  Most remarkably, SMN-treated mice survived well past 250 days of age. 
Figure 2: Study Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves 
 
Source: Foust 2010 [19] 
CNS = central nervous system; GFP = green fluorescent protein; SMN = survival motor neuron; WT = wild type 
a) Shows transduced motor neurons in lumbar spinal cord 
b) 
Western Blots of SMN expression in CNS and muscle 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 25 of 143 
c) Improved righting ability of SMN-treated- similar to WT controls by P13 
d) 
SMN-treated are larger than GFP-treated at P18 
e) Survival of SMN-treated markedly improved compared to GFP- treated 
f)  
Body weight increased in SMN-treated vs GFP 
 
Toxicology biodistribution studies were generated by the 
 [data on file].  In the 
non-Good Laboratory Practice (GLP) studies, 24 mice and 4 non-human primates (NHPs) were 
injected, by way of vascular delivery, with AVXS-101.  To assess toxicity and safety, 
AVXS-101 was injected into P1 wild type Friend Virus B-Type (FVB) mice with either vehicle 
(3 males/6 females) or 3.3 × 1014 vg/kg of scAAV9.CB.SMN (6 males/9 females) via the facial 
temporal vein.  This dose was previously shown to be most efficacious in the SMNΔ7 mouse 
model [19].  P1 mice were used in anticipation of simulating potential clinical studies in infants.  
All mice survived the injection procedure and the initial 24-hour observation period without any 
signs of distress or weight loss.  Body mass was measured and hands-on observations were 
performed weekly for the remainder of the study; neither revealed any difference between 
control and treated cohorts (Figure 3). 
Figure 3 Body Mass of Treated and Control Mice Showed No Difference 
 
 
At 60, 90 and 180 days post-injection, blood from the mice was collected for hematology studies 
including complete blood counts with differentials.  At 90, 120 and 180 days post-injection, 
blood was collected for clinical chemistries assessment (alanine amino transferase [ALT], 
aspartate amino transferase [AST], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], 
electrolytes, and creatine kinase [CK]).  For histopathology, 13 mice were necropsied at 
120 days post-injection and 8 mice at 180 days.  There were no clinically significant results 
observed during from the hematology, clinical chemistry, and histopathology portions of the 
study and trends of both groups were comparable.  Of note, no significant lesions were present in 
any brain or spinal cord sections, although, the sections were frozen and thicker than 5 microns 
which made cellular morphology obscure and subtle changes may not have been identified. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 26 of 143 
In the safety study for the 4 male Cynomolgus Macaques, animals were injected at 90 days of 
age to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
AVXS-101 vector was administered one time by catheterization of the saphenous vein with a 
dose of 6.7 × 1013 vg/kg, which corresponds to the lowest dose tested for which SMNΔ7 mice 
showed a significant increase of survival.  Animals were followed for six months until they were 
sacrificed at approximately 9 months of age.  No adverse effects were seen, and all clinical 
chemistries were normal.  T-cell immune response was tested using Enzyme-linked ImmunoSpot 
(ELISpot) in peripheral blood mononuclear cells (PBMCs), and all were negative at 6 months 
post-injection. 
These mouse and monkey studies can be summarized as follows.  The serum chemistry and 
hematology studies were unremarkable as was the histopathology assessment.  The NHP patients 
animals mounted appropriate immune responses to capsid (but not to transgene), with very high 
transgene expression persisting at 6 months post-injection.  In conclusion, these studies provide 
strong evidence that systemically-delivered scAAV9.CB.SMN is safe and well tolerated, even at 
the high doses required for penetration of the blood-brain barrier [data on file]. 
When newborn FVB mice were given a single IV injection of AVXS-101 at levels up to 
3.3 × 1014 vg/kg on Day 1, there was neither test article-related mortality nor evidence of toxicity 
seen at time points up to 24 weeks after administration.  Treatment-related decreases in mean 
body weight and mean body weight gain, as well as lower activated partial thromboplastin time 
(APTT) values, were mild effects of treatment, but did not result in toxicity.  Activity of 
AVXS-101 was demonstrated by the biodistribution and the presence of a specific transgene 
ribonucleic acid (RNA) expression in brain and spinal cord, the main targeted therapeutic tissues.  
Low levels of antibodies to the AAV9 capsid were found after 12 and 24 weeks in males and 
females given 3.3 × 1014 vg/kg (Group 3).  No alteration was observed in clinical pathology and 
histopathology analyses.  Based on these results, the no observable adverse effect level 
(NOAEL) of AVXS-101 in newborn male and female mice is considered to be 3.3 × 1014 vg/kg. 
Intravenous administration of AAV9 has been shown to be safe and well tolerated when 
administered to mice and monkeys.  The vector has also demonstrated the ability to cross the 
blood brain barrier in both species following IV administration.  Body weight increased, righting 
behavior improved, survival was extended and cardiac deficits returned toward normal in treated 
SMNΔ7 mice when compared to untreated SMNΔ7 mice.  Toxicology studies determined the 
NOAEL of AVXS-101 was 3.3 x 1014 vg/kg and there was no test article mortality or toxicity 
observed up to 24 weeks following IV administration in mice.  Biodistribution to the brain and 
spinal cord was reconfirmed and low levels of antibodies to the AAV9 capsid were observed at 
12 and 24 weeks following the 3.3 x 1014 vg/kg dose.  No alteration was observed in clinical 
pathology and histopathology analyses. 
5.4. 
Clinical Studies 
First-in-human study AVXS-101-CL-101 is an ongoing 2-year study evaluating the efficacy and 
safety of AVXS-101 in 15 SMA Type 1 patients with 2 copies of SMN2.  All patients have 
received a single IV dose of AVXS-101 in 2 cohorts: Cohort 1 (n = 3) received the low dose 
used in this study (equivalent to a dose that doubled mouse lifespan in the SMN∆7 Mouse 
potency assay) and Cohort 2 (n = 12) received the high dose used in this study (equivalent to a 
dose that restored mouse lifespan to greater than 200 days or “full life” in the SMN∆7 Mouse 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 27 of 143 
potency assay).  The dose received by Cohort 2 patients in AVXS-101-CL-101 (proposed 
therapeutic dose) has been demonstrated to be equivalent to the dose to be used in the AVXS-
101-CL-303 study by direct testing using improved analytical methods. 
Preliminary data as of 15 September 2016 indicate that treatment with AVXS-101 results in 
broad improvements in survival, motor function, pulmonary function, and nutritional function.  
All patients in Cohort 2 (proposed therapeutic dose) showed improvements in survival, as 
defined by Finkel et al 2014 [21], with no deaths or requirements for permanent ventilation 
≥ 16 hours/day for ≥ 14 consecutive days through 15 September 2016.  The median age at last 
follow-up for Cohort 2 was 17.3 months, with the oldest patient at 27.4 months of age.  One 
patient in Cohort 1 (lowdose−cohort) had a pulmonary event of increased use of bi-level positive 
airway pressure in advance of surgery related to hypersalivation, a condition experienced by 
some SMA patients.  The event was determined by independent review to represent progression 
of disease and not related to AVXS-101. 
As of September 15, 2016, improvements in motor function, as assessed by the CHOP-INTEND 
scores, were observed with mean increases of 9.0 points in Cohort 1 and 24.8 points in Cohort 2.  
The CHOP-INTEND scores in Cohort 2 were ≥ 40 points for 11/12 patients, ≥ 50 points for 
9/12 patients, and ≥ 60 points (normal) for 3/12 patients. 
As of September 15, 2016, patients in Cohort 2 consistently achieved and maintained key 
developmental motor milestones as summarized below: 
• 11/12 patients achieved head control, 7/12 patients could roll, 11/12 patients could sit with 
support, and 8/12 patients could sit unassisted, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016 
• 7 patients were able to feed themselves, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016, and 5 patients were speaking (1 bilingual) 
• 2 patients were walking independently, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016.  These 2 patients each achieved earlier 
and important developmental milestones such as crawling, standing with support, standing 
alone, and walking with support 
 
As of September 15, 2016, AVXS-101 appears to have a favorable safety profile and appears to 
be generally well-tolerated in this study.  A total of 118 treatment-related AEs were reported 
(34 serious adverse events [SAEs] and 84 nonserious- adverse events [AEs]).  Two SAEs were 
deemed treatment-related in 2 patients, and 3 AEs were deemed treatment-related in 2 patients.  
All treatment-related events consisted of clinically asymptomatic liver enzyme elevations that 
resolved with prednisolone treatment.  There were no clinically significant elevations of 
gammaglutamyl transferase (GGT), alkaline phosphatase or bilirubin, and as such, Hy’s- Law 
was not met.  Other non-treatment-related AEs were expected and were associated with SMA. 
In summary, through September 15, 2016, the consistently positive clinical observations are 
remarkably different from that described in extensive natural history studies, clinical 
publications, the experience of seasoned clinicians, and concurrent SMA Type 1 studies with 
other therapies.  These significant and clinically meaningful responses in patients treated with 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 28 of 143 
AVXS-101 indicate preliminary clinical evidence of a treatment effect that addresses an unmet 
need in this devastating pediatric disease. 
A full understanding of all the risks associated with AVXS-101 is not known at this time.  
Elevated liver function tests have been observed in the ongoing AVXS-101-CL-101 study, which 
is believed to be a T-cell immune response to the AAV9 vector.  None of the liver enzyme 
abnormalities observed in the study were accompanied by clinical sequelae.  Patients could 
experience an allergic response to AVXS-101.  Patients could also develop an immune response 
to the AAV9 viral vector, which could prevent future use of gene transfers using this vector. 
Taken together, results from the clinical and non-clinical studies support further clinical 
investigation of the efficacy and safety of AVXS-101 in patients with SMA Type 1. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 29 of 143 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The co-primary objectives are to: 
• Determine the efficacy of AVXS-101 by demonstrating achievement of developmental 
milestone of functional independent sitting for at least 30 seconds at the 18 months of age 
study visit. 
• Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is 
defined by the avoidance of combined endpoint of either (a) death or (b) permanent 
ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of 
respiratory assistance per day (via non-invasive ventilatory support) for ≥ 14 consecutive 
days in the absence of an acute reversible illness, excluding perioperative ventilation.  
Permanent ventilation, so defined, is considered a surrogate for death. 
 
6.2. 
Secondary Objective 
The co-secondary objectives are to: 
• Determine the effect of AVXS-101 on the on the ability to thrive defined as achieving all of 
the following at 18 months of age 
o Does not receive nutrition through mechanical support (e.g., feeding tube) 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• Determine the effect of AVXS-101 on the ability to remain independent of ventilatory 
support, defined as requiring no daily ventilator support/usage at 18 months of age, excluding 
acute reversible illness and perioperative ventilation, as defined above through assessment of 
actual usage data captured from the device, for patients issued a Trilogy 100 BiPAP device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 30 of 143 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4. 
Safety Objectives 
The safety objectives are to: 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• 
Determine the safety of AVXS-101 based on the development of unacceptable toxicity 
defined as the occurrence of any Common Terminology Criteria for Adverse Events 
(CTCAE) [9] Grade 3 or higher, unanticipated, treatment-related toxicity. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 31 of 143 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, open-label, single-arm, single-dose study of AVXS-101 (gene replacement 
therapy) that will enroll up to twenty (20) patients with SMA Type 1who may be either 
symptomatic or pre-symptomatic with no functional SMN1 gene as well as 1 or 2 copies of 
SMN2 and who are < 6 months (< 180 days) of age at the time of gene replacement therapy 
(Day 1).  Enrolling up to twenty (20) patients under the broader enrollment criteria is projected 
to enable enrollment of at least fifteen (15) patients that meet the Intent-to-Treat Population 
(ITT) criteria.  The ITT population is identified as symptomatic patients with bi-allelic SMN1 
deletions and 2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who 
meet all other study enrollment criteria.  In addition, the first three patients enrolled must meet 
the criteria for the Intent-to-Treat Population to enable a comparison of CHOP-INTEND scores 
at one-month following gene replacement therapy to enable a comparison of patient response 
between AVXS-101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial (AVXS-
101-CL-101). 
The study includes 3 study periods: screening, gene replacement therapy, and follow-up 
(Figure 4).  During the screening period (Days –30 to –2), patients whose parent(s)/legal 
guardian(s) provide informed consent will undergo screening procedures to determine eligibility 
for study enrollment.  Patients who meet the entry criteria will enter the in-patient gene 
replacement therapy period (Day –1 to Day 3).  On Day –1, patients will be admitted to the 
hospital for pre-treatment baseline procedures.  On Day 1, patients will receive a one-time IV 
infusion of AVXS-101 at a dose equivalent to the dose received by the second dosing cohort in 
the Phase 1 study over approximately 60 minutes, and will undergo in-patient safety monitoring 
over the next 48 hours.  Patients may be discharged 48 hours after gene replacement therapy, 
based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of Study 
at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 
assessments until the patient reaches 18 months of age.  Any missed visit should be rescheduled 
as soon as possible, but within 7 days. 
All post-treatment visits will be relative to the date on which gene replacement therapy is 
administered, except for the 14 and 18 months of age visits, which will be relative to the 
patient’s date of birth.  For the 14 and 18 months of age visits, the patient will return within 0 to 
14 days after the date on which the patient reaches 14 and 18 months of age, respectively.  The 
18 months of age visit will also serve as the End of Study visit.  After the End of Study visit, 
eligible patients will be asked to roll over into the long-term follow-up study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 32 of 143 
Figure 4: Study Design 
 
Note: After the End of Study visit at 18 months of age, eligible patients will be asked to roll over into the long-
term follow-up study. 
ET = early termination 
a 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, except 
for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
 
There will be at least a 4 -week dosing interval between dosing of the first three patients to allow 
review of the safety analysis from six time points (day 1, 2, 7, 14, 21, and 30 visits) as well as 
early signals of efficacy including CHOP-INTEND score prior to dosing of the next patient. 
The first three patients enrolled must meet the criteria for the Intent-to-Treat (ITT) Population.  
AveXis will compare the CHOP-INTEND one month improvement for the AVXS-101-CL-303 
patients that meet the ITT criteria to assess the clinical response to the dose 1.1 x 1014 vg/kg as 
being what was expected from the Cohort 2 patients in the Phase 1 trial (AVXS-101-CL-101).  
This comparison will be performed as a per patient assessment for the first three patients.  The 
individual patients who receive their gene therapy at 0-3 months of age will be compared to a 
value of 10 CI points, while patients who receive their gene therapy at >3 but <6 months of age 
will be compared to a value of 5 CI points.  Furthermore, patients from either age group are 
expected to maintain the improvement in the absence of an acute illness or perioperatively.  If 
the expected CI improvements are observed for the first three ITT patients, AveXis will remove 
the 4-week interval between patients and proceed to dose at least 12 additional patients that meet 
the ITT criteria and perform safety and efficacy assessments as described elsewhere in the 
clinical protocol (AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  If the 
expected CI improvements are not observed for the first three ITT patients, AveXis will discuss 
next steps with the FDA before continuing study enrollment. 
In an attempt to dampen the host immune response to the AAV-derived therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion in accordance with the specified 
guidelines for tapering (Section 9.2.1). 
A schedule of study assessments is provided in Appendix 5.  Efficacy will be assessed by 
achievement of the key developmental milestone of functional independent sitting for at 
least 30 seconds at the 18 months of age study visit and survival at 14 months of age (as defined 
in Section 14.1.1.1).  The ability to thrive and the ability to remain independent of ventilatory 
support (as defined in Section 14.1.1.2) will also be assessed.  Additional developmental 
milestones will be assessed using Bayley Scales of Infant and Toddler Development© 
(Version 3) (Section 11).  Safety will be assessed through monitoring AEs, concomitant 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 33 of 143 
medication usage, physical examinations, vital sign assessments, cardiac assessments, and 
laboratory evaluations (Section 12).  Additionally, a Data Safety Monitoring Board (DSMB) will 
review safety data on a quarterly basis, and will also convene within 48 hours should any patient 
experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or 
requires medical treatment (Section 13.1.1.1 and Section 15).  This includes any patient death, 
important clinical laboratory finding, or any complication attributed to administration of gene 
replacement therapy.  In such instances, the DSMB will review the safety information and 
provide its recommendation.  The DSMB can recommend early termination of the study for 
safety reasons. 
7.2. 
Number of Patients 
Up to twenty (20) patients that meet the study entry criteria will be enrolled to enable enrollment 
of at least fifteen (15) patients that meet ITT criteria.  Study enrollment will stop as soon as 
practical following enrollment of the fifteenth patient that meets the ITT criteria. 
7.3. 
Criteria for Study Termination 
An independent DSMB will conduct quarterly and ad hoc reviews of the emerging safety data 
throughout the study as described in Section 15. 
The study will be completed as planned but may be terminated for the following reasons: 
• Development of unacceptable toxicity, defined as the occurrence of any unanticipated 
CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely related to gene 
replacement therapy, and is associated with clinical symptoms and/or requires medical 
treatment 
• DSMB can recommend early termination of the study for safety reasons 
• Study is terminated by Sponsor 
• Regulatory Authority recommendation 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 34 of 143 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients with SMA Type 1 who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1) with proven biallelic- mutations of the SMN1 gene and 1 or 
2 copies of the SMN2 will be enrolled in this study.  Patients may be of any racial, ethnic, or 
gender background. 
8.1. 
Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 
mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of 
the known SMN2 gene modifier mutation (c.859G>C)) 
2. The first three patients enrolled must meet the criteria for the Intent-To-Treat population 
3. Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
4. Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
5. Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab 
prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections 
are also recommended in accordance with American Academy of Pediatrics [26] 
6. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and 
comply with study procedures and visit schedule 
 
8.2. 
Patient Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
1. Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without 
any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation 
does not decrease by ≥ 4 percentage points 
3. Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours/day over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during 
the screening period or requiring ventilatory support while awake over the 7 days prior to 
screening or at any point during the screening period prior to dosing 
4. Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass 
the swallowing test will be allowed to enroll in the study 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 35 of 143 
5. Patients whose weight-for-age is below the third percentile based on World Health 
Organization (WHO) Child Growth Standards [25] 
6. Active viral infection (includes human immunodeficiency virus [HIV] or positive serology 
for hepatitis B or C, or Zika virus) 
7. Serious non- respiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 weeks prior to screening 
8. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 weeks prior to screening 
9. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy 
such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
11. Concomitant use of any of the following: drugs for the treatment of myopathy or neuropathy, 
agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, 
plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 
3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, 
methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay 
(ELISA) binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody 
titer > 1:50, he or she may receive retesting within 30 days of the screening period and will 
be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values (GGT, ALT, and AST > 3 × ULN; bilirubin 
≥ 3.0 mg/dL; creatinine ≥ 1.0 mg/dL; hemoglobin < 8 or > 18 g/dL; white blood cells [WBC] 
> 20,000/cmm) prior to gene replacement therapy 
14. Participation in recent SMA treatment clinical study (with the exception of observational 
cohort studies or non-interventional studies) or receipt of an investigational or commercial 
compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, 
valproic acid) at any time prior to screening for this study.  Oral β-agonists must be 
discontinued at least 30 days prior to gene therapy dosing.  Inhaled albuterol specifically 
prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not 
a contraindication at any time prior to screening for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal 
surgery or tracheostomy) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 36 of 143 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability 
to travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to 
refrain from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 
19. Gestational age at birth < 35 weeks (< 245 days) 
8.3. 
Patient Withdrawal Criteria 
Patients may be discontinued from the study for the following reasons: 
• Death 
− An autopsy will be requested for any patient who expires following participation in a gene 
replacement study [25] (see Autopsy Plan in Appendix 1) 
• Failure to comply with protocol-required visits or study procedures for 3 or more consecutive 
visits that are not rescheduled, unless due to hospitalization 
• Parent(s)/legal guardian(s) withdraws consent 
• Investigator discretion 
 
Early termination procedures should be completed within 14 days for any patient who 
prematurely discontinues the study for any reason, as indicated in Appendix 5. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 37 of 143 
9. 
TREATMENT OF PATIENTS 
It is the responsibility of the Investigator to ensure the safe storage and administration of gene 
replacement therapy. 
9.1. 
Description of Product 
The biological product is a non-replicating recombinant AAV9 containing the complimentary 
deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the 
cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB).  The AAV inverted 
terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, 
thus forming a double-stranded transgene ready for transcription.  This modified ITR, termed a 
“self-complementary” (sc) ITR, has been shown to significantly increase the speed of which the 
transgene is transcribed and the resulting protein is produced.  The biological product, called 
AVXS-101 (formerly scAAV9.CB.hSMN), expresses the human SMN protein in transduced 
cells. 
Table 5: Investigational Product 
 
Investigational Product 
Product Name: 
AVXS-101 
Dosage Form: 
Equivalent to the dose received by the second dosing cohort in the Phase 1 study 
Unit Dose 
1.1 X 1014 vg/kg; Equivalent to the dose received by the Cohort 2 in the Phase 1 
study (AVXS-101-CL-101) as determined by direct product testing with improved 
analytical methods. 
Route of Administration 
Intravenous infusion 
Physical Description 
AVXS-101 is a clear, colorless liquid. 
 
9.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be captured in the electronic Case Report Form (eCRF) 
from 2 weeks prior to administration of gene replacement therapy through the last study visit. 
9.2.1. 
Prophylactic Administration of Prednisolone 
An antigen specific T-cell response to the AAV vector was observed in the ongoing Phase 1 
clinical study (AVXS-101-CL-101) investigating AVXS-101 treatment via IV infusion.  This is 
an expected response between 2 to 4 weeks following gene replacement therapy.  One possible 
consequence to such antigen specific T-cell response is clearance of the transduced cells and loss 
of transgene expression. 
In an attempt to dampen the host immune response to the AAV based- therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion.  After 30 days of treatment, the 
dose of prednisolone can be tapered for patients whose ALT values, AST values, and T-cell 
response are ≤ 2 X ULN for ALT and AST, and < 100 SFC/106 PBMCs in accordance with the 
following treatment guideline: 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 38 of 143 
• Until at least 30 days post-infusion: 1 mg/kg/day 
• Weeks 5 and 6: 0.5 mg/kg/day 
• Weeks 7 and 8: 0.25 mg/kg/day 
• Week 9: prednisolone discontinued 
 
If the AST or ALT values are > 2 X ULN, or if T-cell response is ≥ 100 SFC/106 PBMCs after 
30 days of treatment, the dose of prednisolone will be maintained until the AST and ALT values 
decrease below threshold.  If T-cell response continues past Day 60, Investigator discretion 
should be used considering risk benefit for maintaining prednisolone.  Variance from these 
recommendations will be at the discretion of the Investigator based on potential safety issues for 
each patient. 
9.2.2. 
Prohibited Medications 
Concomitant use of any of the following medications is prohibited: 
• Drugs for treatment of diabetes, myopathy or neuropathy 
• Therapy received with the intent to treat SMA (e.g., nusinersen, valproic acid) 
o Oral β-agonists must be discontinued at least 30 days prior to gene therapy dosing. 
o Inhaled β-agonists may be used to treat respiratory complications of SMA provided 
such medications are dosed at clinically appropriate levels 
• Any investigational medication other than AVXS-101 is prohibited during the study 
• Ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as 
adalimumab, or immunosuppressive therapy within 3 months of starting the study 
(e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV 
immunoglobulin, rituximab) 
 
Corticosteroid usage following completion of the prednisolone taper is permissible as part of 
routine clinical management.  The use of corticosteroids in such circumstances should be 
documented appropriately as a concomitant medication, and the event precipitating its usage 
should be appropriately documented as an adverse event. 
Should the use of corticosteroids (aside from inhaled corticosteroids for bronchospasm) be 
considered as part of care during the course of the prednisolone taper, this medical management 
should be discussed with the medical monitor. 
9.3. 
Treatment Compliance 
AVXS-101 will be administered as a one-time IV injection. 
9.4. 
Randomization and Blinding 
This is an open-label study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 39 of 143 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT 
AVXS-101 is manufactured in accordance with current Good Manufacturing Practices (cGMP).  
Investigational product accountability logs will be maintained by the clinical pharmacy. 
10.1. 
Study Product 
AVXS-101 
10.2. 
Study Product Dose and Dose Justification 
Patients will receive a one-time dose of AVXS-101 at 1.1 X 1014 vg/kg, equivalent to the dose 
received by Cohort 2 in the Phase 1 study via IV infusion administered in the ongoing Phase 1 
clinical study (AVXS-101-CL-101). 
Two doses are being studied in the ongoing Phase 1 clinical study (AVXS-101-CL-101); the 
higher dose (dose received by the Cohort 2 patients) was chosen for the present study as 
preliminary data demonstrated both a dose response and significant clinical benefit thus 
identifying it as the proposed therapeutic dose.  In the Phase 1 study, AVXS-101 demonstrated a 
dose response, with efficacy greater as observed by motor milestone achievement and CHOP-
INTEND scores at the higher dose (received by Cohort 2) than the lower dose (received by 
Cohort 1).  Direct testing of the actual lot of Investigational Medicinal Product (IMP) used in the 
AVXS-101-CL-101 study by an improved and more fully qualified analytical method has 
assigned a value of 1.1 x 1014 vg/kg to the actual dose received by Cohort 2 in this Phase 1 study.  
The same method has been used to establish an equivalent dose for the Phase 3 IMP.  This vg/kg 
value has been further verified in an improved and more fully qualified SMN∆7 Mouse 
Biopotency assay to support a similar extension of mouse life time in direct comparative 
assessment between the Phase 1 and Phase 3 IMP. 
10.3. 
Study Product Packaging and Labeling 
AVXS-101 kits are labeled with a specific kit number and batch/lot number assigned at the 
cGMP facility.  The content of the labeling is in accordance with the local regulatory 
specifications and requirements. 
10.4. 
Study Product Storage 
AVXS-101 kits will be stored in an appropriate, locked room under the responsibility of the 
Investigator or other authorized persons (e.g., pharmacists) in accordance with local regulations, 
policies, and procedures.  Control of storage conditions, especially control of temperature (e.g., 
refrigerated/freezer storage) and information on in-use stability and instructions for handling 
prepared AVXS-101 should be managed in accordance with the Pharmacy Manual. 
The vessel used for delivery of the vector should be resealed in the procedure room and 
processed for destruction and/or return to AveXis in accord with the Pharmacy manual and 
applicable biohazardous waste guidelines for disposal. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 40 of 143 
10.5. 
Study Product Preparation 
Preparation of AVXS-101 will be done aseptically under sterile conditions by a pharmacist and 
will arrive at the clinical site ready for infusion. 
AVXS-101 will be received diluted with normal saline, as outlined in the Pharmacy Manual. 
The total vector genome dose will be calculated based on the patient’s body weight. 
The dose-delivery vessel will be delivered to the designated pediatric intensive care unit 
(PICU) patient room or other appropriate setting (e.g., interventional suite, operating room, 
dedicated procedure room) with immediate access to acute critical care management.  The 
vessel will be delivered in accord with the Pharmacy Manual. 
10.6. 
Study Product Administration 
AVXS-101 infusion will be administered under sterile conditions in a PICU or other appropriate 
setting (e.g., interventional suite, operating room, dedicated procedure room) with immediate 
access to acute critical care management.  AVXS-101 will be delivered one-time through a 
venous catheter inserted into a peripheral limb vein (arm or leg) at a dose equivalent to the dose 
received by the second dosing cohort in the Phase 1 study.  AVXS-101 should be slowly infused 
over approximately 30-60 minutes, dependent upon total volume in accord with the Pharmacy 
Manual, utilizing an infusion set and pump in accordance with the Pharmacy Manual. 
Following administration of gene replacement therapy, patients should return to an appropriate 
designated setting to ensure close monitoring of vital signs and adverse events.  Vital signs will 
be continuously monitored throughout the gene replacement therapy infusion as described in 
Section 12.1.3.  Patients should be maintained in the PICU or other appropriate setting for 
48 hours after the start of gene replacement therapy. 
10.7. 
Dose Adjustment Criteria 
The study investigates a one-time IV infusion of AVXS-101; no dose adjustments are possible. 
10.8. 
Study Product Accountability 
The pharmacist or designee will maintain accurate records of the quantities of AVXS-101 
received, dispensed, destroyed, and/or returned to AveXis.  The pharmacist or designee will 
document the date and time of delivery of the dose vessel to the dose procedure room as well as 
the time the used vessel was returned to AveXis or destroyed as per the Pharmacy Manual. 
10.9. 
Study Product Handling and Disposal 
All materials used for injection, including sterile drapes, needles, and syringes in contact with the 
vector must be sealed in leak-proof containers.  All waste must be sealed in bags bearing the 
biohazard symbol and disposed of in a biohazard waste container. 
All transfers must be done in spill-proof containers.  Individuals manipulating the vector will be 
required to wear personal protective equipment, such as gloves. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 41 of 143 
Any quality issue noticed with the receipt or use of AVXS-101 (e.g., deficiency in condition, 
appearance, pertaining to documentation, labeling, expiration date, etc.) should be promptly 
reported to the Sponsor in accord with procedures outlined in the Pharmacy Manual. 
Under no circumstances will the Investigator supply AVXS-101 to a third party, allow AVXS-
101 to be used other than as directed by this clinical trial protocol, or dispose of AVXS-101 in 
any other manner. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 42 of 143 
11. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed by achievement of the key developmental milestone of functional 
independent sitting for at least 30 seconds at the 18 months of age study visit and survival at 
14 months of age (as defined in Section 14.1.1.1).  The ability to thrive and the ability to remain 
independent of ventilatory support (as defined Section14.1.1.2) will also be assessed at 
18 months of age.  Additional developmental milestones will be assessed using the Bayley 
Scales of Infant and Toddler Development (version 3©).  Efficacy assessments will be performed 
at the times specified in the Table of Assessments (Appendix 5), and should be the first 
assessments performed at any scheduled visit.  All post-treatment visits will be relative to the 
date on which gene replacement therapy is administered except the 14 and 18 months of age 
visits, which will be relative to the patient’s date of birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
11.1. 
Developmental Milestones 
Developmental milestones will be assessed using relevant definitions obtained from the Bayley 
Scales of Infant and Toddler Development (version 3), and will be analyzed to assess efficacy 
(Appendix 2 and Appendix 3).  Achievement of each developmental milestone will be 
determined by the Physical Therapist and confirmed by the central reader (as may be necessary) 
based on an assessment of the submitted videos (Section 11.3).  Developmental milestones will 
be determined at each monthly visit as listed in Section 11.2.1. 
During the Screening visit, the physical therapist will complete an assessment of baseline 
milestone achievement in accordance with Appendix 5; this assessment must address all 
milestones/items noted on Appendix 5 that are at or below the child’s expected function for age, 
and be recorded on video.  The findings must be documented in the source.  Items that are below 
the expected function for age that are not successfully achieved during the baseline evaluation 
should be repeated at subsequent visits until successfully performed. 
The milestones of sitting independently (items 22 and 26) should be assessed at every subsequent 
visit, until attainment of milestone, regardless of starting point on the scale.  These milestones 
must also be assessed at the 18 months of age visit, regardless of previous attainment. 
As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each attained milestone be captured on video. 
A milestone will be considered achieved when demonstrated by a patient and observed with 
video capture confirmation during a physical therapy assessment or observed with video as 
provided by the patient’s family at the patient’s visit at 18 months of age. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 43 of 143 
11.2. 
Motor Function Tests 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones 
The Bayley Scales of Infant and Toddler Development (Version 3) (Appendix 2) is a 
standardized, norm-referenced infant assessment of developmental functioning across 5 domains 
of cognitive, language, motor, social-emotional, and adaptive behavior.  The Bayley Scales will 
be administered by a qualified Physical Therapist. 
The full Bayley Scales will be administered at screening, every 6 months starting at Month 6, 
and at End of Study when the patient reaches 18 months of age (or early termination), whereas 
the gross and fine motor subtests of the motor domain will be administered at each monthly visit. 
Each Bayley Scales/developmental milestone assessment will be video recorded in accordance 
with the AVXS-101-CL-303 Video Manual and may be submitted to the vendor for review by a 
central reader (Section 11.3). 
The following developmental milestones will be assessed: 
• Ability to hold head erect without support 
• Ability to roll from back to both sides 
• Ability to sit with support 
• Ability to sit independently, > 10 seconds; WHO [22] 
• Ability to sit without support for at least 30 seconds 
• Ability to crawl 
• Ability to pull to stand 
• Ability to stand with assistance 
• Ability to stand alone 
• Ability to walk with assistance 
• Ability to walk alone 
 
11.2.2. 
CHOP-INTEND 
The CHOP-INTEND is a motor function scale developed and validated for use specifically to 
monitor motor function status and decline amongst children with SMA Type 1, and will be 
administered by a qualified Physical Therapist.[23,24]  The CHOP-INTEND scale examines 
several aspects of motor function, including head control, righting reactions, and trunk 
movements in supported sitting, supine, and prone positions (Appendix 4).  Anti-gravity 
movements in assisted rolling, ventral suspension, and supported standing will also be measured. 
The CHOP-INTEND will be performed at screening, Day -1, and at each scheduled visit from 
Day 7 through the End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 5).  If Day -1 CHOP-INTEND assessment cannot be conducted, a CHOP-INTEND 
assessment must be completed on Day 1 prior to dose administration. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 44 of 143 
Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not undergo any additional 
CHOP-INTEND examinations. 
Each CHOP-INTEND exam will be video recorded in accordance with the AVXS-101-CL-303 
Video Manual and submitted to the vendor for review by a central reader as may be necessary 
(Section 11.3). 
11.3. 
Video Evidence 
Physical therapy assessments (Bayley Scales and CHOP-INTEND) required at each study visit 
will be video recorded in an effort to produce compelling, demonstrable, documented evidence 
of efficacy, as determined by changes in functional abilities.  AveXis, Inc. (AveXis) will provide 
a secure and confidential upload process for transfer and storage of the videos from 
investigational sites to a contracted third-party vendor that will compile and arrange videos as 
per AveXis requirements.  Any/all videos received at AveXis or the contracted vendor will be 
treated as confidential study data and will be the sole property of AveXis.  AveXis and the 
contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families on the videos, which may be shared with regulatory 
agencies, the medical community, and/or in appropriate venues to discuss the results of this 
clinical study. 
Videos may be provided to an independent, centralized reviewer for unbiased assessment of 
developmental milestone achievement.  The independent reviewer will document whether the 
video displays evidence of having achieved each developmental milestone.  The date of 
developmental milestone achievement will be computed as the earliest date on which video 
evidence demonstrates the achievement of the specified milestone. 
Additionally, the Parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the study.  These videos will be 
handled in the same manner in which the study-derived videos are handled. 
11.4. 
Compound Motor Action Potential 
Peroneal nerve CMAP amplitude will be measured by a qualified electrophysiologist, at all 
clinical sites capable of performing this assessment, using the procedures as described in the 
CMAP Manual (Appendix 6).  CMAP will be measured at screening, every 6 months starting at 
Month 6, and End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 5). 
The CMAP data will be collected for centralized review and interpretation. 
Sites that do not have equipment or appropriately experienced personnel required to perform 
CMAP measurements will not be required to perform these assessments. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 45 of 143 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety parameters include physical examinations, pulmonary examinations, vital signs, capillary 
blood gas assessments, weight and length measurements, 12-lead electrocardiograms (ECGs), 
12-lead Holter monitor recordings, echocardiograms, swallowing tests, laboratory assessments, 
adverse event monitoring, and photographs of the infusion site.  In general, safety assessments 
will be performed at the times specified in the Table of Assessments (Appendix 5).  All post-
treatment visits are relative to the date on which gene replacement therapy is administered until 
the patient reaches 14 months of age, at which point all visits are relative to the patient’s date of 
birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
12.1.1. 
Demographic/Medical History 
Demographic/medical history information will be collected at screening and captured in the 
eCRF.  Information that will be collected includes: 
• Familial history of SMA including affected siblings or parent carriers 
• Gestational age at birth 
• Length/weight/head circumference at birth 
• Hospitalization information from time of birth including number, duration, and reason for 
hospitalizations including International Statistical Classification of Diseases and Related 
Health Problems (ICD-10 codes), if available 
• Historical ventilatory support, if any 
• Historical feeding support, if any 
 
1. Patients are encouraged to follow all routinely scheduled immunizations, as 
recommended by the Center for Disease Control (CDC), throughout the study.  Seasonal 
vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent 
respiratory syncytial virus (RSV) infections are also recommended in accordance with 
American Academy of Pediatrics [26]. 
12.1.2. 
Physical Examinations 
Physical examinations will be conducted by the Investigator or Sub-Investigator at each 
scheduled visit, except Day –1 (Appendix 5).  The Day 1 physical examination will be 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 46 of 143 
performed prior to the start of gene replacement therapy infusion.  Physical examinations include 
a review of the following systems: head, eyes, ears, nose and throat (HEENT), lungs/thorax, 
cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, lymphatic, and 
genitourinary. 
12.1.3. 
Vital Signs/Weight and Length 
Vital sign parameters include blood pressure, respiratory rate, pulse, axillary temperature, and 
pulse oximetry.  Vital signs will be obtained at each study visit (as specified in Appendix 5).  On 
Day 1, vital signs will be continuously monitored throughout the gene replacement therapy 
infusion, and recorded pre-dose and every 15 (± 5) minutes for the first 4 hours after the start of 
infusion, and then every hour (± 15 minutes) until 24 hours after the start of infusion.  Axillary 
temperature will be recorded pre- and post-infusion. 
Weight and length will be measured at each study visit (as specified in Appendix 5).  On Day 1, 
weight and length will be measured pre-dose. 
12.1.4. 
Electrocardiogram 
A 12-lead ECG will be performed at screening, Day –1, pre-dose on Day 1, Day 2, every 
6 months starting at Month 6, and End of Study when the patient reaches 18 months of age (or 
early termination) (Appendix 5).  Additional ECG monitoring will be at the discretion of the 
Investigator as per local institutional guidelines. 
The ECG will be interpreted locally by a cardiologist.  The ECG tracings or ECG machine data 
will be collected for centralized review and interpretation by a cardiologist. 
12.1.5. 
12-Lead Holter Monitor 
A Holter monitor will continuously record the patient’s 12-lead ECG for a total of 72 hours from 
Day –1 (24 hours prior to the start of gene replacement therapy infusion) through 48 hours after 
the start of infusion.  Serial ECG data will be pulled in triplicate from the Holter monitor at the 
following time points: 
•
Pre-dose (within 24 hours prior to gene replacement therapy)
•
2 hours
•
4 hours
•
6 hours
•
8 hours
•
12 hours
•
24 hours
•
36 hours
•
48 hours

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 47 of 143 
Holter monitors will be provided to study sites along with a dedicated laptop for uploading the 
data from the memory cards for centralized review and analysis by a cardiologist within 24 hours 
of data upload.  The Sponsor physician or designee will be notified of any safety concerns from 
the centralized review, and the safety management plan will be followed for documenting and 
reporting of AEs/SAEs. 
12.1.6. 
Echocardiogram 
A standard transthoracic echocardiogram will be performed at screening, every 6 months starting 
at Month 6, and at End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 5). 
12.1.7. 
Pulmonary Examinations 
Pulmonary examinations will be performed by a pulmonologist or appropriate individual as per 
standard institutional practice at each scheduled visit except Day 1 (Appendix 5).  Prior to study 
entry, a pulmonologist or appropriate individual as per standard institutional practice will review 
and document ventilator usage in the 2 weeks prior to screening. 
Patients may be fitted with non-invasive ventilatory support at the discretion of the 
pulmonologist or appropriate individual as per standard institutional practice and/or Investigator.  
Non-invasive ventilatory support equipment will be provided by AveXis through a third-party 
vendor.  Should the patient require non-invasive ventilatory support at any time during the study, 
the equipment provided by AveXis must be used. 
Patients requiring non-invasive ventilatory support will be asked to bring their machine(s) to 
each study visit such that the study staff can remove an SD card which captures actual usage 
data.  The hours per day usage data for each day between visits will be extracted with software 
provided by the device manufacturer into a format that will be transferred/transcribed to the 
clinical database. 
12.1.8. 
Swallowing Test 
A swallowing test will be performed at screening (at the Investigator site), every 6 months 
starting at Month 6, and at End of Study when the patient reaches 18 months of age (or early 
termination) (Appendix 5) to determine if the patient has signs of aspiration.  If the test is 
positive for aspiration, there may be a recommendation for the patient to use an alternate method 
to oral feeding for the duration of the study at the determination of the Investigator and treating 
clinician. 
12.1.9. 
Photographs of Infusion Site 
Photographs will be taken of the infusion site at each scheduled visit from Day 1 (pre-dose) 
through Day 30 (Appendix 5) to monitor healing of the infusion site.  AveXis will provide a 
secure and confidential upload process for transfer and storage of the photographs from the 
investigative sites to a contracted third-party vendor that will compile and arrange photographs 
as per AveXis requirements.  Any/all photographs received at AveXis or the contracted vendor 
will be treated as confidential study data and will be the sole property of AveXis.  AveXis and 
the contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families in the photographs, which may be shared with 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 48 of 143 
regulatory agencies, the medical community, and/or in appropriate venues to discuss the results 
of this clinical study. 
12.1.10. 
Laboratory Assessments 
Blood samples will be collected at each scheduled visit, except Day 1 and Day 3 (as specified in 
Appendix 5).  On Day -1, blood and urine samples will be processed locally for receipt of results 
prior to the start of gene replacement therapy infusion.  Any clinically significant laboratory 
value will be repeated at the discretion of the Investigator. 
Blood samples will be collected and shipped to a central laboratory.  Samples for laboratory tests 
required during the in-patient vector infusion period prior to dosing will be collected and 
processed by the investigative site’s Clinical Laboratory Improvement Amendment (CLIA) 
CLIA-certified local laboratory to ensure receipt of results prior to dosing. 
Table 6: 
Total Blood Volume 
Visit 
Tests 
Total Volume (mL) 
Screening 
Hematology, chemistry/CK-MB, virus serology,  
 immunology sample (AAV9 Ab only),   
diagnostic confirmation sample 
16.9 
Day –1 
Hematology, chemistry, capillary blood gas  
3.3 
Day 2 
Hematology, chemistry, capillary blood gas 
3.3 
Day 7 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.6b 
Day 14 
Hematology, chemistry, immunology sample (AAV9/SMN Ab 
only) 
3.3 
Day 21 
Hematology, chemistry, immunology sample (AAV9/SMN Ab 
only) 
3.3 
Day 30 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.6b 
Day 60 
Hematology, chemistry/CK-MB, 
3.6 
Month 
3/4/5/7/8/10/11/
13/14/16/17 
Hematology, chemistry 
25.3 
Month 6/9/12/15 
Hematology, chemistry/CK-MB 
14.4 
End of Study/ET 
Hematology, chemistry/CK-MB 
3.6 
Maximum Total Volume for Studya 
96.2 
ET = early termination 
a Patients will have different numbers of monthly visits, depending on their age at dosing.  Maximum total volume based on a 
maximum of 16 monthly visits, provided T-cell responses are not elevated at Day 30 requiring additional surveillance 
samples and virus serology is not positive at screening requiring additional testing 
b Immunology sample for IFNγ- ELISpots requires 4-6 mL whole blood.  Immunology sample for ELISA requires 1 mL whole 
blood.  When drawn at the same visit, 4-6 mL is sufficient for both assays. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 49 of 143 
In a case where sufficient blood cannot be collected from a patient, blood will be used in the 
following priority order with the first having greatest priority and last having the least priority: 
1. Safety labs 
a. Chemistry 
b. Hematology 
c. CK-MB 
2. Interferon gamma (IFNγ) ELISpots to detect -T-cell responses 
3. Serum antibody to AAV9 and SMN 
4. Genetic reconfirmation testing 
 
If there is not sufficient blood volume to include the genetic reconfirmation testing sample at the 
screening visit, patient must return before Visit 2.  All patients must have genetic reconfirmation 
testing completed. 
12.1.10.1. Hematology 
Hematology analysis will include a complete blood count with differential and platelet count 
with smear.  Samples will be collected and shipped in accordance with the laboratory manual 
provided by the central laboratory.  Blood samples for hematology analysis will be collected at 
all scheduled visits except Day 1 and Day 3 (Appendix 5). 
Immediate/same-day hematology analyses required during in-patient dosing, as determined by 
the Investigator, will be performed as per investigational site standard procedures at the local 
laboratory.  Investigators will receive hematology results from all study visits from the central 
laboratory. 
12.1.10.2. Blood Chemistry 
Samples will be collected and shipped in accordance with the laboratory manual provided by the 
central laboratory.  Blood samples for chemistry analysis will be collected at all scheduled visits 
except Day 1 and Day 3 (Appendix 5). 
Immediate/same-day chemistry analyses required during in-patient dosing, as determined by the 
Investigator, will be performed as per investigational site standard procedures at the local 
laboratory. 
Chemistry analysis will include the following at all study visits: 
• Serum GGT 
• AST/ALT 
• Serum total bilirubin 
• Direct bilirubin 
• Albumin 
• Glucose 
• Total creatine kinase 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 50 of 143 
• Creatinine 
• BUN 
• Electrolytes 
• Alkaline phosphatase 
Creatine kinase (CK-MB) will be collected at Screening, Day 7, Day 30, Day 60, Month 6, 9, 12, 
15 months of age, and at 18 months of age/End of Study. 
 
Investigators will receive chemistry results from all study visits from the central laboratory 
(except Day -1). 
12.1.10.3. Urinalysis 
Urine samples will be collected in accordance with the laboratory manual provided by the central 
laboratory at all study visits except Day 1 and Day 3 (Appendix 5).  Day -1 urinalysis will be 
performed as per investigational site standard procedures at the local laboratory.  Urinalysis will 
include the following parameters: 
• Color 
• Clarity/turbidity 
• pH 
• Specific gravity 
• Glucose 
• Ketones 
• Nitrites 
• Leukocyte esterase 
• Bilirubin 
• Blood 
• Protein 
• Red Blood Cell 
• White Blood Cell 
• Squamous epithelial cells 
• Casts 
• Crystals 
• Bacteria 
• Yeast 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 51 of 143 
12.1.10.4. Virus Serology 
The administration of an AAV vector has the risk of causing immune-mediated hepatitis.  For 
patients who have HIV or positive serology for hepatitis B or C or Zika virus, administration of 
AAV vector may represent an unreasonable risk; therefore negative serology testing must be 
confirmed at screening, prior to treatment.  These samples will be collected at screening 
(Appendix 5) and shipped in accordance with the laboratory manual provided by the central 
laboratory. 
12.1.10.5. Capillary Blood Gas 
Capillary blood gas will be completed locally at Day –1 and Day 2 (Appendix 5).  A puncture or 
small incision will be made with a lancet or similar device into the cutaneous layer of the 
patient’s skin at a highly vascularized area (heel, finger, toe).  To accelerate blood flow and 
reduce the difference between the arterial and venous gas pressures, the area will be warmed 
prior to the puncture.  As the blood flows freely from the puncture site, the sample will be 
collected in a heparinized glass capillary tube. 
12.1.10.6. Immunology Testing (ELISA and IFNγ- ELISpots) 
Blood samples for immunology testing will be collected and shipped to the central laboratory in 
accordance with the laboratory manual to test for serum antibodies to AAV9 and SMN (ELISA), 
and to perform IFN-γ ELISpots to detect T-cell responses to AAV9 and SMN.  Blood samples 
will be collected at screening (ELISA anti-AAV9 only), Day 7, Day 14 (ELISA anti-
AAV9/SMN only), Day 21 (ELISA anti-AAV9/SMN only), and Day 30 (Appendix 5).  
Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to 
be elevated, based on further discussion with the Principal Investigator and Medical Monitor. 
12.1.10.7. AAV9 Antibody Screen in Mother 
There is potential that the biological mother of the patient may have pre-existing antibodies to 
AAV9 that may be transferred to the patient through breast milk or, theoretically, via placental 
transfer in utero.  Informed consent will be requested from the biological mother of the patient to 
screen the mother for circulating antibodies to AAV9.  Once informed consent has been 
obtained, the mother will have her blood drawn from a peripheral vein at screening and shipped 
to the central laboratory for screening of anti-AAV9 antibodies.  Mothers who test positive for 
antibodies to AAV9 will be asked to refrain from further feedings with breast milk. 
If AAV9 antibodies are identified, the patient must desist in consuming breast milk from the 
biological mother. 
Patients consuming banked breast milk from donor sources that cannot be test for anti-AAV9 
antibodies must be transitioned to formula prior to participation. 
12.1.10.8. Blood for Diagnostic Confirmation Testing 
A blood sample will be collected during the screening visit and shipped to the central laboratory 
in accordance with the laboratory manual for reconfirmation of SMN1 deletions/mutations, 
SMN2 copy number, and absence of exon 7 gene modifier mutation (c.859G>C).  This will be 
done to ensure consistency in diagnostic testing practices. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 52 of 143 
12.1.10.9.   Saliva, Urine, and Stool Collection 
Studies have shown that some vector can be excreted from the body for up to a few weeks after 
injection; this is called “viral shedding.”  Vector shedding can be found in the blood, urine, 
saliva, and stool for up to 1 week following infusion.  The potential health risks associated with 
the shed vector are not fully known at this time; however the health risk is thought to be low as 
the vector cannot replicate.  Regardless, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved instructions should be provided to the patient’s family and care 
giver(s) regarding use of protective gloves if/when they come into direct contact with the 
patient’s bodily fluids and/or waste, as well as good hand-hygiene for a minimum of 2 weeks 
(14 days) after gene replacement therapy.  Additionally, patients are prohibited from donating 
blood for 2 years following the vector infusion. 
Saliva, urine, and stool samples will be collected for viral shedding studies at screening, 24 hours 
postdose-, 48 hours post-dose, Day 7, Day 14, Day 21, and Day 30 (Appendix 5).  Samples will 
be collected, prepared, and shipped as per the laboratory manual. 
A subset of patients at sites opting to participate in the viral shedding sub-study will have 24-
hour total volume urine and fecal samples collected through 24 hour post-dose and through 48 
hours-post dose. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 53 of 143 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1.1. 
Definition of Adverse Events 
13.1.1.1. Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product.  In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no study treatment has been administered. 
All adverse events that occur from the start of gene replacement therapy infusion through the last 
study visit will be collected and recorded in the eCRF. 
All adverse events will be classified in accordance with the CTCAE version 4.03 outlined in 
Table 7. 
 
