Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting But Non-ambulatory Patients With Spinal Muscular Atrophy
Phase: PHASE1
Conditions: Spinal Muscular Atrophy
Sponsor: Novartis Gene Therapies

Protocol Number:  AVXS-101-CL-102 
 
Official Title:  Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting but Non-
ambulatory Patients with Spinal Muscular Atrophy 
 
NCT Number: NCT03381729 
 
Document Date:  17-Jun-2019 

 
 
SIGNATURE PAGE
TITLE CL-102 Clinical Protocol  ID: PRO-744
User
Role
Job Title
Version Decision
Date Signed
Final
Approvers
Vice President,
Clinical
Development
8.0
Accepted 18 Jun 2019 04:23
PM
(America/Chicago)
Final
Approvers
Sr. Vice President
8.0
Accepted 18 Jun 2019 12:24
PM
(America/Chicago)
Final
Approvers
Senior Medical
Director
8.0
Accepted 18 Jun 2019 01:42
PM
(America/Chicago)
Final
Approvers
VP, Global Head of
Safety &
Pharmacovigilance
8.0
Accepted 18 Jun 2019 12:19
PM
(America/Chicago)
Final
Approvers
Senior Director,
Clinical
Operations
8.0
Accepted 18 Jun 2019 12:34
PM
(America/Chicago)
 
 
This is a copy generated on 04 Mar 2020 11:15 AM.   Please refer to ACE
for most recent effective version.  
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Confidential | Proprietary 
Page 1 of 124 
 
 
AVXS-101 
AVXS-101-CL-102 
IND Number: 
15699 
Investigational Product: AVXS-101 
Protocol Title: 
Phase I, Open-Label, Dose Comparison Study of AVXS-101 for 
Sitting but Non-Ambulatory Patients with Spinal Muscular Atrophy 
Indication Studied: 
Spinal Muscular Atrophy 
Sponsor Address: 
AveXis, Inc. 
2275 Half Day Road 
Bannockburn, IL 60015 
Protocol Version / Date: Version 8, Amendment 7 / 17 June 2019 
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 trial patients 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. 
  Effective

AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
Confidential | Proprietary 
Page 2 of 124 
1. 
ADMINISTRATIVE INFORMATION 
1.1. 
Approval 
This study will be conducted with the highest respect for the individual patients in 
accordance with the requirements of this clinical study protocol and in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki 
• The International Council for Harmonisation, Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice E6(R2) 
• 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 of Clinical Development  
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
Sr. Vice President, Regulatory Affairs  
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
Senior Medical Director, Clinical Development  
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
Senior Director of Clinical Operations  
AveXis, Inc. 
 
 
Date (ddMmmyyyy) 
 
 
 
 
Interim Head of Biostatistics 
AveXis, Inc.  
 
 
Date (ddMmmyyyy) 
 
 
 
 
Vice President, Head of Global Patient Safety  
AveXis, Inc. 
 
Date (ddMmmyyyy) 
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AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
Confidential | Proprietary 
Page 3 of 124 
1.2. 
Summary of Changes 
Please see Appendix 3. 
1.3. 
Investigator’s Agreement 
I have received and read the Investigator’s Brochure for AVXS-101.  I have read the AVXS-101-
CL-102 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 Harmonization, Integrated Addendum to ICH E6(R1): Guideline 
for Good Clinical Practice E6 (R2). 
• 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 CFR 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) 
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AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
Confidential | Proprietary 
Page 4 of 124 
1.4. 
Key Contact Information 
Role in Study 
Contact information 
Responsible Physician 
 Medical Director, Clinical Development, 
 
Serious Adverse Event 
Reporting 
 
 
Additional study contact information is provided in the Study Contact List. 
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AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
Confidential | Proprietary 
Page 5 of 124 
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 I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting but Non-
Ambulatory Patients with Spinal Muscular Atrophy 
Study center(s):  11 US investigators 
Studied period (years): 
Estimated date first patient enrolled: Q4 2017 
Estimated date last patient completed: Q2 2021 
Phase of development: 1 
Objectives: 
Safety will be assessed independently for each age cohort: 
Primary: 
• 
To assess the safety and tolerability of intrathecal (IT) administration of AVXS-101 by the 
incidence and severity of adverse events (AEs) 
• 
To determine the optimal dose of AVXS-101 that demonstrates acceptable safety with maximum 
preliminary efficacy administered by IT injection 
Efficacy for patients ≥ 6 months and < 24 months at time of dosing: 
Primary: 
• 
Proportion of patients ≥ 6 months and < 24 months at time of dosing achieving the ability to 
stand without support for at least three seconds (Bayley© Scales of Infant and Toddler 
Development – Gross Motor Subset #40) 
Secondary: 
• 
Proportion of patients that achieve ability to walk without assistance defined as taking at least five 
steps independently displaying coordination and balance (Bayley Scales of Infant and Toddler 
Development – Gross Motor Subset #43) 
Efficacy for patients ≥ 24 months and < 60 months at time of dosing: 
Primary: 
• 
Change in HFMSE from baseline among patients ≥ 24 months at time of dosing 
Secondary: 
• 
Proportion of patients that achieve ability to walk without assistance defined as taking at least five 
steps independently displaying coordination and balance (Bayley Scales of Infant Development –
Gross Motor Subset #43) 
Additionally, compelling, demonstrable, documented evidence of efficacy as determined by changes in 
development abilities as captured during videotaping sessions during site visits and/or provided by 
parent/legal guardian will be collected for all patients in both age groups. 
  Effective

AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
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Page 6 of 124 
Methodology: 
This is a Phase 1, single-dose administration study of infants and children with a genetic diagnosis 
consistent with spinal muscular atrophy (SMA), bi-allelic deletion of survival motor neuron 1 gene 
(SMN1) and 3 copies of survival motor neuron 2 gene (SMN2) without the genetic modifier who are able 
to sit but cannot stand or walk at the time of study entry.  Patients will receive AVXS-101 in a dose 
comparison safety study of two (or three) potential therapeutic doses.  Patients will be stratified in two 
groups, those ≥6 months and < 24 months of age at time of dosing and those ≥ 24 months and 
< 60 months of age at time of dosing.  At least 15 patients ≥6 months and < 24 months, and at least 12 
patients ≥ 24 < 60 months will be enrolled. 
The first cohort will enroll three patients (Cohort 1) ≥6 months and < 24 months of age who will receive 
administration of 6.0 × 1013 vg of AVXS-101 (Dose A).  There will be at least a four week interval 
between the dosing of each patient within the cohort.  AveXis, Inc. (AveXis) will confer with the Data 
Safety Monitoring Board (DSMB) on all Grade III or higher AEs within approximately 48 hours of 
awareness that are possibly, probably or definitely related to the study agent before continuing 
enrollment.  Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment 
of the three patients and based upon the available safety data a decision will be made whether to: a) stop 
due to toxicity, or b) proceed to Cohort 2 using Dose B. 
Should the determination be made to advance to Dose B, three patients < 60 months of age will be 
enrolled (Cohort 2) and will receive administration of 1.2 × 1014 vg of AVXS-101 (Dose B).  Again, 
there will be at least a four-week interval between dosing of the three patients within the cohort.  Based 
on the available safety data from the three Cohort 2 patients and all of the Cohort 1 patients, the DSMB 
will decide and document during quarterly meetings whether further four-week intervals between 
patients dosing is necessary.  AveXis will take this recommendation into consideration and will make 
the final determination whether to persist with four-week intervals between patients dosing going 
forward; the decision will be communicated to sites and Institutional Review Boards (IRBs) in a formal 
sponsor letter.  AveXis will confer with the DSMB on all Grade III or higher AEs within approximately 
48 hours of awareness that are possibly, probably or definitely related to the study agent before 
continuing enrollment.  Safety data will be reviewed by the DSMB during quarterly meetings; following 
enrollment of the first six patients and based upon available safety data, a decision will be made whether 
to: a) stop due to toxicity, or b) continue to enroll an additional 21 patients until there are a total of 12 
patients > 6 months and < 24 months and 12 patients ≥ 24 and < 60 months that have all received Dose 
B. 
Based upon an ongoing assessment of safety and efficacy data from patients treated with the 
1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on all 
available data, this is judged to be safe and necessary, three patients < 60 months of age will receive 
Dose C, 2.4 × 1014 vg administered IT.  A meeting of the DSMB will be called to obtain a 
recommendation on the safety of escalating to a higher dose prior to proceeding.  If a decision is made 
to proceed to testing a higher dose, there will again be a four-week interval between dosing of the first 
three patients receiving Dose C, as in Cohorts 1 and 2.  Safety data will be reviewed by the DSMB 
during quarterly meetings.  Following enrollment of the first three Dose C patients and based upon 
available safety data, the DSMB will be consulted and a decision will be made whether to: a) stop 
dosing Dose C due to safety concerns, or b) continue to enroll an additional 21 patients until there are a 
total of 12 patients > 6 months and < 24 months and 12 patients ≥ 24 and < 60 months that have 
received Dose C. 
Patients from Cohort 3 will be followed for a total of 15 months post-dose.  The primary analyses for 
efficacy will be assessed when all patients reach 12 months post-dose and the primary analyses for 
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Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
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Page 7 of 124 
safety will be assessed when the last patient of Cohort 3 reaches 15 months post-dose (and database lock 
will be performed after the last patient reaches 15 months post-dose). 
Safety will be assessed through monitoring AE reports and concomitant medication usage, and by 
conducting physical examinations, vital sign assessments, cardiovascular evaluations, and laboratory 