Table 7: 
Common Terminology Criteria for Adverse Events 
Grade 
Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting selfcare -ADL.b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Source: Common Terminology Criteria for Adverse Events (version 4.03) [9] 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
Study enrollment will be interrupted should any patient experience an unanticipated CTCAE 
Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the 
gene replacement therapy.  The event will then be reviewed by the DSMB and an evaluation will 
be made as to whether the study should be terminated early following the discontinuation rules. 
Unanticipated CTCAE Grade 3 or higher adverse events that are possibly, probably, or definitely 
related to the gene replacement therapy must be reported within 24 hours to Sponsor and/or 
designee as per study safety management plan to ensure timely escalation to the DSMB. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 54 of 143 
13.1.1.2. Serious Adverse Event 
A SAE is an AE occurring during any study phase (e.g., baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, or comparator that fulfils one or more of the 
following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
All SAEs that occur after signing of the informed consent through the last study visit, whether or 
not they are related to the study product, must be collected and recorded on forms provided by 
the Contract Research Organization. 
13.1.1.3. Other Adverse Event 
The following specific treatment-emergent AE of special interest, which may be searched using 
Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries, will be 
summarized: 
• Elevated liver enzymes 
 
Other adverse events (OAE) will be identified by the Drug Safety Physician and, if applicable, 
also by the Clinical Study Team Physician during the evaluation of safety data for the Clinical 
Study Report.  Significant adverse events of particular clinical importance, other than SAEs and 
those AEs leading to discontinuation of the patient from the study, will be classified as OAEs.  
For each OAE, a narrative may be written and included in the Clinical Study Report. 
13.2. 
Relationship to Study Product 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related, Probably Related, or 
Definitely Related).  The Investigator should decide whether, in his or her medical judgment, 
there is a reasonable possibility that the event may have been caused by the investigational 
product.  If no valid reason exists for suggesting a relationship, then the AE should be classified 
as “unrelated.”  If there is any valid reason, even if undetermined, for suspecting a possible 
cause-and-effect relationship between the investigational product and the occurrence of the AE, 
then the AE should be considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” then the event will be considered related to the investigational product 
for the purposes of expedited regulatory reporting. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 55 of 143 
13.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Information about AEs will be collected from the time of vector infusion 
until the end of the study.  Serious Adverse Event information will be collected from signing of 
consent form until the last study visit.  The AE term should be reported in standard medical 
terminology when possible.  For each AE, the Investigator will evaluate and report the onset 
(date (and time if during Visit 2)), resolution (date (and time if start date during Visit 2)), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the patient to discontinue the study. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 13.1.1.2.  An AE of severe intensity 
may not be considered serious. 
13.4. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of consent form until the last 
study visit.  Any SAEs considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All SAEs must be 
reported to AveXis or designee within 24 hours of the first awareness of the event.  The 
Investigator must complete, sign and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy by fax or 
e-mail to AveXis or designee. 
Additional follow-up information, if required or available, should all be faxed or e-mailed to 
AveXis or designee within 24 hours of receipt and this should be completed on a follow-up SAE 
form and placed with the original SAE information and kept with the appropriate section of the 
eCRF and/or study file. 
AveXis is responsible for notifying the relevant regulatory authorities of certain events.  It is the 
Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at his or 
her site.  Investigators will also be notified of all unexpected, serious, product-related events 
(7/15 Day Safety Reports) that occur during the clinical study.  Each site is responsible for 
notifying its IRB or IEC of these additional SAEs. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 56 of 143 
14. 
STATISTICS 
This section summarizes key aspects of the analysis plan including definitions of co-primary, 
co-secondary, and 
 and safety endpoints, and the methods to be 
used to test the primary effectiveness hypothesis.  Additional details regarding methods for the 
final data analysis will be provided in a separate Statistical Analysis Plan (SAP) which will be 
finalized and submitted to the Investigational New Drug application prior to the enrollment of 
the first patient.  The SAP will detail all analyses and data displays, and will be executed 
according to Standard Operating Procedures in a controlled environment. 
14.1. 
Study Endpoints and Populations 
14.1.1. 
Study Endpoints 
The primary and efficacy endpoint will be compared to the null.  The survival co-primary 
efficacy variable will be evaluated relative to literature-based historical controls (such as the 
Pediatric Neuromuscular Clinical Research Network [PNCR] [21].  These were selected on the 
basis of comparability to the target population and similarity to the investigational device. 
14.1.1.1. Co-Primary Efficacy Endpoint 
The co-primary efficacy endpoints are: 
• The proportion of patients that achieve functional independent sitting for at least 30 seconds 
at the 18 months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler 
Development (Version 3) (Appendix 2), confirmed by video recording, as a patient who sits 
up straight with the head erect for at least 30 seconds. 
• The survival at 14 months of age.  Survival is defined by the avoidance of the combined 
endpoint of either (a) death or (b) permanent ventilation, which is defined by tracheostomy or 
by the requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive 
ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, 
excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
 
An “acute reversible illness” is defined as any condition other than SMA that results in increased 
medical intervention (e.g., increased requirement for respiratory support; use of other 
concomitant medications as rescue) requirements and is expected to be reversible or improved 
following definitive intervention (e.g., surgery, antibiotics) or introduction of escalated 
supportive care, such as hospitalization (e.g., for upper respiratory infection, spontaneous 
fracture).  The specific duration of the condition antecedent intervention shall not be considered 
in the definition of “acute.”  The date of “definitive intervention” shall be defined as the date of 
provision of a procedure (e.g., surgery, etc.) or medication (e.g., antibiotics) intended to cure or 
substantially improve the condition.  For conditions such as viral respiratory infections for which 
supportive care is provided, the date of “definitive intervention” shall be considered the date of 
hospitalization or substantial escalation of care. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 57 of 143 
“Perioperative” use reflects any alteration of ventilatory use related to a surgical or other medical 
procedure of any nature for which the patient received medications that could impair or interfere 
with respiratory function. 
For a patient who develops an acute reversible illness and/or requires perioperative ventilatory 
support, a recovery period not to exceed 21 days following the date of definitive intervention will 
be instituted.  Following this recovery period, the condition will be considered subacute and the 
patient will become evaluable with regards to the surrogate survival endpoint (requirement of 
ventilatory support of ≥ 16 hours/day for 14 or more days). 
14.1.1.2. Co-Secondary Efficacy Endpoint 
The co-secondary efficacy endpoints are: 
• The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate 
thin liquids (as demonstrated through a formal swallowing test) and to maintain weight 
(> third percentile based on World Health Organization [WHO] Child Growth Standards [25] 
for age and gender) without need of gastrostomy or other mechanical or non-oral nutritional 
support at 18 months of age. 
• The proportion of patients who are independent of ventilatory support, defined as requiring 
no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and 
perioperative ventilation, as defined above through assessment of actual usage data captured 
from the device (Phillips Trilogy). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 58 of 143 
• 
 
 
 
 
 
 
 
 
 
 
 
 
14.1.1.4. Safety Endpoints 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• Incidence of elevated LFTs and/or unresolved LFEs 
• Incidence of CTCAE Grade 3 or higher toxicity, treatment-emergent adverse events 
• Clinically significant changes in laboratory values, physical exams, cardiac assessments or 
vital signs 
• Research Immunology Blood Labs including serum antibody to AAV9 and SMN as well as 
IFN-γ ELISpot to detect T cell responses to AAV9 and SMN 
 
14.1.2. 
Statistical Analysis Populations 
14.1.2.1. Intent-to-Treat Population (ITT) 
The ITT population will consist of symptomatic patients with biallelic- deletion mutations of 
SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene 
modifier mutation (c.859G>C) who receive an IV infusion of AVXS-101 at less than 180 days of 
age.  The first three patients enrolled must meet the criteria for the Intent-to-Treat Population. 
14.1.2.2. Efficacy Completers Population 
The efficacy completers analysis population will consist of: 
• All treated patients who reach 14 months of age for the survival endpoint or 18 months of 
age for the endpoint of achievement of functional independent sitting, OR 
• All treated patients who meet discontinuation criteria, discontinue the study due to an AE or 
experience death 
 
14.1.2.3. All Enrolled Population 
The all enrolled population will consist of all patients who receive an IV infusion of AVXS-101.  
Analyses of endpoints in this population are considered descriptive. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 59 of 143 
14.1.2.4. Safety Population 
The safety analysis population will consist of all patients who receive an IV infusion of 
AVXS-101.  All safety analyses will be conducted on the safety analysis population. 
14.2. 
Sample Size Calculation 
This is a pivotal Phase 3, open-label, single-arm, single-dose, study assessing the efficacy and 
safety of AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal 
muscular atrophy (SMA) Type 1 who meet enrollment criteria, may be either symptomatic or 
pre-symptomatic and are genetically defined by no functional survival motor neuron 1 gene 
(SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 months 
(< 180 days) of age at the time of gene replacement therapy (Day 1).  Enrolling up to twenty 
(20) patients under the broader enrollment criteria is projected to enable enrollment of at least 
fifteen (15) patients that meet the Intent-to-Treat Population (ITT) criteria. The ITT population is 
identified as symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without 
the SMN2 gene modifier mutation (c.859G>C) and will comprise the primary population for 
evaluation of the primary and secondary endpoints.  Study power is based upon efficacy analysis 
of the ITT population.  Furthermore, the first three patients enrolled must meet criteria for the 
Intent-To-Treat Population to enable a comparison of CHOP-INTEND scores at one-month 
following gene replacement therapy to enable a comparison of patient response between AVXS-
101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial (AVXS-101-CL-101).  
Patients with 1 copy of SMN2, pre-symptomatic patients and patients with the SMN2 gene 
modifier mutation (c.859G>C) and other permutations outside of those specified in the ITT 
population will be evaluated separately as part of additional subgroup analyses.  Details of all 
analyses will be contained within the Statistical Analysis Plan. 
The two co-primary efficacy endpoints will be assessed in sequence:  The endpoint of functional 
independent sitting will be assessed first and, only if this assessment meets statistical 
significance will the endpoint of survival be assessed. 
Based upon the widely cited natural history of the disease (Pediatric Neuromuscular Clinical 
Research Network [PNCR]) [Neurol. 2014; 83(9):810-817], it is expected that no patients in this 
population would be expected to attain the ability to sit without support or accomplish other 
milestones (rolling over, standing, walking) prior to 18 months of age.  Assuming that the true 
response rate for the primary endpoint is actually zero (or as low as 0.1%) in the population of 
interest of the historical control, the first co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 18 
months of age study visit. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 40% of treated symptomatic patients with bi-allelic deletions of SMN1 and 2 copies of 
SMN2 without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-
primary efficacy endpoint of functional independent sitting for at least 30 seconds at the 18 
months of age study visit.  With the assumption for the true response rate of AVXS-101 for the 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 60 of 143 
primary endpoint being in the range of 30% - 40%, a sample size of 15 patients that meet ITT 
criteria will be enrolled and assuming approximately 30% of patients are excluded from analysis, 
would yield an ITT population that would provide power of > 90% to detect a significant 
difference from 0.1% with α = 0.025 using a 1-sided exact test for a binomial proportion. 
The second co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹, 
where 𝑝𝑝 is the proportion of patients surviving at 14 months of age. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 80% of treated symptomatic patients with biallelic- SMN1 deletions and 2 copies of SMN2 
without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-primary 
efficacy endpoint of survival through 14 months of age.  It is anticipated that 75% of patients in 
the PNCR population would not survive beyond 13.6 months of age, and that these control 
patients will represent a 25% survival rate based upon the natural history of the disease.  With 
this efficacy, an enrolled sample size of  15 patients that meet ITT criteria (assuming 30% of 
patients are excluded from the analysis) would yield an ITT population that would provide power 
of > 80% to detect a significant difference from the historical control with α = 0.05 using a 2-
sided Fisher’s Exact test, comparing to the 26 age and gender matched patients from a published 
natural history observational study performed at 3 large, tertiary care centers in the United States 
(Harvard University, Columbia University, Children’s Hospital of Philadelphia; PNCR). 
14.3. 
Efficacy Analysis 
14.3.1. 
General Considerations 
This study will compare the activity of AVXS-101 administered IV versus the natural 
observational results from PNCR [21] in terms of functional independent sitting and survival 
rate.  The ability to thrive and the ability remain independent of ventilatory support will also be 
assessed. 
The analysis of the co-primary and co-secondary efficacy endpoints will be performed for the 
ITT and efficacy completers population.  The analysis based on the ITT population will be 
considered as the primary analysis.  In the case of missing data, observed data will be used for 
the analyses. 
Unless otherwise specified, the baseline measurement is defined as the last non-missing 
measurement collected prior to or on the day of gene replacement therapy infusion (e.g., on or 
before Day 1 visit). 
14.3.2. 
Primary and Secondary Efficacy Analysis 
Primary and secondary efficacy analyses will be based on the ITT population, those patients that 
are symptomatic with biallelic- deletion mutations of SMN1 and 2 copies of SMN2 without the 
SMN2 gene modifier mutation (c.859G>C).  These analyses are to test the superiority of AVXS-
101 to the results from natural observation study (PNCR) [21]. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 61 of 143 
The first co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1% 
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 18 
months of age study visit. 
The second co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 , 
where 𝑝𝑝 is the proportion surviving at 14 months of age. 
Primary efficacy endpoints will be examined on the ITT population.  Testing for the first co-
primary endpoint, functional independent sitting will first be performed using 1-sided exact 
binomial test.  Only if the null hypothesis of equality in proportion of functional independent sitting 
is rejected at p<0.025, will the co-primary endpoint survival improvement be tested using 2-sided 
Fisher’s Exact test on the ITT population, comparing to matched patients from natural observational 
study (PNCR).  This hierarchy approach strongly protects the Type I error rate. 
The hypothesis for both cosecondary- efficacy endpoints to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1% , 
where p is the proportion of patients maintaining the ability to thrive/are independent of 
ventilatory support. 
One-sided exact binomial tests will be executed for secondary efficacy analyses on the ITT 
population. 
A sensitivity analysis will be conducted by repeating the primary efficacy analysis on the 
efficacy completers analysis population. 
14.4. 
CHOP-INTEND Comparison 
A comparison will be performed of the first three patients CHOP-INTEND scores to the AVXS-
101-CL-101 CHOP-INTEND scores.  The first three patients enrolled must meet the criteria for 
the Intent-to-Treat (ITT) Population.  AveXis will compare the CHOP-INTEND one month 
improvement for the AVXS-101-CL-303 patients that meet the ITT criteria to assess the clinical 
response to the dose 1.1 x 1014 vg/kg as being what was expected from the Cohort 2 patients in 
the Phase 1 trial (AVXS-101-CL-101).  This comparison will be performed as a per patient 
assessment for the first three patients.  The individual patients who receive their gene therapy at 
0-3 months of age will be compared to a value of 10 CI points, while patients who receive their 
gene therapy at >3 but <6 months of age will be compared to a value of 5 CI points.  
Furthermore, patients from either age group are expected to maintain the improvement in the 
absence of an acute illness or perioperatively.  If the expected CI improvements are observed for 
the first three ITT patients, AveXis will remove the 4-week interval between patients and 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 62 of 143 
proceed to dose at least 12 additional patients that meet the ITT criteria and perform safety and 
efficacy assessments as described elsewhere in the clinical protocol (AVXS-101-CL-303) and 
corresponding Statistical Analysis Plan.  If the expected CI improvements are not observed for 
the first three ITT patients, AveXis will discuss next steps with the FDA before continuing study 
enrollment. 
14.5. 
Safety Analysis 
Safety will be assessed through the incidence and severity of AEs, vital sign assessments, cardiac 
assessments, laboratory evaluations (chemistry, hematology, urinalysis, immunology), physical 
examinations, and use of concomitant medications.  Adverse events will be coded in accordance 
with the most current version of the MedDRA coding dictionary. 
Safety analyses will be conducted on safety population, and summarized by subgroup and 
overall. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 63 of 143 
15. 
DATA SAFETY MONITORING BOARD 
The DSMB is an independent multidisciplinary group consisting of clinicians and a 
biostatistician that, collectively, have experience in the management of patients with SMA 
Type 1 and other diseases, and in the conduct and monitoring of randomized clinical studies with 
interim analyses.  The DSMB will be chartered to oversee the safety of patients during the 
conduct of the study, and will act in an advisory capacity to AveXis.  A detailed description of 
the DSMB, its role in this study, and the timing of the scheduled reviews will be described in a 
DSMB Charter. 
The DSMB will routinely convene on a quarterly basis to review emerging safety data from the 
study.  All available safety data from all enrolled patients will be included in such reviews, 
which include, but are not limited to, screen failures, enrollment status, data from safety 
parameters, all SAEs, and other AEs.  Following each meeting, the DSMB will make a 
recommendation as to whether or not the accumulated safety data warrants a suspension or 
discontinuation of the study, a modification to the study, or any additional comments or 
recommendations related to safety.  The DSMB will prepare and provide minutes of their 
meetings to AveXis who will provide copies to the regulatory authorities as appropriate. 
The DSMB will also convene on an ad hoc basis within 48 hours should any patient experience 
an unanticipated CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely 
related to gene replacement therapy, and is associated with clinical symptoms and/or requires 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the 
DSMB will review the safety information and provide its recommendation. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 64 of 143 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of AveXis will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of AveXis or its representatives.  This will be 
documented in a Clinical Study Agreement between AveXis and the Investigator. 
During the study, a monitor from AveXis or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed 
• Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the study.  This will require direct access to all original records for each patient (e.g., clinic 
charts, electronic medical records) 
• Record and report any protocol deviations not previously sent to AveXis 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any SAEs 
have been forwarded to AveXis and those SAEs that met criteria for reporting have been 
forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of AveXis, a regulatory authority, an IEC or an IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of an AveXis 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP) 
guidelines of the International Council for Harmonization (ICH), and any applicable regulatory 
requirements.  The Investigator should contact AveXis immediately if contacted by a regulatory 
agency about an inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 65 of 143 
16.3. 
Institutional Biosafety Committee 
As this study involves gene therapy, the Principal Investigator must obtain approval/favorable 
opinion for the investigation from a designated institutional or independent biosafety committee 
in accordance with institutional requirements and/or guidelines. 
16.4. 
Institutional Review Board/Institutional Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation (Section 18.1).  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 66 of 143 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Qualified individuals designated by the Sponsor will monitor all aspects of the study according 
to GCP, standard operating procedures (SOPs), and for compliance with applicable government 
regulations.  Please see Section 16.1 for more details regarding the quality control and 
monitoring process.  AveXis may also conduct a quality assurance audit any time during or after 
the completion of the study.  Please see Section 16.2 for more details regarding the audit process. 
The Investigator agrees to allow these Sponsor representatives direct access to the clinical data 
and supplies, dispensing and storage areas and if requested, agrees to cooperate fully or assist the 
Sponsor representative.  The Investigator and staff are responsible for being present or available 
for consultation during routinely scheduled site visits conducted by the Sponsor or its designees. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
Investigator, site staff, or representatives of the Sponsor will lead to prompt action by the 
Sponsor to secure compliance.  Continued noncompliance may result in termination of the 
corresponding party’s involvement in the study.  The IRB/IEC and relevant regulatory authority 
will also be informed. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 67 of 143 
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval to AveXis before he or she can enroll any patient into 
the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  AveXis or designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (Appendix 7) and are consistent with ICH/GCP, applicable regulatory 
requirements and the AveXis’ policy on Bioethics. 
18.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the parent(s)/legal guardian(s) are 
given full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study.  The parent(s)/legal guardian(s) must also be notified that they are free to 
discontinue the patient from the study at any time.  The parent(s)/legal guardian(s) should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the parent(s)/legal guardian(s). 
There will be 3 informed consent forms: 
• Parent(s)/legal guardian(s) informed consent form 
• Biological mother baseline AAV9 antibody screening informed consent form 
• Autopsy informed consent form (Appendix 1; if the parent(s)/legal guardian(s) decline an 
autopsy, it will not prevent the patient from participating in the study) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 68 of 143 
19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Electronic Case Report Forms 
Adequate and accurate case records will be maintained and all relevant observations and data 
related to the study will be recorded.  This will include medical history/ physical examination, 
hematology, clinical chemistry and serology results, a check list of inclusion and exclusion 
criteria, product administration, and a record of sample collection, hemodynamic measurements, 
clinical assessments, AEs, and final evaluation. 
Electronic CRFs will be used in this study.  The eCRF will be electronically signed and dated by 
the Principal Investigator or designee after his/her review.  After the completion of the study, 
completed eCRFs will be retained in the archives. 
Completed eCRFs will be reviewed by the study monitor against the source documentation for 
accuracy and completeness.  Once signed by the Investigator, the monitor will transmit the 
completed eCRFs to data management for data validation and database analysis. 
19.2. 
Inspection of Records 
AveXis or designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the product storage area, study product stocks, product accountability records, patient 
charts and study source documents, and other records relative to study conduct. 
19.3. 
Retention of Records 
All primary data that are a result of the original observations and activities of the study and that 
are necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period not less than 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have lapsed since the formal 
discontinuation of the clinical development of the investigational product.  All country/region 
specific requirements that may be more stringent than the 2 years included in ICH shall be 
followed. 
The site will maintain a Clinical Study Document Binder, which will be maintained at the study 
site.  In this binder, there will be tabbed sections for study documents including the following: 
study personnel identification and signature list, patient / subject screening records, patient / 
subject roster (names omitted), protocol and amendments or administrative changes, FDA Form 
1572 (if required), study staff Curricula Vitae, IRB/IEC documentation, an approved sample 
ICF, drug / product accountability records, correspondence, site monitoring reports, blank Data 
Documentation form, and lab accreditations and normal values. The site must keep this binder 
current and available for review by the Sponsor, IRB/IEC, and/or regulatory bodies. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 69 of 143 
20. 
PUBLICATION POLICY 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study.  During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation.  Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and 
information generated by the Investigator) without the consent of the Investigator.  Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document.  All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement.  In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
If the study is being conducted as part of a multicenter clinical study, data from all sites 
participating in the study will be pooled and analyzed by the Sponsor or the Sponsor’s designee.  
The first publication of the study results shall be made in conjunction with the results from other 
study sites as a multicenter publication.  If a multicenter publication is not forthcoming within 
24 months of completion of the study at all sites, the Investigator may publish or present the 
results generated at his or her site. 
The Investigator will provide the Sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication.  The Sponsor shall inform the Investigator in writing of any changes or deletions 
in such presentation or publication required to protect the Sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results.  At the expiration of such 60-day period, the 
Investigator may proceed with the presentation or submission for publication unless the Sponsor 
has notified the institution or the Investigator in writing that such proposed publication or 
presentation discloses the Sponsor’s confidential and proprietary technical information.  Further, 
upon the request of the Sponsor, the Investigator will delay the publication or presentation for an 
additional 90 days to permit the Sponsor to take necessary actions to protect its intellectual 
property interests. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 70 of 143 
21. 
LIST OF REFERENCES 
1. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for 
spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum 
Genet. 2012;20(1):27-32. 
2. Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to 
age, SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-712. 
3. Le TT, McGovern VL, Alwine IE, et al. Temporal requirement for high SMN expression in 
SMA mice. Hum Mol Genet. 2011;20(18):3578-3591. 
4. Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and 
adaptation in spinal muscular atrophy. Arch Neurol. 2012b;69(4):467-473. 
5. Riessland M, Ackermann B, Forster A, et al. SAHA ameliorates the SMA phenotype in two 
mouse models for spinal muscular atrophy. Hum Mol Genet. 2010;19(8):1492-1506. 
6. Dayangac-Erden D, Bora-Tatar G, Dalkara S, Demir AS, Erdem-Yurter H. Carboxylic acid 
derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: a promising 
target for spinal muscular atrophy therapeutics. Arch Med Sci. 2011;7(2):230-234. 
7. www.ClinicalTrials.gov 
8. Darbar IA, Plaggert PG, Resende MB, Zanoteli E, Reed UC. Evaluation of muscle strength 
and motor abilities in children with Type II and III spinal muscle atrophy treated with 
valproic acid. BMC Neurol. 2011;11:36. 
9. US Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events (v4.03). Published May 2009 (Revised June 2010). 
10. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 
2011;68(8):979-984. 
11. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and 
characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-164. 
12. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene 
regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 
1999;96(11):6307-6311. 
13. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH et al. A single 
nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from 
the copy gene SMN2. Hum Mol Genet. 1999;8(7):1177-1183. 
14. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity & SMN protein level in 
spinal muscular atrophy. Nat Genet. 1997;16(3):264-269. 
15. Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights from 
model mice. Curr Neurol Neurosci Rep. 2010;10(2):108-117. 
16. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 
and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and 
prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-368. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 71 of 143 
17. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the 
SMN2 gene. Am J Hum Genet. 2009;85:408-413. 
18. Farrar MA, Vucic S, Johnston HM, et al. Pathophysiological insights derived by natural 
history and motor function of spinal muscular atrophy. J Pediatr. 2013;162(1):155-159. 
19. Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype 
in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010;28(3):271-274. 
20. Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the SMNDelta7 
mouse model of spinal muscular atrophy. Neurobiol Dis. 2007;27(2):207-219. 
21. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular 
atrophy Type I and implications for clinical trials. Neurol. 2014;83(9):810-817. 
22. Wijnhoven TMA, De Onis M, Oyango AW, Wang T, Bjoerneboe GA, Bhandari N, Lartey A, 
Al Rashidi B; WHO Multicentre Growth Reference Study Group. Assessment of gross motor 
development in the WHO multicenter growth reference study. Food Nutr Bull. 
2004;25(1 Supple 1):S37S45. 
23. Glanzman AM, McDermott MP, Montes J, et al.  Validation of the Children's Hospital of 
Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).  Pediatr Phys Ther. 
2011;23(4):322-326. 
24. Glanzman AM, Mazzone E, Main M, et al.  The Children’s Hospital of Philadelphia Infant 
Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability.  
Neuromusc Disord.  2010;20(3):155-161. 
25. Onis, M. "WHO Child Growth Standards based on length/height, weight and age." Acta 
paediatrica 95.S450 (2006): 76-85. 
26. American Academy of Pediatrics: Policy statements--Modified recommendations for use of 
palivizumab for prevention of respiratory syncytial virus infections. Committee on Infectious 
Diseases. Pediatrics. 2009 Dec;124(6):1694-701. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 72 of 143 
22. 
APPENDICES 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 73 of 143 
APPENDIX 1. 
AUTOPSY PLAN 
An autopsy will be requested for any patient who receives gene replacement therapy and expires.  
The autopsy and tissue collection will be performed by a contracted vendor who will deploy a 
pathology assistant to the funeral home of the deceased to perform the autopsy and tissue 
collection.  Standard autopsy incisions will be used to perform the autopsy and pathology 
necessary to determine the cause of death. 
During the procedure, multiple tissues along with the entire spinal cord will be collected for 
research purposes, including up to 7 sections or pieces from each organ and each region of the 
spinal cord.  Upon collection, these tissue samples will be provided to AveXis for analysis.  
Tissue analysis will be done to determine whether the vector transduced the expected motor 
neurons and if the SMN gene was expressed.  These results will demonstrate whether the vector 
delivered the therapeutic gene as expected.  Tissue samples collected will also be available for 
histology and immunohistochemistry, allowing the state of the motor neurons and muscles to be 
examined. 
Specifically, tissue samples from the spinal cord, muscles, and organs will be collected as 
indicated in Table 8.  Tissue samples will be frozen or fixed (e.g., 2% paraformaldehyde) for 
appropriate analysis. 
Families will be asked to consent to the autopsy and authorize tissue collection prior to any sign 
of moribund or death by the clinical team conducting the study.  There are distinct forms for the 
formal autopsy and for the research tissue collection.  This will allow families the flexibility to 
participate in one or both of the research activities.  Declining an autopsy will not prevent 
patients from participating in the study. 
Table 8: Tissue Sample for Analysis 
Brain 
Spinal Cord 
Muscles 
Organs 
Motor cortex 
Cervical spinal cord 
Diaphragm 
Spleen 
Layer 5 motor cortex 
Thoracic spinal cord 
#6/#7 Rib with intercostal 
muscle and nerve 
Kidney 
Brain stem 
Lumbar spinal cord 
Psoas muscle 
Small intestine 
 
Sacral spinal cord 
 
Large intestine 
 
Dorsal root 
 
Pancreas 
 
Cervical level 
 
Stomach 
 
Ventral root 
 
Lung 
 
Cervical level 
 
Heart 
 
DRG root 
 
Liver 
 
Cervical level 
 
Inguinal lymph node 
 
Cerebrospinal fluid 
 
Gonads 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 74 of 143 
APPENDIX 2. 
BAYLEY SCALES OF INFANT AND TODDLER 
DEVELOPMENT (VERSION 3) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 75 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 76 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 77 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 78 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 79 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 80 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 81 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 82 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 83 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 84 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 85 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 86 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 87 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 88 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 89 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 90 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 91 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 92 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 93 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 94 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 95 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 96 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 97 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 98 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 99 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 100 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 101 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 102 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 103 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 104 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 105 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 106 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 107 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 108 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 109 of 143 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 110 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 111 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 112 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 113 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 114 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 115 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 116 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 117 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 119 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 120 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 121 of 143 
APPENDIX 3. 
PERFORMANCE CRITERIA FOR BAYLEY SCALES OF 
INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) DEVELOPMENTAL MILESTONES 
Developmental Milestone 
Head Control – Gross Motor Subtest 
Item #4  
Rolls from Back to Sides – Gross 
Motor Subtest Item #20 
Sits Without Support – Gross Motor 
Subtest Item #26 
Stands With Assistance - Gross Motor 
Subtest Item #33 
Crawls – Gross Motor Subtest 
Item #34 
Pulls to Stand – Gross Motor Subtest 
Item #35 
Walks With Assistance – Gross Motor 
Subtest Item #37 
Stands Alone – Gross Motor Subtest 
Item #40 
Walks Alone – Gross Motor Subtest 
Item #43 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 122 of 143 
APPENDIX 4. 
CHOP-INTEND 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 123 of 143 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 124 of 143 
APPENDIX 5. 
SCHEDULE OF ASSESSMENTS 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Prophylactic Prednisolone 
 
Xq 
X 
X 
X 
X 
X 
X 
Xq 
 
 
AVXS-101 Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Bayley Scales/ Developmental 
Milestonesd (with video)e 
X 
 
 
 
 
 
 
 
Xf 
Xf 
X 
CHOP-INTENDg (with video)e 
X 
Xs 
 
 
 
X 
X 
X 
X 
X 
X 
CMAP 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Demographic/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsh/Weight & Length 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
 
 
 
 
Xj 
X 
12-Lead Holter Monitoringk 
 
X 
X 
X 
X 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Pulmonary Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Photograph of Infusion Site 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology/Chemistry/ 
Urinalysis 
X 
Xo 
 
X 
 
X 
X 
X 
X 
X 
X 
CK-MB 
X 
 
 
 
 
X 
 
 
X 
Xr 
X 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
Capillary Blood Gas 
 
X 
 
X 
 
 
 
 
 
 
 
ELISA anti-AAV9/SMN Ab 
X 
 
 
 
 
X 
X 
X 
Xl 
 
 
Immunology Testing 
(ELISpot) 
 
 
 
 
 
X 
 
 
Xl 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 125 of 143 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Anti-AAV9 Ab Screen in 
Mother 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Diagnostic 
Confirmation Testing 
X 
 
 
 
 
 
 
 
 
 
 
Saliva, Urine, and Stool 
Samples (for viral shedding)p 
X 
 
 
Xm Xm 
X 
X 
X 
X 
 
 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
Collected from 2 weeks before gene replacement therapy until End of Study visit 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; 
CMAP = compound motor action potential; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; 
ELISpot = Enzyme-linked ImmunoSpot; ET = early termination; WHO = World Health Organization 
a The End of Study visit must occur within 0 to 14 days after the date on which the patient reaches 18 months of age (or ET). 
b Day 1 assessments will be performed prior to the start of gene replacement therapy infusion. 
c The 14 months of age visit must occur within 0 to 14 days after the date on which the patient reaches 14 months of age. 
d Developmental milestones will be assessed as defined by Bayley Scales of Infant and Toddler Development, version 3 
(independent sitting will be assessed also by WHO Multicentre Growth Reference Study). 
e Videos may be submitted for review by a central reader. 
f The full Bayley test will be administered every 6 months, starting at Month 6, whereas the Bayley fine and gross motor 
subtests will be administered at each monthly visit. 
g Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not continue CHOP-INTEND assessments.  
h Vital signs include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry 
i Vital signs will be continuously monitored throughout the infusion of gene replacement therapy and recorded every 
15 minutes for the first 4 hours (+/- 5 minutes) after the start of infusion, then every hour (+/- 15 minutes) until 24 hours after 
the start of infusion.  Axillary temperature will be recorded pre- and post-infusion. 
j Completed every 6 months, starting at Month 6. 
k Serial ECG data will be pulled in triplicate from the Holter monitor at the following time points: pre-dose (within 24h), 2h, 
4h, 6h, 8h, 12h, 24h, 36h, and 48h post-dose. 
l Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to be elevated, based on 
further discussion with the Principal Investigator and Medical Monitor. 
m Collected at 24 and 48 hours post-dose. 
n Serious adverse events are collected from signing of the informed consent through the last study visit.  All adverse events that 
occur from the start of gene replacement therapy through the last study visit are collected. 
o Laboratory samples collected on Day -1 to be processed locally, prior to dosing. 
p Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces at 24 and 48 
hours.  All other sites will collect singular urine and feces samples within 24 hours and 48 hours of dosing. 
q Prednisolone to be given 24 hours prior to scheduled AVXS-101 dosing, and continued as per protocol Section 9.2.1. 
r CK-MB to be performed at Day 60, and Month 6, 9, 12, 15 months of age, 18 months of age/EOT). 
s If a Day -1 CHOP-INTEND assessment is not completed, a CHOP-INTEND assessment should be completed on Day 1 prior 
to dose administration. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 126 of 143 
APPENDIX 6. 
COMPOUND MOTOR ACTION POTENTIAL MANUAL 
 
 
 
 
 
Phase 3 Gene Transfer Clinical Study for Spinal Muscular Atrophy Type 1  
Delivering AVXS-101 
 
 
 
 
 
CMAP Manual 
Compound Motor Action Potential (CMAP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 127 of 143 
Materials Needed for the Process 
• Carefusion Disposable Ring Electrode with Leads (order number 019‐439300)  
(4 per visit) 
• Carefusion Tab Electrodes 1.0 meter leads (order number 019‐406600) (1 or 2 per visit) 
• CMAP case report form 
• Infrared temperature probe 
• Electrode gel 
• Warming packs or some other warming source 
• Transpore adhesive tape 
• Alcohol skin prep pads 
• EMG machine 
 
Temperature and Warming 
As only the peroneal motor study will be performed, only lower extremity temperatures will 
need to be assessed.  The temperature should be measured on the surface of the anterior calf 
distal to the recording electrodes and proximal to the ankle.  As the protocol only refers to 
measurement of upper extremity temperatures, by convention a temperature threshold that is 2 
degrees lower, i.e., ≥ 31 degrees Centigrade, should be sufficient. When the temperature is 
measured to be below 31 degrees, a warming procedure should be performed, either with heated 
towels or other authorized devices.  Care must be taken not to apply towels or other devices at 
temperatures that would put the infants at risk of burns, the examiner must test the temperature 
of the warming device against his/her own skin and/or the skin of a parent prior to application.  
As a general rule, the warming device should feel lukewarm, not hot, against an adult’s skin, and 
it should be expected that the warming procedure will take 3−5 minutes.  Scheduling of this 
procedure should allow for both temperature recording and warming procedures. 
Preparation of Skin 
The skin should be cleaned with alcohol (or equivalent) as needed to improve contact with the 
electrodes. 
EMG machine settings 
For the peroneal CMAP measures the filter settings should be 10 Hz to 10 kHz. 
Tibialis Anterior (TA) CMAP Electrode Placement 
For the TA CMAP, the G1 electrode should be placed below the fibular head on the bulk of the 
Tibialis Anterior (TA) muscle belly.  The G2 reference electrode should be placed over the 
tendon above the ankle in a standard “belly-tendon” arrangement.  An adhesive ground electrode 
(Carefusion Tab Electrodes 1.0 meter leads (DIN Style) order number 019‐406600) is placed 
between the stimulating electrodes and the G1 electrode.  Adhesive tape may be used to secure 
any loose electrodes in place. Adhesive tape should not touch other electrodes or other pieces of 
adhesive tape. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 128 of 143 
Supramaximal Nerve Stimulation for TA CMAP 
The stimulator should be a pediatric sized bipolar probe.  The stimulation site should be at or 
proximal to the fibular head.  A maximal response should be obtained (CMAP), using a stimulus 
120% of that producing the maximal response and a stimulus duration of 0.2 msec.  Maximum 
CMAP amplitude and area should be recorded on the Source Document and a printout of the 
CMAP tracing made.  Area is measured only for the initial negative peak.  Subsequent negative 
peaks are not included. 
Alternate G1 Electrode Placements and Repetition of Motor Study 
As the motor point of the tibialis anterior does not have precise landmarks, there is a possibility 
that the G1 electrode will not be placed exactly over the motor point without testing multiple 
sites.  Thus, as tolerated by the patient, the CMAP should be recorded at least three times, with a 
different placement of the G1 electrode each time.  The CMAP with the highest amplitude 
among the trials should be reported. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 129 of 143 
APPENDIX 7. 
DECLARATION OF HELSINKI: ETHICAL 
PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving Human subjects, including research on identifiable 
human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians.  The 
WMA encourages others who are involved in medical research involving Human subjects to adopt 
these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research.  The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving Human subjects. 
6. The primary purpose of medical research involving Human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments).  Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all Human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research patients. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
patients.  The responsibility for the protection of research patients must always rest with the physician 
or other health care professionals and never with the research patients, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
Human subjects in their own countries as well as applicable international norms and standards.  No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research patients set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the environment. 
12. Medical research involving Human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications.  Research on patients or 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 130 of 143 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research patients. 
15. Appropriate compensation and treatment for patients who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving Human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research patients. 
17. All medical research involving Human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving Human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group.  In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving Human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation.  The welfare of animals used for 
research must be respected. 
22. The design and performance of each research study involving Human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed.  The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
patients and information regarding provisions for treating and/or compensating patients who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins.  This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 131 of 143 
must be duly qualified.  It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
patients set forth in this Declaration. 
The committee must have the right to monitor ongoing studies.  The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events.  
No amendment to the protocol may be made without consideration and approval by the committee.  
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research patients and the confidentiality of 
their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as patients in medical research must 
be voluntary.  Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving Human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study.  The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal.  Special attention should be given to the 
specific information needs of individual potential patients as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing.  If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
All medical research patients should be given the option of being informed about the general outcome 
and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress.  In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorized representative.  These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative.  The potential subject’s dissent should be 
respected. 
30. Research involving patients who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group.  In such circumstances the 
physician must seek informed consent from the legally authorized representative.  If no such 
representative is available and if the research cannot be delayed, the study may proceed without 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 132 of 143 
informed consent provided that the specific reasons for involving patients with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee.  Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research.  
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse.  There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research.  In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or where 
for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  Extreme care must be 
taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all patients who still need an intervention identified as beneficial in 
the trial.  This information must also be disclosed to patients during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving Human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research.  Researchers have a duty to make publicly 
available the results of their research on Human subjects and are accountable for the completeness 
and accuracy of their reports.  All parties should adhere to accepted guidelines for ethical reporting.  
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available.  Sources of funding, institutional affiliations and conflicts of interest must be declared in 
the publication.  Reports of research not in accordance with the principles of this Declaration should 
not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering.  
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy.  In all cases, new information must be recorded and, where appropriate, made publicly 
available. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 133 of 143 
APPENDIX 8. 
SUMMARY OF CHANGES 
The section below highlights content changes represented in this version of the protocol.  
Language deleted from Protocol version 2.0 appears in red strike through.  Language added to 
Protocol version 3.0 appears in bold. 
The Amendment 2 version of the protocol (Protocol version 3.0) is updated to clarify the 
datapoints which require review for the first three patients prior to continuing with enrollment.  
Additionally, a Day -1 CHOP-INTEND assessment is added and minor clarifications and 
corrections were included. 
Section 2 
Synopsis 
The synopsis was updated to reflect changes throughout the document. 
Section 7.1 
Overall Study Design 
There will be at least a 4 -week dosing interval between dosing of the first three patients to allow 
review of the safety analysis from six time points (days 1, 2, 7, 14, 21, and 30 visits) as well as 
early signals of efficacy including CHOP-INTEND score prior to dosing of the next patient. 
The first three patients enrolled must meet the criteria for the Intent-to-Treat (ITT) Population.  
AveXis will compare the CHOP-INTEND one month improvement for the AVXS-101-CL-303 
patients that meet the ITT criteria to assess the clinical response to the dose 1.1 x 1014 vg/kg as 
being what was expected from the Cohort 2 patients in the Phase 1 trial (AVXS-101-CL-101).  
This comparison will be performed as a per patient assessment for the first three patients.  The 
individual patients who receive their gene therapy at 0-3 months of age will be compared to a 
value of 10 CI points, while patients who receive their gene therapy at >3 but <6 months of age 
will be compared to a value of 5 CI points.  Furthermore, patients from either age group are 
expected to maintain the improvement in the absence of an acute illness or perioperatively.  If 
the expected CI improvements are observed for the first three ITT patients, AveXis will remove 
the 30 day 4-week interval between patients and proceed to dose at least 12 additional patients 
that meet the ITT criteria and perform safety and efficacy assessments as described elsewhere in 
the clinical protocol (AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  If the 
expected CI improvements are not observed for the first three ITT patients, AveXis will discuss 
next steps with the FDA before continuing study enrollment. 
Rationale for Change 
Language was updated to clarify the datapoints that will be required for the first three patients, 
prior to continuing with enrollment. 
Section 8.2 
Patient Exclusion Criteria 
Exclusion #19: 
Gestational age at birth < 35 weeks (<245 days) 
Rationale for Change 
The use in premature infants may have additional, unknown risks and are excluded. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 134 of 143 
Section 8.3 
Patient Withdrawal Criteria 
Patients may be discontinued from the study for the following reasons: 
•
Death
− An autopsy will be requested for any patient who expires following participation in a
gene replacement study as per the National Institutes of Health’s Guidelines for Research 
Involving Recombinant or Synthetic Nucleic Acid Molecules [25] (see Autopsy Plan in 
Appendix 1) 
Rationale for Change 
The NIH Guidelines revised in 2016 no longer include language requiring autopsies for patients 
participating in gene therapy trials; however AveXis will continue to request autopsies/port-
mortem tissue collection where applicable and allowed. 
Section 9.2.1 Prophylactic Administration of Prednisolone 
In an attempt to dampen the host immune response to the AAV based- therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion.  After 30 days of treatment, the 
dose of prednisolone can be tapered for patients whose ALT values, AST values, and T-cell 
response are below the threshold ≤ 2 X ULN for ALT and AST, and < 100 SFC/106 PBMCs in 
accordance with the following treatment guideline: 
•
Until at least 30 days post-infusion: 1 mg/kg/day
•
Weeks 5 and 6: 0.5 mg/kg/day
•
Weeks 7 and 8: 0.25 mg/kg/dayWeek 9: prednisolone discontinued
Rationale for Change
Removal of ambiguous language.
Section 11.1 
Developmental Milestones 
During the Screening visit, the physical therapist will complete an assessment of baseline 
milestone achievement in accordance with Appendix 5; this assessment must address all 
milestones/items noted on Appendix 5 that are at or below the child’s expected baseline 
function for age, and be recorded on video.  The findings must be documented in the source.  
Items that are below the expected function for age baseline level of assessment that are not 
successfully achieved during the baseline evaluation should be repeated at subsequent visits until 
successfully performed. 
Rationale for Change 
Language updated to clarify the expectations for baseline assessment of motor milestone 
achievements during the Screening visit. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 135 of 143 
Section 11.2.2 
CHOP-INTEND 
The CHOP-INTEND will be performed at screening, Day -1, and at each scheduled visit from 
Day 7 through the End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 5).  If Day -1 CHOP-INTEND assessment cannot be conducted, a CHOP-
INTEND assessment must be completed on Day 1 prior to dose administration. 
Rationale for Change 
A Day -1 CHOP-INTEND assessment has been added to ensure the lowest score for patient’s 
motor function is documented prior to treatment, which will serve as the baseline value.  If a Day 
-1 and Day 1 CHOP-INTEND score are not or cannot be conducted, the Screening visit CHOP-
INTEND score will be considered the baseline value.
Section 12.1.1 
Demographic/Medical History 
Demographic/medical history information will be collected at screening and captured in the 
eCRF.  Information that will be collected includes: 
•
Familial history of SMA including affected siblings or parent carriers
•
Gestational age at birth
•
Length/weight height/head circumference at birth
•
Hospitalization information from time of birth including number, duration, and reason for
hospitalizations including International Statistical Classification of Diseases and Related
Health Problems (ICD-10 codes), if available
•
Historical ventilatory support, if any
Reason for Change
Correction to typographical error.
Section 12.1.10.2 
Blood Chemistry 
Creatine kinase (CK-MB) will be collected at Screening, Day 7, Day 30, Day 60, and every 90 
days Month 6, 9, 12, 15 months of age, and at 18 months of age/End of Study. 
Reason for Change 
Clarification for the CK-MD sample collection schedule. 
Section 13.2 
Relationship to Study Product 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related, Probably Related, or 
Definitely Related).  The Investigator should decide whether, in his or her medical judgment, 
there is a reasonable possibility that the event may have been caused by the investigational 
product.  If no valid reason exists for suggesting a relationship, then the AE should be classified 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 136 of 143 
cause-and-effect relationship between the investigational product and the occurrence of the AE, 
then the AE should be considered “related.” 
Reason for Change 
Template language updated to align with Section 13.1.1.1. 
Section 14.1.2.2 
Efficacy Completers Population 
The efficacy completers analysis population will consist of: 
•
All treated patients who reach 14 months of age for the survival endpoint or 18 months
of age for the endpoint of achievement of functional independent sitting, OR
•
All treated patients who reach 14 months of age, OR
All treated patients who meet discontinuation criteria, discontinue the study due to an AE or
experience death.
Reason for Change 
Updated to align with the analysis plan, in accord with the formal Statistical Analysis Plan 
(SAP). 
Section 14.4 
CHOP-INTEND Comparison 
A comparison will be performed of the first three patients CHOP-INTEND scores to the AVXS-
101-CL-101 CHOP-INTEND scores.  The first three patients enrolled must meet the criteria for
the Intent-to-Treat (ITT) Population.  AveXis will compare the CHOP-INTEND one month
improvement for the AVXS-101-CL-303 patients that meet the ITT criteria to assess the clinical
response to the dose 1.1 x 1014 vg/kg as being what was expected from the Cohort 2 patients in
the Phase 1 trial (AVXS-101-CL-101).  This comparison will be performed as a per patient
assessment for the first three patients.  The individual patients who receive their gene therapy at
0-3 months of age will be compared to a value of 10 CI points, while patients who receive their
gene therapy at >3 but <6 months of age will be compared to a value of 5 CI points.
Furthermore, patients from either age group are expected to maintain the improvement in the
absence of an acute illness or perioperatively.  If the expected CI improvements are observed for
the first three ITT patients, AveXis will remove the 4-week 30 day interval between patients and
proceed to dose at least 12 additional patients that meet the ITT criteria and perform safety and
efficacy assessments as described elsewhere in the clinical protocol (AVXS-101-CL-303) and
corresponding Statistical Analysis Plan.  If the expected CI improvements are not observed for
the first three ITT patients, AveXis will discuss next steps with the FDA before continuing study
enrollment.
Reason for Change 
Providing clarity that patient data will be reviewed/considered after four weeks, not specifically 
at Day 30. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 137 of 143 
Section 21 
List of References 
Reference 25 was removed, as the NIH Guidelines are no longer cited as a reference in Section 
8.3. 
Appendix 5 
Schedule of Assessments 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2
-1
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months 
of Age 
(or ET) 
Window 
± 2 days 
± 7 days 
(0–14 days at 
14 Months 
of Age) 
0–14 days 
Informed Consent 
X 
Prophylactic Prednisolone 
Xq 
X 
X 
X 
X 
X 
X 
Xq 
AVXS-101 Infusion 
X 
Bayley Scales/ Developmental 
Milestonesd (with video)e 
X 
Xf 
Xf 
X 
CHOP-INTENDg (with video)e 
X 
Xs 
X 
X 
X 
X 
X 
X 
CMAP 
X 
Xj 
X 
Demographic/Medical History 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsh/Weight & Length 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG
X 
X 
X 
X 
Xj 
X 
12-Lead Holter Monitoringk
X 
X 
X 
X 
Echocardiogram 
X 
Xj 
X 
Pulmonary Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Test 
X 
Xj 
X 
Photograph of Infusion Site 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry/ 
Urinalysis 
X 
Xo 
X 
X 
X 
X 
X 
X 
X 
CK-MB 
X 
X 
X 
Xr 
X 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 138 of 143 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2
-1
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months 
of Age 
(or ET) 
Window 
± 2 days 
± 7 days 
(0–14 days at 
14 Months 
of Age) 
0–14 days 
Virus Serology 
X 
Capillary Blood Gas 
X 
X 
ELISA anti-AAV9/SMN Ab 
X 
X 
X 
X 
Xl 
Immunology Testing 
(ELISpot)
X 
Xl 
Anti-AAV9 Ab Screen in 
Mother 
X 
Blood for Diagnostic 
Confirmation Testing 
X 
Saliva, Urine, and Stool 
Samples (for viral shedding)p 
X 
Xm Xm 
X 
X 
X 
X 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
Collected from 2 weeks before gene replacement therapy until End of Study 
visit 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; 
CMAP = compound motor action potential; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; 
ELISpot = Enzyme-linked ImmunoSpot; ET = early termination; WHO = World Health Organization 
a The End of Study visit must occur within 0 to 14 days after the date on which the patient reaches 18 months of age (or ET). 
b Day 1 assessments will be performed prior to the start of gene replacement therapy infusion. 
c The 14 months of age visit must occur within 0 to 14 days after the date on which the patient reaches 14 months of age. 
d Developmental milestones will be assessed as defined by Bayley Scales of Infant and Toddler Development, version 3 
(independent sitting will be assessed also by WHO Multicentre Growth Reference Study). 
e Videos may be submitted for review by a central reader. 
f The full Bayley test will be administered every 6 months, starting at Month 6, whereas the Bayley fine and gross motor 
subtests will be administered at each monthly visit.   
g Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not continue CHOP-INTEND assessments.  
h Vital signs include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry 
i Vital signs will be continuously monitored throughout the infusion of gene replacement therapy and recorded every 
15 minutes for the first 4 hours (+/- 5 minutes) after the start of infusion, then every hour (+/- 15 minutes) until 24 hours after 
the start of infusion.  Axillary temperature will be recorded pre- and post-infusion. 
j Completed every 6 months, starting at Month 6. 
k Serial ECG data will be pulled in triplicate from the Holter monitor at the following time points: pre-dose (within 24h), 2h, 
4h, 6h, 8h, 12h, 24h, 36h, and 48h post-dose. 
l Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to be elevated, based on 
further discussion with the Principal Investigator and Medical Monitor. 
m Collected at 24 and 48 hours post-dose. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 139 of 143 
n Serious adverse events are collected from signing of the informed consent through the last study visit.  All adverse events that 
occur from the start of gene replacement therapy through the last study visit are collected. 
o Laboratory samples collected on Day -1 to be processed locally, prior to dosing.
p Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces at 24 and 48
hours.  All other sites will collect singular urine and feces samples within 24 hours and 48 hours of dosing. 
q Prednisolone to be given 24 hours prior to scheduled AVXS-101 dosing, and continued as per protocol Section 9.2.1. 
r CK-MB to be performed at Day 60, and every 90 days (Month 6, 9, 12 months of age, 15 months of age, 18 months of 
age/EOT). 
s  If a Day -1 CHOP-INTEND assessment is not completed, a CHOP-INTEND assessment should be completed on Day 1 
prior to dose administration. 
Rationale for Change 
CHOP-INTEND assessment was added at Day -1 to ensure the lowest functional ability of the 
patient is captured prior to treatment, to serve as the baseline value. 
Appendix 1 
Autopsy Plan 
An autopsy will be requested for any patient who receives gene replacement therapy and expires 
as per the National Institutes of Health Guidelines for Research Involving Recombinant or 
Synthetic Nucleic Acid Molecules [25].  The autopsy and tissue collection will be performed by 
a contracted vendor who will deploy a pathology assistant to the funeral home of the deceased to 
perform the autopsy and tissue collection.  Standard autopsy incisions will be used to perform the 
autopsy and pathology necessary to determine the cause of death. 
Rationale for Change 
The NIH Guidelines revised in 2016 no longer include language requiring autopsies for patients 
participating in gene therapy trials; however AveXis will continue to request autopsies/port-
mortem tissue collection where applicable and allowed. 
Appendix 2 
BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 140 of 143 
Rationale for Change 
Page 21 of the Bayley was accidentally omitted from the original protocol 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 141 of 143 
Appendix 6 
Compound Motor Action Potential Manual 
EMG machine settings 
For both the ulnar and peroneal CMAP measures the filter settings should be 10 Hz to 10 kHz. 
Rationale for Change 
Removed references to ulnar CMAP from the standard manual, to alleviation confusion as only 
peroneal CMAP is required per protocol. 
Temperature and Warming 
As only the peroneal motor study will be performed, only lower extremity temperatures 
will need to be assessed.  The temperature should be measured on the surface of the 
anterior calf distal to the recording electrodes and proximal to the ankle.  As the protocol 
only refers to measurement of upper extremity temperatures, by convention a temperature 
threshold that is 2 degrees lower, i.e., ≥ 31 degrees Centigrade, should be sufficient.  When 
the temperature is measured to be below 31 degrees, a warming procedure should be 
performed, either with heated towels or other authorized devices.  Care must be taken not 
to apply towels or other devices at temperatures that would put the infants at risk of burns, 
the examiner must test the temperature of the warming device against his/her own skin 
and/or the skin of a parent prior to application.  As a general rule, the warming device 
should feel lukewarm, not hot, against an adult’s skin, and it should be expected that the 
warming procedure will take 3-5 minutes.  Scheduling of this procedure should allow for 
both temperature recording and warming procedures. 
Assessment of Normal Limb Temperature 
Since temperature can affect maximum CMAP amplitude, temperature > 33 degrees centigrade 
should be noted prior to preparation of skin for electrode placement.  Temperature should be 
measured using a surface probe on the lateral aspect of the hand just proximal to the fifth digit.  If 
temperature is ≤ 33 degrees centigrade, a warming pack or other warming mechanism should be 
used to warm the hand to > 33 degrees centigrade prior to collecting data.  Limb temperature does 
not need to be reassessed during the procedure. 
Rationale for Change 
As only peroneal CMAP will be performed, minor updates made to the CMAP recording 
procedures. 
Tibialis Anterior (TA) CMAP Electrode Placement 
For the TA CMAP, the G1 electrode should be placed below the fibular head on the bulk of 
the Tibialis Anterior (TA) muscle belly.  The G2 reference electrode should be placed over 
the tendon above the ankle in a standard “belly-tendon” arrangement.  An adhesive 
ground electrode (Carefusion Tab Electrodes 1.0 meter leads (DIN Style) order number 
019‐406600) is placed between the stimulating electrodes and the G1 electrode , or at the 
patella.  Adhesive tape may be used to secure any loose electrodes in place. Adhesive tape 
should not touch other electrodes or other pieces of adhesive tape. 
For the TA CMAP, the G1 electrode should be placed below the fibular head on the bulk of the 
Tibialis Anterior (TA) muscle belly.  The G2 reference electrode should be placed on the patella.  

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 142 of 143 
An adhesive ground electrode (Carefusion Tab Electrodes 1.0 meter leads (DIN Style) order 
number 019‐406600) is placed between the stimulating electrodes and the G1 electrode.  Tape 
should be placed over the electrodes to ensure they stay affixed during the procedure. 
Rationale for Change 
As only peroneal CMAP will be performed, minor updates made to the CMAP recording 
procedures. 
Abductor Digiti Minimi (ADM) CMAP Electrode Placement 
Electrodes used for recording will be Carefusion Disposable Ring Electrode with Leads (order 
number 019‐439300).  For ADM CMAP, these have a longitudinal contact area of up to 106 mm, 
but should be cut so that they cover the body of the ADM, with position orthogonal to muscle 
fiber orientation.  The distance between the ulnar aspect of the pisaform bone (P) and the ulnar 
aspect of the fifth metacarpophalangeal joint (MP‐5) should be measured.  The G1 electrode 
should be placed distal to P, 1/3 of the distance between P and MP‐5, as defined above.  The G2 
reference electrode should be placed on the ulnar aspect of the MP‐5 joint.  See figure below for 
landmarks: 
 
Modified figure from “Anatomic Guide for the Electromyographer” Charles C. Thomas, 
Publisher, 1980, p4. 
Supramaximal nerve stimulation for CMAP 
The stimulator should be a pediatric sized bipolar probe.  The stimulation site should be at the 
distal forearm just proximal to the wrist.  A maximal response should be obtained (CMAP), using a 
stimulus 120% of that producing the maximal response and a stimulus duration of 0.2 msec.  
CMAP maximum amplitude and area should be recorded on the Source Document and a printout 
of the CMAP tracing made.  Area is measured only for the initial negative peak.  Subsequent 
negative peaks are not included. 
Rationale for Change 
As only peroneal CMAP will be performed, minor updates made to the CMAP recording 
procedures. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v3.0 / 21 Dec 2017 
Confidential | Proprietary 
Page 143 of 143 
Alternate G1 electrode placements and repetition of motor study. 
As the motor point of the tibialis anterior does not have precise landmarks, there is a 
possibility that the G1 electrode will not be placed exactly over the motor point without 
testing multiple sites.  Thus, as tolerated by the patient, the CMAP should be recorded at 
least three times, with a different placement of the G1 electrode each time.  The CMAP 
with the highest amplitude among the trials should be reported. 
Rationale for Change 
As only peroneal CMAP will be performed, minor updates made to the CMAP recording 
procedures. 

 
1. 
TITLE PAGE 
AVXS-101 
AVXS-101-CL-303 
IND Number: 
15699 
 
 
Protocol Title: 
Phase 3, Open-Label, Single-Arm, Single-Dose Gene 
Replacement Therapy Clinical Trial for Patients with Spinal 
Muscular Atrophy Type 1 with One or Two SMN2 Copies 
Delivering AVXS-101 by Intravenous Infusion 
Indication Studied: 
Spinal Muscular Atrophy Type 1 
Sponsor Address: 
AveXis, Inc. 
2275 Half Day Road 
Bannockburn, IL 60015 
Protocol Version/Date: 
2.0 / 15 October 2017 
The study will be completed according to the guidelines of Good Clinical Practice.  Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki. 
 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or confidential and 
may not be disclosed unless such disclosure is required by federal or state law or regulations.  In any event, persons 
to whom the information is disclosed must be informed that the information is privileged or confidential and may 
not be further disclosed by them.  These restrictions on disclosure will apply equally to all future information 
supplied to you which is indicated as privileged or confidential. 

$YH;LV,QF
$9;6&/
,QYHVWLJDWLRQDO3URGXFW$9;6
3URWRFROY2FW


$'0,1,675$7,9(,1)250$7,21

$SSURYDO
5(35(6(17$7,9(6)520$YH;LV
7KLVWULDOZLOOEHFRQGXFWHGZLWKWKHKLJKHVWUHVSHFWIRUWKHLQGLYLGXDOSDUWLFLSDQWVLQDFFRUGDQFH
ZLWKWKHUHTXLUHPHQWVRIWKLVFOLQLFDOWULDOSURWRFRODQGDOVRLQDFFRUGDQFHZLWKWKHIROORZLQJ
•
7KHHWKLFDOSULQFLSOHVWKDWKDYHWKHLURULJLQLQWKH'HFODUDWLRQRI+HOVLQNL
•
,QWHUQDWLRQDO&RXQFLOIRU+DUPRQL]DWLRQDQGWKH+DUPRQL]HG7ULSDUWLWH*XLGHOLQHIRU*RRG
&OLQLFDO3UDFWLFH(
•
$OODSSOLFDEOHODZVDQGUHJXODWLRQVLQFOXGLQJZLWKRXWOLPLWDWLRQGDWDSULYDF\ODZVDQG
UHJXODWLRQV
6,*1$785(6PD\EHDSSOLHGHOHFWURQLFDOO\DQGZLOOWKHUHIRUHEHPDLQWDLQHGLQWKH
HOHFWURQLFV\VWHP



9LFH3UHVLGHQW&OLQLFDO'HYHORSPHQW
$YH;LV,QF

'DWHGG0PP\\\\



&KLHI0HGLFDO2IILFHU
$YH;LV,QF

'DWHGG0PP\\\\



6HQLRU9LFH3UHVLGHQW&KLHI5HJXODWRU\DQG4XDOLW\2IILFHU
$YH;LV,QF

'DWHGG0PP\\\\



6U'LUHFWRU+HDGRI&OLQLFDO2SHUDWLRQV
$YH;LV,QF

'DWHGG0PP\\\\



6U'LUHFWRU+HDGRI%LRVWDWLVWLFV
$YH;LV,QF

'DWHGG0PP\\\\

'RFX6LJQ(QYHORSH,')'%'('&%%$)%)






AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 3 of 142 
1.2. 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for AVXS-101.  I have read the AVXS-101-
CL-303 protocol and agree to conduct the study in accordance with the relevant current 
protocol(s).  I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.  I agree to personally conduct or supervise the investigation(s).  I 
also agree to promptly report to the Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others.  Additionally, I will not make any changes in the research 
without IRB/IEC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects.  I agree to protect the safety, rights, privacy, and well-being of study 
participants.  I agree to comply with: 
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations including but not limited to Informed Consent 21 CFR Part 56, Institutional 
Review Board Review in 21 CRF Part 56, Adverse Event Reporting as defined in 
Section 13.4 and in 21 CFR 312.64, Adequate/accurate and accessible records in accordance 
with 21CFR 312.62 and 312.68. 
• Terms outlined in the study site agreement 
• Responsibilities of the Investigator (per regulatory guidelines and applicable regulations) I 
further authorize that my personal information may be processed and transferred in 
accordance with the uses contemplated in this protocol. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator or 
Consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.  Your acceptance of this document constitutes agreement 
that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 
 _________________________________________________ 
Printed Name of Investigator 
 _________________________________________________ 
Signature of Investigator 
 _________________________________________________ 
Date (ddMmmyyyy) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 4 of 142 
1.3. 
Contact Information 
Table 1: 
Important Study Contact Information 
Role in Study 
Name/Address and Telephone Number 
Clinical Study Leader 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Responsible Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Drug Safety Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Serious Adverse Event 
Reporting 
Please see Project Management Plan in TMF or Study Contact list 
in ISF 
24-Hour Emergency Contact 
Please see Study Contact List in ISF 
 
Table 2: 
Study Vendor Listing 
Role in Study 
Name/Address 
Clinical Research 
Organization 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Investigational Product 
Shipment 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Video 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Independent Video Review 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Holter Monitor and  
12-lead Electrocardiogram 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
immunoassays 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
viral shedding studies 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Autopsy 
Please see Project Management Plan in TMF or Study Contact list in ISF 
ISF = Investigator site file; TMF = trial master file 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 5 of 142 
2. 
SYNOPSIS 
Name of Sponsor/Company: AveXis, Inc. 
Name of Investigational Product: AVXS-101 
Name of Active Ingredient: Survival Motor Neuron Gene by Self-Complementary Adeno-Associated 
Virus Serotype 9 (AAV9) 
Title of Study: Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical 
Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering 
AVXS-101 by Intravenous Infusion 
Study Center(s): 10 to 20 United States (US) Investigators 
Studied Period (years): 
Estimated date first patient enrolled: 2Q 2017 
Estimated date last patient completed: 4Q 2019 
Phase of Development: 3 
Objectives: 
Co-Primary 
• 
Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of 
functional independent sitting for at least 30 seconds at the 18 months of age study visit. 
• 
Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is defined by 
the avoidance of combined endpoint of either (a) death or (b) permanent ventilation, which is 
defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via 
non-invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible 
illness, excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
Co-Secondary 
• 
Determine effect of AVXS-101 on the ability to thrive defined as achieving all of the following at 
18 months of age: 
o Does not receive nutrition through mechanical support (e.g., feeding tube) or other non-oral 
method 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• 
Determine the effect of AVXS-101 on the ability to remain independent of ventilatory support, 
defined as requiring no daily ventilator support/usage at 18 months of age 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 6 of 142 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• 
Determine the safety of AVXS-101 based on the development of unacceptable toxicity defined as 
the occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 
higher, unanticipated, treatment-related toxicity 
Methodology: 
Phase 3, open-label, single-arm, single-dose, study of AVXS-101 (gene replacement therapy) in up to 
twenty (20) patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria, may be 
either symptomatic or pre-symptomatic and are genetically defined by no functional survival motor 
neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 
months (< 180 days) of age at the time of gene replacement therapy (Day 1).  Enrolling up to twenty 
(20) patients under the broader enrollment criteria is projected to enable enrollment of at least fifteen 
(15) patients that meet the Intent-to-Treat Population (ITT) criteria.  The ITT population is identified as 
symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene 
modifier mutation (c.859G>C) who meet all other study enrollment criteria.  In addition, the first three 
patients enrolled must meet the criteria for the Intent-to-Treat Population to enable a comparison of 
CHOP-INTEND scores at one-month following gene replacement therapy to enable a comparison of 
patient response between AVXS-101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial 
(AVXS-101-CL-101). 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 7 of 142 
The study includes a screening period, a gene replacement therapy period, and a follow-up period.  
During the screening period (Days –30 to –2), patients whose parent(s)/legal guardian(s) provide 
informed consent will undergo screening procedures to determine eligibility for study enrollment.  
Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day –1 to 
Day 3).  On Day –1, patients will be admitted to the hospital for pre-treatment baseline procedures.  On 
Day 1, patients will receive a one-time intravenous (IV) infusion of AVXS-101, and will undergo 
in-patient safety monitoring over the next 48 hours.  Patients may be discharged 48 hours after the 
infusion, based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of 
Study at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 
assessments until the End of Study when the patient reaches 18 months of age.  After the End of Study 
visit, eligible patients will be asked to rollover into the long-term follow up study. 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, 
except for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
There will be at least a 4 -week dosing interval between dosing of the first three patients to allow review 
of the safety analysis from six time points (days 1, 2, 7, 14, 21, and 30) as well as early signals of 
efficacy including CHOP-INTEND score prior to dosing of the next patient.  The first three patients 
enrolled must meet the criteria for the Intent-to-Treat Population.  AveXis will compare the CHOP-
INTEND one month improvement for the AVXS-101-CL-303 patients that meet the ITT criteria to 
assess the clinical response to the dose 1.1 x 1014 vg/kg as being what was expected from the Cohort 2 
patients in the Phase 1 trial (AVXS-101-CL-101).  This comparison will be performed as a per patient 
assessment for the first three patients.  The individual patients who receive their gene therapy at 0-3 
months of age will be compared to a value of 10 CI points, while patients who receive their gene 
therapy at >3 but <6 months of age will be compared to a value of 5 CI points.  Furthermore, patients 
from either age group are expected to maintain the improvement in the absence of an acute illness or 
perioperatively.  If the expected CI improvements are observed for the first three ITT patients, AveXis 
will remove the 30-day interval between patients and proceed to dose at least 12 additional patients that 
meet the ITT criteria and perform safety and efficacy assessments as described elsewhere in the clinical 
protocol (AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  Study enrollment will stop 
as soon as practical following enrollment of the fifteenth patient that meets the ITT criteria.  If the 
expected CI improvements are not observed for the first three ITT patients, AveXis will discuss next 
steps with the FDA before continuing study enrollment. 
In an attempt to dampen the host immune response to the adeno-associated virus (AAV) derived 
therapy, all patients will receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 
24 hours prior to AVXS-101 infusion until at least 30 days post-infusion.  After 30 days of treatment, 
the dose of prednisolone can be tapered for patients whose alanine aminotransferase (ALT) values, 
aspartate aminotransferase (AST) values, and T-cell response are below the threshold of 2 X ULN for 
ALT and AST, and < 100 SFC/106 PBMCs in accordance with the following treatment guideline: 
1 mg/kg/day until at least 30 days post-infusion, 0.5 mg/kg/day at Weeks 5 and 6, 0.25 mg/kg/day at 
Weeks 7 and 8, and discontinued at Week 9. 
Efficacy will be assessed by achievement of the key developmental milestone of functional independent 
sitting for at least 30 seconds at the 18 months of age study visit and survival at 14 months of age.  The 
ability to thrive (as defined above) and the ability to remain independent of ventilatory support (as 
defined above) will also be assessed at 18 months of age.  Additional developmental milestones will be 
assessed using Bayley Scales of Infant and Toddler Development (Version 3).  Safety will be assessed 
through monitoring adverse events (AEs), concomitant medication usage, physical examinations, vital 
sign assessments, cardiac assessments, and laboratory evaluations.  A Data Safety Monitoring Board 
(DSMB) will review safety data on a quarterly basis, and will also convene within 48 hours should any 
patient experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or requires 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 8 of 142 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the DSMB 
will review the safety information and provide its recommendation.  The DSMB can recommend early 
termination of the study for safety reasons. 
Number of Patients (planned): Up to twenty (20) patients that meet the study enrollment criteria to 
enable at least fifteen (15) patients that meet ITT criteria.  Study enrollment will stop as soon as 
practical following enrollment of the fifteenth patient that meets the ITT criteria. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
1. 
Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or 
point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier 
mutation (c.859G>C))2.   
2.    The first three patients enrolled must meet the criteria for the Intent-To-Treat Population. 
3. 
Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
4. 
Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
5. 
Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab prophylaxis 
(also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also 
recommended in accordance with American Academy of Pediatrics (27) 
6. 
Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply 
with study procedures and visit schedule 
 
 
Exclusion Criteria: 
1. 
Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. 
Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without any 
supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does 
not decrease by ≥ 4 percentage points 
3. 
Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the 
screening period or requiring ventilatory support while awake over the 7 days prior to screening or 
at any point during the screening period prior to dosing 
4.  Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass the 
swallowing test will be allowed to enroll in the study 
5. 
Patients whose weight-for-age is below the third percentile based on World Health Organization 
(WHO) Child Growth Standards[26] 
6. 
Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for 
hepatitis B or C, or Zika virus) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 9 of 142 
7. 
Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 
2 weeks prior to screening 
8. 
Upper or lower respiratory infection requiring medical attention, medical intervention, or increase 
in supportive care of any manner within 4 weeks prior to screening 
9. 
Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy such 
as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients 
11. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents 
used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, 
immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene 
replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) 
binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody titer > 1:50, he 
or she may receive retesting within 30 days of the screening period and will be eligible to 
participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values (international normalized ratio [INR] > 1.4, 
gamma-glutamyl transpeptidase [GGT], ALT, and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, 
creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per 
cmm) prior to gene replacement therapy 
14.  Participation in recent SMA treatment clinical study (with the exception of observational cohort 
studies or non-interventional studies) or receipt of an investigational or commercial compound, 
product, or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any 
time prior to screening for this study.  Oral β-agonists must be discontinued at least 30 days before 
gene therapy dosing.  Inhaled albuterol specifically prescribed for the purposes of respiratory 
(bronchodilator) management is acceptable and not a contraindication at any time prior to screening 
for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal surgery or 
tracheostomy) 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to 
travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain 
from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 10 of 142 
Investigational Product, Dosage and Mode of Administration: 
Patients will receive a one-time dose of AVXS-101 at 1.1 X 1014 vg/kg, a dose determined to be 
equivalent to the dose received by the Cohort 2 patients in the Phase 1 study (AVXS-101-CL-101) by 
direct testing using improved analytical methods. 
Duration of Treatment: 
AVXS-101 will be administered as a one-time IV infusion over approximately 30-60 minutes, 
dependent upon the volume required. 
Reference Therapy, Dosage and Mode of Administration: Not Applicable 
Criteria for Evaluation: 
Efficacy: 
Co-Primary 
• 
Proportion of patients that achieve functional independent sitting for at least 30 seconds at the 18 
months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler Development 
(Version 3), confirmed by video recording, as a patient who sits up straight with head erect for at 
least 30 seconds 
• 
Survival at 14 months of age.  Survival is defined by the avoidance of the combined endpoint of 
either (a) death or (b) permanent ventilation, which is defined by tracheostomy or by the 
requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive ventilatory support) 
for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative 
ventilation.  Permanent ventilation, so defined, is considered a surrogate for death 
Co-Secondary 
• 
The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate thin 
liquids (as demonstrated through a formal swallowing test) and to maintain weight (> third 
percentile based on World Health Organization [WHO] Child Growth Standards [26] for age and 
gender) without need of gastrostomy or other mechanical or non-oral nutritional support at 
18 months of age 
• 
The proportion of patients who are independent of ventilatory support, defined as requiring no daily 
ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative 
ventilation, as defined above through assessment of actual usage data captured from the device 
(Phillips Trilogy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 11 of 142 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• 
Incidence of elevated liver function tests (LFTs) and/or unresolved liver function enzymes (LFEs) 
• 
Incidence of CTCAE Grade 3 or higher toxicity, treatment-emergent adverse events 
• 
Clinically significant changes in laboratory values, physical exams, cardiac assessments or vital 
signs 
• 
Research Immunology Blood Labs including serum antibody to AAV9 and SMN as well as IFN-γ 
Enzyme-linked ImmunoSpot (ELISpot) to detect T-cell responses to AAV9 and SMN 
Statistical Methods: 
This is a pivotal Phase 3, open-label, single-arm, single-dose, study assessing the efficacy and safety of 
AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal muscular atrophy 
(SMA) Type 1 who meet enrollment criteria, may be symptomatic or pre-symptomatic and are 
genetically defined by no functional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival 
motor neuron 2 gene (SMN2) and who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1).  Enrolling up to twenty (20) patients under the broader enrollment criteria 
is projected to enable enrollment of at least fifteen (15) patients that meet the Intent-to-Treat Population 
(ITT) criteria.  The ITT population is identified as symptomatic patients with bi-allelic SMN1 deletions 
and 2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) and will comprise the 
primary population for evaluation of the primary and secondary endpoints.  Study power is based upon 
efficacy analysis of the ITT population.  Furthermore, the first three patients enrolled must meet criteria 
for the Intent-To-Treat Population to enable a comparison of CHOP-INTEND scores at one-month 
following gene replacement therapy to enable a comparison of patient response between AVXS-101-
CL-303 patients and patient results from the Phase 1 trial (AVXS-101-CL-101).  Patients with 1 copy of 
SMN2, pre-symptomatic patients and patients with the SMN2 gene modifier mutation (c.859G>C) will 
be evaluated separately as part of additional subgroup analyses.  Details of all analyses will be contained 
within the Statistical Analysis Plan. 
Based upon widely cited natural history of the disease (Pediatric Neuromuscular Clinical Research 
Network [PNCR]) [Neurol. 2014; 83(9):810-817], it is expected that no patient meeting the study 
entrance criteria (SMN2 copy number of 2 without the SMN2 gene modifier mutation (c.859G>C)) 
would be expected to attain the ability to sit without support for at least 30 seconds at or before the 18 
months of age study visit or other milestones (rolling over, standing, walking) assessed as part of the 
study. 
Assuming that the true response rate for the primary endpoint is actually zero (or as low as 0.1%) in the 
population of interest of the historical control, the first co-primary efficacy endpoint hypothesis is 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 12 of 142 
whether the AVXS-101 treated patients achieve a response rate greater than 0.1%.  Based upon 
preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at least 40% of treated 
patients in the ITT population are expected to achieve the co-primary efficacy endpoint of functional 
independent sitting for at least 30 seconds at the 18 months of age visit.  With the assumption for the 
true response rate of AVXS-101 for the primary endpoint being in the range of 30% - 40%, a sample 
size of 15 patients that meet ITT criteria will be enrolled and assuming approximately 30% of patients 
are excluded from analysis, would yield an ITT population that would provide power of > 90% to detect 
a significant difference from 0.1% with α = 0.025 using a 1-sided exact test for a binomial proportion. 
The second co-primary efficacy endpoint of survival at 14 months of age will be evaluated by 
comparing the results observed in the ITT population with the results from the age and gender-matched 
control patients selected from existing natural history data sets (PNCR) [Neurol. 2014; 83(9):810-
817].  It is anticipated that 75% of patients in the PNCR population would not survive beyond 
13.6 months of age, and that these control patients will represent a 25% survival rate based upon the 
natural history of the disease.  Based upon preliminary results from the ongoing Phase 1 clinical study 
(AVXS-101-CL-101), at least 80% of patients in the ITT population are expected to survive, as defined, 
through 14 months of age.  With this efficacy, an enrolled sample size of 15 patients that meet ITT 
criteria (assuming 30% of patients are excluded from the analysis) would yield an ITT population that 
would provide power of > 80% to detect a significant difference from the historical control with α 
= 0.05 using a 2-sided Fisher’s Exact test. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 13 of 142 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
1. 
ADMINISTRATIVE INFORMATION .......................................................................2 
1.1. 
Approval .......................................................................................................................2 
1.2. 
Investigator’s Agreement ..............................................................................................3 
1.3. 
Contact Information ......................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background .................................................................................................................20 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients ................................................21 
5.3. 
Non-clinical Studies ....................................................................................................23 
5.4. 
Clinical Studies ...........................................................................................................26 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................29 
6.1. 
Primary Objectives .....................................................................................................29 
6.2. 
Secondary Objective ...................................................................................................29 
 
 
6.4. 
Safety Objectives ........................................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 
7.1. 
Overall Study Design ..................................................................................................31 
7.2. 
Number of Patients .....................................................................................................33 
7.3. 
Criteria for Study Termination ...................................................................................33 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................34 
8.1. 
Patient Inclusion Criteria ............................................................................................34 
8.2. 
Patient Exclusion Criteria ...........................................................................................34 
8.3. 
Patient Withdrawal Criteria ........................................................................................36 
9. 
TREATMENT OF PATIENTS ..................................................................................37 
9.1. 
Description of Product ................................................................................................37 
9.2. 
Prior and Concomitant Medications ...........................................................................37 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 14 of 142 
9.2.1. 
Prophylactic Administration of Prednisolone .............................................................37 
9.2.2. 
Prohibited Medications ...............................................................................................38 
9.3. 
Treatment Compliance ................................................................................................38 
9.4. 
Randomization and Blinding ......................................................................................38 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT ....................................39 
10.1. 
Study Product..............................................................................................................39 
10.2. 
Study Product Dose and Dose Justification ................................................................39 
10.3. 
Study Product Packaging and Labeling ......................................................................39 
10.4. 
Study Product Storage ................................................................................................39 
10.5. 
Study Product Preparation ..........................................................................................40 
10.6. 
Study Product Administration ....................................................................................40 
10.7. 
Dose Adjustment Criteria ...........................................................................................40 
10.8. 
Study Product Accountability .....................................................................................40 
10.9. 
Study Product Handling and Disposal ........................................................................40 
11. 
ASSESSMENT OF EFFICACY ................................................................................42 
11.1. 
Developmental Milestones .........................................................................................42 
11.2. 
Motor Function Tests ..................................................................................................43 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones ........43 
11.2.2. 
CHOP-INTEND .........................................................................................................43 
11.3. 
Video Evidence ...........................................................................................................44 
11.4. 
Compound Motor Action Potential ............................................................................44 
12. 
ASSESSMENT OF SAFETY .....................................................................................45 
12.1. 
Safety Parameters .......................................................................................................45 
12.1.1. 
Demographic/Medical History ...................................................................................45 
12.1.2. 
Physical Examinations ................................................................................................45 
12.1.3. 
Vital Signs/Weight and Length ..................................................................................46 
12.1.4. 
Electrocardiogram .......................................................................................................46 
12.1.5. 
12-Lead Holter Monitor ..............................................................................................46 
12.1.6. 
Echocardiogram ..........................................................................................................47 
12.1.7. 
Pulmonary Examinations ............................................................................................47 
12.1.8. 
Swallowing Test .........................................................................................................47 
12.1.9. 
Photographs of Infusion Site ......................................................................................47 
12.1.10. 
Laboratory Assessments .............................................................................................48 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 15 of 142 
12.1.10.1. Hematology .................................................................................................................49 
12.1.10.2. Blood Chemistry .........................................................................................................49 
12.1.10.3. Urinalysis ....................................................................................................................50 
12.1.10.4. Virus Serology ............................................................................................................51 
12.1.10.5. Capillary Blood Gas ...................................................................................................51 
12.1.10.6. Immunology Testing (ELISA and IFN-γ ELISpots) ..................................................51 
12.1.10.7. AAV9 Antibody Screen in Mother .............................................................................51 
12.1.10.8. Blood for Diagnostic Confirmation Testing ...............................................................51 
12.1.10.9. Saliva, Urine, and Stool Collection ............................................................................52 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................53 
13.1.1. 
Definition of Adverse Events .....................................................................................53 
13.1.1.1. 
Adverse Event .............................................................................................................53 
13.1.1.2. 
Serious Adverse Event ................................................................................................54 
13.1.1.3. 
Other Adverse Event ...................................................................................................54 
13.2. 
Relationship to Study Product ....................................................................................54 
13.3. 
Recording Adverse Events .........................................................................................55 
13.4. 
Reporting Adverse Events ..........................................................................................55 
14. 
STATISTICS ..............................................................................................................56 
14.1. 
Study Endpoints and Populations ...............................................................................56 
14.1.1. 
Study Endpoints ..........................................................................................................56 
14.1.1.1. 
Co-Primary Efficacy Endpoint ...................................................................................56 
14.1.1.2. 
Co-Secondary Efficacy Endpoint ...............................................................................57 
 
 
14.1.1.4. 
Safety Endpoints .........................................................................................................58 
14.1.2. 
Statistical Analysis Populations ..................................................................................58 
14.1.2.1. 
Intent-to-Treat Population (ITT) .................................................................................58 
14.1.2.2. 
Efficacy Completers Population .................................................................................58 
14.1.2.3. 
All Enrolled Population ..............................................................................................58 
14.1.2.4. 
Safety Population ........................................................................................................59 
14.2. 
Sample Size Calculation .............................................................................................59 
14.3. 
Efficacy Analysis ........................................................................................................60 
14.3.1. 
General Considerations ...............................................................................................60 
14.3.2. 
Primary and Secondary Efficacy Analysis .................................................................60 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 16 of 142 
14.4. 
CHOP-INTEND Comparison .....................................................................................61 
14.5. 
Safety Analysis ...........................................................................................................62 
15. 
DATA SAFETY MONITORING BOARD ...............................................................63 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................64 
16.1. 
Study Monitoring ........................................................................................................64 
16.2. 
Audits and Inspections ................................................................................................64 
16.3. 
Institutional Biosafety Committee ..............................................................................65 
16.4. 
Institutional Review Board/Institutional Ethics Committee .......................................65 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................66 
18. 
ETHICS ......................................................................................................................67 
18.1. 
Ethics Review .............................................................................................................67 
18.2. 
Ethical Conduct of the Study ......................................................................................67 
18.3. 
Written Informed Consent ..........................................................................................67 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
19.1. 
Electronic Case Report Forms ....................................................................................68 
19.2. 
Inspection of Records .................................................................................................68 
19.3. 
Retention of Records ..................................................................................................68 
20. 
PUBLICATION POLICY ..........................................................................................69 
21. 
LIST OF REFERENCES ............................................................................................70 
22. 
APPENDICES ............................................................................................................72 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................73 
APPENDIX 2. AUTOPSY PLAN ..............................................................................................75 
APPENDIX 3. BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) .............................................................................................................76 
APPENDIX 4. PERFORMANCE CRITERIA FOR BAYLEY SCALES OF INFANT 
AND TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES .........................................................................................................121 
APPENDIX 5. CHOP-INTEND ...............................................................................................122 
APPENDIX 6. COMPOUND MOTOR ACTION POTENTIAL MANUAL ..........................124 
APPENDIX 7. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS...............................127 
APPENDIX 8. SUMMARY OF CHANGES ...........................................................................132 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 17 of 142 
LIST OF TABLES 
Table 1: 
Important Study Contact Information ...........................................................................4 
Table 2: 
Study Vendor Listing ....................................................................................................4 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 4: 
Spinal Muscular Atrophy Classification .....................................................................21 
Table 5: 
Investigational Product ...............................................................................................37 
Table 6: 
Total Blood Volume ...................................................................................................48 
Table 7: 
Common Terminology Criteria for Adverse Events ..................................................53 
Table 8: 
Tissue Sample for Analysis ........................................................................................75 
 
LIST OF FIGURES 
Figure 1: 
Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 
2, and 3 ........................................................................................................................22 
Figure 2: 
Study Results, Including Staining of Transduced Spinal Motor Neurons, 
SMN Expression Levels, Righting Ability, and Weight and Survival Curves ...........24 
Figure 3 
Body Mass of Treated and Control Mice Showed No Difference ..............................25 
Figure 4: 
Study Design ...............................................................................................................32 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 18 of 142 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AAV 
Adeno-associated virus 
AAV9 
Adeno-associated virus serotype 9 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASO 
Antisense oligonucleotide  
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CB 
Chicken-β-actin-hybrid 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CI 
CHOP-INTEND 
CHOP-INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders 
CK 
Creatine kinase 
CK-MB 
Creatine kinase isoenzyme 
CLIA 
Clinical Laboratory Improvement Amendment 
CMAP 
Compound motor action potential 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
First 24-hour interval after the start of gene replacement therapy infusion 
Day –1 
24-hour interval prior to the start of gene replacement therapy infusion  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISpot 
Enzyme-linked ImmunoSpot 
ET 
Early termination 
FVB 
Friend Virus B-Type 
GCP 
Good Clinical Practice 
GFP 
Green fluorescent protein 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HEENT 
Head, eyes, ears, nose, and throat 
HgB 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 19 of 142 
Abbreviation or Specialist Term 
Explanation 
ICD-10 code 
International Statistical Classification of Diseases and Related Health 
Problems 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon gamma 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITR 
Inverted terminal repeat 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFE 
Liver function enzymes 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHP 
Non-human primates 
NOAEL 
No Observable Adverse Effect Level 
OAE 
Other significant Adverse Event 
PBMC 
Peripheral blood mononuclear cells 
PICU 
Pediatric intensive care unit 
PNCR 
Pediatric Neuromuscular Clinical Research Network 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
Self-complementary 
scAAV 
Self-complimentary adeno-associated virus 
scAAV9.CB.SMN 
Self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SMN1 
Survival motor neuron 1 gene 
SMN2 
Survival motor neuron 2 gene 
SOC 
System Organ Class 
TMF 
Trial master file 
US 
United States 
vg/kg 
Vector genome per kilogram 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 20 of 142 
5. 
INTRODUCTION 
Study AVXS-101-CL-303 is a pivotal Phase 3, open-label, single-arm, single-dose, study of 
AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal muscular atrophy 
(SMA) Type 1 who meet enrollment criteria, may be either symptomatic or pre-symptomatic and 
are genetically defined by no functional survival motor neuron 1 gene (SMN1) as well as 1 or 
2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 months (< 180 days) of age at 
the time of gene replacement therapy (Day 1).  Enrolling up to twenty (20) patients under the 
broader enrollment criteria is projected to enable enrollment of at least fifteen (15) patients that 
meet the Intent-to-Treat Population (ITT) criteria.  The first three patients enrolled must meet the 
ITT criteria to enable a comparison of CHOP-INTEND scores at one-month following gene 
replacement therapy to enable a comparison of patient response between AVXS-101-CL-303 
patients and Cohort 2 patient results from the Phase 1 trial (AVXS-101-CL-101). 
In this study, the survival motor neuron (SMN) gene will be transferred using self-
complementary adeno-associated virus (scAAV) Type 9 under control of the chicken-β-actin 
hybrid promoter.  Pre-clinical studies have demonstrated survival of the SMNΔ7 mouse model 
for SMA from a median of 15.5 days to over 1 year, following IV delivery to a facial vein.  
Additionally, preliminary results from an ongoing Phase 1 clinical study (AVXS-101-CL-101) of 
AVXS-101 in SMA Type 1 patients demonstrates broad improvements in survival, motor 
function, pulmonary function, and nutritional function (Section 5.4). 
5.1. 
Background 
Spinal muscular atrophy is a neurogenetic disorder caused by a loss or mutation in the survival 
motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN protein levels 
and a selective dysfunction of motor neurons.  Spinal muscular atrophy is an autosomal 
recessive, early childhood disease with an incidence of approximately 1:10,000 live births [1].  
Spinal muscular atrophy is the leading cause of infant mortality due to genetic diseases.  Disease 
severity and clinical prognosis depends on the number of copies of survival motor neuron 2 gene 
(SMN2).  In its most common and severe form (Type 1), hypotonia and progressive weakness are 
recognized in the first few months of life, leading to diagnosis before 6 months of age and early 
death due to respiratory failure before 2 years of age.  Motor neuron loss in SMA Type 1 is 
profound in the early post-natal period (or may even start in the prenatal period), whereas motor 
neurons in SMA Type 2 and Type 3 patients adapt and compensate during development and 
persist into adult life.  The findings from various neurophysiological and animal studies have 
shown an early loss of motor neurons in the embryonic and early post-natal periods [2,3,4].  
From a clinical perspective, these findings emphasize the importance of first targeting the SMA 
Type 1 group for gene transfer of SMN1 in hopes of rescuing neurons at this critical stage.  The 
goal in continuing the development plan for AVXS-101 is to modify the SMA Type 1 
phenotype, which will hopefully lead to a milder disease course and prolonged survival as seen 
in SMA Type 2 and Type 3 patients. 
Therapeutic efforts in SMA have focused on the potential for small molecules to increase SMN 
levels.  These include deacetylase inhibitors, such as, valproic acid, sodium butyrate, 
phenylbutyrate, and trichostatin A.  These agents activate the SMN2 promoter, resulting in 
increased full-length SMN protein in SMA animal models [5,6].  However, clinical studies 
employing several of these agents, most notably phenylbutyrate, valproic acid, and hydroxyurea, 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 21 of 142 
have not resulted in clinical benefit [7,8].  FDA recently approved Nusinersen, an antisense 
oligonucleotide (ASO) drug designed to increase the production of the SMN protein by 
modulating the splicing of the SMN2 gene, thereby compensating for the underlying genetic 
defect.  Clinical studies have shown some modest promise in improving motor function; however 
the treatment must be administered indefinitely on a quarterly basis via intrathecal injection, 
requires a lengthy induction period prior to effectiveness, and has safety considerations which 
require clinical monitoring.  A single-dose IV administration study of AVXS-101 will provide 
information on the potential gene transfer has in treating SMA Type 1 patients, and will 
hopefully show promise for success in modifying the disease prognosis. 
This is a single-dose study that will include up to 20 Type 1 patients with no functional SMN1 
gene as well as 1 or 2 copies of SMN2 and who are < 6 months (< 180 days) of age at the time 
of gene replacement therapy (Day 1).  The rationale for IV dosing is based upon the need for 
rapid, systemic impact given the severity of the disease in SMA Type 1 and its potential impact 
on systems outside of the central nervous system (CNS) such as the peripheral and autonomic 
nervous systems, heart, pancreas and gastrointestinal tract. 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients 
Patients with SMA Type 1 have been chosen as the target population for this gene therapy study 
based on studies of the natural history of this disease.  The classification of SMA is shown below 
(Table 4) in which SMA Types 0 to 4 are described.  Spinal muscular atrophy is conventionally 
classified into 4 phenotypes on the basis of age at onset and highest motor function achieved, 
with an additional phenotype (Type 0) to describe the severe forms of antenatal-onset SMA. 
Table 4: Spinal Muscular Atrophy Classification 
Type 
Age at Symptom Onset 
Maximum Motor Function 
Life Expectancy 
SMN2 Copy No. 
0 
Fetal 
Nil 
Days – Weeks 
1 
1 
< 6 Months 
1A: B-2 Weeks 
1B: < 3 Months 
1C: > 3 Months 
Never sits 
< 2 years 
1, 2, 3 
2 
6 – 18 Months 
Never walks 
20 – 40 years 
2, 3, 4 
3 
1.5 – 10 Years 
3A: < 3 Years 
3B: > 3 Years 
Walks, regression 
Normal 
3, 4, 5 
4 
> 35 Years 
Slow decline 
Normal 
4, 5 
Source: Adapted from Kolb 2011 [10] 
SMN2 = survival motor neuron 2 gene 
 
Spinal muscular atrophy Type 1 patients, by definition, never attain independent sitting and have 
hypotonia within the first 6 months of life.  Spinal muscular atrophy Type 1 is the leading 
genetic cause of infant death with an onset at ≤ 6 months of age (Table 4).  In contrast, SMA 
Type 2 manifests within the first 18 months, and children afflicted with this condition are able to 
maintain sitting unassisted but never walk independently.  Spinal muscular atrophy Type 3 
patients attain the ability to walk unaided (Type 3a have onset 18 months to 3 years of age; 
Type 3b have onset > 3 years of age).  Spinal muscular atrophy Type 4 is an adult onset disease.  