evaluations (chemistry, hematology, coagulation, urinalysis, immunology).  Patients will be observed at 
the hospital for 48 hours post IT injection.  Patients will return for follow-up visits according to the 
Schedule of Assessments (SoA). 
An autopsy and tissue collection process will be in place for those patients who consent to 
autopsy/tissue collection for research purposes. 
Upon study completion, study patients will be invited to participate in a long-term follow-up study 
conducted under a separate protocol. 
Number of patients (planned): 27 (up to 51, if Dose C tested) 
Diagnosis and main criteria for inclusion: 
Patients with a genetic diagnosis consistent with SMA, bi-allelic deletion of SMN1 and 3 copies of 
SMN2 without the genetic modifier who demonstrate the ability to sit unassisted for 10 or more seconds 
but cannot stand or walk at the time of study entry. 
Inclusion Criteria: 
1. Patients ≥6 months and ≤ 60 months (1800 days) of age at time of dosing following diagnostic 
confirmation during screening period by genotype who demonstrate the ability to sit unassisted 
for 10 or more seconds but cannot stand or walk 
• 
Diagnostic confirmation by genotype includes lab documentation of homozygous absence 
of SMN1 exon 7; with exactly three copies of SMN2 
2. Negative gene testing for SMN2 gene modifier mutation (c.859G>C) 
3. Onset of clinical signs and symptoms consistent with SMA at < 12 months of age 
4. Able to sit independently and not standing or walking independently.  Definition of sitting 
independently is defined by the World Health Organization Multicentre Growth Reference Study 
(WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds.  
Child should not use arms or hands to balance body or support position (Wijnhoven 2004) 
5. Meet age-appropriate institutional criteria for use of anesthesia and sedation, as 
determined necessary by the Investigator 
6. Be up-to-date on childhood vaccines including palivizumab prophylaxis (also known as Synagis) 
to prevent respiratory syncytial virus (RSV) infections in accordance with the recommendations of 
the American Academy of Pediatrics (AAP 2009) 
7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process 
Exclusion Criteria: 
1. Current or historical ability to stand or walk independently  
2. Contraindications for spinal tap procedure or administration of IT therapy (e.g., spina bifida, 
meningitis, impairment, clotting abnormalities, or obstructive spinal hardware preventing 
effective access to cerebrospinal fluid [CSF] space) or presence of an implanted shunt for the 
drainage of CSF or an implanted central nervous system (CNS) catheter 
3. Severe contractures as determined by designated Physical Therapist(s) at screening that 
interfere with either the ability to attain/demonstrate functional measures (e.g., standing, 
walking) or interferes with ability to receive IT dosing 
4. Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination 
5. Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose 
administration 
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AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
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6. Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry 
< 95% saturation at screening while the patient is awake, or for high altitudes > 1000 m, oxygen 
saturation < 92% while the patient is awake  
• 
Pulse oximetry saturation must not decrease ≥ four percentage points between screening and 
highest value on day of dosing 
7. Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two 
weeks prior to dosing 
8. Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral 
methods (i.e., nasogastric tube or nasojejunal tube) or patients whose weight-for-age falls below 
the 3rd percentile based on World Health Organization (WHO) Child Growth Standards 
(Onis 2006).  Placement of a permanent gastrostomy prior to screening is not an exclusion. 
9. Active viral infection (includes human immunodeficiency virus (HIV) or serology positive for 
hepatitis B or C, or Zika virus) 
10. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization 
within two weeks prior to study entry 
11. Respiratory infection requiring medical attention, medical intervention or increase in supportive 
care of any manner within four weeks prior to study entry 
12. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis or meningitis) within four 
weeks before study dosing or concomitant illness that in the opinion of the Principal 
Investigator (PI) creates unnecessary risks for gene transfer such as: 
• 
Major renal or hepatic impairment 
• 
Known seizure disorder 
• 
Diabetes mellitus 
• 
Idiopathic hypocalciuria 
• 
Symptomatic cardiomyopathy 
13. History of bacterial meningitis or brain or spinal cord disease, including tumors, or abnormalities 
by magnetic resonance imaging (MRI) or computerized tomography (CT) that would interfere 