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 22 of 142 
The genetic cause for SMA is well established and is intimately involved with one’s prognosis.  
All forms of SMA are autosomal recessive in inheritance and are caused by deletions or 
mutations of the SMN1 gene. 
Humans also carry a second nearly identical copy of the SMN1 gene called SMN2 [11].  Both the 
SMN1 and SMN2 genes express SMN protein; however, the amount of functional full-length 
protein produced by SMN2 is only 10 to 15% of that produced by SMN1 [11,12,13].  Although 
SMN2 cannot completely compensate for the loss of the SMN1 gene, patients with milder forms 
of SMA generally have higher SMN2 copy numbers [14,15].  Quantitative analysis of SMN2 
copies in 375 patients with Type 1, 2, or 3 SMA showed a significant correlation between SMN2 
copy number and SMA Type, as well as, duration of survival.  In a large early study by 
Feldkotter et al 2002, 2 copies of SMN2 was 97% predictive for developing SMA Type 1, 
3 copies of SMN2 was 83% predictive for developing SMA Type 2, and 4 copies of SMN2 was 
84% predictive of SMA Type 3 [16].  As these percentages do not reflect the possible impact of 
modifier mutations such as that described by Prior et al 2009 [17], they may understate the 
relationship between copy number (in the absence of a genetic modifier) and clinical phenotype.  
Among 113 patients with Type 1 SMA, 9 with one SMN2 copy lived < 11 months, 88/94 with 
two SMN2 copies lived < 21 months, and 8/10 with three SMN2 copies lived 33 to 66 months.  
Even more refined data describing this relationship has been generated, and has also influenced 
our choice of the study target group. 
The severity of SMA Type 1 is demonstrated by prognosis as illustrated in Kaplan-Meier 
survival curves shown in Figure 1. 
Figure 1: Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 2, 
and 3 
 
n = number of patients 
Source: Farrar 2013 [18] 
In Figure 1, the relative stability of the clinical course of SMA Type 2 and Type 3 is dramatically 
illustrated.  Perhaps most importantly, these findings show that outcome differences are related 
to the number of SMN2 copies that enable motor neurons to adapt and compensate during the 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 23 of 142 
growth of the child and persist into adult life.  This contrasts with SMA Type 1 where motor 
neuron loss is profound in the early post-natal period (or may even start in the prenatal period, 
especially for SMA Type 1 patients presenting in first 3 months of life).  The findings in Figure 1 
confirm other pieces of evidence from neurophysiological studies and animal studies that also 
show early loss of motor neurons in the embryonic and early post-natal periods [2,3,4]. 
There is reason to believe that there are few safety issues to be concerned about when targeting 
the SMA Type 1 group in this gene therapy clinical study.  Overexpression of SMN has been 
shown to be well tolerated in both mice and non-human primates, and in humans, a high copy 
number of SMN2 poses no risk (as seen in Type 2, 3, and 4 patients who have high SMN2 copy 
number), allowing for use of robust, ubiquitous expression systems (like the CB-promoter) to 
ensure sustained, high-level SMN expression.  Additionally, it is important to point out that 
recombinant scAAV can be employed for this study because of the small size of the SMN gene.  
This enables efficient packaging and allows for efficient gene transfer with lower viral titers (a 
safety consideration), compared with prototypical single-stranded adeno-associated virus (AAV) 
vectors. 
Recent studies using self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron (scAAV9.CB.SMN) show a robust post-natal rescue of SMNΔ7 
mice with correction of motor function, neuromuscular electrophysiology and survival after a 
one-time delivery of vector [19].  Intravenous scAAV9 is able to transduce neurons, muscle and 
vascular endothelium, all of which have been proposed as target cells for SMA treatment. 
5.3. 
Non-clinical Studies 
A mouse model was developed by the 
 after a generation of multiple 
variants.  It was found that the double transgenic, referred to as the SMNΔ7 mouse, provided the 
most suitable model to study gene transfer [20].  Studies performed in the 
 
have shown that injecting 5 × 1011 viral genomes of scAAV9.CB.SMN into the facial vein on 
Day 1 old mice rescues the SMNΔ7 mouse model [19].  Figure 2 shows the results of these 
studies, including staining of transduced spinal motor neurons, SMN expression levels, righting 
ability, and weight and survival curves.  Approximately 42 ± 2% of lumbar spinal motor neurons 
were transduced in scAAV9.CB.GFP treated mice.  SMN transduction was shown by real time 
polymerase chain reaction (RT-PCR) in the mice.  GFP transduction was observed by 
microscopy.  Both constructs were in AAV9 and had transduction of motor neurons.  SMN 
levels were increased as well, in brain, spinal cord, and muscle of scAAV9.CB.SMN-treated 
animals, compared to untreated SMNΔ7 mice (although lower than wild type [WT] controls).  
SMNΔ7 animals treated with either scAAV9.CB.SMN or scAAV9.CB.GFP on post-natal Day 1 
were assessed for their righting ability and were compared to WT control mice and untreated 
mice.  Wild type controls could right themselves quickly, whereas the SMN- and green 
fluorescent protein (GFP)-treated SMA animals showed difficulty at P5.  However, by P13, 
90% of SMN-treated animals could right themselves compared with 20% of GFP-treated 
controls and 0% of untreated SMA animals.  At P18, SMN-treated animals were larger than 
GFP-treated animals, but smaller than WT controls.  Locomotive ability of the SMN-treated 
mice was nearly identical to WT controls, as assayed by open field testing and wheel running. 
Survival of SMN-treated SMNΔ7 animals compared with GFP-treated SMNΔ7 animals was 
significantly improved.  No GFP-treated control animals survived past P22 and had a median life 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 24 of 142 
span of 15.5 days.  The weights of GFP mice peaked at P10 and then precipitously declined until 
death, while SMN mice showed a steady weight gain until around P40 with it stabilizing at 17 g 
(about half the weight of WT controls).  The smaller size of corrected animals is likely related to 
the tropism and incomplete transduction of scAAV9, resulting in a ‘chimeric’ animal in which 
some cells were not transduced.  Additionally, the smaller size suggests an embryonic role for 
SMN.  Most remarkably, SMN-treated mice survived well past 250 days of age. 
Figure 2: Study Results, Including Staining of Transduced Spinal Motor Neurons, SMN 
Expression Levels, Righting Ability, and Weight and Survival Curves 
Source: Foust 2010 [19] 
CNS = central nervous system; GFP = green fluorescent protein; SMN = survival motor neuron; WT = wild type 
a)   Shows transduced motor neurons in lumbar spinal cord
b) Western Blots of SMN expression in CNS and muscle
c)   Improved righting ability of SMN-treated- similar to WT controls by P13
d) SMN-treated are larger than GFP-treated at P18
e)   Survival of SMN-treated markedly improved compared to GFP- treated
f) Body weight increased in SMN-treated vs GFP

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 25 of 142 
Toxicology biodistribution studies were generated by the 
 [data on file].  In the 
non-Good Laboratory Practice (GLP) studies, 24 mice and 4 non-human primates (NHPs) were 
injected, by way of vascular delivery, with AVXS-101.  To assess toxicity and safety, 
AVXS-101 was injected into P1 wild type Friend Virus B-Type (FVB) mice with either vehicle 
(3 males/6 females) or 3.3 × 1014 vg/kg of scAAV9.CB.SMN (6 males/9 females) via the facial 
temporal vein.  This dose was previously shown to be most efficacious in the SMNΔ7 mouse 
model [19].  P1 mice were used in anticipation of simulating potential clinical studies in infants.  
All mice survived the injection procedure and the initial 24-hour observation period without any 
signs of distress or weight loss.  Body mass was measured and hands-on observations were 
performed weekly for the remainder of the study; neither revealed any difference between 
control and treated cohorts (Figure 3). 
Figure 3 Body Mass of Treated and Control Mice Showed No Difference 
 
 
At 60, 90 and 180 days post-injection, blood from the mice was collected for hematology studies 
including complete blood counts with differentials.  At 90, 120 and 180 days post-injection, 
blood was collected for clinical chemistries assessment (alanine amino transferase [ALT], 
aspartate amino transferase [AST], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], 
electrolytes, and creatine kinase [CK]).  For histopathology, 13 mice were necropsied at 
120 days post-injection and 8 mice at 180 days.  There were no clinically significant results 
observed during from the hematology, clinical chemistry, and histopathology portions of the 
study and trends of both groups were comparable.  Of note, no significant lesions were present in 
any brain or spinal cord sections, although, the sections were frozen and thicker than 5 microns 
which made cellular morphology obscure and subtle changes may not have been identified. 
In the safety study for the 4 male Cynomolgus Macaques, animals were injected at 90 days of 
age to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
AVXS-101 vector was administered one time by catheterization of the saphenous vein with a 
dose of 6.7 × 1013 vg/kg, which corresponds to the lowest dose tested for which SMNΔ7 mice 
showed a significant increase of survival.  Animals were followed for six months until they were 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 26 of 142 
sacrificed at approximately 9 months of age.  No adverse effects were seen, and all clinical 
chemistries were normal.  T-cell immune response was tested using Enzyme-linked ImmunoSpot 
(ELISpot) in peripheral blood mononuclear cells (PBMCs), and all were negative at 6 months 
post-injection. 
These mouse and monkey studies can be summarized as follows.  The serum chemistry and 
hematology studies were unremarkable as was the histopathology assessment.  The NHP patients 
animals mounted appropriate immune responses to capsid (but not to transgene), with very high 
transgene expression persisting at 6 months post-injection.  In conclusion, these studies provide 
strong evidence that systemically-delivered scAAV9.CB.SMN is safe and well tolerated, even at 
the high doses required for penetration of the blood-brain barrier [data on file]. 
When newborn FVB mice were given a single IV injection of AVXS-101 at levels up to 
3.3 × 1014 vg/kg on Day 1, there was neither test article-related mortality nor evidence of toxicity 
seen at time points up to 24 weeks after administration.  Treatment-related decreases in mean 
body weight and mean body weight gain, as well as lower activated partial thromboplastin time 
(APTT) values, were mild effects of treatment, but did not result in toxicity.  Activity of 
AVXS-101 was demonstrated by the biodistribution and the presence of a specific transgene 
ribonucleic acid (RNA) expression in brain and spinal cord, the main targeted therapeutic tissues.  
Low levels of antibodies to the AAV9 capsid were found after 12 and 24 weeks in males and 
females given 3.3 × 1014 vg/kg (Group 3).  No alteration was observed in clinical pathology and 
histopathology analyses.  Based on these results, the no observable adverse effect level 
(NOAEL) of AVXS-101 in newborn male and female mice is considered to be 3.3 × 1014 vg/kg. 
Intravenous administration of AAV9 has been shown to be safe and well tolerated when 
administered to mice and monkeys.  The vector has also demonstrated the ability to cross the 
blood brain barrier in both species following IV administration.  Body weight increased, righting 
behavior improved, survival was extended and cardiac deficits returned toward normal in treated 
SMNΔ7 mice when compared to untreated SMNΔ7 mice.  Toxicology studies determined the 
NOAEL of AVXS-101 was 3.3 x 1014 vg/kg and there was no test article mortality or toxicity 
observed up to 24 weeks following IV administration in mice.  Biodistribution to the brain and 
spinal cord was reconfirmed and low levels of antibodies to the AAV9 capsid were observed at 
12 and 24 weeks following the 3.3 x 1014 vg/kg dose.  No alteration was observed in clinical 
pathology and histopathology analyses. 
5.4. 
Clinical Studies 
First-in-human study AVXS-101-CL-101 is an ongoing 2-year study evaluating the efficacy and 
safety of AVXS-101 in 15 SMA Type 1 patients with 2 copies of SMN2.  All patients have 
received a single IV dose of AVXS-101 in 2 cohorts: Cohort 1 (n = 3) received the low dose 
used in this study (equivalent to a dose that doubled mouse lifespan in the SMN∆7 Mouse 
potency assay) and Cohort 2 (n = 12) received the high dose used in this study (equivalent to a 
dose that restored mouse lifespan to greater than 200 days or “full life” in the SMN∆7 Mouse 
potency assay).  The dose received by Cohort 2 patients in AVXS-101-CL-101 (proposed 
therapeutic dose) has been demonstrated to be equivalent to the dose to be used in the AVXS-
101-CL-303 study by direct testing using improved analytical methods. 
Preliminary data as of 15 September 2016 indicate that treatment with AVXS-101 results in 
broad improvements in survival, motor function, pulmonary function, and nutritional function.  

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 27 of 142 
All patients in Cohort 2 (proposed therapeutic dose) showed improvements in survival, as 
defined by Finkel et al 2014 [21], with no deaths or requirements for permanent ventilation 
≥ 16 hours/day for ≥ 14 consecutive days through 15 September 2016.  The median age at last 
follow-up for Cohort 2 was 17.3 months, with the oldest patient at 27.4 months of age.  One 
patient in Cohort 1 (low-dose cohort) had a pulmonary event of increased use of bi-level positive 
airway pressure in advance of surgery related to hypersalivation, a condition experienced by 
some SMA patients.  The event was determined by independent review to represent progression 
of disease and not related to AVXS-101. 
As of September 15, 2016, improvements in motor function, as assessed by the CHOP-INTEND 
scores, were observed with mean increases of 9.0 points in Cohort 1 and 24.8 points in Cohort 2.  
The CHOP-INTEND scores in Cohort 2 were ≥ 40 points for 11/12 patients, ≥ 50 points for 
9/12 patients, and ≥ 60 points (normal) for 3/12 patients. 
As of September 15, 2016, patients in Cohort 2 consistently achieved and maintained key 
developmental motor milestones as summarized below: 
• 11/12 patients achieved head control, 7/12 patients could roll, 11/12 patients could sit with 
support, and 8/12 patients could sit unassisted, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016 
• 7 patients were able to feed themselves, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016, and 5 patients were speaking (1 bilingual) 
• 2 patients were walking independently, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016.  These 2 patients each achieved earlier 
and important developmental milestones such as crawling, standing with support, standing 
alone, and walking with support 
 
As of September 15, 2016, AVXS-101 appears to have a favorable safety profile and appears to 
be generally well-tolerated in this study.  A total of 118 treatment-related AEs were reported 
(34 serious adverse events [SAEs] and 84 non-serious adverse events [AEs]).  Two SAEs were 
deemed treatment-related in 2 patients, and 3 AEs were deemed treatment-related in 2 patients.  
All treatment-related events consisted of clinically asymptomatic liver enzyme elevations that 
resolved with prednisolone treatment.  There were no clinically significant elevations of 
gamma-glutamyl transferase (GGT), alkaline phosphatase or bilirubin, and as such, Hy’s Law 
was not met.  Other non-treatment-related AEs were expected and were associated with SMA. 
In summary, through September 15, 2016, the consistently positive clinical observations are 
remarkably different from that described in extensive natural history studies, clinical 
publications, the experience of seasoned clinicians, and concurrent SMA Type 1 studies with 
other therapies.  These significant and clinically meaningful responses in patients treated with 
AVXS-101 indicate preliminary clinical evidence of a treatment effect that addresses an unmet 
need in this devastating pediatric disease. 
A full understanding of all the risks associated with AVXS-101 is not known at this time.  
Elevated liver function tests have been observed in the ongoing AVXS-101-CL-101 study, which 
is believed to be a T-cell immune response to the AAV9 vector.  None of the liver enzyme 
abnormalities observed in the study were accompanied by clinical sequelae.  Patients could 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 28 of 142 
experience an allergic response to AVXS-101.  Patients could also develop an immune response 
to the AAV9 viral vector, which could prevent future use of gene transfers using this vector. 
Taken together, results from the clinical and non-clinical studies support further clinical 
investigation of the efficacy and safety of AVXS-101 in patients with SMA Type 1. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 29 of 142 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The co-primary objectives are to: 
• Determine the efficacy of AVXS-101 by demonstrating achievement of developmental 
milestone of functional independent sitting for at least 30 seconds at the 18 months of age 
study visit. 
• Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is 
defined by the avoidance of combined endpoint of either (a) death or (b) permanent 
ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of 
respiratory assistance per day (via non-invasive ventilatory support) for ≥ 14 consecutive 
days in the absence of an acute reversible illness, excluding perioperative ventilation.  
Permanent ventilation, so defined, is considered a surrogate for death. 
 
6.2. 
Secondary Objective 
The co-secondary objectives are to: 
• Determine the effect of AVXS-101 on the on the ability to thrive defined as achieving all of 
the following at 18 months of age 
o Does not receive nutrition through mechanical support (e.g., feeding tube) 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• Determine the effect of AVXS-101 on the ability to remain independent of ventilatory 
support, defined as requiring no daily ventilator support/usage at 18 months of age, excluding 
acute reversible illness and perioperative ventilation, as defined above through assessment of 
actual usage data captured from the device, for patients issued a Trilogy 100 BiPAP device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 30 of 142 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4. 
Safety Objectives 
The safety objectives are to: 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• 
Determine the safety of AVXS-101 based on the development of unacceptable toxicity 
defined as the occurrence of any Common Terminology Criteria for Adverse Events 
(CTCAE) [9] Grade 3 or higher, unanticipated, treatment-related toxicity. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 31 of 142 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, open-label, single-arm, single-dose study of AVXS-101 (gene replacement 
therapy) that will enroll up to twenty (20) patients with SMA Type 1who may be either 
symptomatic or pre-symptomatic with no functional SMN1 gene as well as 1 or 2 copies of 
SMN2 and who are < 6 months (< 180 days) of age at the time of gene replacement therapy 
(Day 1).  Enrolling up to twenty (20) patients under the broader enrollment criteria is projected 
to enable enrollment of at least fifteen (15) patients that meet the Intent-to-Treat Population 
(ITT) criteria.  The ITT population is identified as symptomatic patients with bi-allelic SMN1 
deletions and 2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who 
meet all other study enrollment criteria.  In addition, the first three patients enrolled must meet 
the criteria for the Intent-to-Treat Population to enable a comparison of CHOP-INTEND scores 
at one-month following gene replacement therapy to enable a comparison of patient response 
between AVXS-101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial (AVXS-
101-CL-101). 
The study includes 3 study periods: screening, gene replacement therapy, and follow-up 
(Figure 4).  During the screening period (Days –30 to –2), patients whose parent(s)/legal 
guardian(s) provide informed consent will undergo screening procedures to determine eligibility 
for study enrollment.  Patients who meet the entry criteria will enter the in-patient gene 
replacement therapy period (Day –1 to Day 3).  On Day –1, patients will be admitted to the 
hospital for pre-treatment baseline procedures.  On Day 1, patients will receive a one-time IV 
infusion of AVXS-101 at a dose equivalent to the dose received by the second dosing cohort in 
the Phase 1 study over approximately 60 minutes, and will undergo in-patient safety monitoring 
over the next 48 hours.  Patients may be discharged 48 hours after gene replacement therapy, 
based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of Study 
at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 
assessments until the patient reaches 18 months of age.  Any missed visit should be rescheduled 
as soon as possible, but within 7 days. 
All post-treatment visits will be relative to the date on which gene replacement therapy is 
administered, except for the 14 and 18 months of age visits, which will be relative to the 
patient’s date of birth.  For the 14 and 18 months of age visits, the patient will return within 0 to 
14 days after the date on which the patient reaches 14 and 18 months of age, respectively.  The 
18 months of age visit will also serve as the End of Study visit.  After the End of Study visit, 
eligible patients will be asked to roll over into the long-term follow-up study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 32 of 142 
Figure 4: Study Design 
 
Note: After the End of Study visit at 18 months of age, eligible patients will be asked to roll over into the long-
term follow-up study. 
ET = early termination 
a 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, except 
for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
 
There will be at least a 4 -week dosing interval between dosing of the first three patients to allow 
review of the safety analysis from six time points (days 1, 2, 7, 14, 21, and 30) as well as early 
signals of efficacy including CHOP-INTEND score prior to dosing of the next patient. 
The first three patients enrolled must meet the criteria for the Intent-to-Treat (ITT) Population.  
AveXis will compare the CHOP-INTEND one month improvement for the AVXS-101-CL-303 
patients that meet the ITT criteria to assess the clinical response to the dose 1.1 x 1014 vg/kg as 
being what was expected from the Cohort 2 patients in the Phase 1 trial (AVXS-101-CL-101).  
This comparison will be performed as a per patient assessment for the first three patients.  The 
individual patients who receive their gene therapy at 0-3 months of age will be compared to a 
value of 10 CI points, while patients who receive their gene therapy at >3 but <6 months of age 
will be compared to a value of 5 CI points.  Furthermore, patients from either age group are 
expected to maintain the improvement in the absence of an acute illness or perioperatively.  If 
the expected CI improvements are observed for the first three ITT patients, AveXis will remove 
the 30-day interval between patients and proceed to dose at least 12 additional patients that meet 
the ITT criteria and perform safety and efficacy assessments as described elsewhere in the 
clinical protocol (AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  If the 
expected CI improvements are not observed for the first three ITT patients, AveXis will discuss 
next steps with the FDA before continuing study enrollment. 
In an attempt to dampen the host immune response to the AAV-derived therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion in accordance with the specified 
guidelines for tapering (Section 9.2.1). 
A schedule of study assessments is provided in Appendix 1.  Efficacy will be assessed by 
achievement of the key developmental milestone of functional independent sitting for at 
least 30 seconds at the 18 months of age study visit and survival at 14 months of age (as defined 
in Section 14.1.1.1).  The ability to thrive and the ability to remain independent of ventilatory 
support (as defined in Section 14.1.1.2) will also be assessed.  Additional developmental 
milestones will be assessed using Bayley Scales of Infant and Toddler Development© 
(Version 3) (Section 11).  Safety will be assessed through monitoring AEs, concomitant 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 33 of 142 
medication usage, physical examinations, vital sign assessments, cardiac assessments, and 
laboratory evaluations (Section 12).  Additionally, a Data Safety Monitoring Board (DSMB) will 
review safety data on a quarterly basis, and will also convene within 48 hours should any patient 
experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or 
requires medical treatment (Section 13.1.1.1 and Section 15).  This includes any patient death, 
important clinical laboratory finding, or any complication attributed to administration of gene 
replacement therapy.  In such instances, the DSMB will review the safety information and 
provide its recommendation.  The DSMB can recommend early termination of the study for 
safety reasons. 
7.2. 
Number of Patients 
Up to twenty (20) patients that meet the study enrollment entry criteria will be enrolled to enable 
enrollment of at least fifteen (15) patients that meet ITT criteria.  Study enrollment will stop as 
soon as practical following enrollment of the fifteenth patient that meets the ITT criteria. 
7.3. 
Criteria for Study Termination 
An independent DSMB will conduct quarterly and ad hoc reviews of the emerging safety data 
throughout the study as described in Section 15. 
The study will be completed as planned but may be terminated for the following reasons: 
• Development of unacceptable toxicity, defined as the occurrence of any unanticipated 
CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely related to gene 
replacement therapy, and is associated with clinical symptoms and/or requires medical 
treatment 
• DSMB can recommend early termination of the study for safety reasons 
• Study is terminated by Sponsor 
• Regulatory Authority recommendation 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 34 of 142 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients with SMA Type 1 who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1) with proven bi-allelic mutations of the SMN1 gene and 1 or 
2 copies of the SMN2 will be enrolled in this study.  Patients may be of any racial, ethnic, or 
gender background. 
8.1. 
Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 
mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of 
the known SMN2 gene modifier mutation (c.859G>C)) 
2. The first three patients enrolled must meet the criteria for the Intent-To-Treat population 
3. Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
4. Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
5. Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab 
prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections 
are also recommended in accordance with American Academy of Pediatrics (27) 
6. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and 
comply with study procedures and visit schedule 
 
8.2. 
Patient Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
1. Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without 
any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation 
does not decrease by ≥ 4 percentage points 
3. Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours/day over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during 
the screening period or requiring ventilatory support while awake over the 7 days prior to 
screening or at any point during the screening period prior to dosing 
4. Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass 
the swallowing test will be allowed to enroll in the study 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 35 of 142 
5. Patients whose weight-for-age is below the third percentile based on World Health 
Organization (WHO) Child Growth Standards [26] 
6. Active viral infection (includes human immunodeficiency virus [HIV] or positive serology 
for hepatitis B or C, or Zika virus) 
7. Serious non- respiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 weeks prior to screening 
8. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 weeks prior to screening 
9. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy 
such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
11. Concomitant use of any of the following: drugs for the treatment of myopathy or neuropathy, 
agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, 
plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 
3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, 
methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay 
(ELISA) binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody 
titer > 1:50, he or she may receive retesting within 30 days of the screening period and will 
be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values (international normalized ratio [INR] > 1.4; 
GGT, ALT, and AST > 3 × ULN; bilirubin ≥ 3.0 mg/dL; creatinine ≥ 1.0 mg/dL; hemoglobin 
< 8 or > 18 g/dL; white blood cells [WBC] > 20,000/cmm) prior to gene replacement therapy 
14. Participation in recent SMA treatment clinical study (with the exception of observational 
cohort studies or non-interventional studies) or receipt of an investigational or commercial 
compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, 
valproic acid) at any time prior to screening for this study.  Oral β-agonists must be 
discontinued at least 30 days prior to gene therapy dosing.  Inhaled albuterol specifically 
prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not 
a contraindication at any time prior to screening for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal 
surgery or tracheostomy) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 36 of 142 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability 
to travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to 
refrain from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 
8.3. 
Patient Withdrawal Criteria 
Patients may be discontinued from the study for the following reasons: 
• Death 
− An autopsy will be requested for any patient who expires following participation in a gene 
replacement study as per the National Institutes of Health’s Guidelines for Research 
Involving Recombinant or Synthetic Nucleic Acid Molecules [25] (see Autopsy Plan in 
Appendix 2) 
• Failure to comply with protocol-required visits or study procedures for 3 or more consecutive 
visits that are not rescheduled, unless due to hospitalization 
• Parent(s)/legal guardian(s) withdraws consent 
• Investigator discretion 
 
Early termination procedures should be completed within 14 days for any patient who 
prematurely discontinues the study for any reason, as indicated in Appendix 1. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 37 of 142 
9. 
TREATMENT OF PATIENTS 
It is the responsibility of the Investigator to ensure the safe storage and administration of gene 
replacement therapy. 
9.1. 
Description of Product 
The biological product is a non-replicating recombinant AAV9 containing the complimentary 
deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the 
cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB).  The AAV inverted 
terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, 
thus forming a double-stranded transgene ready for transcription.  This modified ITR, termed a 
“self-complementary” (sc) ITR, has been shown to significantly increase the speed of which the 
transgene is transcribed and the resulting protein is produced.  The biological product, called 
AVXS-101 (formerly scAAV9.CB.hSMN), expresses the human SMN protein in transduced 
cells. 
Table 5: Investigational Product 
 
Investigational Product 
Product Name: 
AVXS-101 
Dosage Form: 
Equivalent to the dose received by the second dosing cohort in the Phase 1 study 
Unit Dose 
1.1 X 1014 vg/kg; Equivalent to the dose received by the Cohort 2 in the Phase 1 
study (AVXS-101-CL-101) as determined by direct product testing with improved 
analytical methods. 
Route of Administration 
Intravenous infusion 
Physical Description 
AVXS-101 is a clear, colorless liquid. 
 
9.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be captured in the electronic Case Report Form (eCRF) 
from 2 weeks prior to administration of gene replacement therapy through the last study visit. 
9.2.1. 
Prophylactic Administration of Prednisolone 
An antigen specific T-cell response to the AAV vector was observed in the ongoing Phase 1 
clinical study (AVXS-101-CL-101) investigating AVXS-101 treatment via IV infusion.  This is 
an expected response between 2 to 4 weeks following gene replacement therapy.  One possible 
consequence to such antigen specific T-cell response is clearance of the transduced cells and loss 
of transgene expression. 
In an attempt to dampen the host immune response to the AAV-based therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion.  After 30 days of treatment, the 
dose of prednisolone can be tapered for patients whose ALT values, AST values, and T-cell 
response are below the threshold of ≤ 2 X ULN for ALT and AST, and < 100 SFC/106 PBMCs 
in accordance with the following treatment guideline: 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 38 of 142 
• Until at least 30 days post-infusion: 1 mg/kg/day 
• Weeks 5 and 6: 0.5 mg/kg/day 
• Weeks 7 and 8: 0.25 mg/kg/day 
• Week 9: prednisolone discontinued 
 
If the AST or ALT values are > 2 X ULN, or if T-cell response is ≥ 100 SFC/106 PBMCs after 
30 days of treatment, the dose of prednisolone will be maintained until the AST and ALT values 
decrease below threshold.  If T-cell response continues past Day 60, Investigator discretion 
should be used considering risk benefit for maintaining prednisolone.  Variance from these 
recommendations will be at the discretion of the Investigator based on potential safety issues for 
each patient. 
9.2.2. 
Prohibited Medications 
Concomitant use of any of the following medications is prohibited: 
• Drugs for treatment of diabetes, myopathy or neuropathy 
• Therapy received with the intent to treat SMA (e.g., nusinersen, valproic acid) 
o Oral β-agonists must be discontinued at least 30 days prior to gene therapy dosing.   
o Inhaled β-agonists may be used to treat respiratory complications of SMA provided 
such medications are dosed at clinically appropriate levels 
• Any investigational medication other than AVXS-101 is prohibited during the study 
• Ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as 
adalimumab, or immunosuppressive therapy within 3 months of starting the study 
(e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV 
immunoglobulin, rituximab) 
 
Corticosteroid usage following completion of the prednisolone taper is permissible as part of 
routine clinical management.  The use of corticosteroids in such circumstances should be 
documented appropriately as a concomitant medication, and the event precipitating its usage 
should be appropriately documented as an adverse event. 
Should the use of corticosteroids (aside from inhaled corticosteroids for bronchospasm) be 
considered as part of care during the course of the prednisolone taper, this medical management 
should be discussed with the medical monitor. 
9.3. 
Treatment Compliance 
AVXS-101 will be administered as a one-time IV injection. 
9.4. 
Randomization and Blinding 
This is an open-label study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 39 of 142 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT 
AVXS-101 is manufactured in accordance with current Good Manufacturing Practices (cGMP).  
Investigational product accountability logs will be maintained by the clinical pharmacy. 
10.1. 
Study Product 
AVXS-101 
10.2. 
Study Product Dose and Dose Justification 
Patients will receive a one-time dose of AVXS-101 at 1.1 X 1014 vg/kg, equivalent to the dose 
received by Cohort 2 in the Phase 1 study via IV infusion administered in the ongoing Phase 1 
clinical study (AVXS-101-CL-101). 
Two doses are being studied in the ongoing Phase 1 clinical study (AVXS-101-CL-101); the 
higher dose (dose received by the Cohort 2 patients) was chosen for the present study as 
preliminary data demonstrated both a dose response and significant clinical benefit thus 
identifying it as the proposed therapeutic dose.  In the Phase 1 study, AVXS-101 demonstrated a 
dose response, with efficacy greater as observed by motor milestone achievement and CHOP-
INTEND scores at the higher dose (received by Cohort 2) than the lower dose (received by 
Cohort 1).  Direct testing of the actual lot of Investigational Medicinal Product (IMP) used in the 
AVXS-101-CL-101 study by an improved and more fully qualified analytical method has 
assigned a value of 1.1 x 1014 vg/kg to the actual dose received by Cohort 2 in this Phase 1 study.  
The same method has been used to establish an equivalent dose for the Phase 3 IMP.  This vg/kg 
value has been further verified in an improved and more fully qualified SMN∆7 Mouse 
Biopotency assay to support a similar extension of mouse life time in direct comparative 
assessment between the Phase 1 and Phase 3 IMP. 
10.3. 
Study Product Packaging and Labeling 
AVXS-101 kits are labeled with a specific kit number and batch/lot number assigned at the 
cGMP facility.  The content of the labeling is in accordance with the local regulatory 
specifications and requirements. 
10.4. 
Study Product Storage 
AVXS-101 kits will be stored in an appropriate, locked room under the responsibility of the 
Investigator or other authorized persons (e.g., pharmacists) in accordance with local regulations, 
policies, and procedures.  Control of storage conditions, especially control of temperature (e.g., 
refrigerated/freezer storage) and information on in-use stability and instructions for handling 
prepared AVXS-101 should be managed in accordance with the Pharmacy Manual. 
The vessel used for delivery of the vector should be resealed in the procedure room and 
processed for destruction and/or return to AveXis in accord with the Pharmacy manual and 
applicable biohazardous waste guidelines for disposal. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 40 of 142 
10.5. 
Study Product Preparation 
Preparation of AVXS-101 will be done aseptically under sterile conditions by a pharmacist and 
will arrive at the clinical site ready for infusion. 
AVXS-101 will be received diluted with normal saline, as outlined in the Pharmacy Manual. 
The total vector genome dose will be calculated based on the patient’s body weight. 
The dose-delivery vessel will be delivered to the designated pediatric intensive care unit 
(PICU) patient room or other appropriate setting (e.g., interventional suite, operating room, 
dedicated procedure room) with immediate access to acute critical care management.  The 
vessel will be delivered in accord with the Pharmacy Manual. 
10.6. 
Study Product Administration 
AVXS-101 infusion will be administered under sterile conditions in a PICU or other appropriate 
setting (e.g., interventional suite, operating room, dedicated procedure room) with immediate 
access to acute critical care management.  AVXS-101 will be delivered one-time through a 
venous catheter inserted into a peripheral limb vein (arm or leg) at a dose equivalent to the dose 
received by the second dosing cohort in the Phase 1 study.  AVXS-101 should be slowly infused 
over approximately 30-60 minutes, dependent upon total volume in accord with the Pharmacy 
Manual, utilizing an infusion set and pump in accordance with the Pharmacy Manual. 
Following administration of gene replacement therapy, patients should return to an appropriate 
designated setting to ensure close monitoring of vital signs and adverse events.  Vital signs will 
be continuously monitored throughout the gene replacement therapy infusion as described in 
Section 12.1.3.  Patients should be maintained in the PICU or other appropriate setting for 
48 hours after the start of gene replacement therapy. 
10.7. 
Dose Adjustment Criteria 
The study investigates a one-time IV infusion of AVXS-101; no dose adjustments are possible. 
10.8. 
Study Product Accountability 
The pharmacist or designee will maintain accurate records of the quantities of AVXS-101 
received, dispensed, destroyed, and/or returned to AveXis.  The pharmacist or designee will 
document the date and time of delivery of the dose vessel to the dose procedure room as well as 
the time the used vessel was returned to AveXis or destroyed as per the Pharmacy Manual. 
10.9. 
Study Product Handling and Disposal 
All materials used for injection, including sterile drapes, needles, and syringes in contact with the 
vector must be sealed in leak-proof containers.  All waste must be sealed in bags bearing the 
biohazard symbol and disposed of in a biohazard waste container. 
All transfers must be done in spill-proof containers.  Individuals manipulating the vector will be 
required to wear personal protective equipment, such as gloves. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 41 of 142 
Any quality issue noticed with the receipt or use of AVXS-101 (e.g., deficiency in condition, 
appearance, pertaining to documentation, labeling, expiration date, etc.) should be promptly 
reported to the Sponsor in accord with procedures outlined in the Pharmacy Manual. 
Under no circumstances will the Investigator supply AVXS-101 to a third party, allow AVXS-
101 to be used other than as directed by this clinical trial protocol, or dispose of AVXS-101 in 
any other manner. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 42 of 142 
11. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed by achievement of the key developmental milestone of functional 
independent sitting for at least 30 seconds at the 18 months of age study visit and survival at 
14 months of age (as defined in Section 14.1.1.1).  The ability to thrive and the ability to remain 
independent of ventilatory support (as defined Section14.1.1.2) will also be assessed at 
18 months of age.  Additional developmental milestones will be assessed using the Bayley 
Scales of Infant and Toddler Development (version 3©).  Efficacy assessments will be performed 
at the times specified in the Table of Assessments (Appendix 1), and should be the first 
assessments performed at any scheduled visit.  All post-treatment visits will be relative to the 
date on which gene replacement therapy is administered except the 14 and 18 months of age 
visits, which will be relative to the patient’s date of birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
11.1. 
Developmental Milestones 
Developmental milestones will be assessed using relevant definitions obtained from the Bayley 
Scales of Infant and Toddler Development (version 3), and will be analyzed to assess efficacy 
(Appendix 3 and Appendix 4).  Achievement of each developmental milestone will be 
determined by the Physical Therapist and confirmed by the central reader (as may be necessary) 
based on an assessment of the submitted videos (Section 11.3).  Developmental milestones will 
be determined at each monthly visit as listed in Section 11.2.1. 
During the Screening visit, the physical therapist will complete an assessment of baseline 
milestone achievement in accordance with Appendix 1; this assessment must address all 
milestones/items noted on Appendix 1 that are at or below the child’s baseline function, and be 
recorded on video.  The findings must be documented in the source.  Items that are below the 
baseline level of assessment that are not successfully achieved during the baseline evaluation 
should be repeated at subsequent visits until successfully performed. 
The milestones of sitting independently (items 22 and 26) should be assessed at every subsequent 
visit, until attainment of milestone, regardless of starting point on the scale.  These milestones 
must also be assessed at the 18 months of age visit, regardless of previous attainment. 
As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each attained milestone be captured on video. 
A milestone will be considered achieved when demonstrated by a patient and observed with 
video capture confirmation during a physical therapy assessment or observed with video as 
provided by the patient’s family at the patient’s visit at 18 months of age. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 43 of 142 
11.2. 
Motor Function Tests 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones 
The Bayley Scales of Infant and Toddler Development (Version 3) (Appendix 3) is a 
standardized, norm-referenced infant assessment of developmental functioning across 5 domains 
of cognitive, language, motor, social-emotional, and adaptive behavior.  The Bayley Scales will 
be administered by a qualified Physical Therapist. 
The full Bayley Scales will be administered at screening, every 6 months starting at Month 6, 
and at End of Study when the patient reaches 18 months of age (or early termination), whereas 
the gross and fine motor subtests of the motor domain will be administered at each monthly visit. 
Each Bayley Scales/developmental milestone assessment will be video recorded in accordance 
with the AVXS-101-CL-303 Video Manual and may be submitted to the vendor for review by a 
central reader (Section 11.3). 
The following developmental milestones will be assessed: 
• Ability to hold head erect without support 
• Ability to roll from back to both sides 
• Ability to sit with support 
• Ability to sit independently, > 10 seconds; WHO [22] 
• Ability to sit without support for at least 30 seconds 
• Ability to crawl 
• Ability to pull to stand 
• Ability to stand with assistance 
• Ability to stand alone 
• Ability to walk with assistance 
• Ability to walk alone 
11.2.2. 
CHOP-INTEND 
The CHOP-INTEND is a motor function scale developed and validated for use specifically to 
monitor motor function status and decline amongst children with SMA Type 1, and will be 
administered by a qualified Physical Therapist.[23,24]  The CHOP-INTEND scale examines 
several aspects of motor function, including head control, righting reactions, and trunk 
movements in supported sitting, supine, and prone positions (Appendix 5).  Anti-gravity 
movements in assisted rolling, ventral suspension, and supported standing will also be measured. 
The CHOP-INTEND will be performed at screening and at each scheduled visit from Day 7 
through the End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 1). 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 44 of 142 
Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not undergo any additional 
CHOP-INTEND examinations. 
Each CHOP-INTEND exam will be video recorded in accordance with the AVXS-101-CL-303 
Video Manual and submitted to the vendor for review by a central reader as may be necessary 
(Section 11.3). 
11.3. 
Video Evidence 
Physical therapy assessments (Bayley Scales and CHOP-INTEND) required at each study visit 
will be video recorded in an effort to produce compelling, demonstrable, documented evidence 
of efficacy, as determined by changes in functional abilities.  AveXis, Inc. (AveXis) will provide 
a secure and confidential upload process for transfer and storage of the videos from 
investigational sites to a contracted third-party vendor that will compile and arrange videos as 
per AveXis requirements.  Any/all videos received at AveXis or the contracted vendor will be 
treated as confidential study data and will be the sole property of AveXis.  AveXis and the 
contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families on the videos, which may be shared with regulatory 
agencies, the medical community, and/or in appropriate venues to discuss the results of this 
clinical study. 
Videos may be provided to an independent, centralized reviewer for unbiased assessment of 
developmental milestone achievement.  The independent reviewer will document whether the 
video displays evidence of having achieved each developmental milestone.  The date of 
developmental milestone achievement will be computed as the earliest date on which video 
evidence demonstrates the achievement of the specified milestone. 
Additionally, the Parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the study.  These videos will be 
handled in the same manner in which the study-derived videos are handled. 
11.4. 
Compound Motor Action Potential 
Peroneal nerve CMAP amplitude will be measured by a qualified electrophysiologist, at all 
clinical sites capable of performing this assessment, using the procedures as described in the 
CMAP Manual (Appendix 6).  CMAP will be measured at screening, every 6 months starting at 
Month 6, and End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 1). 
The CMAP data will be collected for centralized review and interpretation. 
Sites that do not have equipment or appropriately experienced personnel required to perform 
CMAP measurements will not be required to perform these assessments. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 45 of 142 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety parameters include physical examinations, pulmonary examinations, vital signs, capillary 
blood gas assessments, weight and length measurements, 12-lead electrocardiograms (ECGs), 
12-lead Holter monitor recordings, echocardiograms, swallowing tests, laboratory assessments, 
adverse event monitoring, and photographs of the infusion site.  In general, safety assessments 
will be performed at the times specified in the Table of Assessments (Appendix 1).  All post-
treatment visits are relative to the date on which gene replacement therapy is administered until 
the patient reaches 14 months of age, at which point all visits are relative to the patient’s date of 
birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
12.1.1. 
Demographic/Medical History 
Demographic/medical history information will be collected at screening and captured in the 
eCRF.  Information that will be collected includes: 
• Familial history of SMA including affected siblings or parent carriers 
• Gestational age at birth 
• Length/height/head circumference at birth 
• Hospitalization information from time of birth including number, duration, and reason for 
hospitalizations including International Statistical Classification of Diseases and Related 
Health Problems (ICD-10 codes), if available 
• Historical ventilatory support, if any 
• Historical feeding support, if any 
 
1. Patients are encouraged to follow all routinely scheduled immunizations, as 
recommended by the Center for Disease Control (CDC), throughout the study.  Seasonal 
vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent 
respiratory syncytial virus (RSV) infections are also recommended in accordance with 
American Academy of Pediatrics (27). 
12.1.2. 
Physical Examinations 
Physical examinations will be conducted by the Investigator or Sub-Investigator at each 
scheduled visit, except Day –1 (Appendix 1).  The Day 1 physical examination will be 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 46 of 142 
performed prior to the start of gene replacement therapy infusion.  Physical examinations include 
a review of the following systems: head, eyes, ears, nose and throat (HEENT), lungs/thorax, 
cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, lymphatic, and 
genitourinary. 
12.1.3. 
Vital Signs/Weight and Length 
Vital sign parameters include blood pressure, respiratory rate, pulse, axillary temperature, and 
pulse oximetry.  Vital signs will be obtained at each study visit (as specified in Appendix 1).  On 
Day 1, vital signs will be continuously monitored throughout the gene replacement therapy 
infusion, and recorded pre-dose and every 15 (± 5) minutes for the first 4 hours after the start of 
infusion, and then every hour (± 15 minutes) until 24 hours after the start of infusion.  Axillary 
temperature will be recorded pre- and post-infusion. 
Weight and length will be measured at each study visit (as specified in Appendix 1).  On Day 1, 
weight and length will be measured pre-dose. 
12.1.4. 
Electrocardiogram 
A 12-lead ECG will be performed at screening, Day –1, pre-dose on Day 1, Day 2, every 
6 months starting at Month 6, and End of Study when the patient reaches 18 months of age (or 
early termination) (Appendix 1).  Additional ECG monitoring will be at the discretion of the 
Investigator as per local institutional guidelines. 
The ECG will be interpreted locally by a cardiologist.  The ECG tracings or ECG machine data 
will be collected for centralized review and interpretation by a cardiologist. 
12.1.5. 
12-Lead Holter Monitor 
A Holter monitor will continuously record the patient’s 12-lead ECG for a total of 72 hours from 
Day –1 (24 hours prior to the start of gene replacement therapy infusion) through 48 hours after 
the start of infusion.  Serial ECG data will be pulled in triplicate from the Holter monitor at the 
following time points: 
• Pre-dose (within 24 hours prior to gene replacement therapy) 
• 2 hours 
• 4 hours 
• 6 hours 
• 8 hours 
• 12 hours 
• 24 hours 
• 36 hours 
• 48 hours 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 47 of 142 
Holter monitors will be provided to study sites along with a dedicated laptop for uploading the 
data from the memory cards for centralized review and analysis by a cardiologist within 24 hours 
of data upload.  The Sponsor physician or designee will be notified of any safety concerns from 
the centralized review, and the safety management plan will be followed for documenting and 
reporting of AEs/SAEs. 
12.1.6. 
Echocardiogram 
A standard transthoracic echocardiogram will be performed at screening, every 6 months starting 
at Month 6, and at End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 1). 
12.1.7. 
Pulmonary Examinations 
Pulmonary examinations will be performed by a pulmonologist or appropriate individual as per 
standard institutional practice at each scheduled visit except Day 1 (Appendix 1).  Prior to study 
entry, a pulmonologist or appropriate individual as per standard institutional practice will review 
and document ventilator usage in the 2 weeks prior to screening. 
Patients may be fitted with non-invasive ventilatory support at the discretion of the 
pulmonologist or appropriate individual as per standard institutional practice and/or Investigator.  
Non-invasive ventilatory support equipment will be provided by AveXis through a third-party 
vendor.  Should the patient require non-invasive ventilatory support at any time during the study, 
the equipment provided by AveXis must be used. 
Patients requiring non-invasive ventilatory support will be asked to bring their machine(s) to 
each study visit such that the study staff can remove an SD card which captures actual usage 
data.  The hours per day usage data for each day between visits will be extracted with software 
provided by the device manufacturer into a format that will be transferred/transcribed to the 
clinical database. 
12.1.8. 
Swallowing Test 
A swallowing test will be performed at screening (at the Investigator site), every 6 months 
starting at Month 6, and at End of Study when the patient reaches 18 months of age (or early 
termination) (Appendix 1) to determine if the patient has signs of aspiration.  If the test is 
positive for aspiration, there may be a recommendation for the patient to use an alternate method 
to oral feeding for the duration of the study at the determination of the Investigator and treating 
clinician. 
12.1.9. 
Photographs of Infusion Site 
Photographs will be taken of the infusion site at each scheduled visit from Day 1 (pre-dose) 
through Day 30 (Appendix 1) to monitor healing of the infusion site.  AveXis will provide a 
secure and confidential upload process for transfer and storage of the photographs from the 
investigative sites to a contracted third-party vendor that will compile and arrange photographs 
as per AveXis requirements.  Any/all photographs received at AveXis or the contracted vendor 
will be treated as confidential study data and will be the sole property of AveXis.  AveXis and 
the contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families in the photographs, which may be shared with 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 48 of 142 
regulatory agencies, the medical community, and/or in appropriate venues to discuss the results 
of this clinical study. 
12.1.10. 
Laboratory Assessments 
Blood samples will be collected at each scheduled visit, except Day 1 and Day 3 (as specified in 
Appendix 1).  On Day -1, blood and urine samples will be processed locally for receipt of results 
prior to the start of gene replacement therapy infusion.  Any clinically significant laboratory 
value will be repeated at the discretion of the Investigator. 
Blood samples will be collected and shipped to a central laboratory.  Samples for laboratory tests 
required during the in-patient vector infusion period prior to dosing will be collected and 
processed by the investigative site’s Clinical Laboratory Improvement Amendment (CLIA) 
CLIA-certified local laboratory to ensure receipt of results prior to dosing. 
Table 6: 
Total Blood Volume 
Visit 
Tests 
Total Volume (mL) 
Screening 
Hematology, chemistry/CK-MB, virus serology,  
 immunology sample (AAV9 Ab only),   
diagnostic confirmation sample 
16.9 
Day –1 
Hematology, chemistry, capillary blood gas  
3.3 
Day 2 
Hematology, chemistry, capillary blood gas 
3.3 
Day 7 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.6b 
Day 14 
Hematology, chemistry, immunology sample (AAV9/SMN Ab 
only) 
3.3 
Day 21 
Hematology, chemistry, immunology sample (AAV9/SMN Ab 
only) 
3.3 
Day 30 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.6b 
Day 60 
Hematology, chemistry/CK-MB, 
3.6 
Month 
3/4/5/7/8/10/11/
13/14/16/17 
Hematology, chemistry 
25.3 
Month 6/9/12/15 
Hematology, chemistry/CK-MB 
14.4 
End of Study/ET 
Hematology, chemistry/CK-MB 
3.6 
Maximum Total Volume for Studya 
96.2 
ET = early termination 
a Patients will have different numbers of monthly visits, depending on their age at dosing.  Maximum total volume based on a 
maximum of 16 monthly visits, provided T-cell responses are not elevated at Day 30 requiring additional surveillance 
samples and virus serology is not positive at screening requiring additional testing 
b Immunology sample for IFN-γ ELISpots requires 4-6 mL whole blood.  Immunology sample for ELISA requires 1 mL whole 
blood.  When drawn at the same visit, 4-6 mL is sufficient for both assays. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 49 of 142 
In a case where sufficient blood cannot be collected from a patient, blood will be used in the 
following priority order with the first having greatest priority and last having the least priority: 
1. Safety labs 
a. Chemistry 
b. Hematology 
c. CK-MB 
2. Interferon gamma (IFN-γ) ELISpots to detect T-cell responses 
3. Serum antibody to AAV9 and SMN 
4. Genetic reconfirmation testing 
 
If there is not sufficient blood volume to include the genetic reconfirmation testing sample at the 
screening visit, patient must return before Visit 2.  All patients must have genetic reconfirmation 
testing completed. 
12.1.10.1. Hematology 
Hematology analysis will include a complete blood count with differential and platelet count 
with smear.  Samples will be collected and shipped in accordance with the laboratory manual 
provided by the central laboratory.  Blood samples for hematology analysis will be collected at 
all scheduled visits except Day 1 and Day 3 (Appendix 1). 
Immediate/same-day hematology analyses required during in-patient dosing, as determined by 
the Investigator, will be performed as per investigational site standard procedures at the local 
laboratory.  Investigators will receive hematology results from all study visits from the central 
laboratory. 
12.1.10.2. Blood Chemistry 
Samples will be collected and shipped in accordance with the laboratory manual provided by the 
central laboratory.  Blood samples for chemistry analysis will be collected at all scheduled visits 
except Day 1 and Day 3 (Appendix 1). 
Immediate/same-day chemistry analyses required during in-patient dosing, as determined by the 
Investigator, will be performed as per investigational site standard procedures at the local 
laboratory. 
Chemistry analysis will include the following at all study visits: 
• Serum GGT 
• AST/ALT 
• Serum total bilirubin 
• Direct bilirubin 
• Albumin 
• Glucose 
• Total creatine kinase  

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 50 of 142 
•
Creatinine
•
BUN
•
Electrolytes
•
Alkaline phosphatase
Creatine kinase (CK-MB) will be collected at Screening, Day 7, Day 30, Day 60, every 90 days, 
and at End of Study. 
Investigators will receive chemistry results from all study visits from the central laboratory 
(except Day -1). 
12.1.10.3. Urinalysis 
Urine samples will be collected in accordance with the laboratory manual provided by the central 
laboratory at all study visits except Day 1 and Day 3 (Appendix 1).  Day -1 urinalysis will be 
performed as per investigational site standard procedures at the local laboratory.  Urinalysis will 
include the following parameters: 
•
Color
•
Clarity/turbidity
•
pH
•
Specific gravity
•
Glucose
•
Ketones
•
Nitrites
•
Leukocyte esterase
•
Bilirubin
•
Blood
•
Protein
•
Red Blood Cell
•
White Blood Cell
•
Squamous epithelial cells
•
Casts
•
Crystals
•
Bacteria 
•
Yeast

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 51 of 142 
12.1.10.4. Virus Serology 
The administration of an AAV vector has the risk of causing immune-mediated hepatitis.  For 
patients who have HIV or positive serology for hepatitis B or C or Zika virus, administration of 
AAV vector may represent an unreasonable risk; therefore negative serology testing must be 
confirmed at screening, prior to treatment.  These samples will be collected at screening 
(Appendix 1) and shipped in accordance with the laboratory manual provided by the central 
laboratory. 
12.1.10.5. Capillary Blood Gas 
Capillary blood gas will be completed locally at Day –1 and Day 2 (Appendix 1).  A puncture or 
small incision will be made with a lancet or similar device into the cutaneous layer of the 
patient’s skin at a highly vascularized area (heel, finger, toe).  To accelerate blood flow and 
reduce the difference between the arterial and venous gas pressures, the area will be warmed 
prior to the puncture.  As the blood flows freely from the puncture site, the sample will be 
collected in a heparinized glass capillary tube. 
12.1.10.6. Immunology Testing (ELISA and IFN-γ ELISpots) 
Blood samples for immunology testing will be collected and shipped to the central laboratory in 
accordance with the laboratory manual to test for serum antibodies to AAV9 and SMN (ELISA), 
and to perform IFN-γ ELISpots to detect T-cell responses to AAV9 and SMN.  Blood samples 
will be collected at screening (ELISA anti-AAV9 only), Day 7, Day 14 (ELISA anti-
AAV9/SMN only), Day 21 (ELISA anti-AAV9/SMN only), and Day 30 (Appendix 1).  
Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to 
be elevated, based on further discussion with the Principal Investigator and Medical Monitor. 
12.1.10.7. AAV9 Antibody Screen in Mother 
There is potential that the biological mother of the patient may have pre-existing antibodies to 
AAV9 that may be transferred to the patient through breast milk or, theoretically, via placental 
transfer in utero.  Informed consent will be requested from the biological mother of the patient to 
screen the mother for circulating antibodies to AAV9.  Once informed consent has been 
obtained, the mother will have her blood drawn from a peripheral vein at screening and shipped 
to the central laboratory for screening of anti-AAV9 antibodies.  Mothers who test positive for 
antibodies to AAV9 will be asked to refrain from further feedings with breast milk. 
If AAV9 antibodies are identified, the patient must desist in consuming breast milk from the 
biological mother. 
Patients consuming banked breast milk from donor sources that cannot be test for anti-AAV9 
antibodies must be transitioned to formula prior to participation. 
12.1.10.8. Blood for Diagnostic Confirmation Testing 
A blood sample will be collected during the screening visit and shipped to the central laboratory 
in accordance with the laboratory manual for reconfirmation of SMN1 deletions/mutations, 
SMN2 copy number, and absence of exon 7 gene modifier mutation (c.859G>C).  This will be 
done to ensure consistency in diagnostic testing practices. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 52 of 142 
12.1.10.9.   Saliva, Urine, and Stool Collection 
Studies have shown that some vector can be excreted from the body for up to a few weeks after 
injection; this is called “viral shedding.”  Vector shedding can be found in the blood, urine, 
saliva, and stool for up to 1 week following infusion.  The potential health risks associated with 
the shed vector are not fully known at this time; however the health risk is thought to be low as 
the vector cannot replicate.  Regardless, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved instructions should be provided to the patient’s family and care 
giver(s) regarding use of protective gloves if/when they come into direct contact with the 
patient’s bodily fluids and/or waste, as well as good hand-hygiene for a minimum of 2 weeks 
(14 days) after gene replacement therapy.  Additionally, patients are prohibited from donating 
blood for 2 years following the vector infusion. 
Saliva, urine, and stool samples will be collected for viral shedding studies at screening, 24 hours 
post-dose, 48 hours post-dose, Day 7, Day 14, Day 21, and Day 30 (Appendix 1).  Samples will 
be collected, prepared, and shipped as per the laboratory manual. 
A subset of patients at sites opting to participate in the viral shedding sub-study will have 24-
hour total volume urine and fecal samples collected through 24 hour post-dose and through 48 
hours-post dose. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 53 of 142 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1.1. 
Definition of Adverse Events 
13.1.1.1. Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product.  In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no study treatment has been administered. 
All adverse events that occur from the start of gene replacement therapy infusion through the last 
study visit will be collected and recorded in the eCRF. 
All adverse events will be classified in accordance with the CTCAE version 4.03 outlined in 
Table 7. 
 