with the lumbar puncture (LP) procedures or CSF circulation 
14. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
15. Known allergy or hypersensitivity to iodine or iodine-containing products 
16. 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, or immunosuppressive therapy within 3 months of 
study dosing (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, 
intravenous (IV) immunoglobulin, rituximab) 
17. Inability to withhold use of laxatives or diuretics in the 24 hours prior to dose administration 
18. Anti-AAV9 antibody titers >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 
19. Clinically significant abnormal laboratory values (gamma glutamyl transferase [GGT], alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST), or total bilirubin > 2 × upper 
limit of normal (ULN), 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.  Patients with an 
elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be 
excluded. 
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AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
Confidential | Proprietary 
Page 9 of 124 
20. Participation in recent SMA treatment clinical trial or receipt of an investigational or approved 
compound product or therapy received with the intent to treat SMA (e.g., valproic acid, 
nusinersen) at any time prior to screening for this study 
• 
Oral beta agonists must be discontinued 30 days prior to 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 
21. Expectation of major surgical procedures during the 1-year study assessment period (e.g., spinal 
surgery or tracheostomy) 
22. Inability or unwillingness to comply with study procedures or inability to travel for repeat visits 
23. Unwillingness to keep study results/observations confidential or to refrain from posting 
confidential study results/observations on social media sites 
24. Refusal to sign consent form 
Investigational product, dosage and mode of administration:  
This is an open-label dose comparison study involving up to three AVXS-101 dosing cohorts of three 
patients each. 
The AVXS-101 dosing cohorts are as follows: 
• 
Cohort 1 (n=3) AVXS-101 6.0 × 1013 vg (Dose A) 
• 
Cohort 2 (n=3) AVXS-101 1.2 × 1014 vg (Dose B) 
• 
Cohort 3 (optional) (n=3) AVXS-101 2.4 × 1014 vg (Dose C) 
AVXS-101 will be delivered to the IT injection procedure location premixed with 1.5 mL of an 
appropriate 
 approved and labeled for pediatric use for radiographic monitoring of the 
injection via lumbar IT injection.  The total volume of AVXS-101 
 will NOT exceed 
8 mL.  Sedation/anesthesia is required for all patients receiving AVXS-101.  Method and medications 
will be at the discretion of the local anesthesiologist but should incorporate a sufficient degree of 
sedation or anxiolysis to ensure analgesia and lack of movement for the procedure and post-procedure 
Trendelenburg positioning placement (tilted head-down at 30° for 15 minutes).  Patients will be placed 
in the Trendelenburg position, at 30°, for 15 minutes following administration of the AVXS-101 vector 
to enhance distribution to cervical and brain regions. 
In an attempt to dampen the host immune response to the adeno-associated virus (AAV) derived 
therapy, patients will receive prophylactic prednisolone (glucocorticoid) (approximately 1 mg/kg/day) 
24 hours prior to AVXS-101 dosing.  Treatment will continue for approximately 30 days in accordance 
with specified guidelines for tapering.   
Liver function testing should guide each step of the taper, and liver function tests should be checked 
prior to prednisolone discontinuation.  If the GGT, AST, or ALT values are ≥ 2 × ULN, then the 
present dose of prednisolone will be adjusted as needed until the GGT, AST, and ALT values decrease 
below threshold, at which point the taper may continue.  Liver function tests should also be checked 
approximately 2 weeks after the taper has concluded and prednisolone has been discontinued to 
evaluate for rebound elevation of GGT, AST or ALT levels.  Variance from these recommendations 
will be at the discretion of the Investigator based on potential safety issues for each patient.  If another 
glucocorticoid is used in place of prednisolone by the Investigator, similar considerations should be 
taken into account after 30 days and tapered as appropriate and at the discretion of the Investigator. 
Based on the outcome of the safety analysis at the time of first applicable DSMB review of each 
cohort following enrollment of the third patient in each cohort, a decision will be made to stop the 
study due to toxicity, escalate to the next cohort or expand a cohort. 
Duration of treatment:  Single dose 
Reference therapy, dosage and mode of administration:  Not applicable 
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Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