Table 7: 
Common Terminology Criteria for Adverse Events 
Grade 
Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Source: Common Terminology Criteria for Adverse Events (version 4.03) [9] 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
Study enrollment will be interrupted should any patient experience an unanticipated CTCAE 
Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the 
gene replacement therapy.  The event will then be reviewed by the DSMB and an evaluation will 
be made as to whether the study should be terminated early following the discontinuation rules. 
Unanticipated CTCAE Grade 3 or higher adverse events that are possibly, probably, or definitely 
related to the gene replacement therapy must be reported within 24 hours to Sponsor and/or 
designee as per study safety management plan to ensure timely escalation to the DSMB. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 54 of 142 
13.1.1.2. Serious Adverse Event 
A SAE is an AE occurring during any study phase (e.g., baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, or comparator that fulfils one or more of the 
following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
All SAEs that occur after signing of the informed consent through the last study visit, whether or 
not they are related to the study product, must be collected and recorded on forms provided by 
the Contract Research Organization. 
13.1.1.3. Other Adverse Event 
The following specific treatment-emergent AE of special interest, which may be searched using 
Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries, will be 
summarized: 
• Elevated liver enzymes 
 
Other adverse events (OAE) will be identified by the Drug Safety Physician and, if applicable, 
also by the Clinical Study Team Physician during the evaluation of safety data for the Clinical 
Study Report.  Significant adverse events of particular clinical importance, other than SAEs and 
those AEs leading to discontinuation of the patient from the study, will be classified as OAEs.  
For each OAE, a narrative may be written and included in the Clinical Study Report. 
13.2. 
Relationship to Study Product 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related or Probably Related).  The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.”  If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” then the event will be considered related to the investigational product 
for the purposes of expedited regulatory reporting. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 55 of 142 
13.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Information about AEs will be collected from the time of vector infusion 
until the end of the study.  Serious Adverse Event information will be collected from signing of 
consent form until the last study visit.  The AE term should be reported in standard medical 
terminology when possible.  For each AE, the Investigator will evaluate and report the onset 
(date (and time if during Visit 2)), resolution (date (and time if start date during Visit 2)), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the patient to discontinue the study. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 13.1.1.2.  An AE of severe intensity 
may not be considered serious. 
13.4. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of consent form until the last 
study visit.  Any SAEs considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All SAEs must be 
reported to AveXis or designee within 24 hours of the first awareness of the event.  The 
Investigator must complete, sign and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy by fax or 
e-mail to AveXis or designee. 
Additional follow-up information, if required or available, should all be faxed or e-mailed to 
AveXis or designee within 24 hours of receipt and this should be completed on a follow-up SAE 
form and placed with the original SAE information and kept with the appropriate section of the 
eCRF and/or study file. 
AveXis is responsible for notifying the relevant regulatory authorities of certain events.  It is the 
Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at his or 
her site.  Investigators will also be notified of all unexpected, serious, product-related events 
(7/15 Day Safety Reports) that occur during the clinical study.  Each site is responsible for 
notifying its IRB or IEC of these additional SAEs. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 56 of 142 
14. 
STATISTICS 
This section summarizes key aspects of the analysis plan including definitions of co-primary, 
co-secondary, and 
 and safety endpoints, and the methods to be 
used to test the primary effectiveness hypothesis.  Additional details regarding methods for the 
final data analysis will be provided in a separate Statistical Analysis Plan (SAP) which will be 
finalized and submitted to the Investigational New Drug application prior to the enrollment of 
the first patient.  The SAP will detail all analyses and data displays, and will be executed 
according to Standard Operating Procedures in a controlled environment. 
14.1. 
Study Endpoints and Populations 
14.1.1. 
Study Endpoints 
The primary and efficacy endpoint will be compared to the null.  The survival co-primary 
efficacy variable will be evaluated relative to literature-based historical controls (such as the 
Pediatric Neuromuscular Clinical Research Network [PNCR] [21].  These were selected on the 
basis of comparability to the target population and similarity to the investigational device. 
14.1.1.1. Co-Primary Efficacy Endpoint 
The co-primary efficacy endpoints are: 
• The proportion of patients that achieve functional independent sitting for at least 30 seconds 
at the 18 months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler 
Development (Version 3) (Appendix 3), confirmed by video recording, as a patient who sits 
up straight with the head erect for at least 30 seconds. 
• The survival at 14 months of age.  Survival is defined by the avoidance of the combined 
endpoint of either (a) death or (b) permanent ventilation, which is defined by tracheostomy or 
by the requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive 
ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, 
excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
 
An “acute reversible illness” is defined as any condition other than SMA that results in increased 
medical intervention (e.g., increased requirement for respiratory support; use of other 
concomitant medications as rescue) requirements and is expected to be reversible or improved 
following definitive intervention (e.g., surgery, antibiotics) or introduction of escalated 
supportive care, such as hospitalization (e.g., for upper respiratory infection, spontaneous 
fracture).  The specific duration of the condition antecedent intervention shall not be considered 
in the definition of “acute.”  The date of “definitive intervention” shall be defined as the date of 
provision of a procedure (e.g., surgery, etc.) or medication (e.g., antibiotics) intended to cure or 
substantially improve the condition.  For conditions such as viral respiratory infections for which 
supportive care is provided, the date of “definitive intervention” shall be considered the date of 
hospitalization or substantial escalation of care. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 57 of 142 
“Perioperative” use reflects any alteration of ventilatory use related to a surgical or other medical 
procedure of any nature for which the patient received medications that could impair or interfere 
with respiratory function. 
For a patient who develops an acute reversible illness and/or requires perioperative ventilatory 
support, a recovery period not to exceed 21 days following the date of definitive intervention will 
be instituted.  Following this recovery period, the condition will be considered subacute and the 
patient will become evaluable with regards to the surrogate survival endpoint (requirement of 
ventilatory support of ≥ 16 hours/day for 14 or more days). 
14.1.1.2. Co-Secondary Efficacy Endpoint 
The co-secondary efficacy endpoints are: 
• The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate 
thin liquids (as demonstrated through a formal swallowing test) and to maintain weight 
(> third percentile based on World Health Organization [WHO] Child Growth Standards [26] 
for age and gender) without need of gastrostomy or other mechanical or non-oral nutritional 
support at 18 months of age. 
• The proportion of patients who are independent of ventilatory support, defined as requiring 
no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and 
perioperative ventilation, as defined above through assessment of actual usage data captured 
from the device (Phillips Trilogy). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 58 of 142 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.1.1.4. Safety Endpoints 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• Incidence of elevated LFTs and/or unresolved LFEs 
• Incidence of CTCAE Grade 3 or higher toxicity, treatment-emergent adverse events 
• Clinically significant changes in laboratory values, physical exams, cardiac assessments or 
vital signs 
• Research Immunology Blood Labs including serum antibody to AAV9 and SMN as well as 
IFN-γ ELISpot to detect T cell responses to AAV9 and SMN 
 
14.1.2. 
Statistical Analysis Populations 
14.1.2.1. Intent-to-Treat Population (ITT) 
The ITT population will consist of symptomatic patients with bi-allelic deletion mutations of 
SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene 
modifier mutation (c.859G>C) who receive an IV infusion of AVXS-101 at less than 180 days of 
age.  The first three patients enrolled must meet the criteria for the Intent-to-Treat Population. 
14.1.2.2. Efficacy Completers Population 
The efficacy completers analysis population will consist of: 
• All treated patients who reach 14 months of age, OR 
• All treated patients who meet discontinuation criteria, discontinue the study due to an AE or 
death 
 
14.1.2.3. All Enrolled Population 
The all enrolled population will consist of all patients who receive an IV infusion of AVXS-101.  
Analyses of endpoints in this population are considered descriptive. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 59 of 142 
14.1.2.4. Safety Population 
The safety analysis population will consist of all patients who receive an IV infusion of 
AVXS-101.  All safety analyses will be conducted on the safety analysis population. 
14.2. 
Sample Size Calculation 
This is a pivotal Phase 3, open-label, single-arm, single-dose, study assessing the efficacy and 
safety of AVXS-101 (gene replacement therapy) in up to twenty (20) patients with spinal 
muscular atrophy (SMA) Type 1 who meet enrollment criteria, may be either symptomatic or 
pre-symptomatic and are genetically defined by no functional survival motor neuron 1 gene 
(SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2) and who are < 6 months 
(< 180 days) of age at the time of gene replacement therapy (Day 1).  Enrolling up to twenty 
(20) patients under the broader enrollment criteria is projected to enable enrollment of at least 
fifteen (15) patients that meet the Intent-to-Treat Population (ITT) criteria. The ITT population is 
identified as symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without 
the SMN2 gene modifier mutation (c.859G>C) and will comprise the primary population for 
evaluation of the primary and secondary endpoints.  Study power is based upon efficacy analysis 
of the ITT population.  Furthermore, the first three patients enrolled must meet criteria for the 
Intent-To-Treat Population to enable a comparison of CHOP-INTEND scores at one-month 
following gene replacement therapy to enable a comparison of patient response between AVXS-
101-CL-303 patients and Cohort 2 patient results from the Phase 1 trial (AVXS-101-CL-101).  
Patients with 1 copy of SMN2, pre-symptomatic patients and patients with the SMN2 gene 
modifier mutation (c.859G>C) and other permutations outside of those specified in the ITT 
population will be evaluated separately as part of additional subgroup analyses.  Details of all 
analyses will be contained within the Statistical Analysis Plan. 
The two co-primary efficacy endpoints will be assessed in sequence:  The endpoint of functional 
independent sitting will be assessed first and, only if this assessment meets statistical 
significance will the endpoint of survival be assessed. 
Based upon the widely cited natural history of the disease (Pediatric Neuromuscular Clinical 
Research Network [PNCR]) [Neurol. 2014; 83(9):810-817], it is expected that no patients in this 
population would be expected to attain the ability to sit without support or accomplish other 
milestones (rolling over, standing, walking) prior to 18 months of age.  Assuming that the true 
response rate for the primary endpoint is actually zero (or as low as 0.1%) in the population of 
interest of the historical control, the first co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 18 
months of age study visit. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 40% of treated symptomatic patients with bi-allelic deletions of SMN1 and 2 copies of 
SMN2 without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-
primary efficacy endpoint of functional independent sitting for at least 30 seconds at the 18 
months of age study visit.  With the assumption for the true response rate of AVXS-101 for the 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 60 of 142 
primary endpoint being in the range of 30% - 40%, a sample size of 15 patients that meet ITT 
criteria will be enrolled and assuming approximately 30% of patients are excluded from analysis, 
would yield an ITT population that would provide power of > 90% to detect a significant 
difference from 0.1% with α = 0.025 using a 1-sided exact test for a binomial proportion. 
The second co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐸𝐸𝐿𝐿, 
where 𝑝𝑝 is the proportion of patients surviving at 14 months of age. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 80% of treated symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 
without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-primary 
efficacy endpoint of survival through 14 months of age.  It is anticipated that 75% of patients in 
the PNCR population would not survive beyond 13.6 months of age, and that these control 
patients will represent a 25% survival rate based upon the natural history of the disease.  With 
this efficacy, an enrolled sample size of  15 patients that meet ITT criteria (assuming 30% of 
patients are excluded from the analysis) would yield an ITT population that would provide power 
of > 80% to detect a significant difference from the historical control with α = 0.05 using a 2-
sided Fisher’s Exact test, comparing to the 26 age and gender matched patients from a published 
natural history observational study performed at 3 large, tertiary care centers in the United States 
(Harvard University, Columbia University, Children’s Hospital of Philadelphia; PNCR). 
14.3. 
Efficacy Analysis 
14.3.1. 
General Considerations 
This study will compare the activity of AVXS-101 administered IV versus the natural 
observational results from PNCR [21] in terms of functional independent sitting and survival 
rate.  The ability to thrive and the ability remain independent of ventilatory support will also be 
assessed. 
The analysis of the co-primary and co-secondary efficacy endpoints will be performed for the 
ITT and efficacy completers population.  The analysis based on the ITT population will be 
considered as the primary analysis.  In the case of missing data, observed data will be used for 
the analyses. 
Unless otherwise specified, the baseline measurement is defined as the last non-missing 
measurement collected prior to or on the day of gene replacement therapy infusion (e.g., on or 
before Day 1 visit). 
14.3.2. 
Primary and Secondary Efficacy Analysis 
Primary and secondary efficacy analyses will be based on the ITT population, those patients that 
are symptomatic with bi-allelic deletion mutations of SMN1 and 2 copies of SMN2 without the 
SMN2 gene modifier mutation (c.859G>C).  These analyses are to test the superiority of AVXS-
101 to the results from natural observation study (PNCR) [21]. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 61 of 142 
The first co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1% 
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 18 
months of age study visit. 
The second co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 , 
where 𝑝𝑝 is the proportion surviving at 14 months of age. 
Primary efficacy endpoints will be examined on the ITT population.  Testing for the first co-
primary endpoint, functional independent sitting will first be performed using 1-sided exact 
binomial test.  Only if the null hypothesis of equality in proportion of functional independent sitting 
is rejected at p<0.025, will the co-primary endpoint survival improvement be tested using 2-sided 
Fisher’s Exact test on the ITT population, comparing to matched patients from natural observational 
study (PNCR).  This hierarchy approach strongly protects the Type I error rate. 
The hypothesis for both co-secondary efficacy endpoints to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1% , 
where p is the proportion of patients maintaining the ability to thrive/are independent of 
ventilatory support. 
One-sided exact binomial tests will be executed for secondary efficacy analyses on the ITT 
population.   
A sensitivity analysis will be conducted by repeating the primary efficacy analysis on the 
efficacy completers analysis population. 
14.4. 
CHOP-INTEND Comparison 
A comparison will be performed of the first three patients CHOP-INTEND scores to the AVXS-
101-CL-101 CHOP-INTEND scores.  The first three patients enrolled must meet the criteria for 
the Intent-to-Treat (ITT) Population.  AveXis will compare the CHOP-INTEND one month 
improvement for the AVXS-101-CL-303 patients that meet the ITT criteria to assess the clinical 
response to the dose 1.1 x 1014 vg/kg as being what was expected from the Cohort 2 patients in 
the Phase 1 trial (AVXS-101-CL-101).  This comparison will be performed as a per patient 
assessment for the first three patients.  The individual patients who receive their gene therapy at 
0-3 months of age will be compared to a value of 10 CI points, while patients who receive their 
gene therapy at >3 but <6 months of age will be compared to a value of 5 CI points.  
Furthermore, patients from either age group are expected to maintain the improvement in the 
absence of an acute illness or perioperatively.  If the expected CI improvements are observed for 
the first three ITT patients, AveXis will remove the 30-day interval between patients and proceed 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 62 of 142 
to dose at least 12 additional patients that meet the ITT criteria and perform safety and efficacy 
assessments as described elsewhere in the clinical protocol (AVXS-101-CL-303) and 
corresponding Statistical Analysis Plan.  If the expected CI improvements are not observed for 
the first three ITT patients, AveXis will discuss next steps with the FDA before continuing study 
enrollment. 
14.5. 
Safety Analysis 
Safety will be assessed through the incidence and severity of AEs, vital sign assessments, cardiac 
assessments, laboratory evaluations (chemistry, hematology, urinalysis, immunology), physical 
examinations, and use of concomitant medications.  Adverse events will be coded in accordance 
with the most current version of the MedDRA coding dictionary. 
Safety analyses will be conducted on safety population, and summarized by subgroup and 
overall. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 63 of 142 
15. 
DATA SAFETY MONITORING BOARD 
The DSMB is an independent multidisciplinary group consisting of clinicians and a 
biostatistician that, collectively, have experience in the management of patients with SMA 
Type 1 and other diseases, and in the conduct and monitoring of randomized clinical studies with 
interim analyses.  The DSMB will be chartered to oversee the safety of patients during the 
conduct of the study, and will act in an advisory capacity to AveXis.  A detailed description of 
the DSMB, its role in this study, and the timing of the scheduled reviews will be described in a 
DSMB Charter. 
The DSMB will routinely convene on a quarterly basis to review emerging safety data from the 
study.  All available safety data from all enrolled patients will be included in such reviews, 
which include, but are not limited to, screen failures, enrollment status, data from safety 
parameters, all SAEs, and other AEs.  Following each meeting, the DSMB will make a 
recommendation as to whether or not the accumulated safety data warrants a suspension or 
discontinuation of the study, a modification to the study, or any additional comments or 
recommendations related to safety.  The DSMB will prepare and provide minutes of their 
meetings to AveXis who will provide copies to the regulatory authorities as appropriate. 
The DSMB will also convene on an ad hoc basis within 48 hours should any patient experience 
an unanticipated CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely 
related to gene replacement therapy, and is associated with clinical symptoms and/or requires 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the 
DSMB will review the safety information and provide its recommendation. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 64 of 142 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of AveXis will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of AveXis or its representatives.  This will be 
documented in a Clinical Study Agreement between AveXis and the Investigator. 
During the study, a monitor from AveXis or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed 
• Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the study.  This will require direct access to all original records for each patient (e.g., clinic 
charts, electronic medical records) 
• Record and report any protocol deviations not previously sent to AveXis 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any SAEs 
have been forwarded to AveXis and those SAEs that met criteria for reporting have been 
forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of AveXis, a regulatory authority, an IEC or an IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of an AveXis 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP) 
guidelines of the International Council for Harmonization (ICH), and any applicable regulatory 
requirements.  The Investigator should contact AveXis immediately if contacted by a regulatory 
agency about an inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 65 of 142 
16.3. 
Institutional Biosafety Committee 
As this study involves gene therapy, the Principal Investigator must obtain approval/favorable 
opinion for the investigation from a designated institutional or independent biosafety committee 
in accordance with institutional requirements and/or guidelines. 
16.4. 
Institutional Review Board/Institutional Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation (Section 18.1).  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 66 of 142 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Qualified individuals designated by the Sponsor will monitor all aspects of the study according 
to GCP, standard operating procedures (SOPs), and for compliance with applicable government 
regulations.  Please see Section 16.1 for more details regarding the quality control and 
monitoring process.  AveXis may also conduct a quality assurance audit any time during or after 
the completion of the study.  Please see Section 16.2 for more details regarding the audit process. 
The Investigator agrees to allow these Sponsor representatives direct access to the clinical data 
and supplies, dispensing and storage areas and if requested, agrees to cooperate fully or assist the 
Sponsor representative.  The Investigator and staff are responsible for being present or available 
for consultation during routinely scheduled site visits conducted by the Sponsor or its designees. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
Investigator, site staff, or representatives of the Sponsor will lead to prompt action by the 
Sponsor to secure compliance.  Continued noncompliance may result in termination of the 
corresponding party’s involvement in the study.  The IRB/IEC and relevant regulatory authority 
will also be informed. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 67 of 142 
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval to AveXis before he or she can enroll any patient into 
the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  AveXis or designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (Appendix 7) and are consistent with ICH/GCP, applicable regulatory 
requirements and the AveXis’ policy on Bioethics. 
18.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the parent(s)/legal guardian(s) are 
given full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study.  The parent(s)/legal guardian(s) must also be notified that they are free to 
discontinue the patient from the study at any time.  The parent(s)/legal guardian(s) should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the parent(s)/legal guardian(s). 
There will be 3 informed consent forms: 
• Parent(s)/legal guardian(s) informed consent form 
• Biological mother baseline AAV9 antibody screening informed consent form 
• Autopsy informed consent form (Appendix 2; if the parent(s)/legal guardian(s) decline an 
autopsy, it will not prevent the patient from participating in the study) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 68 of 142 
19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Electronic Case Report Forms 
Adequate and accurate case records will be maintained and all relevant observations and data 
related to the study will be recorded.  This will include medical history/ physical examination, 
hematology, clinical chemistry and serology results, a check list of inclusion and exclusion 
criteria, product administration, and a record of sample collection, hemodynamic measurements, 
clinical assessments, AEs, and final evaluation. 
Electronic CRFs will be used in this study.  The eCRF will be electronically signed and dated by 
the Principal Investigator or designee after his/her review.  After the completion of the study, 
completed eCRFs will be retained in the archives. 
Completed eCRFs will be reviewed by the study monitor against the source documentation for 
accuracy and completeness.  Once signed by the Investigator, the monitor will transmit the 
completed eCRFs to data management for data validation and database analysis. 
19.2. 
Inspection of Records 
AveXis or designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the product storage area, study product stocks, product accountability records, patient 
charts and study source documents, and other records relative to study conduct. 
19.3. 
Retention of Records 
All primary data that are a result of the original observations and activities of the study and that 
are necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period not less than 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have lapsed since the formal 
discontinuation of the clinical development of the investigational product.  All country/region 
specific requirements that may be more stringent than the 2 years included in ICH shall be 
followed. 
The site will maintain a Clinical Study Document Binder, which will be maintained at the study 
site.  In this binder, there will be tabbed sections for study documents including the following: 
study personnel identification and signature list, patient / subject screening records, patient / 
subject roster (names omitted), protocol and amendments or administrative changes, FDA Form 
1572 (if required), study staff Curricula Vitae, IRB/IEC documentation, an approved sample 
ICF, drug / product accountability records, correspondence, site monitoring reports, blank Data 
Documentation form, and lab accreditations and normal values. The site must keep this binder 
current and available for review by the Sponsor, IRB/IEC, and/or regulatory bodies. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 69 of 142 
20.
PUBLICATION POLICY
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study.  During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation.  Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and 
information generated by the Investigator) without the consent of the Investigator.  Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document.  All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement.  In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
If the study is being conducted as part of a multicenter clinical study, data from all sites 
participating in the study will be pooled and analyzed by the Sponsor or the Sponsor’s designee.  
The first publication of the study results shall be made in conjunction with the results from other 
study sites as a multicenter publication.  If a multicenter publication is not forthcoming within 
24 months of completion of the study at all sites, the Investigator may publish or present the 
results generated at his or her site. 
The Investigator will provide the Sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication.  The Sponsor shall inform the Investigator in writing of any changes or deletions 
in such presentation or publication required to protect the Sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results.  At the expiration of such 60-day period, the 
Investigator may proceed with the presentation or submission for publication unless the Sponsor 
has notified the institution or the Investigator in writing that such proposed publication or 
presentation discloses the Sponsor’s confidential and proprietary technical information.  Further, 
upon the request of the Sponsor, the Investigator will delay the publication or presentation for an 
additional 90 days to permit the Sponsor to take necessary actions to protect its intellectual 
property interests. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 70 of 142 
21. 
LIST OF REFERENCES 
1. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for 
spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum 
Genet. 2012;20(1):27-32. 
2. Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to 
age, SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-712. 
3. Le TT, McGovern VL, Alwine IE, et al. Temporal requirement for high SMN expression in 
SMA mice. Hum Mol Genet. 2011;20(18):3578-3591. 
4. Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and 
adaptation in spinal muscular atrophy. Arch Neurol. 2012b;69(4):467-473. 
5. Riessland M, Ackermann B, Forster A, et al. SAHA ameliorates the SMA phenotype in two 
mouse models for spinal muscular atrophy. Hum Mol Genet. 2010;19(8):1492-1506. 
6. Dayangac-Erden D, Bora-Tatar G, Dalkara S, Demir AS, Erdem-Yurter H. Carboxylic acid 
derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: a promising 
target for spinal muscular atrophy therapeutics. Arch Med Sci. 2011;7(2):230-234. 
7. www.ClinicalTrials.gov 
8. Darbar IA, Plaggert PG, Resende MB, Zanoteli E, Reed UC. Evaluation of muscle strength 
and motor abilities in children with Type II and III spinal muscle atrophy treated with 
valproic acid. BMC Neurol. 2011;11:36. 
9. US Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events (v4.03). Published May 2009 (Revised June 2010). 
10. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 
2011;68(8):979-984. 
11. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and 
characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-164. 
12. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene 
regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 
1999;96(11):6307-6311. 
13. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH et al. A single 
nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from 
the copy gene SMN2. Hum Mol Genet. 1999;8(7):1177-1183. 
14. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity & SMN protein level in 
spinal muscular atrophy. Nat Genet. 1997;16(3):264-269. 
15. Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights from 
model mice. Curr Neurol Neurosci Rep. 2010;10(2):108-117. 
16. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 
and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and 
prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-368. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 71 of 142 
17. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the 
SMN2 gene. Am J Hum Genet. 2009;85:408-413. 
18. Farrar MA, Vucic S, Johnston HM, et al. Pathophysiological insights derived by natural 
history and motor function of spinal muscular atrophy. J Pediatr. 2013;162(1):155-159. 
19. Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype 
in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010;28(3):271-274. 
20. Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the SMNDelta7 
mouse model of spinal muscular atrophy. Neurobiol Dis. 2007;27(2):207-219. 
21. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular 
atrophy Type I and implications for clinical trials. Neurol. 2014;83(9):810-817. 
22. Wijnhoven TMA, De Onis M, Oyango AW, Wang T, Bjoerneboe GA, Bhandari N, Lartey A, 
Al Rashidi B; WHO Multicentre Growth Reference Study Group. Assessment of gross motor 
development in the WHO multicenter growth reference study. Food Nutr Bull. 
2004;25(1 Supple 1):S37S45. 
23. Glanzman AM, McDermott MP, Montes J, et al.  Validation of the Children's Hospital of 
Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).  Pediatr Phys Ther. 
2011;23(4):322-326. 
24. Glanzman AM, Mazzone E, Main M, et al.  The Children’s Hospital of Philadelphia Infant 
Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability.  
Neuromusc Disord.  2010;20(3):155-161. 
25. National Institutes of Health’s Guidelines for Research Involving Recombinant or Synthetic 
Nucleic Acid Molecules, Apr 2016. 
26. Onis, M. "WHO Child Growth Standards based on length/height, weight and age." Acta 
paediatrica 95.S450 (2006): 76-85. 
27. American Academy of Pediatrics: Policy statements--Modified recommendations for use of 
palivizumab for prevention of respiratory syncytial virus infections. Committee on Infectious 
Diseases. Pediatrics. 2009 Dec;124(6):1694-701. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 72 of 142 
22. 
APPENDICES 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 73 of 142 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Prophylactic Prednisolone 
 
Xq 
X 
X 
X 
X 
X 
X 
Xq 
 
 
AVXS-101 Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Bayley Scales/ Developmental 
Milestonesd (with video)e 
X 
 
 
 
 
 
 
 
Xf 
Xf 
X 
CHOP-INTENDg (with video)e 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
CMAP 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Demographic/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsh/Weight & Length 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
 
 
 
 
Xj 
X 
12-Lead Holter Monitoringk 
 
X 
X 
X 
X 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Pulmonary Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Photograph of Infusion Site 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology/Chemistry/ 
Urinalysis 
X 
Xo 
 
X 
 
X 
X 
X 
X 
X 
X 
CK-MB 
X 
 
 
 
 
X 
 
 
X 
Xr 
X 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
Capillary Blood Gas 
 
X 
 
X 
 
 
 
 
 
 
 
ELISA anti-AAV9/SMN Ab 
X 
 
 
 
 
X 
X 
X 
Xl 
 
 
Immunology Testing 
(ELISpot) 
 
 
 
 
 
X 
 
 
Xl 
 
 
Anti-AAV9 Ab Screen in 
Mother 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Diagnostic 
Confirmation Testing 
X 
 
 
 
 
 
 
 
 
 
 
Saliva, Urine, and Stool 
Samples (for viral shedding)p 
X 
 
 
Xm Xm 
X 
X 
X 
X 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 74 of 142 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
Collected from 2 weeks before gene replacement therapy until End of Study 
visit 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; 
CMAP = compound motor action potential; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; 
ELISpot = Enzyme-linked ImmunoSpot; ET = early termination; WHO = World Health Organization 
a The End of Study visit must occur within 0 to 14 days after the date on which the patient reaches 18 months of age (or ET). 
b Day 1 assessments will be performed prior to the start of gene replacement therapy infusion. 
c The 14 months of age visit must occur within 0 to 14 days after the date on which the patient reaches 14 months of age. 
d Developmental milestones will be assessed as defined by Bayley Scales of Infant and Toddler Development, version 3 
(independent sitting will be assessed also by WHO Multicentre Growth Reference Study). 
e Videos may be submitted for review by a central reader. 
f The full Bayley test will be administered every 6 months, starting at Month 6, whereas the Bayley fine and gross motor 
subtests will be administered at each monthly visit.   
g Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not continue CHOP-INTEND assessments.  
h Vital signs include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry 
i Vital signs will be continuously monitored throughout the infusion of gene replacement therapy and recorded every 
15 minutes for the first 4 hours (+/- 5 minutes) after the start of infusion, then every hour (+/- 15 minutes) until 24 hours after 
the start of infusion.  Axillary temperature will be recorded pre- and post-infusion. 
j Completed every 6 months, starting at Month 6. 
k Serial ECG data will be pulled in triplicate from the Holter monitor at the following time points: pre-dose (within 24h), 2h, 
4h, 6h, 8h, 12h, 24h, 36h, and 48h post-dose. 
l Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to be elevated, based on 
further discussion with the Principal Investigator and Medical Monitor. 
m Collected at 24 and 48 hours post-dose. 
n Serious adverse events are collected from signing of the informed consent through the last study visit.  All adverse events that 
occur from the start of gene replacement therapy through the last study visit are collected. 
o Laboratory samples collected on Day -1 to be processed locally, prior to dosing.   
p Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces at 24 and 48 
hours.  All other sites will collect singular urine and feces samples within 24 hours and 48 hours of dosing. 
q Prednisolone to be given 24 hours prior to scheduled AVXS-101 dosing, and continued as per protocol Section 9.2.1. 
r CK-MB to be performed at Day 60, and every 90 days (Month 6, 9, 12 months of age, 15 months of age, 18 months of 
age/EOT). 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 75 of 142 
APPENDIX 2. 
AUTOPSY PLAN 
An autopsy will be requested for any patient who receives gene replacement therapy and expires 
as per the National Institutes of Health Guidelines for Research Involving Recombinant or 
Synthetic Nucleic Acid Molecules [25].  The autopsy and tissue collection will be performed by 
a contracted vendor who will deploy a pathology assistant to the funeral home of the deceased to 
perform the autopsy and tissue collection.  Standard autopsy incisions will be used to perform the 
autopsy and pathology necessary to determine the cause of death. 
During the procedure, multiple tissues along with the entire spinal cord will be collected for 
research purposes, including up to 7 sections or pieces from each organ and each region of the 
spinal cord.  Upon collection, these tissue samples will be provided to AveXis for analysis.  
Tissue analysis will be done to determine whether the vector transduced the expected motor 
neurons and if the SMN gene was expressed.  These results will demonstrate whether the vector 
delivered the therapeutic gene as expected.  Tissue samples collected will also be available for 
histology and immunohistochemistry, allowing the state of the motor neurons and muscles to be 
examined. 
Specifically, tissue samples from the spinal cord, muscles, and organs will be collected as 
indicated in Table 8.  Tissue samples will be frozen or fixed (e.g., 2% paraformaldehyde) for 
appropriate analysis. 
Families will be asked to consent to the autopsy and authorize tissue collection prior to any sign 
of moribund or death by the clinical team conducting the study.  There are distinct forms for the 
formal autopsy and for the research tissue collection.  This will allow families the flexibility to 
participate in one or both of the research activities.  Declining an autopsy will not prevent 
patients from participating in the study. 
Table 8: Tissue Sample for Analysis 
Brain 
Spinal Cord 
Muscles 
Organs 
Motor cortex 
Cervical spinal cord 
Diaphragm 
Spleen 
Layer 5 motor cortex 
Thoracic spinal cord 
#6/#7 Rib with intercostal 
muscle and nerve 
Kidney 
Brain stem 
Lumbar spinal cord 
Psoas muscle 
Small intestine 
 
Sacral spinal cord 
 
Large intestine 
 
Dorsal root 
 
Pancreas 
 
Cervical level 
 
Stomach 
 
Ventral root 
 
Lung 
 
Cervical level 
 
Heart 
 
DRG root 
 
Liver 
 
Cervical level 
 
Inguinal lymph node 
 
Cerebrospinal fluid 
 
Gonads 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 76 of 142 
APPENDIX 3. 
BAYLEY SCALES OF INFANT AND TODDLER 
DEVELOPMENT (VERSION 3) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 77 of 142 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 78 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 79 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 80 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 81 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 82 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 83 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 84 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 85 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 86 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 87 of 142 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 88 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 89 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 90 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 91 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 92 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 93 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 94 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 95 of 142 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 96 of 142 
 
 

$YH;LV,QF
$9;6&/
,QYHVWLJDWLRQDO3URGXFW$9;6
3URWRFROY2FW
&RQILGHQWLDO_3URSULHWDU\
3DJHRI



$YH;LV,QF
$9;6&/
,QYHVWLJDWLRQDO3URGXFW$9;6
3URWRFROY2FW
&RQILGHQWLDO_3URSULHWDU\
3DJHRI


AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 99 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 100 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 101 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 102 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 103 of 142 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 104 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 105 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 106 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 107 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 108 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 109 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 110 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 111 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 112 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 113 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 114 of 142 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 115 of 142 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 116 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 117 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 118 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 119 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 120 of 142 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 121 of 142 
APPENDIX 4. 
PERFORMANCE CRITERIA FOR BAYLEY SCALES OF 
INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) DEVELOPMENTAL MILESTONES 
Developmental Milestone 
Head Control – Gross Motor Subtest 
Item #4  
Rolls from Back to Sides – Gross 
Motor Subtest Item #20 
Sits Without Support – Gross Motor 
Subtest Item #26 
Stands With Assistance - Gross Motor 
Subtest Item #33 
Crawls – Gross Motor Subtest 
Item #34 
Pulls to Stand – Gross Motor Subtest 
Item #35 
Walks With Assistance – Gross Motor 
Subtest Item #37 
Stands Alone – Gross Motor Subtest 
Item #40 
Walks Alone – Gross Motor Subtest 
Item #43 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 122 of 142 
APPENDIX 5. 
CHOP-INTEND 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 123 of 142 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 124 of 142 
APPENDIX 6. 
COMPOUND MOTOR ACTION POTENTIAL MANUAL 
 
 
 
 
 
Phase 3 Gene Transfer Clinical Study for Spinal Muscular Atrophy Type 1  
Delivering AVXS-101 
 
 
 
 
 
CMAP Manual 
Compound Motor Action Potential (CMAP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 125 of 142 
Materials Needed for the Process 
• Carefusion Disposable Ring Electrode with Leads (order number 019-439300) (4 per 
visit) 
• Carefusion Tab Electrodes 1.0 meter leads (order number 019-406600) (1 or 2 per visit) 
• CMAP case report form 
• Infrared temperature probe 
• Electrode gel 
• Warming packs or some other warming source 
• Transpore adhesive tape 
• Alcohol skin prep pads 
• EMG machine 
 
Assessment of Normal Limb Temperature 
Since temperature can affect maximum CMAP amplitude, temperature > 33 degrees centigrade 
should be noted prior to preparation of skin for electrode placement.  Temperature should be 
measured using a surface probe on the lateral aspect of the hand just proximal to the fifth digit.  If 
temperature is ≤ 33 degrees centigrade, a warming pack or other warming mechanism should be 
used to warm the hand to > 33 degrees centigrade prior to collecting data.  Limb temperature does 
not need to be reassessed during the procedure. 
Preparation of Skin 
The skin should be cleaned with alcohol (or equivalent) as needed to improve contact with the 
electrodes. 
EMG machine settings 
For both the ulnar and peroneal CMAP measures the filter settings should be 10 Hz to 10 kHz. 
Tibialis Anterior (TA) CMAP Electrode Placement 
For the TA CMAP, the G1 electrode should be placed below the fibular head on the bulk of the 
Tibialis Anterior (TA) muscle belly.  The G2 reference electrode should be placed on the patella.  
An adhesive ground electrode (Carefusion Tab Electrodes 1.0 meter leads (DIN Style) order 
number 019-406600) is placed between the stimulating electrodes and the G1 electrode.  Tape 
should be placed over the electrodes to ensure they stay affixed during the procedure. 
Supramaximal nerve stimulation for TA CMAP 
The stimulator should be a pediatric sized bipolar probe.  The stimulation site should be at or 
proximal to the fibular head.  A maximal response should be obtained (CMAP), using a stimulus 
120% of that producing the maximal response and a stimulus duration of 0.2 msec.  Maximum 
CMAP amplitude and area should be recorded on the Source Document and a printout of the 
CMAP tracing made.  Area is measured only for the initial negative peak.  Subsequent negative 
peaks are not included. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 126 of 142 
Abductor Digiti Minimi (ADM) CMAP Electrode Placement 
Electrodes used for recording will be Carefusion Disposable Ring Electrode with Leads (order 
number 019-439300).  For ADM CMAP, these have a longitudinal contact area of up to 106 mm, 
but should be cut so that they cover the body of the ADM, with position orthogonal to muscle 
fiber orientation.  The distance between the ulnar aspect of the pisaform bone (P) and the ulnar 
aspect of the fifth metacarpophalangeal joint (MP-5) should be measured.  The G1 electrode 
should be placed distal to P, 1/3 of the distance between P and MP-5, as defined above.  The G2 
reference electrode should be placed on the ulnar aspect of the MP-5 joint.  See figure below for 
landmarks: 
 
 
 
Modified figure from “Anatomic Guide for the Electromyographer” Charles C. 
Thomas, Publisher, 1980, p4. 
 
Supramaximal nerve stimulation for CMAP 
The stimulator should be a pediatric sized bipolar probe.  The stimulation site should be at the 
distal forearm just proximal to the wrist.  A maximal response should be obtained (CMAP), using a 
stimulus 120% of that producing the maximal response and a stimulus duration of 0.2 msec.  
CMAP maximum amplitude and area should be recorded on the Source Document and a printout 
of the CMAP tracing made.  Area is measured only for the initial negative peak.  Subsequent 
negative peaks are not included. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 127 of 142 
APPENDIX 7. 
DECLARATION OF HELSINKI: ETHICAL 
PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving Human subjects, including research on identifiable 
human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians.  The 
WMA encourages others who are involved in medical research involving Human subjects to adopt 
these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research.  The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving Human subjects. 
6. The primary purpose of medical research involving Human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments).  Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all Human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research patients. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
patients.  The responsibility for the protection of research patients must always rest with the physician 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 128 of 142 
or other health care professionals and never with the research patients, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
Human subjects in their own countries as well as applicable international norms and standards.  No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research patients set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the environment. 
12. Medical research involving Human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications.  Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research patients. 
15. Appropriate compensation and treatment for patients who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving Human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research patients. 
17. All medical research involving Human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving Human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 129 of 142 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group.  In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving Human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation.  The welfare of animals used for 
research must be respected. 
22. The design and performance of each research study involving Human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed.  The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
patients and information regarding provisions for treating and/or compensating patients who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins.  This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified.  It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
patients set forth in this Declaration. 
The committee must have the right to monitor ongoing studies.  The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events.  
No amendment to the protocol may be made without consideration and approval by the committee.  
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research patients and the confidentiality of 
their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as patients in medical research must 
be voluntary.  Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving Human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 130 of 142 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study.  The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal.  Special attention should be given to the 
specific information needs of individual potential patients as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing.  If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
All medical research patients should be given the option of being informed about the general outcome 
and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress.  In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorized representative.  These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative.  The potential subject’s dissent should be 
respected. 
30. Research involving patients who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group.  In such circumstances the 
physician must seek informed consent from the legally authorized representative.  If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving patients with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee.  Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research.  
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse.  There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research.  In such situations the research may be done 
only after consideration and approval of a research ethics committee. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 131 of 142 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or where 
for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  Extreme care must be 
taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all patients who still need an intervention identified as beneficial in 
the trial.  This information must also be disclosed to patients during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving Human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research.  Researchers have a duty to make publicly 
available the results of their research on Human subjects and are accountable for the completeness 
and accuracy of their reports.  All parties should adhere to accepted guidelines for ethical reporting.  
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available.  Sources of funding, institutional affiliations and conflicts of interest must be declared in 
the publication.  Reports of research not in accordance with the principles of this Declaration should 
not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering.  
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy.  In all cases, new information must be recorded and, where appropriate, made publicly 
available. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 132 of 142 
APPENDIX 8. 
SUMMARY OF CHANGES 
The section below highlights content changes represented in this version of the protocol.  
Language deleted from Protocol version 1.0 appears in red strike through.  Language added to 
Protocol version 2.0 appears in bold. 
The Amendment 1 version of the protocol (Protocol version 2.0) is updated to include cardiac 
enzyme monitoring (CK-MB) and to require a total of 15 patients meeting the intent-to-treat 
criteria to be enrolled. 
Section 2 
Synopsis 
Section was updated as per changes throughout the document; however one area reflects 
information that is not captured elsewhere in the document: 
Section 5.1 
Background 
Therapeutic efforts in SMA have focused on the potential for small molecules to increase SMN 
levels.  These include deacetylase inhibitors, such as, valproic acid, sodium butyrate, 
phenylbutyrate, and trichostatin A.  These agents activate the SMN2 promoter, resulting in 
increased full-length SMN protein in SMA animal models [5,6].  However, clinical studies 
employing several of these agents, most notably phenylbutyrate, valproic valporic acid, and 
hydroxyurea, have not resulted in clinical benefit [7,8].  FDA recently approved Nusinersen, an 
antisense oligonucleotide (ASO) drug designed to increase the production of the SMN protein by 
modulating the splicing of the SMN2 gene, thereby compensating for the underlying genetic 
defect.  Clinical studies have shown some modest promise in improving motor function; however 
the treatment must be administered indefinitely on a quarterly basis via intrathecal injection, 
requires a lengthy induction period prior to effectiveness, and has safety considerations which 
require clinical monitoring.  A single-dose IV administration study of AVXS-101 will provide 
information on the potential gene transfer has in treating SMA Type 1 patients, and will 
hopefully show promise for success in modifying the disease prognosis. 
This is a single-dose study that will include up to 20 15 Type 1 patients with no functional 
SMN1 gene as well as 1 or 2 copies of SMN2 and who are < 6 months (< 180 days) of age at 
the time of gene replacement therapy (Day 1).  The rationale for IV dosing is based upon the 
need for rapid, systemic impact given the severity of the disease in SMA Type 1 and its potential 
impact on systems outside of the central nervous system (CNS) such as the peripheral and 
autonomic nervous systems, heart, pancreas and gastrointestinal tract. 
Rationale for Change 
Corrected typographical error in first paragraph.  Second paragraph reflects revision in study 
design, which requires enrollment of 15 patients meeting the ITT criteria. 
Section 5.4 
Clinical Studies 
First-in-human study AVXS-101-CL-101 is an ongoing 2-year study evaluating the efficacy and 
safety of AVXS-101 in 15 SMA Type 1 patients with 2 copies of SMN2.  All patients have 
received a single IV dose of AVXS-101 in 2 cohorts: Cohort 1 (n = 3) received the low dose 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 133 of 142 
used in this study (equivalent to a dose that doubled mouse lifespan in the SMN∆ 6X1013 
vg/kg7 Mouse potency assay) and Cohort 2 (n = 12) received the high dose used in this study 
(equivalent to a dose that restored mouse lifespan to greater than 200 days or “full life” in 
the SMN∆7 Mouse potency assay).  The dose received by Cohort 2 patients in AVXS-101-
CL-101 2.0 X 1014 vg/kg  (proposed therapeutic dose) has been demonstrated to be equivalent 
to the dose to be used in the AVXS-101-CL-303 study by direct testing using improved 
analytical methods. 
Rationale for Change 
Removed references to doses measured by qPCR, for clarity, and provided further information as 
to the method by which it has been determined that the AVXS-101-CL-303 is equivalent to the 
phase 1 study cohort 2 dose. 
Section 7.1 
Overall Study Design 
This is a Phase 3, open-label, single-arm, single-dose study of AVXS-101 (gene replacement 
therapy) that will enroll up to twenty (20) in patients with SMA Type 1who may be either 
symptomatic or pre-symptomatic with no functional SMN1 gene as well as 1 or 2 copies of 
SMN2 and who are.  Fifteen (15) patients< 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1).  Enrolling up to twenty (20) patients under the broader 
enrollment criteria is projected to enable enrollment of at least fifteen (15) patients that 
meet the Intent-to-Treat Population (ITT) criteria.  The ITT population is identified as 
symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without the 
SMN2 gene modifier mutation (c.859G>C) who meet all other study enrollment criteria.  In 
addition, the first three patients enrolled must meet the criteria for the Intent-to-Treat 
Population to enable a comparison of CHOP-INTEND scores at one-month following gene 
replacement therapy to enable a comparison of patient response between AVXS-101-CL-
303 patients and Cohort 2 patient results from the Phase 1 trial (AVXS-101-CL-101). 
The first three patients enrolled must meet the criteria for the Intent-to-Treat (ITT) 
Population.  AveXis will compare the CHOP-INTEND one month improvement for the 
AVXS-101-CL-303 patients that meet the ITT criteria to assess the clinical response to the 
dose 1.1 x 1014 vg/kg as being what was expected from the Cohort 2 patients in the Phase 1 
trial (AVXS-101-CL-101).  This comparison will be performed as a per patient assessment 
for the first three patients.  The individual patients who receive their gene therapy at 0-3 
months of age will be compared to a value of 10 CI points, while patients who receive their 
gene therapy at >3 but <6 months of age will be compared to a value of 5 CI points.  
Furthermore, patients from either age group are expected to maintain the improvement in 
the absence of an acute illness or perioperatively.  If the expected CI improvements are 
observed for the first three ITT patients, AveXis will remove the 30-day interval between 
patients and proceed to dose at least 12 additional patients that meet the ITT criteria and 
perform safety and efficacy assessments as described elsewhere in the clinical protocol 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 134 of 142 
(AVXS-101-CL-303) and corresponding Statistical Analysis Plan.  If the expected CI 
improvements are not observed for the first three ITT patients, AveXis will discuss next 
steps with the FDA before continuing study enrollment. 
Rationale for Change 
Comparability of the AVXS-101 GMP product to the AVXS-101 product utilized in the Phase 1 
study (AVXS-101-CL-101) will be assessed by reviewing data from the first three patients, 
ensuring the clinical response is similar to what was observed in the previous study. 
Section 7.2 
Number of Patients 
Up to twenty (20) patients that meet the study entry criteria will be enrolled to enable 
enrollment of at least fifteen (15) patients that meet ITT criteria.  Study enrollment will 
stop as soon as practical following enrollment of the fifteenth patient that meets the ITT 
criteria. 
A total of 15 patients will be enrolled. 
Rationale for Change 
Protocol revisions reflect alignment with agency request for analysis of at least 15 patients 
meeting the intent-to-treat population criteria. 
Section 8.1 
Patient Inclusion Criteria 
Inclusion criteria have been re-numbered to accommodate inclusion of an additional criterion. 
Criterion #2:  The first thee patients enrolled must meet the criteria for the Intent-To-
Treat population 
Rationale for Change 
The Intent-to-Treat Population matches the patient population enrolled in Cohort 2 of the Phase 1 
study (AVXS-101-CL-101).  Ensuring the first three patients enrolled match these criteria will 
ensure appropriate assessment of the expected efficacy, based on Chop-Intend improvements. 
Section 9.1 
Description of Product 
Table 5: Investigational Product 
 
Investigational Product 
Product Name: 
AVXS-101 
Dosage Form: 
Equivalent to the dose received by the second dosing cohort in the Phase 1 
study 
Unit Dose 
1.1 X 1014 vg/kg; Equivalent to the dose received by Cohort 1 the second dosing 
cohort in the Phase 1 study (AVXS-101-CL-101) as determined by direct 
product testing with improved analytical methods. 
Route of Administration 
Intravenous infusion 
Physical Description 
AVXS-101 is a clear, colorless liquid. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 135 of 142 
Rationale for Change 
The unit dose was updated to reflect the AVXS-101 dose determined through ddPCR with 
AveXis GMP product. 
Section 10.2 
Study Product Dose and Dose Justification 
Patients will receive a one-time dose of AVXS-101 at 1.1 X 1014 vg/kg, equivalent to the dose 
received by Cohort 2 the second dosing cohort in the Phase 1 study via IV infusion administered 
in the ongoing Phase 1 clinical study (AVXS-101-CL-101). 
Two doses (2.0 x 1014 vg/kg and 6.7 x 1013 vg/kg) are being studied in the ongoing Phase 1 
clinical study (AVXS-101-CL-101); the higher dose (dose received by the Cohort 2 patients 
2.0 x 1014 vg/kg) was chosen for the present study as preliminary data demonstrated both a dose 
response and significant clinical benefit thus identifying it 2.0 x 1014 vg/kg as the proposed 
therapeutic dose.  In the Phase 1 study, AVXS-101 demonstrated a dose response, with 
efficacy greater as observed by motor milestone achievement and CHOP-INTEND scores 
at the higher dose (received by Cohort 2) than the lower dose (received by Cohort 1).  
Direct testing of the actual lot of Investigational Medicinal Product (IMP) used in the 
AVXS-101-CL-101 study by an improved and more fully qualified analytical method has 
assigned a value of 1.1 x 1014 vg/kg to the actual dose received by Cohort 2 in this Phase 1 
study.  The same method has been used to establish an equivalent dose for the Phase 3 
IMP.  This vg/kg value has been further verified in an improved and more fully qualified 
SMN∆7 Mouse Biopotency assay to support a similar extension of mouse life time in direct 
comparative assessment between the Phase 1 and Phase 3 IMP minimum dose that is 
clinically effective. 
Rationale for Change 
The dose was updated to reflect the AVXS-101 dose determined through ddPCR with AveXis 
GMP product.  Language was added to clarify that the higher dose studied in the Phase 1 AVXS-
101-CL-101 is considered the therapeutic dose, and to explain the reason the dose used in this 
study has a different numerical value.  The dose used in the AVXS-101-CL-101 study was 
measured by qPCR; the AveXis GMP AVXS-101 is measured by ddPCR. 
Section 12.1.10 
Laboratory Assessments 
Table 6: Total Blood Volume 
Visit 
Tests 
Total Volume (mL) 
Screening 
Hematology, chemistry/CK-MB, virus serology, capillary blood 
gas,, immunology sample (AAV9 Ab only),   
diagnostic confirmation sample 
16.96 
Day –1 
Hematology, chemistry, capillary blood gas  
3.3 
Day -1 
Capillary blood gas 
1 
Day 2 
Hematology, chemistry, capillary blood gas 
3.3 
Day 7 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.66.3-8.3b 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 136 of 142 
Visit 
Tests 
Total Volume (mL) 
Day 14 
Hematology, chemistry, immunology sample  
(AAV9 Ab/SMN only) 
3.36.3-8.3b 
Day 21 
Hematology, chemistry, immunology sample  
(AAV9 Ab/SMN only) 
3.36.3-8.3b 
Day 30 
Hematology, chemistry/CK-MB, immunology sample 
(ELISA/ELISpot) 
7.6-9.66.3-8.3b 
Day 60 
Hematology, chemistry/CK-MB 
3.6 
Month 
3/4/5/7/8/10/11/
13/14/16/17 
Hematology, chemistry 
25.3 
Month 
6/9/12/15 
Monthly 
Hematology, chemistry/CK-MB 
14.436.8 
End of Study/ET 
Hematology, chemistry/CK-MB 
3.62.3 
Maximum Total Volume for Studya 
96.296.5 
ET = early termination 
a Patients will have different numbers of monthly visits, depending on their age at dosing.  Maximum total volume based on a 
maximum of 16 monthly visits, provided T-cell responses are not elevated at Day 30 requiring additional surveillance 
samples and virus serology is not positive at screening requiring additional testing 
b Immunology sample for IFN-γ ELISpots requires 4-6 mL whole blood.  Immunology sample for ELISA requires 1 mL 
whole blood.  When drawn at the same visit, 4-6 mL is sufficient for both assays. 
 