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Criteria for evaluation: 
Safety will be assessed independently for each age cohort: 
• 
Incidence of Common Terminology Criteria for Adverse Events (CTCAE) Grade III or 
higher toxicity, treatment-emergent AEs 
• 
Incidence of complications or AEs related to IT injection 
• 
Clinically significant changes in laboratory values, physical exams, cardiovascular 
evaluations or vital signs 
• 
Research Immunology Blood Labs: Serum antibody to AAV9 and SMN, interferon gamma 
(IFN-γ) Enzyme-Linked ImmunoSpot (ELISpot) to detect T-cell responses to AAV9 and 
SMN 
Efficacy for patients ≥6 months and < 24 months at time of dosing: 
Primary: 
• 
Proportion of patients ≥6 months and < 24 months at time of dosing that achieve ability to 
stand alone (Bayley Scales of Infant and Toddler Development –Gross Motor Subset #40) 
Secondary: 
• 
Proportion of patients that achieve ability to walk without assistance defined as taking at 
least five steps independently displaying coordination and balance (Bayley Scales of Infant 
and Toddler Development –Gross Motor Subset #43) 
Efficacy for patients ≥ 24 months and < 60 months at time of dosing: 
Primary: 
• 
Change from baseline in HFMSE among patients ≥ 24 months of age at time of dosing 
Secondary: 
• 
Proportion of patients that achieve ability to walk without assistance defined as taking at 
least five steps independently displaying coordination and balance (Bayley Scales of Infant 
and Toddler Development –Gross Motor Subset #43) 
Additionally, compelling, demonstrable, documented evidence of efficacy as determined by changes in 
developmental abilities as captured during videotaping sessions during site visits and/or provided by 
parent/legal guardian will be collected for all patients in each age group. 
Statistical Methods: 
This is a Phase 1 trial with determination of optimal dose as primary objective, using both safety and 
efficacy measures on motor function assessments.  Secondary outcomes include the achievement of 
milestones and change from baseline on HFMSE and fine and gross motor portions of the Bayley 
Scales of Infant and Toddler Development. 
This study is designed to assess the impact of AVXS-101 on non-ambulatory young children with 
SMA who have 3 copies of SMN2.  Data will be compared with patient-level data drawn from a widely 
(peer-reviewed) published natural history dataset collected by the Pediatric Neuromuscular Clinical 
Research (PNCR) network. 
Patients will be stratified into 2 groups based upon age at dosing:  15 patients will be enrolled aged 
≥6 months and < 24 months at dosing, and 12 patients will be enrolled who are aged 24 months to 
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AveXis, Inc. 
Protocol Number: AVXS-101-CL-102 
Investigational Product: AVXS-101 
Protocol Version 8, Amendment 7 / 17 June 2019 
Confidential | Proprietary 
Page 11 of 124 
< 60 months at the time of dosing. Up to an additional 24 patients, 12 aged ≥6 months and 
< 24 months at dosing, and 12 aged 24 months to < 60 months will be enrolled if the decision to 
escalate to Dose C is made. 
The primary efficacy endpoint for the cohort of patients ≥6 months and < 24 months of age at time of 
dosing will be the proportion who achieve the ability to stand without support up to the 12-month 
study visit.  The secondary efficacy endpoint will be the proportion of patients ≥6 months and 
< 24 months of age at the time of dosing who achieve the ability to walk without assistance up to the 
12-month study visit.  Based upon patient-level data available from the PNCR dataset, 14% of patients 
with SMN2=3 who meet the study criteria for patients ≥6 months and < 24 months of age achieved the 
ability to stand without support, and 10% achieved the ability to walk without assistance.  We expect 
85% of treated patients ≥6 months and < 24 months of age to achieve the ability to stand unassisted 
and 60% achieve the ability to walk without support.  With this efficacy, a sample size of 12 patients 
would provide power of > 90% to detect a significant difference compared with the matched control 
cohort with α = 0.05 using a two-sample 2-sided superiority Fisher exact test. 
The primary efficacy endpoint for the cohort of patients between 24 months and < 60 months of age at 
time of dosing will be the change from baseline in HFMSE over 12 months.  The secondary efficacy 
endpoint for patients between 24 months and < 60 months of age at the time of dosing will be the 
proportion of patients who achieve the ability to walk without assistance up to the 12-month study 
visit.  We expect to observe an 8-point increase in HFMSE.  With this efficacy, a sample size of 12 
patients would provide power of > 90% to detect a significant difference with α = 0.05 when compared 
to patient-level data available from the PNCR dataset using two-sample analysis of variance 
(ANOVA). 
 