In a case where sufficient blood cannot be collected from a patient, blood will be used in the 
following priority order with the first having greatest priority and last having the least priority: 
5. Safety labs 
a. Chemistry 
b. Hematology 
c. CK-MB 
6. Interferon gamma (IFN-γ) ELISpots to detect T-cell responses 
7. Serum antibody to AAV9 and SMN 
8. Genetic reconfirmation testing 
 
Rationale for Change 
Additional cardiac enzyme monitoring was added to the schedule of assessments; to 
accommodate these additional blood samples, the capillary blood gas and IFN-γ ELISpot collect 
schedules were reduced to comply with maximum total blood volume allowances.  Additionally, 
further detail was added to the laboratory sample prioritization schedule. 
Section 12.1.10.2 
Blood Chemistry 
Creatine kinase (CK-MB) will be collected at Screening, Day 7, Day 30, Day 60, every 90 
days, and at End of Study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 137 of 142 
Rational for Change 
Additional cardiac enzyme monitoring was added to ensure patient safety.  Recent toxicology 
studies performed in mice affected with SMA Type 1 demonstrated microscopic 
degeneration/generation of tissues in the heart. 
Section 12.1.10.5 
Capillary Blood Gas 
Capillary blood gas will be completed locally at screening Day –1, pre-dose on Day 1, and Day 2 
().  A puncture or small incision will be made with a lancet or similar device into the cutaneous 
layer of the patient’s skin at a highly vascularized area (heel, finger, toe).  To accelerate blood 
flow and reduce the difference between the arterial and venous gas pressures, the area will be 
warmed prior to the puncture.  As the blood flows freely from the puncture site, the sample will 
be collected in a heparinized glass capillary tube. 
Rationale for Change 
Additional cardiac enzyme monitoring was added to the schedule of assessments; to 
accommodate these additional blood samples, the capillary blood gas and IFN-γ ELISpot collect 
schedules were reduced to comply with maximum total blood volume allowances. 
Section 12.1.10.6 
Immunology Testing (ELISA and IFN-γ ELISpots) 
Blood samples for immunology testing will be collected and shipped to the central laboratory in 
accordance with the laboratory manual to test for serum antibodies to AAV9 and SMN (ELISA), 
and to perform IFN-γ ELISpots to detect T-cell responses to AAV9 and SMN.  Blood samples 
will be collected at screening (ELISA anti-AAV9 only), Day 7, Day 14 (ELISA anti-
AAV9/SMN only), Day 21 (ELISA anti-AAV9/SMN only), and Day 30 ().  Additional 
sampling may be performed at subsequent time points if ELISpot value(s) continue to be 
elevated, based on further discussion with the Principal Investigator and Medical Monitor. 
Rationale for Change 
Additional cardiac enzyme monitoring was added to the schedule of assessments; to 
accommodate these additional blood samples, the capillary blood gas and IFN-γ ELISpot collect 
schedules were reduced to comply with maximum total blood volume allowances. 
Section 14.1.2.1 
Intent-to-Treat Population 
The ITT population will consist of symptomatic patients with bi-allelic deletion mutations of 
SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene 
modifier mutation (c.859G>C) who receive an IV infusion of AVXS-101 at less than 180 days of 
age.  All primary and secondary efficacy analyses and subgroup analyses will be conducted on the 
ITT population.  The first three patients enrolled must meet the criteria for the Intent-to-Treat 
Population. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 138 of 142 
Rationale for Change 
The Intent-to-Treat Population matches the patient population enrolled in Cohort 2 of the Phase 1 
study (AVXS-101-CL-101).  Ensuring the first three patients enrolled match these criteria will 
ensure appropriate assessment of the expected efficacy, based on CHOP-INTEND 
improvements. 
Section 14.2 
Sample Size Calculation 
This is a pivotal Phase 3, open-label, single-arm, single-dose, study assessing the efficacy 
and safety of AVXS-101 (gene replacement therapy) in up to twenty (20) patients with 
spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria, may be either 
symptomatic or pre-symptomatic and are genetically defined by no functional survival 
motor neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2) 
and who are < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 
1).  Enrolling up to twenty (20) patients under the broader enrollment criteria is projected 
to enable enrollment of at least fifteen (15) patients that meet the Intent-to-Treat 
Population (ITT) criteria. The ITT population is identified as symptomatic patients with 
bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene modifier mutation 
(c.859G>C) and will comprise the primary population for evaluation of the primary and 
secondary endpoints.  Study power is based upon efficacy analysis of the ITT population.  
Furthermore, the first three patients enrolled must meet criteria for the Intent-To-Treat 
Population to enable a comparison of CHOP-INTEND scores at one-month following gene 
replacement therapy to enable a comparison of patient response between AVXS-101-CL-
303 patients and Cohort 2 patient results from the Phase 1 trial (AVXS-101-CL-101).  
Patients with 1 copy of SMN2, pre-symptomatic patients and patients with the SMN2 gene 
modifier mutation (c.859G>C) and other permutations outside of those specified in the ITT 
population will be evaluated separately as part of additional subgroup analyses.  Details of 
all analyses will be contained within the Statistical Analysis Plan. 
The current study will enroll 15 patients.  Only those patients with baseline symptoms, bi-allelic 
deletion mutations of SMN1 and 2 copies of SMN2 without the SMN2 gene modifier mutation 
(c.859G>C), ITT population will be assessed for the primary and secondary efficacy analyses.  
The study power is based upon efficacy analysis of the ITT population. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 40% of treated symptomatic patients with bi-allelic deletions of SMN1 and 2 copies of 
SMN2 without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-
primary efficacy endpoint of functional independent sitting for at least 30 seconds at the 18 
months of age study visit.  With the assumption for the true response rate of AVXS-101 for the 
primary endpoint being in the range of 30% - 40%, a sample size of 15 patients that meet ITT 
criteria will be enrolled and (assuming approximately 30% of patients do not qualify for the 
ITT population or are otherwise excluded from the analysis, would yield an ITT population 
that) would provide power of > 90% to detect a significant difference from 0.1% with α 
= 0.02505 using a 1-sided exact test for a binomial proportion. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 139 of 142 
The second co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹, 
where 𝑝𝑝 is the proportion of patients surviving at 14 months of age. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 80% of treated symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 
without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-primary 
efficacy endpoint of survival through 14 months of age.  It is anticipated that 75% of patients in 
the PNCR population would not survive beyond 13.6 months of age, and that these control 
patients will represent a 25% survival rate based upon the natural history of the disease.  With 
this efficacy, an enrolled a sample size of  15 patients that meet ITT criteria (assuming 30% of 
patients do not qualify for the ITT  or are otherwise excluded from the analysis) would yield an 
ITT population that would provide power of > 80% to detect a significant difference from the 
historical control with α = 0.05 using a two sample 2-sided Fisher’s Exact test, comparing to 
the 26 age and gender matched patients from a published natural history observational study 
performed at 3 large, tertiary care centers in the United States (Harvard University, Columbia 
University, Children’s Hospital of Philadelphia; PNCR). 
Rationale for Change 
The Intent-to-Treat Population matches the patient population enrolled in Cohort 2 of the Phase 1 
study (AVXS-101-CL-101).  Ensuring the first three patients enrolled match these criteria will 
ensure appropriate assessment of the expected efficacy, based on CHOP-INTEND 
improvements.  The change in alpha for the exact binomial test is due to agreement with the 
agency that a 1-sided test for bionomial proportion should be utilized with an alpha = 0.025. 
Section 14.3.2 
Primary and Secondary Efficacy Analysis 
Primary and secondary efficacy analyses will be based on the ITT population, those patients that 
are symptomatic with bi-allelic deletion mutations of SMN1 and 2 copies of SMN2 without the 
SMN2 gene modifier mutation (c.859G>C).  These analyses are to test the superiority of AVXS-
101 to the results from natural observation study (PNCR) [21]. 
The first co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1% 
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 18 
months of age study visit. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 140 of 142 
The second co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 , 
where 𝑝𝑝 is the proportion surviving at 14 months of age. 
Primary efficacy endpoints will be examined on the ITT population.  Testing for the first co-
primary endpoint, functional independent sitting will first be performed using 1-sided exact 
binomial test.  Only if the null hypothesis of equality in proportion of functional independent sitting 
is rejected at p<0.02505, will the co-primary endpoint survival improvement be tested using 2-sided 
Fisher’s Exact test on the ITT population, comparing to matched patients from natural observational 
study (PNCR).  This hierarchy approach strongly protects the Type I error rate. 
Rationale for Change 
Correction to the definition for the intent-to-treat population; clarification that this must include 
patients that are symptomatic at baseline. 
Section 14.4 
CHOP-INTEND Comparison 
A comparison will be performed of the first three patients CHOP-INTEND scores to the 
AVXS-101-CL-101 CHOP-INTEND scores.  The first three patients enrolled must meet the 
criteria for the Intent-to-Treat (ITT) Population.  AveXis will compare the CHOP-
INTEND one month improvement for the AVXS-101-CL-303 patients that meet the ITT 
criteria to assess the clinical response to the dose 1.1 x 1014 vg/kg as being what was 
expected from the Cohort 2 patients in the Phase 1 trial (AVXS-101-CL-101).  This 
comparison will be performed as a per patient assessment for the first three patients.  The 
individual patients who receive their gene therapy at 0-3 months of age will be compared to 
a value of 10 CI points, while patients who receive their gene therapy at >3 but <6 months 
of age will be compared to a value of 5 CI points.  Furthermore, patients from either age 
group are expected to maintain the improvement in the absence of an acute illness or 
perioperatively.  If the expected CI improvements are observed for the first three ITT 
patients, AveXis will remove the 30-day interval between patients and proceed to dose at 
least 12 additional patients that meet the ITT criteria and perform safety and efficacy 
assessments as described elsewhere in the clinical protocol (AVXS-101-CL-303) and 
corresponding Statistical Analysis Plan.  If the expected CI improvements are not observed 
for the first three ITT patients, AveXis will discuss next steps with the FDA before 
continuing study enrollment. 
Rationale for Change 
Language added because this comparison is now planned. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 141 of 142 
Appendix 1 
Schedule of Assessments 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Prophylactic Prednisolone 
 
Xq 
X 
X 
X 
X 
X 
X 
Xq 
 
 
AVXS-101 Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Bayley Scales/ Developmental 
Milestonesd (with video)e 
X 
 
 
 
 
 
 
 
Xf 
Xf 
X 
CHOP-INTENDg (with video)e 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
CMAP 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Demographic/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsh/Weight & Length 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
 
 
 
 
Xj 
X 
12-Lead Holter Monitoringk 
 
X 
X 
X 
X 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Pulmonary Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Photograph of Infusion Site 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology/Chemistry/ 
Urinalysis 
X 
Xo 
 
X 
 
X 
X 
X 
X 
X 
X 
CK-MB 
X 
 
 
 
 
X 
 
 
X 
Xr 
X 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
Capillary Blood Gas 
X 
X 
X 
X 
 
 
 
 
 
 
 
ELISA anti-AAV9/SMN Ab 
X 
 
 
 
 
X 
X 
X 
Xl 
 
 
Immunology Testing 
(ELISA anti-SMN Ab and ELISpot) 
 
 
 
 
 
X 
X 
X 
Xl 
 
 
Anti-AAV9 Ab Screen in 
Mother 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Diagnostic 
Confirmation Testing 
X 
 
 
 
 
 
 
 
 
 
 
Saliva, Urine, and Stool 
Samples (for viral shedding)p 
X 
 
 
Xm Xm 
X 
X 
X 
X 
 
 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
Collected from 2 weeks before gene replacement therapy until End of Study 
visit 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v2.0 / 15 Oct 2017 
Confidential | Proprietary 
Page 142 of 142 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; 
CMAP = compound motor action potential; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; 
ELISpot = Enzyme-linked ImmunoSpot; ET = early termination; WHO = World Health Organization 
a The End of Study visit must occur within 0 to 14 days after the date on which the patient reaches 18 months of age (or ET). 
b Day 1 assessments will be performed prior to the start of gene replacement therapy infusion. 
c The 14 months of age visit must occur within 0 to 14 days after the date on which the patient reaches 14 months of age. 
d Developmental milestones will be assessed as defined by Bayley Scales of Infant and Toddler Development, version 3 
(independent sitting will be assessed also by WHO Multicentre Growth Reference Study). 
e Videos may be submitted for review by a central reader. 
f The full Bayley test will be administered every 6 months, starting at Month 6, whereas the Bayley fine and gross motor 
subtests will be administered at each monthly visit. 
g Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not continue CHOP-INTEND assessments. 
h Vital signs include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry. 
i Vital signs will be continuously monitored throughout the infusion of gene replacement therapy and recorded every 
15 minutes for the first 4 hours (+/- 5 minutes) after the start of infusion, then every hour (+/- 15 minutes) until 24 hours after 
the start of infusion.  Axillary temperature will be recorded pre- and post-infusion. 
j Completed every 6 months, starting at Month 6. 
k Serial ECG data will be pulled in triplicate from the Holter monitor at the following time points: pre-dose (within 24h), 2h, 
4h, 6h, 8h, 12h, 24h, 36h, and 48h post-dose. 
l Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to be elevated, based on 
further discussion with the Principal Investigator and Medical Monitor. 
m Collected at 24 and 48 hours post-dose. 
n Serious adverse events are collected from signing of the informed consent through the last study visit.  All adverse events that 
occur from the start of gene replacement therapy through the last study visit are collected. 
o Laboratory samples collected on Day -1 to be processed locally, prior to dosing. 
p Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces at 24 and 48 
hours.  All other sites will collect singular urine and feces samples within 24 hours and 48 hours of dosing. 
q Prednisolone to be given 24 hours prior to scheduled AVXS-101 dosing, and continued as per protocol Section 9.2.1. 
r CK-MB to be performed at Day 60, and every 90 days (Month 6, 9, 12 months of age, 15 months of age, 18 months of 
age/EOT). 
 
Rationale for Change 
Additional cardiac enzyme monitoring was added to the schedule of assessments; to 
accommodate these additional blood samples, the capillary blood gas and IFN-γ ELISpot collect 
schedules were reduced to comply with maximum total blood volume allowances.  Additionally, 
further detail was added to the laboratory sample prioritization schedule. 

 
1. 
TITLE PAGE 
AVXS-101 
AVXS-101-CL-303 
IND Number: 
15699 
 
 
Protocol Title: 
Phase 3, Open-Label, Single-Arm, Single-Dose Gene 
Replacement Therapy Clinical Trial for Patients with Spinal 
Muscular Atrophy Type 1 with One or Two SMN2 Copies 
Delivering AVXS-101 by Intravenous Infusion 
Indication Studied: 
Spinal Muscular Atrophy Type 1 
Sponsor Address: 
AveXis, Inc. 
2275 Half Day Road 
Bannockburn, IL 60015 
Protocol Version/Date: 
1.0/ 29 Mar 2017 
The study will be completed according to the guidelines of Good Clinical Practice.  Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki. 
 
Confidentiality Statement 
The information in this document contains trade and commercial information that is privileged or confidential and 
may not be disclosed unless such disclosure is required by federal or state law or regulations.  In any event, persons 
to whom the information is disclosed must be informed that the information is privileged or confidential and may 
not be further disclosed by them.  These restrictions on disclosure will apply equally to all future information 
supplied to you which is indicated as privileged or confidential. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 2 of 126 
1. 
ADMINISTRATIVE INFORMATION 
1.1. 
Approval 
REPRESENTATIVES FROM AveXis: 
This trial will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical trial protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki 
• 
International Council for Harmonization and the Harmonized Tripartite Guideline for Good 
Clinical Practice E6 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations  
SIGNATURES (may be applied electronically and will therefore be maintained in the 
electronic system): 
 
 
 
 
 
Vice President Clinical Development and Medical Affairs 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Chief Medical Officer 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Senior Vice President, Chief Regulatory and Quality Officer 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Sr. Director, Head of Clinical Operations 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 
 
 
Biostatistician 
AveXis, Inc. 
 
Date (ddMmmyyyy) 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 3 of 126 
1.2. 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for AVXS-101.  I have read the AVXS-101-
CL-303 protocol and agree to conduct the study in accordance with the relevant current 
protocol(s).  I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.  I agree to personally conduct or supervise the investigation(s).  I 
also agree to promptly report to the Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others.  Additionally, I will not make any changes in the research 
without IRB/IEC approval, except where necessary to eliminate apparent immediate hazards to 
human subjects.  I agree to protect the safety, rights, privacy, and well-being of study 
participants.  I agree to comply with:  
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations including but not limited to Informed Consent 21 CFR Part 56, Institutional 
Review Board Review in 21 CRF Part 56, Adverse Event Reporting as defined in 
Section 13.4 and in 21 CFR 312.64, Adequate/accurate and accessible records in accordance 
with 21CFR 312.62 and 312.68. 
• Terms outlined in the study site agreement  
• Responsibilities of the Investigator (per regulatory guidelines and applicable regulations) I 
further authorize that my personal information may be processed and transferred in 
accordance with the uses contemplated in this protocol. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator or 
Consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.  Your acceptance of this document constitutes agreement 
that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 
 _________________________________________________ 
Printed Name of Investigator 
 _________________________________________________ 
Signature of Investigator 
 _________________________________________________ 
Date (ddMmmyyyy) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 4 of 126 
1.3. 
Contact Information 
Table 1: 
Important Study Contact Information 
Role in Study 
Name/ 
Address and Telephone Number 
Clinical Study Leader 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Responsible Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Drug Safety Physician 
Please see Project Communication Plan in the Trial Master File 
(TMF) or Study Contact list in the Investigator Site File (ISF) 
Serious Adverse Event 
Reporting 
Please see Project Management Plan in TMF or Study Contact list 
in ISF 
24-Hour Emergency Contact 
Please see Study Contact List in ISF 
 
Table 2: 
Study Vendor Listing 
Role in Study 
Name/Address 
Clinical Research 
Organization 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Investigational Product 
Shipment 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Video 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Independent Video Review 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Holter Monitor and  
12-lead Electrocardiogram 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
immunoassays 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratory- 
viral shedding studies 
Please see Project Management Plan in TMF or Study Contact list in ISF 
Autopsy 
Please see Project Management Plan in TMF or Study Contact list in ISF 
ISF = Investigator site file; TMF = trial master file 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 5 of 126 
2. 
SYNOPSIS 
Name of Sponsor/Company: AveXis, Inc. 
Name of Investigational Product: AVXS-101 
Name of Active Ingredient: Survival Motor Neuron Gene by Self‐Complementary Adeno-Associated 
Virus Serotype 9 (AAV9) 
Title of Study: Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical 
Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering 
AVXS-101 by Intravenous Infusion 
Study Center(s): 10 to 20 United States (US) Investigators 
Studied Period (years): 
Estimated date first patient enrolled: 2Q 2017 
Estimated date last patient completed: 4Q 2019 
Phase of Development: 3 
Objectives: 
Co-Primary 
• 
Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of 
functional independent sitting for at least 30 seconds at the 18 months of age study visit. 
• 
Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is defined by 
the avoidance of combined endpoint of either (a) death or (b) permanent ventilation, which is 
defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via 
non-invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible 
illness, excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
Co-Secondary 
• 
Determine effect of AVXS-101 on the ability to thrive defined as achieving all of the following at 
18 months of age: 
o Does not receive nutrition through mechanical support (e.g., feeding tube) or other non-oral 
method 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• 
Determine the effect of AVXS-101 on the ability to remain independent of ventilatory support, 
defined as requiring no daily ventilator support/usage at 18 months of age 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 6 of 126 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• 
Determine the safety of AVXS-101 based on the development of unacceptable toxicity defined as 
the occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 
higher, unanticipated, treatment-related toxicity 
Methodology: 
Phase 3, open-label, single-arm, single-dose, study of AVXS-101 (gene replacement therapy) in patients 
with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined 
by nonfunctional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 
2 gene (SMN2).  Fifteen (15) patients < 6 months (< 180 days) of age at the time of gene replacement 
therapy (Day 1) will be enrolled. 
The study includes a screening period, a gene replacement therapy period, and a follow-up period.  
During the screening period (Days –30 to –2), patients whose parent(s)/legal guardian(s) provide 
informed consent will undergo screening procedures to determine eligibility for study enrollment.  
Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day –1 to 
Day 3).  On Day –1, patients will be admitted to the hospital for pre-treatment baseline procedures.  On 
Day 1, patients will receive a one-time intravenous (IV) infusion of AVXS-101, and will undergo 
in-patient safety monitoring over the next 48 hours.  Patients may be discharged 48 hours after the 
infusion, based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of 
Study at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 7 of 126 
assessments until the End of Study when the patient reaches 18 months of age.  After the End of Study 
visit, eligible patients will be asked to rollover into the long-term follow up study. 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, 
except for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
There will be at least a 4 week dosing interval between dosing of the first three patients to allow review 
of the safety analysis from six time points (days 1, 2, 7, 14, 21, and 30) as well as early signals of 
efficacy including CHOP-INTEND score prior to dosing of the next patient. 
In an attempt to dampen the host immune response to the adeno-associated virus (AAV) derived 
therapy, all patients will receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 
24 hours prior to AVXS-101 infusion until at least 30 days post-infusion.  After 30 days of treatment, 
the dose of prednisolone can be tapered for patients whose alanine aminotransferase (ALT) values, 
aspartate aminotransferase (AST) values, and T-cell response are below the threshold of 2 X ULN for 
ALT and AST, and < 100 SFC/106 PBMCs in accordance with the following treatment guideline: 
1 mg/kg/day until at least 30 days post-infusion, 0.5 mg/kg/day at Weeks 5 and 6, 0.25 mg/kg/day at 
Weeks 7 and 8, and discontinued at Week 9. 
Efficacy will be assessed by achievement of the key developmental milestone of functional independent 
sitting for at least 30 seconds at the 18 months of age study visit and survival at 14 months of age.  The 
ability to thrive (as defined above) and the ability to remain independent of ventilatory support (as 
defined above) will also be assessed at 18 months of age.  Additional developmental milestones will be 
assessed using Bayley Scales of Infant and Toddler Development (Version 3).  Safety will be assessed 
through monitoring adverse events (AEs), concomitant medication usage, physical examinations, vital 
sign assessments, cardiac assessments, and laboratory evaluations.  A Data Safety Monitoring Board 
(DSMB) will review safety data on a quarterly basis, and will also convene within 48 hours should any 
patient experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or requires 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the DSMB 
will review the safety information and provide its recommendation.  The DSMB can recommend early 
termination of the study for safety reasons. 
Number of Patients (planned): 15 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
1. 
Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or 
point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier 
mutation (c.859G>C)) 
2. 
Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
3. 
Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
4. 
Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab prophylaxis 
(also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also 
recommended in accordance with American Academy of Pediatrics (27) 
5. 
Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply 
with study procedures and visit schedule 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 8 of 126 
Exclusion Criteria: 
1. 
Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. 
Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without any 
supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does 
not decrease by ≥ 4 percentage points 
3. 
Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the 
screening period or requiring ventilatory support while awake over the 7 days prior to screening or 
at any point during the screening period prior to dosing 
4.  Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass the 
swallowing test will be allowed to enroll in the study 
5. 
Patients whose weight-for-age is below the third percentile based on World Health Organization 
(WHO) Child Growth Standards[26] 
6. 
Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for 
hepatitis B or C, or Zika virus) 
7. 
Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 
2 weeks prior to screening 
8. 
Upper or lower respiratory infection requiring medical attention, medical intervention, or increase 
in supportive care of any manner within 4 weeks prior to screening 
9. 
Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy such 
as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients 
11. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents 
used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, 
immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene 
replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, 
cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) 
binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody titer > 1:50, he 
or she may receive retesting within 30 days of the screening period and will be eligible to 
participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values (international normalized ratio [INR] > 1.4, 
gamma-glutamyl transpeptidase [GGT], ALT, and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, 
creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per 
cmm) prior to gene replacement therapy 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 9 of 126 
14.  Participation in recent SMA treatment clinical study (with the exception of observational cohort 
studies or non-interventional studies) or receipt of an investigational or commercial compound, 
product, or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any 
time prior to screening for this study.  Oral β-agonists must be discontinued at least 30 days before 
gene therapy dosing.  Inhaled albuterol specifically prescribed for the purposes of respiratory 
(bronchodilator) management is acceptable and not a contraindication at any time prior to screening 
for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal surgery or 
tracheostomy) 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to 
travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain 
from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 
Investigational Product, Dosage and Mode of Administration: 
Patients will receive a one-time dose of AVXS-101 at a dose equivalent to the dose received by the 
second dosing cohort in the Phase 1 study, as administered in AVXS-101-CL-101. 
Duration of Treatment: 
AVXS-101 will be administered as a one-time IV infusion over approximately 30-60 minutes, 
dependent upon the volume required. 
Reference Therapy, Dosage and Mode of Administration: Not Applicable 
Criteria for Evaluation: 
Efficacy: 
Co-Primary 
• 
Proportion of patients that achieve functional independent sitting for at least 30 seconds at the 18 
months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler Development 
(Version 3), confirmed by video recording, as a patient who sits up straight with head erect for at 
least 30 seconds 
• 
Survival at 14 months of age.  Survival is defined by the avoidance of the combined endpoint of 
either (a) death or (b) permanent ventilation, which is defined by tracheostomy or by the 
requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive ventilatory support) 
for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative 
ventilation.  Permanent ventilation, so defined, is considered a surrogate for death 
Co-Secondary 
• 
The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate thin 
liquids (as demonstrated through a formal swallowing test) and to maintain weight (> third 
percentile based on World Health Organization [WHO] Child Growth Standards [26] for age and 
gender) without need of gastrostomy or other mechanical or non-oral nutritional support at 
18 months of age 
• 
The proportion of patients who are independent of ventilatory support, defined as requiring no daily 
ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 10 of 126 
ventilation, as defined above through assessment of actual usage data captured from the device 
(Phillips Trilogy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• 
Incidence of elevated liver function tests (LFTs) and/or unresolved liver function enzymes (LFEs) 
• 
Incidence of CTCAE Grade 3 or higher toxicity, treatment-emergent adverse events 
• 
Clinically significant changes in laboratory values, physical exams, cardiac assessments or vital 
signs 
• 
Research Immunology Blood Labs including serum antibody to AAV9 and SMN as well as IFN-γ 
Enzyme-linked ImmunoSpot (ELISpot) to detect T-cell responses to AAV9 and SMN 
Statistical Methods: 
This is a pivotal Phase 3 study assessing the efficacy and safety of AVXS-101.  Details of all analysis 
will be contained within the Statistical Analysis Plan. 
The primary and secondary efficacy analyses will be performed on the population of symptomatic 
patients with bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene modifier mutation 
(c.859G>C).  While the study may enroll a small number of additional patients, the above will comprise 
the population for evaluation of the primary and secondary endpoints and will be referred to as the 
Intent-To-Treat (ITT) population hereafter.  Study power is based upon efficacy analysis of this 
subpopulation.  Patients with 1 copy of SMN2, pre-symptomatic patients and patients with the SMN2 
gene modifier mutation (c.859G>C) will be evaluated separately as part of additional subgroup 
analyses.  Fifteen (15) patients will be enrolled to ensure a reasonably robust safety database at the time 
of the Biologics License Application submission. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 11 of 126 
Based upon widely cited natural history of the disease (Pediatric Neuromuscular Clinical Research 
Network [PNCR]) [Neurol. 2014; 83(9):810-817], it is expected that no patient meeting the study 
entrance criteria (SMN2 copy number of 2 without the SMN2 gene modifier mutation (c.859G>C)) 
would be expected to attain the ability to sit without support for at least 30 seconds at or before the 18 
months of age study visit or other milestones (rolling over, standing, walking) assessed as part of the 
study. 
Assuming that the true response rate for the primary endpoint is actually zero (or as low as 0.1%) in the 
population of interest of the historical control, the first co-primary efficacy endpoint hypothesis is 
whether the AVXS-101 treated patients achieve a response rate greater than 0.1%.  Based upon 
preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at least 40% of treated 
patients in the ITT population are expected to achieve the co-primary efficacy endpoint of functional 
independent sitting for at least 30 seconds at the 18 months of age visit.  With the assumption for the 
true response rate of AVXS-101 for the primary endpoint being in the range of 30% - 40%, an evaluable 
sample size of 15 patients (assuming 30% of patients do not qualify for the ITT population or are 
otherwise excluded from analysis) would provide power of > 90% to detect a significant difference from 
0.1% with α = 0.05 using a 1-sided exact test for a binomial proportion. 
The second co-primary efficacy endpoint of survival at 14 months of age will be evaluated by 
comparing the results observed in the ITT population with the results from the age and gender-matched 
control patients selected from existing natural history data sets (PNCR) [Neurol. 2014; 83(9):810-
817].  It is anticipated that 75% of patients in the PNCR population would not survive beyond 
13.6 months of age, and that these control patients will represent a 25% survival rate based upon the 
natural history of the disease.  Based upon preliminary results from the ongoing Phase 1 clinical study 
(AVXS-101-CL-101), at least 80% of patients in the ITT population are expected to survive, as defined, 
through 14 months of age.  With this efficacy, an evaluable sample size of 15 patients (assuming 30% of 
patients do not qualify for the ITT or are otherwise excluded from the analysis) would provide power 
of > 80% to detect a significant difference from the historical control with α = 0.05 using a 2-sided 
Fisher’s Exact test. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 12 of 126 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
1. 
ADMINISTRATIVE INFORMATION .......................................................................2 
1.1. 
Approval .......................................................................................................................2 
1.2. 
Investigator’s Agreement ..............................................................................................3 
1.3. 
Contact Information ......................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Background .................................................................................................................19 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients ................................................20 
5.3. 
Non-clinical Studies ....................................................................................................22 
5.4. 
Clinical Studies ...........................................................................................................25 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................27 
6.1. 
Primary Objectives .....................................................................................................27 
6.2. 
Secondary Objective ...................................................................................................27 
 
 
6.4. 
Safety Objectives ........................................................................................................28 
7. 
INVESTIGATIONAL PLAN .....................................................................................29 
7.1. 
Overall Study Design ..................................................................................................29 
7.2. 
Number of Patients .....................................................................................................30 
7.3. 
Criteria for Study Termination ...................................................................................30 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................31 
8.1. 
Patient Inclusion Criteria ............................................................................................31 
8.2. 
Patient Exclusion Criteria ...........................................................................................31 
8.3. 
Patient Withdrawal Criteria ........................................................................................33 
9. 
TREATMENT OF PATIENTS ..................................................................................34 
9.1. 
Description of Product ................................................................................................34 
9.2. 
Prior and Concomitant Medications ...........................................................................34 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 13 of 126 
9.2.1. 
Prophylactic Administration of Prednisolone .............................................................34 
9.2.2. 
Prohibited Medications ...............................................................................................35 
9.3. 
Treatment Compliance ................................................................................................35 
9.4. 
Randomization and Blinding ......................................................................................35 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT ....................................36 
10.1. 
Study Product..............................................................................................................36 
10.2. 
Study Product Dose and Dose Justification ................................................................36 
10.3. 
Study Product Packaging and Labeling ......................................................................36 
10.4. 
Study Product Storage ................................................................................................36 
10.5. 
Study Product Preparation ..........................................................................................36 
10.6. 
Study Product Administration ....................................................................................37 
10.7. 
Dose Adjustment Criteria ...........................................................................................37 
10.8. 
Study Product Accountability .....................................................................................37 
10.9. 
Study Product Handling and Disposal ........................................................................37 
11. 
ASSESSMENT OF EFFICACY ................................................................................38 
11.1. 
Developmental Milestones .........................................................................................38 
11.2. 
Motor Function Tests ..................................................................................................39 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones ........39 
11.2.2. 
CHOP-INTEND .........................................................................................................39 
11.3. 
Video Evidence ...........................................................................................................40 
11.4. 
Compound Motor Action Potential ............................................................................40 
12. 
ASSESSMENT OF SAFETY .....................................................................................41 
12.1. 
Safety Parameters .......................................................................................................41 
12.1.1. 
Demographic/Medical History ...................................................................................41 
12.1.2. 
Physical Examinations ................................................................................................41 
12.1.3. 
Vital Signs/Weight and Length ..................................................................................42 
12.1.4. 
Electrocardiogram .......................................................................................................42 
12.1.5. 
12-Lead Holter Monitor ..............................................................................................42 
12.1.6. 
Echocardiogram ..........................................................................................................43 
12.1.7. 
Pulmonary Examinations ............................................................................................43 
12.1.8. 
Swallowing Test .........................................................................................................43 
12.1.9. 
Photographs of Infusion Site ......................................................................................43 
12.1.10. 
Laboratory Assessments .............................................................................................44 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 14 of 126 
12.1.10.1. Hematology .................................................................................................................45 
12.1.10.2. Blood Chemistry .........................................................................................................45 
12.1.10.3. Urinalysis ....................................................................................................................46 
12.1.10.4. Virus Serology ............................................................................................................46 
12.1.10.5. Capillary Blood Gas ...................................................................................................46 
12.1.10.6. Immunology Testing (ELISA and IFN-γ ELISpots) ..................................................47 
12.1.10.7. AAV9 Antibody Screen in Mother .............................................................................47 
12.1.10.8. Blood for Diagnostic Confirmation Testing ...............................................................47 
12.1.10.9. Saliva, Urine, and Stool Collection ............................................................................47 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................49 
13.1.1. 
Definition of Adverse Events .....................................................................................49 
13.1.1.1. 
Adverse Event .............................................................................................................49 
13.1.1.2. 
Serious Adverse Event ................................................................................................50 
13.1.1.3. 
Other Adverse Event ...................................................................................................50 
13.2. 
Relationship to Study Product ....................................................................................50 
13.3. 
Recording Adverse Events .........................................................................................51 
13.4. 
Reporting Adverse Events ..........................................................................................51 
14. 
STATISTICS ..............................................................................................................52 
14.1. 
Study Endpoints and Populations ...............................................................................52 
14.1.1. 
Study Endpoints ..........................................................................................................52 
14.1.1.1. 
Co-Primary Efficacy Endpoint ...................................................................................52 
14.1.1.2. 
Co-Secondary Efficacy Endpoint ...............................................................................53 
 
 
14.1.1.4. 
Safety Endpoints .........................................................................................................54 
14.1.2. 
Statistical Analysis Populations ..................................................................................54 
14.1.2.1. 
Intent-to-Treat Population (ITT) .................................................................................54 
14.1.2.2. 
Efficacy Completers Population .................................................................................54 
14.1.2.3. 
All Enrolled Population ..............................................................................................54 
14.1.2.4. 
Safety Population ........................................................................................................54 
14.2. 
Sample Size Calculation .............................................................................................55 
14.3. 
Efficacy Analysis ........................................................................................................56 
14.3.1. 
General Considerations ...............................................................................................56 
14.3.2. 
Primary and Secondary Efficacy Analysis .................................................................56 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 15 of 126 
14.4. 
Safety Analysis ...........................................................................................................57 
15. 
DATA SAFETY MONITORING BOARD ...............................................................58 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................59 
16.1. 
Study Monitoring ........................................................................................................59 
16.2. 
Audits and Inspections ................................................................................................59 
16.3. 
Institutional Biosafety Committee ..............................................................................60 
16.4. 
Institutional Review Board/Institutional Ethics Committee .......................................60 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61 
18. 
ETHICS ......................................................................................................................62 
18.1. 
Ethics Review .............................................................................................................62 
18.2. 
Ethical Conduct of the Study ......................................................................................62 
18.3. 
Written Informed Consent ..........................................................................................62 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................63 
19.1. 
Electronic Case Report Forms ....................................................................................63 
19.2. 
Inspection of Records .................................................................................................63 
19.3. 
Retention of Records ..................................................................................................63 
20. 
PUBLICATION POLICY ..........................................................................................64 
21. 
LIST OF REFERENCES ............................................................................................65 
22. 
APPENDICES ............................................................................................................67 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................68 
APPENDIX 2. AUTOPSY PLAN ..............................................................................................70 
APPENDIX 3. BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) .............................................................................................................71 
APPENDIX 4. PERFORMANCE CRITERIA FOR BAYLEY SCALES OF INFANT 
AND TODDLER DEVELOPMENT (VERSION 3) DEVELOPMENTAL 
MILESTONES .........................................................................................................116 
APPENDIX 5. CHOP-INTEND ...............................................................................................117 
APPENDIX 6. COMPOUND MOTOR ACTION POTENTIAL MANUAL ..........................119 
APPENDIX 7. DECLARATION OF HELSINKI: ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS...............................122 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 16 of 126 
LIST OF TABLES 
Table 1: 
Important Study Contact Information ...........................................................................4 
Table 2: 
Study Vendor Listing ....................................................................................................4 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................17 
Table 4: 
Spinal Muscular Atrophy Classification .....................................................................20 
Table 5: 
Investigational Product ...............................................................................................34 
Table 6: 
Total Blood Volume ...................................................................................................44 
Table 7: 
Common Terminology Criteria for Adverse Events ..................................................49 
Table 9: 
Tissue Sample for Analysis ........................................................................................70 
 
LIST OF FIGURES 
Figure 1: 
Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 
2, and 3 ........................................................................................................................21 
Figure 2: 
Study Results, Including Staining of Transduced Spinal Motor Neurons, 
SMN Expression Levels, Righting Ability, and Weight and Survival Curves ...........23 
Figure 3 
Body Mass of Treated and Control Mice Showed No Difference ..............................24 
Figure 4: 
Study Design ...............................................................................................................29 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 17 of 126 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AAV 
Adeno-associated virus 
AAV9 
Adeno-associated virus serotype 9 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASO 
Antisense oligonucleotide  
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CB 
Chicken-β-actin-hybrid 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CHOP-INTEND 
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders 
CK 
Creatine kinase 
CLIA 
Clinical Laboratory Improvement Amendment 
CMAP 
Compound motor action potential 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CTCAE 
Common Terminology Criteria for Adverse Events 
Day 1 
First 24-hour interval after the start of gene replacement therapy infusion 
Day –1 
24-hour interval prior to the start of gene replacement therapy infusion  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELISpot 
Enzyme-linked ImmunoSpot 
ET 
Early termination 
FVB 
Friend Virus B-Type 
GCP 
Good Clinical Practice 
GFP 
Green fluorescent protein 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HEENT 
Head, eyes, ears, nose, and throat 
HgB 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 18 of 126 
Abbreviation or Specialist Term 
Explanation 
ICD-10 code 
International Statistical Classification of Diseases and Related Health 
Problems 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon gamma 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITR 
Inverted terminal repeat 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFE 
Liver function enzymes 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHP 
Non-human primates 
NOAEL 
No Observable Adverse Effect Level 
OAE 
Other significant Adverse Event 
PBMC 
Peripheral blood mononuclear cells 
PICU 
Pediatric intensive care unit 
PNCR 
Pediatric Neuromuscular Clinical Research Network 
RNA 
Ribonucleic acid 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
Self-complementary 
scAAV 
Self-complimentary adeno-associated virus 
scAAV9.CB.SMN 
Self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron 
SMA 
Spinal muscular atrophy 
SMN 
Survival motor neuron 
SMN1 
Survival motor neuron 1 gene 
SMN2 
Survival motor neuron 2 gene 
SOC 
System Organ Class 
TMF 
Trial master file 
US 
United States 
vg/kg 
Vector genome per kilogram 
WBC 
White blood cell 
WHO 
World Health Organization 
WT 
Wild type 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 19 of 126 
5. 
INTRODUCTION 
Study AVXS-101-CL-303 is a pivotal Phase 3 clinical gene therapy study investigating the 
efficacy and safety of a single intravenous (IV) infusion of AVXS-101 in up to 15 patients with 
Type 1 spinal muscular atrophy (SMA) with 1 or 2 copies of SMN2.  The survival motor neuron 
(SMN) gene will be transferred using self-complementary adeno-associated virus (scAAV) 
Type 9 under control of the chicken-β-actin hybrid promoter.  Pre-clinical studies have 
demonstrated survival of the SMNΔ7 mouse model for SMA from a median of 15.5 days to over 
1 year, following IV delivery to a facial vein.  Additionally, preliminary results from an ongoing 
Phase 1 clinical study (AVXS-101-CL-101) of AVXS-101 in SMA Type 1 patients demonstrates 
broad improvements in survival, motor function, pulmonary function, and nutritional function 
(Section 5.4). 
5.1. 
Background 
Spinal muscular atrophy is a neurogenetic disorder caused by a loss or mutation in the survival 
motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN protein levels 
and a selective dysfunction of motor neurons.  Spinal muscular atrophy is an autosomal 
recessive, early childhood disease with an incidence of approximately 1:10,000 live births [1].  
Spinal muscular atrophy is the leading cause of infant mortality due to genetic diseases.  Disease 
severity and clinical prognosis depends on the number of copies of survival motor neuron 2 gene 
(SMN2).  In its most common and severe form (Type 1), hypotonia and progressive weakness are 
recognized in the first few months of life, leading to diagnosis before 6 months of age and early 
death due to respiratory failure before 2 years of age.  Motor neuron loss in SMA Type 1 is 
profound in the early post-natal period (or may even start in the prenatal period), whereas motor 
neurons in SMA Type 2 and Type 3 patients adapt and compensate during development and 
persist into adult life.  The findings from various neurophysiological and animal studies have 
shown an early loss of motor neurons in the embryonic and early post-natal periods [2,3,4].  
From a clinical perspective, these findings emphasize the importance of first targeting the SMA 
Type 1 group for gene transfer of SMN2 in hopes of rescuing neurons at this critical stage.  The 
goal in continuing the development plan for AVXS-101 is to modify the SMA Type 1 
phenotype, which will hopefully lead to a milder disease course and prolonged survival as seen 
in SMA Type 2 and Type 3 patients. 
Therapeutic efforts in SMA have focused on the potential for small molecules to increase SMN 
levels.  These include deacetylase inhibitors, such as, valproic acid, sodium butyrate, 
phenylbutyrate, and trichostatin A.  These agents activate the SMN2 promoter, resulting in 
increased full-length SMN protein in SMA animal models [5,6].  However, clinical studies 
employing several of these agents, most notably phenylbutyrate, valporic acid, and hydroxyurea, 
have not resulted in clinical benefit [7,8].  FDA recently approved Nusinersen, an antisense 
oligonucleotide (ASO) drug designed to increase the production of the SMN protein by 
modulating the splicing of the SMN2 gene, thereby compensating for the underlying genetic 
defect.  Clinical studies have shown some modest promise in improving motor function; however 
the treatment must be administered indefinitely on a quarterly basis via intrathecal injection, 
requires a lengthy induction period prior to effectiveness, and has safety considerations which 
require clinical monitoring.  A single-dose IV administration study of AVXS-101 will provide 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 20 of 126 
information on the potential gene transfer has in treating SMA Type 1 patients, and will 
hopefully show promise for success in modifying the disease prognosis. 
This is a single-dose study that will include up to 15 Type 1 patients with 1 or 2 copies of SMN2.  
The rationale for IV dosing is based upon the need for rapid, systemic impact given the severity 
of the disease in SMA Type 1 and its potential impact on systems outside of the central nervous 
system (CNS) such as the peripheral and autonomic nervous systems, heart, pancreas and 
gastrointestinal tract. 
5.2. 
Rationale for Gene Transfer to SMA Type 1 Patients 
Patients with SMA Type 1 have been chosen as the target population for this gene therapy study 
based on studies of the natural history of this disease.  The classification of SMA is shown below 
(Table 4) in which SMA Types 0 to 4 are described.  Spinal muscular atrophy is conventionally 
classified into 4 phenotypes on the basis of age at onset and highest motor function achieved, 
with an additional phenotype (Type 0) to describe the severe forms of antenatal-onset SMA. 
Table 4: 
Spinal Muscular Atrophy Classification 
Type 
Age at Symptom Onset 
Maximum Motor Function 
Life Expectancy 
SMN2 Copy No. 
0 
Fetal 
Nil 
Days – Weeks 
1 
1 
< 6 Months 
1A: B-2 Weeks 
1B: < 3 Months 
1C: > 3 Months 
Never sits 
< 2 years 
1, 2, 3 
2 
6 – 18 Months 
Never walks 
20 – 40 years 
2, 3, 4 
3 
1.5 – 10 Years 
3A: < 3 Years 
3B: > 3 Years 
Walks, regression 
Normal 
3, 4, 5 
4 
> 35 Years 
Slow decline 
Normal 
4, 5 
Source: Adapted from Kolb 2011 [10] 
SMN2 = survival motor neuron 2 gene 
 
Spinal muscular atrophy Type 1 patients, by definition, never attain independent sitting and have 
hypotonia within the first 6 months of life.  Spinal muscular atrophy Type 1 is the leading 
genetic cause of infant death with an onset at ≤ 6 months of age (Table 4).  In contrast, SMA 
Type 2 manifests within the first 18 months, and children afflicted with this condition are able to 
maintain sitting unassisted but never walk independently.  Spinal muscular atrophy Type 3 
patients attain the ability to walk unaided (Type 3a have onset 18 months to 3 years of age; 
Type 3b have onset > 3 years of age).  Spinal muscular atrophy Type 4 is an adult onset disease.  
The genetic cause for SMA is well established and is intimately involved with one’s prognosis.  
All forms of SMA are autosomal recessive in inheritance and are caused by deletions or 
mutations of the SMN1 gene. 
Humans also carry a second nearly identical copy of the SMN1 gene called SMN2 [11].  Both the 
SMN1 and SMN2 genes express SMN protein; however, the amount of functional full-length 
protein produced by SMN2 is only 10 to 15% of that produced by SMN1 [11,12,13].  Although 
SMN2 cannot completely compensate for the loss of the SMN1 gene, patients with milder forms 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 21 of 126 
of SMA generally have higher SMN2 copy numbers [14,15].  Quantitative analysis of SMN2 
copies in 375 patients with Type 1, 2, or 3 SMA showed a significant correlation between SMN2 
copy number and SMA Type, as well as, duration of survival.  In a large early study by 
Feldkotter et al 2002, 2 copies of SMN2 was 97% predictive for developing SMA Type 1, 
3 copies of SMN2 was 83% predictive for developing SMA Type 2, and 4 copies of SMN2 was 
84% predictive of SMA Type 3 [16].  As these percentages do not reflect the possible impact of 
modifier mutations such as that described by Prior et al 2009 [17], they may understate the 
relationship between copy number (in the absence of a genetic modifier) and clinical phenotype.  
Among 113 patients with Type 1 SMA, 9 with one SMN2 copy lived < 11 months, 88/94 with 
two SMN2 copies lived < 21 months, and 8/10 with three SMN2 copies lived 33 to 66 months.  
Even more refined data describing this relationship has been generated, and has also influenced 
our choice of the study target group. 
The severity of SMA Type 1 is demonstrated by prognosis as illustrated in Kaplan-Meier 
survival curves shown in Figure 1. 
Figure 1: 
Kaplan-Meier Survival Curves and Survival Probabilities for SMA Types 1, 
2, and 3 
 
n = number of patients 
Source: Farrar 2013 [18] 
 
In Figure 1, the relative stability of the clinical course of SMA Type 2 and Type 3 is dramatically 
illustrated.  Perhaps most importantly, these findings show that outcome differences are related 
to the number of SMN2 copies that enable motor neurons to adapt and compensate during the 
growth of the child and persist into adult life.  This contrasts with SMA Type 1 where motor 
neuron loss is profound in the early post-natal period (or may even start in the prenatal period, 
especially for SMA Type 1 patients presenting in first 3 months of life).  The findings in Figure 1 
confirm other pieces of evidence from neurophysiological studies and animal studies that also 
show early loss of motor neurons in the embryonic and early post-natal periods [2,3,4]. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 22 of 126 
There is reason to believe that there are few safety issues to be concerned about when targeting 
the SMA Type 1 group in this gene therapy clinical study.  Overexpression of SMN has been 
shown to be well tolerated in both mice and non-human primates, and in humans, a high copy 
number of SMN2 poses no risk (as seen in Type 2, 3, and 4 patients who have high SMN2 copy 
number), allowing for use of robust, ubiquitous expression systems (like the CB-promoter) to 
ensure sustained, high-level SMN expression.  Additionally, it is important to point out that 
recombinant scAAV can be employed for this study because of the small size of the SMN gene.  
This enables efficient packaging and allows for efficient gene transfer with lower viral titers (a 
safety consideration), compared with prototypical single-stranded adeno-associated virus (AAV) 
vectors. 
Recent studies using self-complimentary adeno-associated virus serotype 9 chicken-β-actin-
hybrid survival motor neuron (scAAV9.CB.SMN) show a robust post-natal rescue of SMNΔ7 
mice with correction of motor function, neuromuscular electrophysiology and survival after a 
one-time delivery of vector [19].  Intravenous scAAV9 is able to transduce neurons, muscle and 
vascular endothelium, all of which have been proposed as target cells for SMA treatment. 
5.3. 
Non-clinical Studies 
A mouse model was developed by the 
 after a generation of multiple 
variants.  It was found that the double transgenic, referred to as the SMNΔ7 mouse, provided the 
most suitable model to study gene transfer [20].  Studies performed in the 
 
have shown that injecting 5 × 1011 viral genomes of scAAV9.CB.SMN into the facial vein on 
Day 1 old mice rescues the SMNΔ7 mouse model [19].  Figure 2 shows the results of these 
studies, including staining of transduced spinal motor neurons, SMN expression levels, righting 
ability, and weight and survival curves.  Approximately 42 ± 2% of lumbar spinal motor neurons 
were transduced in scAAV9.CB.GFP treated mice.  SMN transduction was shown by real time 
polymerase chain reaction (RT-PCR) in the mice.  GFP transduction was observed by 
microscopy.  Both constructs were in AAV9 and had transduction of motor neurons.  SMN 
levels were increased as well, in brain, spinal cord, and muscle of scAAV9.CB.SMN-treated 
animals, compared to untreated SMNΔ7 mice (although lower than wild type [WT] controls).  
SMNΔ7 animals treated with either scAAV9.CB.SMN or scAAV9.CB.GFP on post-natal Day 1 
were assessed for their righting ability and were compared to WT control mice and untreated 
mice.  Wild type controls could right themselves quickly, whereas the SMN- and green 
fluorescent protein (GFP)-treated SMA animals showed difficulty at P5.  However, by P13, 
90% of SMN-treated animals could right themselves compared with 20% of GFP-treated 
controls and 0% of untreated SMA animals.  At P18, SMN-treated animals were larger than 
GFP-treated animals, but smaller than WT controls.  Locomotive ability of the SMN-treated 
mice was nearly identical to WT controls, as assayed by open field testing and wheel running. 
Survival of SMN-treated SMNΔ7 animals compared with GFP-treated SMNΔ7 animals was 
significantly improved.  No GFP-treated control animals survived past P22 and had a median life 
span of 15.5 days.  The weights of GFP mice peaked at P10 and then precipitously declined until 
death, while SMN mice showed a steady weight gain until around P40 with it stabilizing at 17 g 
(about half the weight of WT controls).  The smaller size of corrected animals is likely related to 
the tropism and incomplete transduction of scAAV9, resulting in a ‘chimeric’ animal in which 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 23 of 126 
some cells were not transduced.  Additionally, the smaller size suggests an embryonic role for 
SMN.  Most remarkably, SMN-treated mice survived well past 250 days of age. 
Figure 2: 
Study Results, Including Staining of Transduced Spinal Motor Neurons, 
SMN Expression Levels, Righting Ability, and Weight and Survival Curves 
 
Source: Foust 2010 [19] 
CNS = central nervous system; GFP = green fluorescent protein; SMN = survival motor neuron; WT = wild type 
a) Shows transduced motor neurons in lumbar spinal cord 
b) 
Western Blots of SMN expression in CNS and muscle 
c) Improved righting ability of SMN-treated- similar to WT controls by P13 
d) 
SMN-treated are larger than GFP-treated at P18 
e) Survival of SMN-treated markedly improved compared to GFP- treated 
f)  
Body weight increased in SMN-treated vs GFP 
 
Toxicology biodistribution studies were generated by the 
 [data on file].  In the 
non-Good Laboratory Practice (GLP) studies, 24 mice and 4 non-human primates (NHPs) were 
injected, by way of vascular delivery, with AVXS-101.  To assess toxicity and safety, 
AVXS-101 was injected into P1 wild type Friend Virus B-Type (FVB) mice with either vehicle 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 24 of 126 
(3 males/6 females) or 3.3 × 1014 vg/kg of scAAV9.CB.SMN (6 males/9 females) via the facial 
temporal vein.  This dose was previously shown to be most efficacious in the SMNΔ7 mouse 
model [19].  P1 mice were used in anticipation of simulating potential clinical studies in infants.  
All mice survived the injection procedure and the initial 24-hour observation period without any 
signs of distress or weight loss.  Body mass was measured and hands-on observations were 
performed weekly for the remainder of the study; neither revealed any difference between 
control and treated cohorts (Figure 3). 
Figure 3 
Body Mass of Treated and Control Mice Showed No Difference 
 
 
At 60, 90 and 180 days post-injection, blood from the mice was collected for hematology studies 
including complete blood counts with differentials.  At 90, 120 and 180 days post-injection, 
blood was collected for clinical chemistries assessment (alanine amino transferase [ALT], 
aspartate amino transferase [AST], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], 
electrolytes, and creatine kinase [CK]).  For histopathology, 13 mice were necropsied at 
120 days post-injection and 8 mice at 180 days.  There were no clinically significant results 
observed during from the hematology, clinical chemistry, and histopathology portions of the 
study and trends of both groups were comparable.  Of note, no significant lesions were present in 
any brain or spinal cord sections, although, the sections were frozen and thicker than 5 microns 
which made cellular morphology obscure and subtle changes may not have been identified. 
In the safety study for the 4 male Cynomolgus Macaques, animals were injected at 90 days of 
age to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
AVXS-101 vector was administered one time by catheterization of the saphenous vein with a 
dose of 6.7 × 1013 vg/kg, which corresponds to the lowest dose tested for which SMNΔ7 mice 
showed a significant increase of survival.  Animals were followed for six months until they were 
sacrificed at approximately 9 months of age.  No adverse effects were seen, and all clinical 
chemistries were normal.  T-cell immune response was tested using Enzyme-linked ImmunoSpot 
(ELISpot) in peripheral blood mononuclear cells (PBMCs), and all were negative at 6 months 
post-injection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 25 of 126 
These mouse and monkey studies can be summarized as follows.  The serum chemistry and 
hematology studies were unremarkable as was the histopathology assessment.  The NHP patients 
animals mounted appropriate immune responses to capsid (but not to transgene), with very high 
transgene expression persisting at 6 months post-injection.  In conclusion, these studies provide 
strong evidence that systemically-delivered scAAV9.CB.SMN is safe and well tolerated, even at 
the high doses required for penetration of the blood-brain barrier [data on file]. 
When newborn FVB mice were given a single IV injection of AVXS-101 at levels up to 
3.3 × 1014 vg/kg on Day 1, there was neither test article-related mortality nor evidence of toxicity 
seen at time points up to 24 weeks after administration.  Treatment-related decreases in mean 
body weight and mean body weight gain, as well as lower activated partial thromboplastin time 
(APTT) values, were mild effects of treatment, but did not result in toxicity.  Activity of 
AVXS-101 was demonstrated by the biodistribution and the presence of a specific transgene 
ribonucleic acid (RNA) expression in brain and spinal cord, the main targeted therapeutic tissues.  
Low levels of antibodies to the AAV9 capsid were found after 12 and 24 weeks in males and 
females given 3.3 × 1014 vg/kg (Group 3).  No alteration was observed in clinical pathology and 
histopathology analyses.  Based on these results, the no observable adverse effect level 
(NOAEL) of AVXS-101 in newborn male and female mice is considered to be 3.3 × 1014 vg/kg. 
Intravenous administration of AAV9 has been shown to be safe and well tolerated when 
administered to mice and monkeys.  The vector has also demonstrated the ability to cross the 
blood brain barrier in both species following IV administration.  Body weight increased, righting 
behavior improved, survival was extended and cardiac deficits returned toward normal in treated 
SMNΔ7 mice when compared to untreated SMNΔ7 mice.  Toxicology studies determined the 
NOAEL of AVXS-101 was 3.3 x 1014 vg/kg and there was no test article mortality or toxicity 
observed up to 24 weeks following IV administration in mice.  Biodistribution to the brain and 
spinal cord was reconfirmed and low levels of antibodies to the AAV9 capsid were observed at 
12 and 24 weeks following the 3.3 x 1014 vg/kg dose.  No alteration was observed in clinical 
pathology and histopathology analyses. 
5.4. 
Clinical Studies 
First-in-human study AVXS-101-CL-101 is an ongoing 2-year study evaluating the efficacy and 
safety of AVXS-101 in 15 SMA Type 1 patients with 2 copies of SMN2.  All patients have 
received a single IV dose of AVXS-101 in 2 cohorts: Cohort 1 (n = 3) received 6.7 × 1013 vg/kg 
and Cohort 2 (n = 12) received 2.0 × 1014 vg/kg (proposed therapeutic dose). 
Preliminary data as of 15 September 2016 indicate that treatment with AVXS-101 results in 
broad improvements in survival, motor function, pulmonary function, and nutritional function.  
All patients in Cohort 2 (proposed therapeutic dose) showed improvements in survival, as 
defined by Finkel et al 2014 [21], with no deaths or requirements for permanent ventilation 
≥ 16 hours/day for ≥ 14 consecutive days through 15 September 2016.  The median age at last 
follow-up for Cohort 2 was 17.3 months, with the oldest patient at 27.4 months of age.  One 
patient in Cohort 1 (low-dose cohort) had a pulmonary event of increased use of bi-level positive 
airway pressure in advance of surgery related to hypersalivation, a condition experienced by 
some SMA patients.  The event was determined by independent review to represent progression 
of disease and not related to AVXS-101. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 26 of 126 
As of September 15, 2016, improvements in motor function, as assessed by the CHOP-INTEND 
scores, were observed with mean increases of 9.0 points in Cohort 1 and 24.8 points in Cohort 2.  
The CHOP-INTEND scores in Cohort 2 were ≥ 40 points for 11/12 patients, ≥ 50 points for 
9/12 patients, and ≥ 60 points (normal) for 3/12 patients. 
As of September 15, 2016, patients in Cohort 2 consistently achieved and maintained key 
developmental motor milestones as summarized below: 
• 11/12 patients achieved head control, 7/12 patients could roll, 11/12 patients could sit with 
support, and 8/12 patients could sit unassisted, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016 
• 7 patients were able to feed themselves, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016, and 5 patients were speaking (1 bilingual) 
• 2 patients were walking independently, including 1 patient whose achievement of this 
milestone was confirmed after 15 September 2016.  These 2 patients each achieved earlier 
and important developmental milestones such as crawling, standing with support, standing 
alone, and walking with support 
 
As of September 15, 2016, AVXS-101 appears to have a favorable safety profile and appears to 
be generally well-tolerated in this study.  A total of 118 treatment-related AEs were reported 
(34 serious adverse events [SAEs] and 84 non-serious adverse events [AEs]).  Two SAEs were 
deemed treatment-related in 2 patients, and 3 AEs were deemed treatment-related in 2 patients.  
All treatment-related events consisted of clinically asymptomatic liver enzyme elevations that 
resolved with prednisolone treatment.  There were no clinically significant elevations of 
gamma-glutamyl transferase (GGT), alkaline phosphatase or bilirubin, and as such, Hy’s Law 
was not met.  Other non-treatment-related AEs were expected and were associated with SMA. 
In summary, through September 15, 2016, the consistently positive clinical observations are 
remarkably different from that described in extensive natural history studies, clinical 
publications, the experience of seasoned clinicians, and concurrent SMA Type 1 studies with 
other therapies.  These significant and clinically meaningful responses in patients treated with 
AVXS-101 indicate preliminary clinical evidence of a treatment effect that addresses an unmet 
need in this devastating pediatric disease. 
A full understanding of all the risks associated with AVXS-101 is not known at this time.  
Elevated liver function tests have been observed in the ongoing AVXS-101-CL-101 study, which 
is believed to be a T-cell immune response to the AAV9 vector.  None of the liver enzyme 
abnormalities observed in the study were accompanied by clinical sequelae.  Patients could 
experience an allergic response to AVXS-101.  Patients could also develop an immune response 
to the AAV9 viral vector, which could prevent future use of gene transfers using this vector. 
Taken together, results from the clinical and non-clinical studies support further clinical 
investigation of the efficacy and safety of AVXS-101 in patients with SMA Type 1. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 27 of 126 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The co-primary objectives are to: 
• Determine the efficacy of AVXS-101 by demonstrating achievement of developmental 
milestone of functional independent sitting for at least 30 seconds at the 18 months of age 
study visit. 
• Determine the efficacy of AVXS-101 based on survival at 14 months of age.  Survival is 
defined by the avoidance of combined endpoint of either (a) death or (b) permanent 
ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of 
respiratory assistance per day (via non-invasive ventilatory support) for ≥ 14 consecutive 
days in the absence of an acute reversible illness, excluding perioperative ventilation.  
Permanent ventilation, so defined, is considered a surrogate for death. 
 
6.2. 
Secondary Objective 
The co-secondary objectives are to: 
• Determine the effect of AVXS-101 on the on the ability to thrive defined as achieving all of 
the following at 18 months of age 
o Does not receive nutrition through mechanical support (e.g., feeding tube) 
o Ability to tolerate thin liquids as demonstrated through a formal swallowing test 
o Maintains weight (> third percentile for age and gender) 
• Determine the effect of AVXS-101 on the ability to remain independent of ventilatory 
support, defined as requiring no daily ventilator support/usage at 18 months of age, excluding 
acute reversible illness and perioperative ventilation, as defined above through assessment of 
actual usage data captured from the device, for patients issued a Trilogy 100 BiPAP device 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 28 of 126 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4. 
Safety Objectives 
The safety objectives are to: 
• 
Evaluate the safety of AVXS-101 in patients with SMA Type 1 
• 
Determine the safety of AVXS-101 based on the development of unacceptable toxicity 
defined as the occurrence of any Common Terminology Criteria for Adverse Events 
(CTCAE) [9] Grade 3 or higher, unanticipated, treatment-related toxicity. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 29 of 126 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, open-label, single-arm, single-dose study of AVXS-101 (gene replacement 
therapy) in patients with SMA Type 1 with 1 or 2 copies of SMN2.  Fifteen (15) patients 
< 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be 
enrolled. 
The study includes 3 study periods: screening, gene replacement therapy, and follow-up 
(Figure 4).  During the screening period (Days –30 to –2), patients whose parent(s)/legal 
guardian(s) provide informed consent will undergo screening procedures to determine eligibility 
for study enrollment.  Patients who meet the entry criteria will enter the in-patient gene 
replacement therapy period (Day –1 to Day 3).  On Day –1, patients will be admitted to the 
hospital for pre-treatment baseline procedures.  On Day 1, patients will receive a one-time IV 
infusion of AVXS-101 at a dose equivalent to the dose received by the second dosing cohort in 
the Phase 1 study over approximately 60 minutes, and will undergo in-patient safety monitoring 
over the next 48 hours.  Patients may be discharged 48 hours after gene replacement therapy, 
based on Investigator judgment.  During the outpatient follow-up period (Days 4 to End of Study 
at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety 
assessments until the patient reaches 18 months of age.  Any missed visit should be rescheduled 
as soon as possible, but within 7 days. 
All post-treatment visits will be relative to the date on which gene replacement therapy is 
administered, except for the 14 and 18 months of age visits, which will be relative to the 
patient’s date of birth.  For the 14 and 18 months of age visits, the patient will return within 0 to 
14 days after the date on which the patient reaches 14 and 18 months of age, respectively.  The 
18 months of age visit will also serve as the End of Study visit.  After the End of Study visit, 
eligible patients will be asked to roll over into the long-term follow-up study. 
Figure 4: 
Study Design 
 
Note: After the End of Study visit at 18 months of age, eligible patients will be asked to roll over into the long-
term follow-up study. 
ET = early termination 
a 
All post-treatment visits will be relative to the date on which gene replacement therapy is administered, except 
for the 14 and 18 months of age visits, which will be relative to the patient’s date of birth. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 30 of 126 
There will be at least a 4 week dosing interval between dosing of the first three patients to allow 
review of the safety analysis from six time points (days 1, 2, 7, 14, 21, and 30) as well as early 
signals of efficacy including CHOP-INTEND score prior to dosing of the next patient. 
In an attempt to dampen the host immune response to the AAV-derived therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion in accordance with the specified 
guidelines for tapering (Section 9.2.1). 
A schedule of study assessments is provided in Appendix 1.  Efficacy will be assessed by 
achievement of the key developmental milestone of functional independent sitting for at 
least 30 seconds at the 18 months of age study visit and survival at 14 months of age (as defined 
in Section 14.1.1.1).  The ability to thrive and the ability to remain independent of ventilatory 
support (as defined in Section 14.1.1.2) will also be assessed.  Additional developmental 
milestones will be assessed using Bayley Scales of Infant and Toddler Development© 
(Version 3) (Section 11).  Safety will be assessed through monitoring AEs, concomitant 
medication usage, physical examinations, vital sign assessments, cardiac assessments, and 
laboratory evaluations (Section 12).  Additionally, a Data Safety Monitoring Board (DSMB) will 
review safety data on a quarterly basis, and will also convene within 48 hours should any patient 
experience an unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably, or 
definitely related to gene replacement therapy, and is associated with clinical symptoms and/or 
requires medical treatment (Section 13.1.1.1 and Section 15).  This includes any patient death, 
important clinical laboratory finding, or any complication attributed to administration of gene 
replacement therapy.  In such instances, the DSMB will review the safety information and 
provide its recommendation.  The DSMB can recommend early termination of the study for 
safety reasons. 
7.2. 
Number of Patients 
A total of 15 patients will be enrolled. 
7.3. 
Criteria for Study Termination 
An independent DSMB will conduct quarterly and ad hoc reviews of the emerging safety data 
throughout the study as described in Section 15. 
The study will be completed as planned but may be terminated for the following reasons: 
• Development of unacceptable toxicity, defined as the occurrence of any unanticipated 
CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely related to gene 
replacement therapy, and is associated with clinical symptoms and/or requires medical 
treatment 
• DSMB can recommend early termination of the study for safety reasons 
• Study is terminated by Sponsor 
• Regulatory Authority recommendation 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 31 of 126 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients with SMA Type 1 who are < 6 months (< 180 days) of age at the time of gene 
replacement therapy (Day 1) with proven bi-allelic mutations of the SMN1 gene and 1 or 
2 copies of the SMN2 will be enrolled in this study.  Patients may be of any racial, ethnic, or 
gender background. 
8.1. 
Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Patients with SMA Type 1 as determined by the following features: 
a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 
mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of 
the known SMN2 gene modifier mutation (c.859G>C)) 
2. Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion 
3. Patients must have a swallowing evaluation test performed prior to administration of gene 
replacement therapy 
4. Up-to-date on childhood vaccinations.  Seasonal vaccinations that include palivizumab 
prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections 
are also recommended in accordance with American Academy of Pediatrics (27) 
5. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and 
comply with study procedures and visit schedule 
 
8.2. 
Patient Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
1. Previous, planned or expected scoliosis repair surgery/procedure during the study assessment 
period 
2. Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without 
any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation 
< 92% awake or asleep without any supplemental oxygen or respiratory support 
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation 
does not decrease by ≥ 4 percentage points 
3. Tracheostomy or current use or requirement of non-invasive ventilatory support averaging 
≥ 6 hours/day over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during 
the screening period or requiring ventilatory support while awake over the 7 days prior to 
screening or at any point during the screening period prior to dosing 
4. Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal 
swallowing test performed as part of screening.  Patients with a gastrostomy tube who pass 
the swallowing test will be allowed to enroll in the study 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 32 of 126 
5. Patients whose weight-for-age is below the third percentile based on World Health 
Organization (WHO) Child Growth Standards [26] 
6. Active viral infection (includes human immunodeficiency virus [HIV] or positive serology 
for hepatitis B or C, or Zika virus) 
7. Serious non- respiratory tract illness requiring systemic treatment and/or hospitalization 
within 2 weeks prior to screening 
8. Upper or lower respiratory infection requiring medical attention, medical intervention, or 
increase in supportive care of any manner within 4 weeks prior to screening 
9. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis or meningitis) within 
4 weeks before administration of gene replacement therapy or concomitant illness that, in the 
opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy 
such as: 
a. Major renal or hepatic impairment 
b. Known seizure disorder 
c. Diabetes mellitus 
d. Idiopathic hypocalcuria 
e. Symptomatic cardiomyopathy 
10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
11. Concomitant use of any of the following: drugs for the treatment of myopathy or neuropathy, 
agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, 
plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 
3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, 
methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) 
12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay 
(ELISA) binding immunoassay.  Should a potential patient demonstrate Anti-AAV9 antibody 
titer > 1:50, he or she may receive retesting within 30 days of the screening period and will 
be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50 
13. Clinically significant abnormal laboratory values (international normalized ratio [INR] > 1.4; 
GGT, ALT, and AST > 3 × ULN; bilirubin ≥ 3.0 mg/dL; creatinine ≥ 1.0 mg/dL; hemoglobin 
< 8 or > 18 g/dL; white blood cells [WBC] > 20,000/cmm) prior to gene replacement therapy 
14. Participation in recent SMA treatment clinical study (with the exception of observational 
cohort studies or non-interventional studies) or receipt of an investigational or commercial 
compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, 
valproic acid) at any time prior to screening for this study.  Oral β-agonists must be 
discontinued at least 30 days prior to gene therapy dosing.  Inhaled albuterol specifically 
prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not 
a contraindication at any time prior to screening for this study 
15. Expectation of major surgical procedures during the study assessment period (e.g., spinal 
surgery or tracheostomy) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 33 of 126 
16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability 
to travel for repeat visits 
17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to 
refrain from posting confidential study results/observations on social media sites 
18. Parent(s)/legal guardian(s) refuses to sign consent form 
8.3. 
Patient Withdrawal Criteria 
Patients may be discontinued from the study for the following reasons: 
• Death 
− An autopsy will be requested for any patient who expires following participation in a gene 
replacement study as per the National Institutes of Health’s Guidelines for Research 
Involving Recombinant or Synthetic Nucleic Acid Molecules [25] (see Autopsy Plan in 
Appendix 2) 
• Failure to comply with protocol-required visits or study procedures for 3 or more consecutive 
visits that are not rescheduled, unless due to hospitalization 
• Parent(s)/legal guardian(s) withdraws consent 
• Investigator discretion 
 
Early termination procedures should be completed within 14 days for any patient who 
prematurely discontinues the study for any reason, as indicated in Appendix 1. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 34 of 126 
9. 
TREATMENT OF PATIENTS 
It is the responsibility of the Investigator to ensure the safe storage and administration of gene 
replacement therapy. 
9.1. 
Description of Product 
The biological product is a non-replicating recombinant AAV9 containing the complimentary 
deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the 
cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB).  The AAV inverted 
terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, 
thus forming a double-stranded transgene ready for transcription.  This modified ITR, termed a 
“self-complementary” (sc) ITR, has been shown to significantly increase the speed of which the 
transgene is transcribed and the resulting protein is produced.  The biological product, called 
AVXS-101 (formerly scAAV9.CB.hSMN), expresses the human SMN protein in transduced 
cells. 
Table 5: 
Investigational Product 
 
Investigational Product 
Product Name: 
AVXS-101 
Dosage Form: 
Equivalent to the dose received by the second dosing cohort in the Phase 1 study 
Unit Dose 
Equivalent to the dose received by the second dosing cohort in the Phase 1 study 
Route of Administration 
Intravenous infusion 
Physical Description 
AVXS-101 is a clear, colorless liquid. 
 
9.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be captured in the electronic Case Report Form (eCRF) 
from 2 weeks prior to administration of gene replacement therapy through the last study visit. 
9.2.1. 
Prophylactic Administration of Prednisolone 
An antigen specific T-cell response to the AAV vector was observed in the ongoing Phase 1 
clinical study (AVXS-101-CL-101) investigating AVXS-101 treatment via IV infusion.  This is 
an expected response between 2 to 4 weeks following gene replacement therapy.  One possible 
consequence to such antigen specific T-cell response is clearance of the transduced cells and loss 
of transgene expression. 
In an attempt to dampen the host immune response to the AAV-based therapy, all patients will 
receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to 
gene replacement therapy until at least 30 days post-infusion.  After 30 days of treatment, the 
dose of prednisolone can be tapered for patients whose ALT values, AST values, and T-cell 
response are below the threshold of ≤ 2 X ULN for ALT and AST, and < 100 SFC/106 PBMCs 
in accordance with the following treatment guideline: 
• Until at least 30 days post-infusion: 1 mg/kg/day 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 35 of 126 
• Weeks 5 and 6: 0.5 mg/kg/day 
• Weeks 7 and 8: 0.25 mg/kg/day 
• Week 9: prednisolone discontinued 
 
If the AST or ALT values are > 2 X ULN, or if T-cell response is ≥ 100 SFC/106 PBMCs after 
30 days of treatment, the dose of prednisolone will be maintained until the AST and ALT values 
decrease below threshold.  If T-cell response continues past Day 60, Investigator discretion 
should be used considering risk benefit for maintaining prednisolone.  Variance from these 
recommendations will be at the discretion of the Investigator based on potential safety issues for 
each patient. 
9.2.2. 
Prohibited Medications 
Concomitant use of any of the following medications is prohibited: 
• Drugs for treatment of diabetes, myopathy or neuropathy 
• Therapy received with the intent to treat SMA (e.g., nusinersen, valproic acid) 
o Oral β-agonists must be discontinued at least 30 days prior to gene therapy dosing.   
o Inhaled β-agonists may be used to treat respiratory complications of SMA provided 
such medications are dosed at clinically appropriate levels 
• Any investigational medication other than AVXS-101 is prohibited during the study 
• Ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as 
adalimumab, or immunosuppressive therapy within 3 months of starting the study 
(e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV 
immunoglobulin, rituximab) 
 
Corticosteroid usage following completion of the prednisolone taper is permissible as part of 
routine clinical management.  The use of corticosteroids in such circumstances should be 
documented appropriately as a concomitant medication, and the event precipitating its usage 
should be appropriately documented as an adverse event. 
Should the use of corticosteroids (aside from inhaled corticosteroids for bronchospasm) be 
considered as part of care during the course of the prednisolone taper, this medical management 
should be discussed with the medical monitor. 
9.3. 
Treatment Compliance 
AVXS-101 will be administered as a one-time IV injection. 
9.4. 
Randomization and Blinding 
This is an open-label study. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 36 of 126 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT 
AVXS-101 is manufactured in accordance with current Good Manufacturing Practices (cGMP).  
Investigational product accountability logs will be maintained by the clinical pharmacy. 
10.1. 
Study Product 
AVXS-101 
10.2. 
Study Product Dose and Dose Justification 
Patients will receive a one-time dose of AVXS-101 equivalent to the dose received by the second 
dosing cohort in the Phase 1 study via IV infusion administered in the ongoing Phase 1 clinical 
study (AVXS-101-CL-101). 
Two doses (2.0 × 1014 vg/kg and 6.7 × 1013 vg/kg) are being studied in the ongoing Phase 1 
clinical study (AVXS-101-CL-101); the higher dose (2.0 × 1014 vg/kg) was chosen for the 
present study as preliminary data demonstrated both a dose response and significant clinical 
benefit thus identifying 2.0 × 1014 vg/kg, as the minimum dose that is clinically effective. 
10.3. 
Study Product Packaging and Labeling 
AVXS-101 kits are labeled with a specific kit number and batch/lot number assigned at the 
cGMP facility.  The content of the labeling is in accordance with the local regulatory 
specifications and requirements. 
10.4. 
Study Product Storage 
AVXS-101 kits will be stored in an appropriate, locked room under the responsibility of the 
Investigator or other authorized persons (e.g., pharmacists) in accordance with local regulations, 
policies, and procedures.  Control of storage conditions, especially control of temperature (e.g., 
refrigerated/freezer storage) and information on in-use stability and instructions for handling 
prepared AVXS-101 should be managed in accordance with the Pharmacy Manual. 
The vessel used for delivery of the vector should be resealed in the procedure room and 
processed for destruction and/or return to AveXis in accord with the Pharmacy manual and 
applicable biohazardous waste guidelines for disposal. 
10.5. 
Study Product Preparation 
Preparation of AVXS-101 will be done aseptically under sterile conditions by a pharmacist and 
will arrive at the clinical site ready for infusion. 
AVXS-101 will be received diluted with normal saline, as outlined in the Pharmacy Manual. 
The total vector genome dose will be calculated based on the patient’s body weight. 
The dose-delivery vessel will be delivered to the designated pediatric intensive care unit 
(PICU) patient room or other appropriate setting (e.g., interventional suite, operating room, 
dedicated procedure room) with immediate access to acute critical care management.  The 
vessel will be delivered in accord with the Pharmacy Manual. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 37 of 126 
10.6. 
Study Product Administration 
AVXS-101 infusion will be administered under sterile conditions in a PICU or other appropriate 
setting (e.g., interventional suite, operating room, dedicated procedure room) with immediate 
access to acute critical care management.  AVXS-101 will be delivered one-time through a 
venous catheter inserted into a peripheral limb vein (arm or leg) at a dose equivalent to the dose 
received by the second dosing cohort in the Phase 1 study.  AVXS-101 should be slowly infused 
over approximately 30-60 minutes, dependent upon total volume in accord with the Pharmacy 
Manual, utilizing an infusion set and pump in accordance with the Pharmacy Manual. 
Following administration of gene replacement therapy, patients should return to an appropriate 
designated setting to ensure close monitoring of vital signs and adverse events.  Vital signs will 
be continuously monitored throughout the gene replacement therapy infusion as described in 
Section 12.1.3.  Patients should be maintained in the PICU or other appropriate setting for 
48 hours after the start of gene replacement therapy. 
10.7. 
Dose Adjustment Criteria 
The study investigates a one-time IV infusion of AVXS-101; no dose adjustments are possible. 
10.8. 
Study Product Accountability 
The pharmacist or designee will maintain accurate records of the quantities of AVXS-101 
received, dispensed, destroyed, and/or returned to AveXis.  The pharmacist or designee will 
document the date and time of delivery of the dose vessel to the dose procedure room as well as 
the time the used vessel was returned to AveXis or destroyed as per the Pharmacy Manual. 
10.9. 
Study Product Handling and Disposal 
All materials used for injection, including sterile drapes, needles, and syringes in contact with the 
vector must be sealed in leak-proof containers.  All waste must be sealed in bags bearing the 
biohazard symbol and disposed of in a biohazard waste container. 
All transfers must be done in spill-proof containers.  Individuals manipulating the vector will be 
required to wear personal protective equipment, such as gloves. 
Any quality issue noticed with the receipt or use of AVXS-101 (e.g., deficiency in condition, 
appearance, pertaining to documentation, labeling, expiration date, etc.) should be promptly 
reported to the Sponsor in accord with procedures outlined in the Pharmacy Manual. 
Under no circumstances will the Investigator supply AVXS-101 to a third party, allow AVXS-
101 to be used other than as directed by this clinical trial protocol, or dispose of AVXS-101 in 
any other manner. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 38 of 126 
11. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed by achievement of the key developmental milestone of functional 
independent sitting for at least 30 seconds at the 18 months of age study visit and survival at 
14 months of age (as defined in Section 14.1.1.1).  The ability to thrive and the ability to remain 
independent of ventilatory support (as defined Section14.1.1.2) will also be assessed at 
18 months of age.  Additional developmental milestones will be assessed using the Bayley 
Scales of Infant and Toddler Development (version 3©).  Efficacy assessments will be performed 
at the times specified in the Table of Assessments (Appendix 1), and should be the first 
assessments performed at any scheduled visit.  All post-treatment visits will be relative to the 
date on which gene replacement therapy is administered except the 14 and 18 months of age 
visits, which will be relative to the patient’s date of birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
11.1. 
Developmental Milestones 
Developmental milestones will be assessed using relevant definitions obtained from the Bayley 
Scales of Infant and Toddler Development (version 3), and will be analyzed to assess efficacy 
(Appendix 3 and Appendix 4).  Achievement of each developmental milestone will be 
determined by the Physical Therapist and confirmed by the central reader (as may be necessary) 
based on an assessment of the submitted videos (Section 11.3).  Developmental milestones will 
be determined at each monthly visit as listed in Section 11.2.1. 
During the Screening visit, the physical therapist will complete an assessment of baseline 
milestone achievement in accordance with Appendix 1; this assessment must address all 
milestones/items noted on Appendix 1 that are at or below the child’s baseline function, and be 
recorded on video.  The findings must be documented in the source.  Items that are below the 
baseline level of assessment that are not successfully achieved during the baseline evaluation 
should be repeated at subsequent visits until successfully performed. 
The milestones of sitting independently (items 22 and 26) should be assessed at every subsequent 
visit, until attainment of milestone, regardless of starting point on the scale.  These milestones 
must also be assessed at the 18 months of age visit, regardless of previous attainment. 
As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each attained milestone be captured on video. 
A milestone will be considered achieved when demonstrated by a patient and observed with 
video capture confirmation during a physical therapy assessment or observed with video as 
provided by the patient’s family at the patient’s visit at 18 months of age. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 39 of 126 
11.2. 
Motor Function Tests 
11.2.1. 
Bayley Scales of Infant and Toddler Development/Developmental Milestones 
The Bayley Scales of Infant and Toddler Development (Version 3) (Appendix 3) is a 
standardized, norm-referenced infant assessment of developmental functioning across 5 domains 
of cognitive, language, motor, social-emotional, and adaptive behavior.  The Bayley Scales will 
be administered by a qualified Physical Therapist. 
The full Bayley Scales will be administered at screening, every 6 months starting at Month 6, 
and at End of Study when the patient reaches 18 months of age (or early termination), whereas 
the gross and fine motor subtests of the motor domain will be administered at each monthly visit. 
Each Bayley Scales/developmental milestone assessment will be video recorded in accordance 
with the AVXS-101-CL-303 Video Manual and may be submitted to the vendor for review by a 
central reader (Section 11.3). 
The following developmental milestones will be assessed: 
• Ability to hold head erect without support 
• Ability to roll from back to both sides 
• Ability to sit with support 
• Ability to sit independently, > 10 seconds; WHO [22] 
• Ability to sit without support for at least 30 seconds 
• Ability to crawl 
• Ability to pull to stand 
• Ability to stand with assistance 
• Ability to stand alone 
• Ability to walk with assistance 
• Ability to walk alone 
11.2.2. 
CHOP-INTEND 
The CHOP-INTEND is a motor function scale developed and validated for use specifically to 
monitor motor function status and decline amongst children with SMA Type 1, and will be 
administered by a qualified Physical Therapist.[23,24]  The CHOP-INTEND scale examines 
several aspects of motor function, including head control, righting reactions, and trunk 
movements in supported sitting, supine, and prone positions (Appendix 5).  Anti-gravity 
movements in assisted rolling, ventral suspension, and supported standing will also be measured. 
The CHOP-INTEND will be performed at screening and at each scheduled visit from Day 7 
through the End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 1). 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 40 of 126 
Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not undergo any additional 
CHOP-INTEND examinations. 
Each CHOP-INTEND exam will be video recorded in accordance with the AVXS-101-CL-303 
Video Manual and submitted to the vendor for review by a central reader as may be necessary 
(Section 11.3). 
11.3. 
Video Evidence 
Physical therapy assessments (Bayley Scales and CHOP-INTEND) required at each study visit 
will be video recorded in an effort to produce compelling, demonstrable, documented evidence 
of efficacy, as determined by changes in functional abilities.  AveXis, Inc. (AveXis) will provide 
a secure and confidential upload process for transfer and storage of the videos from 
investigational sites to a contracted third-party vendor that will compile and arrange videos as 
per AveXis requirements.  Any/all videos received at AveXis or the contracted vendor will be 
treated as confidential study data and will be the sole property of AveXis.  AveXis and the 
contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families on the videos, which may be shared with regulatory 
agencies, the medical community, and/or in appropriate venues to discuss the results of this 
clinical study. 
Videos may be provided to an independent, centralized reviewer for unbiased assessment of 
developmental milestone achievement.  The independent reviewer will document whether the 
video displays evidence of having achieved each developmental milestone.  The date of 
developmental milestone achievement will be computed as the earliest date on which video 
evidence demonstrates the achievement of the specified milestone. 
Additionally, the Parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the study.  These videos will be 
handled in the same manner in which the study-derived videos are handled. 
11.4. 
Compound Motor Action Potential 
Peroneal nerve CMAP amplitude will be measured by a qualified electrophysiologist, at all 
clinical sites capable of performing this assessment, using the procedures as described in the 
CMAP Manual (Appendix 6).  CMAP will be measured at screening, every 6 months starting at 
Month 6, and End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 1). 
The CMAP data will be collected for centralized review and interpretation. 
Sites that do not have equipment or appropriately experienced personnel required to perform 
CMAP measurements will not be required to perform these assessments. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 41 of 126 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety parameters include physical examinations, pulmonary examinations, vital signs, capillary 
blood gas assessments, weight and length measurements, 12-lead electrocardiograms (ECGs), 
12-lead Holter monitor recordings, echocardiograms, swallowing tests, laboratory assessments, 
adverse event monitoring, and photographs of the infusion site.  In general, safety assessments 
will be performed at the times specified in the Table of Assessments (Appendix 1).  All post-
treatment visits are relative to the date on which gene replacement therapy is administered until 
the patient reaches 14 months of age, at which point all visits are relative to the patient’s date of 
birth. 
Unless otherwise noted, visit windows for the outpatient follow-up visits are as follows: 
• Days 7, 14, 21, and 30: ± 2 days 
• Monthly visits starting at Month 2: ± 7 days 
• 14 months of age visit: 0 to 14 days after the patient reaches 14 months of age 
• 18 months of age/End of Study visit: 0 to 14 days after the patient reaches 18 months of age 
 
12.1.1. 
Demographic/Medical History 
Demographic/medical history information will be collected at screening and captured in the 
eCRF.  Information that will be collected includes: 
• Familial history of SMA including affected siblings or parent carriers 
• Gestational age at birth 
• Length/height/head circumference at birth 
• Hospitalization information from time of birth including number, duration, and reason for 
hospitalizations including International Statistical Classification of Diseases and Related 
Health Problems (ICD-10 codes), if available 
• Historical ventilatory support, if any 
• Historical feeding support, if any 
 
1. Patients are encouraged to follow all routinely scheduled immunizations, as 
recommended by the Center for Disease Control (CDC), throughout the study.  Seasonal 
vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent 
respiratory syncytial virus (RSV) infections are also recommended in accordance with 
American Academy of Pediatrics (27). 
12.1.2. 
Physical Examinations 
Physical examinations will be conducted by the Investigator or Sub-Investigator at each 
scheduled visit, except Day –1 (Appendix 1).  The Day 1 physical examination will be 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 42 of 126 
performed prior to the start of gene replacement therapy infusion.  Physical examinations include 
a review of the following systems: head, eyes, ears, nose and throat (HEENT), lungs/thorax, 
cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, lymphatic, and 
genitourinary. 
12.1.3. 
Vital Signs/Weight and Length 
Vital sign parameters include blood pressure, respiratory rate, pulse, axillary temperature, and 
pulse oximetry.  Vital signs will be obtained at each study visit (as specified in Appendix 1).  On 
Day 1, vital signs will be continuously monitored throughout the gene replacement therapy 
infusion, and recorded pre-dose and every 15 (± 5) minutes for the first 4 hours after the start of 
infusion, and then every hour (± 15 minutes) until 24 hours after the start of infusion.  Axillary 
temperature will be recorded pre- and post-infusion. 
Weight and length will be measured at each study visit (as specified in Appendix 1).  On Day 1, 
weight and length will be measured pre-dose. 
12.1.4. 
Electrocardiogram 
A 12-lead ECG will be performed at screening, Day –1, pre-dose on Day 1, Day 2, every 
6 months starting at Month 6, and End of Study when the patient reaches 18 months of age (or 
early termination) (Appendix 1).  Additional ECG monitoring will be at the discretion of the 
Investigator as per local institutional guidelines. 
The ECG will be interpreted locally by a cardiologist.  The ECG tracings or ECG machine data 
will be collected for centralized review and interpretation by a cardiologist. 
12.1.5. 
12-Lead Holter Monitor 
A Holter monitor will continuously record the patient’s 12-lead ECG for a total of 72 hours from 
Day –1 (24 hours prior to the start of gene replacement therapy infusion) through 48 hours after 
the start of infusion.  Serial ECG data will be pulled in triplicate from the Holter monitor at the 
following time points: 
• Pre-dose (within 24 hours prior to gene replacement therapy) 
• 2 hours 
• 4 hours 
• 6 hours 
• 8 hours 
• 12 hours 
• 24 hours 
• 36 hours 
• 48 hours 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 43 of 126 
Holter monitors will be provided to study sites along with a dedicated laptop for uploading the 
data from the memory cards for centralized review and analysis by a cardiologist within 24 hours 
of data upload.  The Sponsor physician or designee will be notified of any safety concerns from 
the centralized review, and the safety management plan will be followed for documenting and 
reporting of AEs/SAEs. 
12.1.6. 
Echocardiogram 
A standard transthoracic echocardiogram will be performed at screening, every 6 months starting 
at Month 6, and at End of Study when the patient reaches 18 months of age (or early termination) 
(Appendix 1). 
12.1.7. 
Pulmonary Examinations 
Pulmonary examinations will be performed by a pulmonologist or appropriate individual as per 
standard institutional practice at each scheduled visit except Day 1 (Appendix 1).  Prior to study 
entry, a pulmonologist or appropriate individual as per standard institutional practice will review 
and document ventilator usage in the 2 weeks prior to screening. 
Patients may be fitted with non-invasive ventilatory support at the discretion of the 
pulmonologist or appropriate individual as per standard institutional practice and/or Investigator.  
Non-invasive ventilatory support equipment will be provided by AveXis through a third-party 
vendor.  Should the patient require non-invasive ventilatory support at any time during the study, 
the equipment provided by AveXis must be used. 
Patients requiring non-invasive ventilatory support will be asked to bring their machine(s) to 
each study visit such that the study staff can remove an SD card which captures actual usage 
data.  The hours per day usage data for each day between visits will be extracted with software 
provided by the device manufacturer into a format that will be transferred/transcribed to the 
clinical database. 
12.1.8. 
Swallowing Test 
A swallowing test will be performed at screening (at the Investigator site), every 6 months 
starting at Month 6, and at End of Study when the patient reaches 18 months of age (or early 
termination) (Appendix 1) to determine if the patient has signs of aspiration.  If the test is 
positive for aspiration, there may be a recommendation for the patient to use an alternate method 
to oral feeding for the duration of the study at the determination of the Investigator and treating 
clinician. 
12.1.9. 
Photographs of Infusion Site 
Photographs will be taken of the infusion site at each scheduled visit from Day 1 (pre-dose) 
through Day 30 (Appendix 1) to monitor healing of the infusion site.  AveXis will provide a 
secure and confidential upload process for transfer and storage of the photographs from the 
investigative sites to a contracted third-party vendor that will compile and arrange photographs 
as per AveXis requirements.  Any/all photographs received at AveXis or the contracted vendor 
will be treated as confidential study data and will be the sole property of AveXis.  AveXis and 
the contracted vendor will provide this secure, encrypted transfer and storage solution to properly 
protect the identities of patients/families in the photographs, which may be shared with 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 44 of 126 
regulatory agencies, the medical community, and/or in appropriate venues to discuss the results 
of this clinical study. 
12.1.10. 
Laboratory Assessments 
Blood samples will be collected at each scheduled visit, except Day 1 and Day 3 (as specified in 
Appendix 1).  On Day -1, blood and urine samples will be processed locally for receipt of results 
prior to the start of gene replacement therapy infusion.  Any clinically significant laboratory 
value will be repeated at the discretion of the Investigator. 
Blood samples will be collected and shipped to a central laboratory.  Samples for laboratory tests 
required during the in-patient vector infusion period prior to dosing will be collected and 
processed by the investigative site’s Clinical Laboratory Improvement Amendment (CLIA) 
CLIA-certified local laboratory to ensure receipt of results prior to dosing. 
Table 6: 
Total Blood Volume 
Visit 
Tests 
Total Volume (mL) 
Screening 
Hematology, chemistry, virus serology,  
capillary blood gas, immunology sample (AAV9 Ab only),   
diagnostic confirmation sample 
16.6 
Day –1 
Hematology, chemistry, capillary blood gas  
3.3 
Day 1 
Capillary blood gas 
1 
Day 2 
Hematology, chemistry, capillary blood gas 
3.3 
Day 7 
Hematology, chemistry, immunology sample 
6.3-8.3b 
Day 14 
Hematology, chemistry, immunology sample 
6.3-8.3b 
Day 21 
Hematology, chemistry, immunology sample 
6.3-8.3b 
Day 30 
Hematology, chemistry, immunology sample 
6.3-8.3b 
Monthly  
Hematology, chemistry 
36.8 
End of Study/ET 
Hematology, chemistry 
2.3 
Maximum Total Volume for Studya 
96.5 
ET = early termination 
a Patients will have different numbers of monthly visits, depending on their age at dosing.  Maximum total volume based on a 
maximum of 16 monthly visits, provided T-cell responses are not elevated at Day 30 requiring additional surveillance 
samples and virus serology is not positive at screening requiring additional testing 
b Immunology sample requires 4-6 mL whole blood 
 
In a case where sufficient blood cannot be collected from a patient, blood will be used in the 
following priority order with the first having greatest priority and last having the least priority: 
1. Safety labs 
2. Interferon gamma (IFN-γ) ELISpots to detect T-cell responses 
3. Serum antibody to AAV9 and SMN 
4. Genetic reconfirmation testing 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 45 of 126 
If there is not sufficient blood volume to include the genetic reconfirmation testing sample at the 
screening visit, patient must return before Visit 2.  All patients must have genetic reconfirmation 
testing completed. 
12.1.10.1. Hematology 
Hematology analysis will include a complete blood count with differential and platelet count 
with smear.  Samples will be collected and shipped in accordance with the laboratory manual 
provided by the central laboratory.  Blood samples for hematology analysis will be collected at 
all scheduled visits except Day 1 and Day 3 (Appendix 1). 
Immediate/same-day hematology analyses required during in-patient dosing, as determined by 
the Investigator, will be performed as per investigational site standard procedures at the local 
laboratory.  Investigators will receive hematology results from all study visits from the central 
laboratory. 
12.1.10.2. Blood Chemistry 
Samples will be collected and shipped in accordance with the laboratory manual provided by the 
central laboratory.  Blood samples for chemistry analysis will be collected at all scheduled visits 
except Day 1 and Day 3 (Appendix 1). 
Immediate/same-day chemistry analyses required during in-patient dosing, as determined by the 
Investigator, will be performed as per investigational site standard procedures at the local 
laboratory. 
Chemistry analysis will include the following at all study visits: 
• Serum GGT 
• AST/ALT 
• Serum total bilirubin 
• Direct bilirubin 
• Albumin 
• Glucose 
• Total creatine kinase  
• Creatinine 
• BUN 
• Electrolytes 
• Alkaline phosphatase 
 
Investigators will receive chemistry results from all study visits from the central laboratory 
(except Day -1). 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 46 of 126 
12.1.10.3. Urinalysis 
Urine samples will be collected in accordance with the laboratory manual provided by the central 
laboratory at all study visits except Day 1 and Day 3 (Appendix 1).  Day -1 urinalysis will be 
performed as per investigational site standard procedures at the local laboratory.  Urinalysis will 
include the following parameters: 
• Color 
• Clarity/turbidity 
• pH 
• Specific gravity 
• Glucose 
• Ketones 
• Nitrites 
• Leukocyte esterase 
• Bilirubin 
• Blood 
• Protein 
• Red Blood Cell 
• White Blood Cell 
• Squamous epithelial cells 
• Casts 
• Crystals 
• Bacteria 
• Yeast 
 
12.1.10.4. Virus Serology 
The administration of an AAV vector has the risk of causing immune-mediated hepatitis.  For 
patients who have HIV or positive serology for hepatitis B or C or Zika virus, administration of 
AAV vector may represent an unreasonable risk; therefore negative serology testing must be 
confirmed at screening, prior to treatment.  These samples will be collected at screening 
(Appendix 1) and shipped in accordance with the laboratory manual provided by the central 
laboratory. 
12.1.10.5. Capillary Blood Gas 
Capillary blood gas will be completed locally at screening, Day –1, pre-dose on Day 1, and 
Day 2 (Appendix 1).  A puncture or small incision will be made with a lancet or similar device 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 47 of 126 
into the cutaneous layer of the patient’s skin at a highly vascularized area (heel, finger, toe).  To 
accelerate blood flow and reduce the difference between the arterial and venous gas pressures, 
the area will be warmed prior to the puncture.  As the blood flows freely from the puncture site, 
the sample will be collected in a heparinized glass capillary tube. 
12.1.10.6. Immunology Testing (ELISA and IFN-γ ELISpots) 
Blood samples for immunology testing will be collected and shipped to the central laboratory in 
accordance with the laboratory manual to test for serum antibodies to AAV9 and SMN (ELISA), 
and to perform IFN-γ ELISpots to detect T-cell responses to AAV9 and SMN.  Blood samples 
will be collected at screening (ELISA anti-AAV9 only), Day 7, Day 14, Day 21, and Day 30 
(Appendix 1).  Additional sampling may be performed at subsequent time points if ELISpot 
value(s) continue to be elevated, based on further discussion with the Principal Investigator and 
Medical Monitor. 
12.1.10.7. AAV9 Antibody Screen in Mother 
There is potential that the biological mother of the patient may have pre-existing antibodies to 
AAV9 that may be transferred to the patient through breast milk or, theoretically, via placental 
transfer in utero.  Informed consent will be requested from the biological mother of the patient to 
screen the mother for circulating antibodies to AAV9.  Once informed consent has been 
obtained, the mother will have her blood drawn from a peripheral vein at screening and shipped 
to the central laboratory for screening of anti-AAV9 antibodies.  Mothers who test positive for 
antibodies to AAV9 will be asked to refrain from further feedings with breast milk. 
If AAV9 antibodies are identified, the patient must desist in consuming breast milk from the 
biological mother. 
Patients consuming banked breast milk from donor sources that cannot be test for anti-AAV9 
antibodies must be transitioned to formula prior to participation. 
12.1.10.8. Blood for Diagnostic Confirmation Testing 
A blood sample will be collected during the screening visit and shipped to the central laboratory 
in accordance with the laboratory manual for reconfirmation of SMN1 deletions/mutations, 
SMN2 copy number, and absence of exon 7 gene modifier mutation (c.859G>C).  This will be 
done to ensure consistency in diagnostic testing practices. 
12.1.10.9.   Saliva, Urine, and Stool Collection 
Studies have shown that some vector can be excreted from the body for up to a few weeks after 
injection; this is called “viral shedding.”  Vector shedding can be found in the blood, urine, 
saliva, and stool for up to 1 week following infusion.  The potential health risks associated with 
the shed vector are not fully known at this time; however the health risk is thought to be low as 
the vector cannot replicate.  Regardless, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved instructions should be provided to the patient’s family and care 
giver(s) regarding use of protective gloves if/when they come into direct contact with the 
patient’s bodily fluids and/or waste, as well as good hand-hygiene for a minimum of 2 weeks 
(14 days) after gene replacement therapy.  Additionally, patients are prohibited from donating 
blood for 2 years following the vector infusion. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 48 of 126 
Saliva, urine, and stool samples will be collected for viral shedding studies at screening, 24 hours 
post-dose, 48 hours post-dose, Day 7, Day 14, Day 21, and Day 30 (Appendix 1).  Samples will 
be collected, prepared, and shipped as per the laboratory manual. 
A subset of patients at sites opting to participate in the viral shedding sub-study will have 24-
hour total volume urine and fecal samples collected through 24 hour post-dose and through 48 
hours-post dose. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 49 of 126 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1.1. 
Definition of Adverse Events 
13.1.1.1. Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product.  In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no study treatment has been administered. 
All adverse events that occur from the start of gene replacement therapy infusion through the last 
study visit will be collected and recorded in the eCRF. 
All adverse events will be classified in accordance with the CTCAE version 4.03 outlined in 
Table 7. 
 
Table 7: 
Common Terminology Criteria for Adverse Events 
Grade 
Definition 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Source: Common Terminology Criteria for Adverse Events (version 4.03) [9] 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
Study enrollment will be interrupted should any patient experience an unanticipated CTCAE 
Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the 
gene replacement therapy.  The event will then be reviewed by the DSMB and an evaluation will 
be made as to whether the study should be terminated early following the discontinuation rules. 
Unanticipated CTCAE Grade 3 or higher adverse events that are possibly, probably, or definitely 
related to the gene replacement therapy must be reported within 24 hours to Sponsor and/or 
designee as per study safety management plan to ensure timely escalation to the DSMB. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 50 of 126 
13.1.1.2. Serious Adverse Event 
A SAE is an AE occurring during any study phase (e.g., baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, or comparator that fulfils one or more of the 
following: 
• Results in death 
• It is immediately life-threatening 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
All SAEs that occur after signing of the informed consent through the last study visit, whether or 
not they are related to the study product, must be collected and recorded on forms provided by 
the Contract Research Organization. 
13.1.1.3. Other Adverse Event 
The following specific treatment-emergent AE of special interest, which may be searched using 
Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries, will be 
summarized: 
• Elevated liver enzymes 
 
Other adverse events (OAE) will be identified by the Drug Safety Physician and, if applicable, 
also by the Clinical Study Team Physician during the evaluation of safety data for the Clinical 
Study Report.  Significant adverse events of particular clinical importance, other than SAEs and 
those AEs leading to discontinuation of the patient from the study, will be classified as OAEs.  
For each OAE, a narrative may be written and included in the Clinical Study Report. 
13.2. 
Relationship to Study Product 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related or Probably Related).  The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.”  If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” then the event will be considered related to the investigational product 
for the purposes of expedited regulatory reporting. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 51 of 126 
13.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  Information about AEs will be collected from the time of vector infusion 
until the end of the study.  Serious Adverse Event information will be collected from signing of 
consent form until the last study visit.  The AE term should be reported in standard medical 
terminology when possible.  For each AE, the Investigator will evaluate and report the onset 
(date (and time if during Visit 2)), resolution (date (and time if start date during Visit 2)), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the patient to discontinue the study. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 13.1.1.2.  An AE of severe intensity 
may not be considered serious. 
13.4. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of consent form until the last 
study visit.  Any SAEs considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported.  All SAEs must be 
reported to AveXis or designee within 24 hours of the first awareness of the event.  The 
Investigator must complete, sign and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy by fax or 
e-mail to AveXis or designee. 
Additional follow-up information, if required or available, should all be faxed or e-mailed to 
AveXis or designee within 24 hours of receipt and this should be completed on a follow-up SAE 
form and placed with the original SAE information and kept with the appropriate section of the 
eCRF and/or study file. 
AveXis is responsible for notifying the relevant regulatory authorities of certain events.  It is the 
Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at his or 
her site.  Investigators will also be notified of all unexpected, serious, product-related events 
(7/15 Day Safety Reports) that occur during the clinical study.  Each site is responsible for 
notifying its IRB or IEC of these additional SAEs. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 52 of 126 
14. 
STATISTICS 
This section summarizes key aspects of the analysis plan including definitions of co-primary, 
co-secondary, and 
 and safety endpoints, and the methods to be 
used to test the primary effectiveness hypothesis.  Additional details regarding methods for the 
final data analysis will be provided in a separate Statistical Analysis Plan (SAP) which will be 
finalized and submitted to the Investigational New Drug application prior to the enrollment of 
the first patient.  The SAP will detail all analyses and data displays, and will be executed 
according to Standard Operating Procedures in a controlled environment. 
14.1. 
Study Endpoints and Populations 
14.1.1. 
Study Endpoints 
The primary and efficacy endpoint will be compared to the null.  The survival co-primary 
efficacy variable will be evaluated relative to literature-based historical controls (such as the 
Pediatric Neuromuscular Clinical Research Network [PNCR] [21].  These were selected on the 
basis of comparability to the target population and similarity to the investigational device. 
14.1.1.1. Co-Primary Efficacy Endpoint 
The co-primary efficacy endpoints are: 
• The proportion of patients that achieve functional independent sitting for at least 30 seconds 
at the 18 months of age study visit.  It is defined by the Bayley Scales of Infant and Toddler 
Development (Version 3) (Appendix 3), confirmed by video recording, as a patient who sits 
up straight with the head erect for at least 30 seconds. 
• The survival at 14 months of age.  Survival is defined by the avoidance of the combined 
endpoint of either (a) death or (b) permanent ventilation, which is defined by tracheostomy or 
by the requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive 
ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, 
excluding perioperative ventilation.  Permanent ventilation, so defined, is considered a 
surrogate for death. 
 
An “acute reversible illness” is defined as any condition other than SMA that results in increased 
medical intervention (e.g., increased requirement for respiratory support; use of other 
concomitant medications as rescue) requirements and is expected to be reversible or improved 
following definitive intervention (e.g., surgery, antibiotics) or introduction of escalated 
supportive care, such as hospitalization (e.g., for upper respiratory infection, spontaneous 
fracture).  The specific duration of the condition antecedent intervention shall not be considered 
in the definition of “acute.”  The date of “definitive intervention” shall be defined as the date of 
provision of a procedure (e.g., surgery, etc.) or medication (e.g., antibiotics) intended to cure or 
substantially improve the condition.  For conditions such as viral respiratory infections for which 
supportive care is provided, the date of “definitive intervention” shall be considered the date of 
hospitalization or substantial escalation of care. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 53 of 126 
“Perioperative” use reflects any alteration of ventilatory use related to a surgical or other medical 
procedure of any nature for which the patient received medications that could impair or interfere 
with respiratory function. 
For a patient who develops an acute reversible illness and/or requires perioperative ventilatory 
support, a recovery period not to exceed 21 days following the date of definitive intervention will 
be instituted.  Following this recovery period, the condition will be considered subacute and the 
patient will become evaluable with regards to the surrogate survival endpoint (requirement of 
ventilatory support of ≥ 16 hours/day for 14 or more days). 
14.1.1.2. Co-Secondary Efficacy Endpoint 
The co-secondary efficacy endpoints are: 
• The proportion of patients maintaining the ability to thrive, defined as the ability to tolerate 
thin liquids (as demonstrated through a formal swallowing test) and to maintain weight 
(> third percentile based on World Health Organization [WHO] Child Growth Standards [26] 
for age and gender) without need of gastrostomy or other mechanical or non-oral nutritional 
support at 18 months of age. 
• The proportion of patients who are independent of ventilatory support, defined as requiring 
no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and 
perioperative ventilation, as defined above through assessment of actual usage data captured 
from the device (Phillips Trilogy). 
 
14.1.1.3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 54 of 126 
• 
 
 
 
 
 
 
 
 
 
 
14.1.1.4. Safety Endpoints 
Assessment of the safety and tolerability of AVXS-101 treatment, including: 
• Incidence of elevated LFTs and/or unresolved LFEs 
• Incidence of CTCAE Grade 3 or higher toxicity, treatment-emergent adverse events 
• Clinically significant changes in laboratory values, physical exams, cardiac assessments or 
vital signs 
• Research Immunology Blood Labs including serum antibody to AAV9 and SMN as well as 
IFN-γ ELISpot to detect T cell responses to AAV9 and SMN 
 
14.1.2. 
Statistical Analysis Populations 
14.1.2.1. Intent-to-Treat Population (ITT) 
The ITT population will consist of symptomatic patients with bi-allelic deletion mutations of 
SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene 
modifier mutation (c.859G>C) who receive an IV infusion of AVXS-101 at less than 180 days of 
age.  All primary and secondary efficacy analyses and subgroup analyses will be conducted on the 
ITT population. 
14.1.2.2. Efficacy Completers Population 
The efficacy completers analysis population will consist of: 
• All treated patients who reach 14 months of age, OR 
• All treated patients who meet discontinuation criteria, discontinue the study due to an AE or 
death 
 
14.1.2.3. All Enrolled Population 
The all enrolled population will consist of all patients who receive an IV infusion of AVXS-101.  
Analyses of endpoints in this population are considered descriptive. 
14.1.2.4. Safety Population 
The safety analysis population will consist of all patients who receive an IV infusion of 
AVXS-101.  All safety analyses will be conducted on the safety analysis population. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 55 of 126 
14.2. 
Sample Size Calculation 
The current study will enroll 15 patients.  Only those patients with baseline symptoms, bi-allelic 
deletion mutations of SMN1 and 2 copies of SMN2 without the SMN2 gene modifier mutation 
(c.859G>C), ITT population will be assessed for the primary and secondary efficacy analyses.  
The study power is based upon efficacy analysis of the ITT population. 
The two co-primary efficacy endpoints will be assessed in sequence:  The endpoint of functional 
independent sitting will be assessed first and, only if this assessment meets statistical 
significance will the endpoint of survival be assessed. 
Based upon widely cited natural history of the disease (Pediatric Neuromuscular Clinical 
Research Network [PNCR]) [Neurol. 2014; 83(9):810-817], it is expected that no patients in this 
population would be expected to attain the ability to sit without support or accomplish other 
milestones (rolling over, standing, walking) prior to 18 months of age.  Assuming that the true 
response rate for the primary endpoint is actually zero (or as low as 0.1%) in the population of 
interest of the historical control, the first co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 18 
months of age study visit. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 40% of treated symptomatic patients with bi-allelic deletions of SMN1 and 2 copies of 
SMN2 without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-
primary efficacy endpoint of functional independent sitting for at least 30 seconds at the 18 
months of age study visit.  With the assumption for the true response rate of AVXS-101 being in 
the range of 30% - 40%, a sample size of 15 patients (assuming 30% of patients do not qualify 
for the ITT population or are otherwise excluded from the analysis) would provide power of > 
90% to detect a significant difference with α 0.05 using a 1-sided exact test for a binomial 
proportion. 
The second co-primary efficacy endpoint hypothesis: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹  
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹, 
where 𝑝𝑝 is the proportion of patients surviving at 14 months of age. 
Based upon preliminary results from the ongoing Phase 1 clinical study AVXS-101-CL-101, at 
least 80% of treated symptomatic patients with bi-allelic SMN1 deletions and 2 copies of SMN2 
without the SMN2 gene modifier mutation (c.859G>C) are expected to achieve the co-primary 
efficacy endpoint of survival through 14 months of age.  It is anticipated that 75% of patients in 
the PNCR population would not survive beyond 13.6 months of age, and that these control 
patients will represent a 25% survival rate based upon the natural history of the disease.  With 
this efficacy, a sample size of  15 patients (assuming 30% of patients do not qualify for the ITT  
or are otherwise excluded from the analysis) would provide power of > 80% to detect a 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 56 of 126 
significant difference with α 0.05 using a two sample 2-sided Fisher’s exact test, comparing to 
the 26 age and gender matched patients from a published natural history observational study 
performed at 3 large, tertiary care centers in the United States (Harvard University, Columbia 
University, Children’s Hospital of Philadelphia; PNCR). 
14.3. 
Efficacy Analysis 
14.3.1. 
General Considerations 
This study will compare the activity of AVXS-101 administered IV versus the natural 
observational results from PNCR [21] in terms of functional independent sitting and survival 
rate.  The ability to thrive and the ability remain independent of ventilatory support will also be 
assessed. 
The analysis of the co-primary and co-secondary efficacy endpoints will be performed for the 
ITT and efficacy completers populations.  The analysis based on the ITT population will be 
considered as the primary analysis.  In the case of missing data, observed data will be used for 
the analyses. 
Unless otherwise specified, the baseline measurement is defined as the last non-missing 
measurement collected prior to or on the day of gene replacement therapy infusion (e.g., on or 
before Day 1 visit). 
14.3.2. 
Primary and Secondary Efficacy Analysis 
Primary and secondary efficacy analyses will be based on the ITT population, those patients with 
bi-allelic deletion mutations of SMN1 and 2 copies of SMN2 without the SMN2 gene modifier 
mutation (c.859G>C).  These analyses are to test the superiority of AVXS-101 to the results 
from natural observation study (PNCR) [21]. 
The first co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1% 
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1%, 
where 𝑝𝑝 is the proportion of functional independent sitting for at least 30 seconds at the 18 
months of age study visit. 
The second co-primary efficacy hypothesis to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 ≠𝑝𝑝𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 , 
where 𝑝𝑝 is the proportion surviving at 14 months of age. 
Primary efficacy endpoints will be examined on ITT population.  Testing for the first co-primary 
endpoint, functional independent sitting will first be performed using 1-sided exact binomial test.  
Only if the null hypothesis of equality in proportion of functional independent sitting is rejected at 
p<0.05, will the co-primary endpoint survival improvement be tested using 2-sided Fisher’s Exact 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 57 of 126 
test on ITT population, comparing to matched patients from natural observational study (PNCR).  
This hierarchy approach strongly protects the Type I error rate. 
The hypothesis for both co-secondary efficacy endpoints to be tested is: 
𝐇𝐇𝟎𝟎: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 = 0.1%    
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑡𝑡ℎ𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎  
𝐇𝐇𝐚𝐚: 𝑝𝑝𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴−101 > 0.1% , 
where p is the proportion of patients maintaining the ability to thrive/are independent of 
ventilatory support. 
One-sided exact binomial tests will be executed for secondary efficacy analyses in ITT 
population.   
A sensitivity analysis will be conducted by repeating the primary efficacy analysis on the 
efficacy completers analysis population. 
14.4. 
Safety Analysis 
Safety will be assessed through the incidence and severity of AEs, vital sign assessments, cardiac 
assessments, laboratory evaluations (chemistry, hematology, urinalysis, immunology), physical 
examinations, and use of concomitant medications.  Adverse events will be coded in accordance 
with the most current version of the MedDRA coding dictionary. 
Safety analyses will be conducted on safety population, and summarized by subgroup and 
overall. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 58 of 126 
15. 
DATA SAFETY MONITORING BOARD 
The DSMB is an independent multidisciplinary group consisting of clinicians and a 
biostatistician that, collectively, have experience in the management of patients with SMA 
Type 1 and other diseases, and in the conduct and monitoring of randomized clinical studies with 
interim analyses.  The DSMB will be chartered to oversee the safety of patients during the 
conduct of the study, and will act in an advisory capacity to AveXis  A detailed description of 
the DSMB, its role in this study, and the timing of the scheduled reviews will be described in a 
DSMB Charter. 
The DSMB will routinely convene on a quarterly basis to review emerging safety data from the 
study.  All available safety data from all enrolled patients will be included in such reviews, 
which include, but are not limited to, screen failures, enrollment status, data from safety 
parameters, all SAEs, and other AEs.  Following each meeting, the DSMB will make a 
recommendation as to whether or not the accumulated safety data warrants a suspension or 
discontinuation of the study, a modification to the study, or any additional comments or 
recommendations related to safety.  The DSMB will prepare and provide minutes of their 
meetings to AveXis who will provide copies to the regulatory authorities as appropriate. 
The DSMB will also convene on an ad hoc basis within 48 hours should any patient experience 
an unanticipated CTCAE Grade 3 or higher AE/toxicity that is possibly, probably, or definitely 
related to gene replacement therapy, and is associated with clinical symptoms and/or requires 
medical treatment.  This includes any patient death, important clinical laboratory finding, or any 
complication attributed to administration of gene replacement therapy.  In such instances, the 
DSMB will review the safety information and provide its recommendation. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 59 of 126 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of AveXis will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of AveXis or its representatives.  This will be 
documented in a Clinical Study Agreement between AveXis and the Investigator. 
During the study, a monitor from AveXis or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed 
• Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the study.  This will require direct access to all original records for each patient (e.g., clinic 
charts, electronic medical records) 
• Record and report any protocol deviations not previously sent to AveXis 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any SAEs 
have been forwarded to AveXis and those SAEs that met criteria for reporting have been 
forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of AveXis, a regulatory authority, an IEC or an IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of an AveXis 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP) 
guidelines of the International Council for Harmonization (ICH), and any applicable regulatory 
requirements.  The Investigator should contact AveXis immediately if contacted by a regulatory 
agency about an inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 60 of 126 
16.3. 
Institutional Biosafety Committee 
As this study involves gene therapy, the Principal Investigator must obtain approval/favorable 
opinion for the investigation from a designated institutional or independent biosafety committee 
in accordance with institutional requirements and/or guidelines. 
16.4. 
Institutional Review Board/Institutional Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation (Section 18.1).  
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 61 of 126 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Qualified individuals designated by the Sponsor will monitor all aspects of the study according 
to GCP, standard operating procedures (SOPs), and for compliance with applicable government 
regulations.  Please see Section 16.1 for more details regarding the quality control and 
monitoring process.  AveXis may also conduct a quality assurance audit any time during or after 
the completion of the study.  Please see Section 16.2 for more details regarding the audit process. 
The Investigator agrees to allow these Sponsor representatives direct access to the clinical data 
and supplies, dispensing and storage areas and if requested, agrees to cooperate fully or assist the 
Sponsor representative.  The Investigator and staff are responsible for being present or available 
for consultation during routinely scheduled site visits conducted by the Sponsor or its designees. 
Noncompliance with the protocol, ICH, GCP, or local regulatory requirements by an 
Investigator, site staff, or representatives of the Sponsor will lead to prompt action by the 
Sponsor to secure compliance.  Continued noncompliance may result in termination of the 
corresponding party’s involvement in the study.  The IRB/IEC and relevant regulatory authority 
will also be informed. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 62 of 126 
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC, as appropriate.  The 
Investigator must submit written approval to AveXis before he or she can enroll any patient into 
the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  AveXis or designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (Appendix 7) and are consistent with ICH/GCP, applicable regulatory 
requirements and the AveXis’ policy on Bioethics. 
18.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the parent(s)/legal guardian(s) are 
given full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study.  The parent(s)/legal guardian(s) must also be notified that they are free to 
discontinue the patient from the study at any time.  The parent(s)/legal guardian(s) should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the parent(s)/legal guardian(s). 
There will be 3 informed consent forms: 
• Parent(s)/legal guardian(s) informed consent form 
• Biological mother baseline AAV9 antibody screening informed consent form 
• Autopsy informed consent form (Appendix 2; if the parent(s)/legal guardian(s) decline an 
autopsy, it will not prevent the patient from participating in the study) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 63 of 126 
19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Electronic Case Report Forms 
Adequate and accurate case records will be maintained and all relevant observations and data 
related to the study will be recorded.  This will include medical history/ physical examination, 
hematology, clinical chemistry and serology results, a check list of inclusion and exclusion 
criteria, product administration, and a record of sample collection, hemodynamic measurements, 
clinical assessments, AEs, and final evaluation. 
Electronic CRFs will be used in this study.  The eCRF will be electronically signed and dated by 
the Principal Investigator or designee after his/her review.  After the completion of the study, 
completed eCRFs will be retained in the archives. 
Completed eCRFs will be reviewed by the study monitor against the source documentation for 
accuracy and completeness.  Once signed by the Investigator, the monitor will transmit the 
completed eCRFs to data management for data validation and database analysis. 
19.2. 
Inspection of Records 
AveXis or designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the product storage area, study product stocks, product accountability records, patient 
charts and study source documents, and other records relative to study conduct. 
19.3. 
Retention of Records 
All primary data that are a result of the original observations and activities of the study and that 
are necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period not less than 2 years after the last approval of a 
marketing application in an ICH region, and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have lapsed since the formal 
discontinuation of the clinical development of the investigational product.  All country/region 
specific requirements that may be more stringent than the 2 years included in ICH shall be 
followed. 
The site will maintain a Clinical Study Document Binder, which will be maintained at the study 
site.  In this binder, there will be tabbed sections for study documents including the following: 
study personnel identification and signature list, patient / subject screening records, patient / 
subject roster (names omitted), protocol and amendments or administrative changes, FDA Form 
1572 (if required), study staff Curricula Vitae, IRB/IEC documentation, an approved sample 
ICF, drug / product accountability records, correspondence, site monitoring reports, blank Data 
Documentation form, and lab accreditations and normal values. The site must keep this binder 
current and available for review by the Sponsor, IRB/IEC, and/or regulatory bodies. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 64 of 126 
20. 
PUBLICATION POLICY 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study.  During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation.  Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and 
information generated by the Investigator) without the consent of the Investigator.  Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document.  All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement.  In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
If the study is being conducted as part of a multicenter clinical study, data from all sites 
participating in the study will be pooled and analyzed by the Sponsor or the Sponsor’s designee.  
The first publication of the study results shall be made in conjunction with the results from other 
study sites as a multicenter publication.  If a multicenter publication is not forthcoming within 
24 months of completion of the study at all sites, the Investigator may publish or present the 
results generated at his or her site. 
The Investigator will provide the Sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication.  The Sponsor shall inform the Investigator in writing of any changes or deletions 
in such presentation or publication required to protect the Sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results.  At the expiration of such 60-day period, the 
Investigator may proceed with the presentation or submission for publication unless the Sponsor 
has notified the institution or the Investigator in writing that such proposed publication or 
presentation discloses the Sponsor’s confidential and proprietary technical information.  Further, 
upon the request of the Sponsor, the Investigator will delay the publication or presentation for an 
additional 90 days to permit the Sponsor to take necessary actions to protect its intellectual 
property interests. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 65 of 126 
21. 
LIST OF REFERENCES 
1. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for 
spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum 
Genet. 2012;20(1):27-32. 
2. Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to 
age, SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-712. 
3. Le TT, McGovern VL, Alwine IE, et al. Temporal requirement for high SMN expression in 
SMA mice. Hum Mol Genet. 2011;20(18):3578-3591. 
4. Farrar MA, Vucic S, Johnston HM, Kiernan MC. Corticomotoneuronal integrity and 
adaptation in spinal muscular atrophy. Arch Neurol. 2012b;69(4):467-473. 
5. Riessland M, Ackermann B, Forster A, et al. SAHA ameliorates the SMA phenotype in two 
mouse models for spinal muscular atrophy. Hum Mol Genet. 2010;19(8):1492-1506. 
6. Dayangac-Erden D, Bora-Tatar G, Dalkara S, Demir AS, Erdem-Yurter H. Carboxylic acid 
derivatives of histone deacetylase inhibitors induce full length SMN2 transcripts: a promising 
target for spinal muscular atrophy therapeutics. Arch Med Sci. 2011;7(2):230-234. 
7. www.ClinicalTrials.gov 
8. Darbar IA, Plaggert PG, Resende MB, Zanoteli E, Reed UC. Evaluation of muscle strength 
and motor abilities in children with Type II and III spinal muscle atrophy treated with 
valproic acid. BMC Neurol. 2011;11:36. 
9. US Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events (v4.03). Published May 2009 (Revised June 2010). 
10. Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 
2011;68(8):979-984. 
11. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and 
characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-164. 
12. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene 
regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 
1999;96(11):6307-6311. 
13. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH et al. A single 
nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from 
the copy gene SMN2. Hum Mol Genet. 1999;8(7):1177-1183. 
14. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity & SMN protein level in 
spinal muscular atrophy. Nat Genet. 1997;16(3):264-269. 
15. Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights from 
model mice. Curr Neurol Neurosci Rep. 2010;10(2):108-117. 
16. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 
and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and 
prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358-368. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 66 of 126 
17. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the 
SMN2 gene. Am J Hum Genet. 2009;85:408-413. 
18. Farrar MA, Vucic S, Johnston HM, et al. Pathophysiological insights derived by natural 
history and motor function of spinal muscular atrophy. J Pediatr. 2013;162(1):155-159. 
19. Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype 
in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010;28(3):271-274. 
20. Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the SMNDelta7 
mouse model of spinal muscular atrophy. Neurobiol Dis. 2007;27(2):207-219. 
21. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular 
atrophy Type I and implications for clinical trials. Neurol. 2014;83(9):810-817. 
22. Wijnhoven TMA, De Onis M, Oyango AW, Wang T, Bjoerneboe GA, Bhandari N, Lartey A, 
Al Rashidi B; WHO Multicentre Growth Reference Study Group. Assessment of gross motor 
development in the WHO multicenter growth reference study. Food Nutr Bull. 
2004;25(1 Supple 1):S37S45. 
23. Glanzman AM, McDermott MP, Montes J, et al.  Validation of the Children's Hospital of 
Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).  Pediatr Phys Ther. 
2011;23(4):322-326. 
24. Glanzman AM, Mazzone E, Main M, et al.  The Children’s Hospital of Philadelphia Infant 
Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability.  
Neuromusc Disord.  2010;20(3):155-161. 
25. National Institutes of Health’s Guidelines for Research Involving Recombinant or Synthetic 
Nucleic Acid Molecules, Apr 2016. 
26. Onis, M. "WHO Child Growth Standards based on length/height, weight and age." Acta 
paediatrica 95.S450 (2006): 76-85. 
27. American Academy of Pediatrics: Policy statements--Modified recommendations for use of 
palivizumab for prevention of respiratory syncytial virus infections. Committee on Infectious 
Diseases. Pediatrics. 2009 Dec;124(6):1694-701. 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 67 of 126 
22. 
APPENDICES 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 68 of 126 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Prophylactic Prednisolone 
 
Xq 
X 
X 
X 
X 
X 
X 
Xq 
 
 
AVXS-101 Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Bayley Scales/ Developmental 
Milestonesd (with video)e 
X 
 
 
 
 
 
 
 
Xf 
Xf 
X 
CHOP-INTENDg (with video)e 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
CMAP 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Demographic/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsh/Weight & Length 
X 
X 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
 
 
 
 
Xj 
X 
12-Lead Holter Monitoringk 
 
X 
X 
X 
X 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Pulmonary Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Swallowing Test 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Photograph of Infusion Site 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology/Chemistry/ 
Urinalysis 
X 
Xo 
 
X 
 
X 
X 
X 
X 
X 
X 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
Capillary Blood Gas 
X 
X 
X 
X 
 
 
 
 
 
 
 
ELISA anti-AAV9 Ab 
X 
 
 
 
 
X 
X 
X 
Xl 
 
 
Immunology Testing 
(ELISA anti-SMN Ab and ELISpot) 
 
 
 
 
 
X 
X 
X 
Xl 
 
 
Anti-AAV9 Ab Screen in 
Mother 
X 
 
 
 
 
 
 
 
 
 
 
Blood for Diagnostic 
Confirmation Testing 
X 
 
 
 
 
 
 
 
 
 
 
Saliva, Urine, and Stool 
Samples (for viral shedding)p 
X 
 
 
Xm Xm 
X 
X 
X 
X 
 
 
Adverse Eventsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 69 of 126 
Study Period 
Screening 
Gene Replacement 
Therapy 
(In-patient) 
Follow-up 
(Outpatient) 
Visit # 
1 
2 
3 
4 
5 
6 
7+ 
End of 
Studya 
# of Days in Study 
–30 to –2 
-1 
1b 
2 
3 
7 
14 
21 
30 
Monthlyc 
18 Months  
of Age 
(or ET) 
Window 
 
 
 
 
 
± 2 days 
± 7 days 
(0–14 days at  
14 Months  
of Age) 
0–14 days 
Prior and Concomitant 
Medications 
Collected from 2 weeks before gene replacement therapy until End of Study 
visit 
Note: Missed visits should be rescheduled as soon as possible, but within 7 days. 
Ab = antibody; CHOP-INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; 
CMAP = compound motor action potential; ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; 
ELISpot = Enzyme-linked ImmunoSpot; ET = early termination; WHO = World Health Organization 
a The End of Study visit must occur within 0 to 14 days after the date on which the patient reaches 18 months of age (or ET). 
b Day 1 assessments will be performed prior to the start of gene replacement therapy infusion. 
c The 14 months of age visit must occur within 0 to 14 days after the date on which the patient reaches 14 months of age. 
d Developmental milestones will be assessed as defined by Bayley Scales of Infant and Toddler Development, version 3 
(independent sitting will be assessed also by WHO Multicentre Growth Reference Study). 
e Videos may be submitted for review by a central reader. 
f The full Bayley test will be administered every 6 months, starting at Month 6, whereas the Bayley fine and gross motor 
subtests will be administered at each monthly visit.   
g Patients who achieve 3 consecutive CHOP-INTEND scores ≥ 58 will not continue CHOP-INTEND assessments.  
h Vital signs include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry 
i Vital signs will be continuously monitored throughout the infusion of gene replacement therapy and recorded every 
15 minutes for the first 4 hours (+/- 5 minutes) after the start of infusion, then every hour (+/- 15 minutes) until 24 hours after 
the start of infusion.  Axillary temperature will be recorded pre- and post-infusion. 
j Completed every 6 months, starting at Month 6. 
k Serial ECG data will be pulled in triplicate from the Holter monitor at the following time points: pre-dose (within 24h), 2h, 
4h, 6h, 8h, 12h, 24h, 36h, and 48h post-dose. 
l Additional sampling may be performed at subsequent time points if ELISpot value(s) continue to be elevated, based on 
further discussion with the Principal Investigator and Medical Monitor. 
m Collected at 24 and 48 hours post-dose. 
n Serious adverse events are collected from signing of the informed consent through the last study visit.  All adverse events that 
occur from the start of gene replacement therapy through the last study visit are collected. 
o Laboratory samples collected on Day 1 to be processed locally, prior to dosing.   
p Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces at 24 and 48 
hours.  All other sites will collect singular urine and feces samples within 24 hours and 48 hours of dosing. 
q Prednisolone to be given 24 hours prior to scheduled AVXS-101 dosing, and continued as per protocol Section 9.2.1. 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 70 of 126 
APPENDIX 2. 
AUTOPSY PLAN 
An autopsy will be requested for any patient who receives gene replacement therapy and expires 
as per the National Institutes of Health Guidelines for Research Involving Recombinant or 
Synthetic Nucleic Acid Molecules [25].  The autopsy and tissue collection will be performed by 
a contracted vendor who will deploy a pathology assistant to the funeral home of the deceased to 
perform the autopsy and tissue collection.  Standard autopsy incisions will be used to perform the 
autopsy and pathology necessary to determine the cause of death. 
During the procedure, multiple tissues along with the entire spinal cord will be collected for 
research purposes, including up to 7 sections or pieces from each organ and each region of the 
spinal cord.  Upon collection, these tissue samples will be provided to AveXis for analysis.  
Tissue analysis will be done to determine whether the vector transduced the expected motor 
neurons and if the SMN gene was expressed.  These results will demonstrate whether the vector 
delivered the therapeutic gene as expected.  Tissue samples collected will also be available for 
histology and immunohistochemistry, allowing the state of the motor neurons and muscles to be 
examined. 
Specifically, tissue samples from the spinal cord, muscles, and organs will be collected as 
indicated in Table 9.  Tissue samples will be frozen or fixed (e.g., 2% paraformaldehyde) for 
appropriate analysis. 
Families will be asked to consent to the autopsy and authorize tissue collection prior to any sign 
of moribund or death by the clinical team conducting the study.  There are distinct forms for the 
formal autopsy and for the research tissue collection.  This will allow families the flexibility to 
participate in one or both of the research activities.  Declining an autopsy will not prevent 
patients from participating in the study. 
Table 8: 
Tissue Sample for Analysis 
Brain 
Spinal Cord 
Muscles 
Organs 
Motor cortex 
Cervical spinal cord 
Diaphragm 
Spleen 
Layer 5 motor cortex 
Thoracic spinal cord 
#6/#7 Rib with intercostal 
muscle and nerve 
Kidney 
Brain stem 
Lumbar spinal cord 
Psoas muscle 
Small intestine 
 
Sacral spinal cord 
 
Large intestine 
 
Dorsal root 
 
Pancreas 
 
Cervical level 
 
Stomach 
 
Ventral root 
 
Lung 
 
Cervical level 
 
Heart 
 
DRG root 
 
Liver 
 
Cervical level 
 
Inguinal lymph node 
 
Cerebrospinal fluid 
 
Gonads 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 71 of 126 
APPENDIX 3. 
BAYLEY SCALES OF INFANT AND TODDLER 
DEVELOPMENT (VERSION 3) 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 72 of 126 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 73 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 74 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 75 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 76 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 77 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 78 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 79 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 80 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 81 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 82 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 83 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 84 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 85 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 86 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 87 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 88 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 89 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 90 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 91 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 92 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 93 of 126 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 94 of 126 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 95 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 96 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 97 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 98 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 99 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 100 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 101 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 102 of 126 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 103 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 104 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 105 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 106 of 126 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 107 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 108 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 109 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 110 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 111 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 112 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 113 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 114 of 126 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 115 of 126 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 116 of 126 
APPENDIX 4. 
PERFORMANCE CRITERIA FOR BAYLEY SCALES OF 
INFANT AND TODDLER DEVELOPMENT 
(VERSION 3) DEVELOPMENTAL MILESTONES 
Developmental Milestone 
Head Control – Gross Motor Subtest 
Item #4  
Rolls from Back to Sides – Gross 
Motor Subtest Item #20 
Sits Without Support – Gross Motor 
Subtest Item #26 
Stands With Assistance - Gross Motor 
Subtest Item #33 
Crawls – Gross Motor Subtest 
Item #34 
Pulls to Stand – Gross Motor Subtest 
Item #35 
Walks With Assistance – Gross Motor 
Subtest Item #37 
Stands Alone – Gross Motor Subtest 
Item #40 
Walks Alone – Gross Motor Subtest 
Item #43 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 117 of 126 
APPENDIX 5. 
CHOP-INTEND 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 118 of 126 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 119 of 126 
APPENDIX 6. 
COMPOUND MOTOR ACTION POTENTIAL MANUAL 
 
 
 
 
 
Phase 3 Gene Transfer Clinical Study for Spinal Muscular Atrophy Type 1  
Delivering AVXS-101 
 
 
 
 
 
CMAP Manual 
Compound Motor Action Potential (CMAP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 120 of 126 
Materials Needed for the Process 
• Carefusion Disposable Ring Electrode with Leads (order number 019‐439300) (4 per 
visit) 
• Carefusion Tab Electrodes 1.0 meter leads (order number 019‐406600) (1 or 2 per visit) 
• CMAP case report form 
• Infrared temperature probe 
• Electrode gel 
• Warming packs or some other warming source 
• Transpore adhesive tape 
• Alcohol skin prep pads 
• EMG machine 
 
Assessment of Normal Limb Temperature 
Since temperature can affect maximum CMAP amplitude, temperature > 33 degrees centigrade 
should be noted prior to preparation of skin for electrode placement.  Temperature should be 
measured using a surface probe on the lateral aspect of the hand just proximal to the fifth digit.  If 
temperature is ≤ 33 degrees centigrade, a warming pack or other warming mechanism should be 
used to warm the hand to > 33 degrees centigrade prior to collecting data.  Limb temperature does 
not need to be reassessed during the procedure. 
Preparation of Skin 
The skin should be cleaned with alcohol (or equivalent) as needed to improve contact with the 
electrodes. 
EMG machine settings 
For both the ulnar and peroneal CMAP measures the filter settings should be 10 Hz to 10 kHz. 
Tibialis Anterior (TA) CMAP Electrode Placement 
For the TA CMAP, the G1 electrode should be placed below the fibular head on the bulk of the 
Tibialis Anterior (TA) muscle belly.  The G2 reference electrode should be placed on the patella.  
An adhesive ground electrode (Carefusion Tab Electrodes 1.0 meter leads (DIN Style) order 
number 019‐406600) is placed between the stimulating electrodes and the G1 electrode.  Tape 
should be placed over the electrodes to ensure they stay affixed during the procedure. 
Supramaximal nerve stimulation for TA CMAP 
The stimulator should be a pediatric sized bipolar probe.  The stimulation site should be at or 
proximal to the fibular head.  A maximal response should be obtained (CMAP), using a stimulus 
120% of that producing the maximal response and a stimulus duration of 0.2 msec.  Maximum 
CMAP amplitude and area should be recorded on the Source Document and a printout of the 
CMAP tracing made.  Area is measured only for the initial negative peak.  Subsequent negative 
peaks are not included. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 121 of 126 
Abductor Digiti Minimi (ADM) CMAP Electrode Placement 
Electrodes used for recording will be Carefusion Disposable Ring Electrode with Leads (order 
number 019‐439300).  For ADM CMAP, these have a longitudinal contact area of up to 106 mm, 
but should be cut so that they cover the body of the ADM, with position orthogonal to muscle 
fiber orientation.  The distance between the ulnar aspect of the pisaform bone (P) and the ulnar 
aspect of the fifth metacarpophalangeal joint (MP‐5) should be measured.  The G1 electrode 
should be placed distal to P, 1/3 of the distance between P and MP‐5, as defined above.  The G2 
reference electrode should be placed on the ulnar aspect of the MP‐5 joint.  See figure below for 
landmarks: 
 
 
 
Modified figure from “Anatomic Guide for the Electromyographer” Charles C. 
Thomas, Publisher, 1980, p4. 
 
Supramaximal nerve stimulation for CMAP 
The stimulator should be a pediatric sized bipolar probe.  The stimulation site should be at the 
distal forearm just proximal to the wrist.  A maximal response should be obtained (CMAP), using a 
stimulus 120% of that producing the maximal response and a stimulus duration of 0.2 msec.  
CMAP maximum amplitude and area should be recorded on the Source Document and a printout 
of the CMAP tracing made.  Area is measured only for the initial negative peak.  Subsequent 
negative peaks are not included. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 122 of 126 
APPENDIX 7. 
DECLARATION OF HELSINKI: ETHICAL 
PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving Human subjects, including research on identifiable 
human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians.  The 
WMA encourages others who are involved in medical research involving Human subjects to adopt 
these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research.  The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving Human subjects. 
6. The primary purpose of medical research involving Human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments).  Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all Human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research patients. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
patients.  The responsibility for the protection of research patients must always rest with the physician 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 123 of 126 
or other health care professionals and never with the research patients, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
Human subjects in their own countries as well as applicable international norms and standards.  No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research patients set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the environment. 
12. Medical research involving Human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications.  Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research patients. 
15. Appropriate compensation and treatment for patients who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving Human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research patients. 
17. All medical research involving Human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented.  The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving Human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 124 of 126 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group.  In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving Human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation.  The welfare of animals used for 
research must be respected. 
22. The design and performance of each research study involving Human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed.  The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
patients and information regarding provisions for treating and/or compensating patients who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins.  This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified.  It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
patients set forth in this Declaration. 
The committee must have the right to monitor ongoing studies.  The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events.  
No amendment to the protocol may be made without consideration and approval by the committee.  
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research patients and the confidentiality of 
their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as patients in medical research must 
be voluntary.  Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving Human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 125 of 126 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study.  The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal.  Special attention should be given to the 
specific information needs of individual potential patients as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing.  If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed. 
All medical research patients should be given the option of being informed about the general outcome 
and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress.  In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorized representative.  These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative.  The potential subject’s dissent should be 
respected. 
30. Research involving patients who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group.  In such circumstances the 
physician must seek informed consent from the legally authorized representative.  If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving patients with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee.  Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research.  
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse.  There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research.  In such situations the research may be done 
only after consideration and approval of a research ethics committee. 

AveXis, Inc. 
AVXS-101-CL-303 
Investigational Product: AVXS-101 
Protocol v1.0 / 29 Mar 2017 
Confidential | Proprietary 
Page 126 of 126 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or where 
for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  Extreme care must be 
taken to avoid abuse of this option. 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all patients who still need an intervention identified as beneficial in 
the trial.  This information must also be disclosed to patients during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving Human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research.  Researchers have a duty to make publicly 
available the results of their research on Human subjects and are accountable for the completeness 
and accuracy of their reports.  All parties should adhere to accepted guidelines for ethical reporting.  
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available.  Sources of funding, institutional affiliations and conflicts of interest must be declared in 
the publication.  Reports of research not in accordance with the principles of this Declaration should 
not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering.  
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy.  In all cases, new information must be recorded and, where appropriate, made publicly 
available.