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Investigational Product: AVXS-101 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
ADMINISTRATIVE INFORMATION .......................................................................2 
1.1. 
Approval .......................................................................................................................2 
1.2. 
Summary of Changes ....................................................................................................3 
1.3. 
Investigator’s Agreement ..............................................................................................3 
1.4. 
Key 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 ......................................................................................................20 
5.1. 
Background and Preliminary Data ..............................................................................20 
5.2. 
Rationale for Gene Transfer to SMA Type 2/3 Patients.............................................21 
5.3. 
Non-Clinical Studies ...................................................................................................23 
5.3.1. 
Trendelenburg Positioning Improves CSF Delivery ..................................................27 
5.4. 
Clinical Studies ...........................................................................................................27 
5.5. 
Risks ...........................................................................................................................27 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................31 
6.1. 
Primary Objectives .....................................................................................................31 
6.1.1. 
Primary Objective: patients ≥ 6 months and < 24 months of age at time of 
dosing ..........................................................................................................................31 
6.1.2. 
Primary Objective: patients ≥ 24 months and < 60 months of age at time of 
dosing ..........................................................................................................................31 
6.2. 
Secondary Objective ...................................................................................................31 
6.3. 
 
6.3.1. 
 
6.3.2. 
 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Overall Study Design ..................................................................................................32 
7.2. 
Number of Patients .....................................................................................................40 
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7.3. 
Treatment Assignment ................................................................................................40 
7.4. 
Dose Adjustment Criteria ...........................................................................................40 
7.5. 
Criteria for Study Termination ...................................................................................40 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................41 
8.1. 
Patient Inclusion Criteria ............................................................................................41 
8.2. 
Patient Exclusion Criteria ...........................................................................................41 
8.3. 
Patient Withdrawal Criteria and Discontinuation .......................................................43 
9. 
TREATMENT OF PATIENTS ..................................................................................44 
9.1. 
Description of Study Product......................................................................................44 
9.2. 
Prior and Concomitant Medications ...........................................................................44 
9.2.1. 
Prophylactic Administration of Prednisolone .............................................................44 
9.2.2. 
Prohibited Medications ...............................................................................................45 
9.2.3. 
Vaccinations ...............................................................................................................45 
9.3. 
Treatment Compliance ................................................................................................45 
9.4. 
Randomization and Blinding ......................................................................................45 
10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT ....................................46 
10.1. 
Study Product..............................................................................................................46 
10.2. 
Study Product Dose and Dose Justification ................................................................46 
10.3. 
Study Product Packaging and Labeling ......................................................................46 
10.4. 
Study Product Storage and Destruction ......................................................................46 
10.5. 
Study Product Preparation ..........................................................................................46 
10.6. 
Study Product Administration ....................................................................................47 
10.6.1. 
Post-Administration Procedures .................................................................................47 
10.7. 
Dose Escalation ..........................................................................................................48 
10.8. 
Study Product Accountability .....................................................................................49 
10.9. 
Study Product Handling and Disposal ........................................................................49 
11. 
ASSESSMENT OF EFFICACY ................................................................................50 
11.1. 
Physical Assessments .................................................................................................50 
11.1.1. 
Hammersmith Functional Motor Scale- Expanded ....................................................50 
11.1.2. 
Bayley Scales of Infant and Toddler Development ....................................................50 
11.2. 
Motor Milestone Development Survey ......................................................................50 
11.3. 
Video Evidence ...........................................................................................................51 
12. 
ASSESSMENT OF SAFETY.....................................................................................52 
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12.1. 
Safety Parameters .......................................................................................................52 
12.1.1. 
Dose Limiting Toxicity...............................................................................................52 
12.1.2. 
Discontinuation Rules .................................................................................................52 
12.2. 
Demographic/Medical History ...................................................................................53 
12.3. 
Vital Signs ..................................................................................................................53 
12.4. 
Weight and Length/Height .........................................................................................53 
12.5. 
Physical Examination .................................................................................................53 
12.6. 
Vaccination Recommendations ..................................................................................54 
12.7. 
Electrocardiogram .......................................................................................................54 
12.8. 
12-Lead Holter Monitor ..............................................................................................54 
12.9. 
Echocardiogram ..........................................................................................................55 
12.10. 
Spinal X-ray ................................................................................................................55 
12.11. 
Pulmonary Exam ........................................................................................................55 
12.12. 
 
12.13. 
Photographs of Injection Site......................................................................................56 
12.14. 
Laboratory Assessments .............................................................................................56 
12.14.1. 
Hematology.................................................................................................................58 
12.14.2. 
Serum Chemistry ........................................................................................................58 
12.14.3. 
Virus Serology ............................................................................................................59 
12.14.4. 
Coagulation Studies ....................................................................................................59 
12.14.5. 
Urinalysis ....................................................................................................................59 
12.14.6. 
Capillary Blood Gas ...................................................................................................60 
12.14.7. 
Research Immunology Blood .....................................................................................60 
12.14.8. 
Baseline Screening of Biological Mother ...................................................................60 
12.14.9. 
Blood for Diagnostic Confirmation Testing ...............................................................60 
12.14.10. 
Saliva, Urine, and Stool Collection ............................................................................61 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................62 
13.1. 
Definition of Adverse Events .....................................................................................62 
13.1.1. 
Adverse Event .............................................................................................................62 
13.1.2. 
Serious Adverse Event ................................................................................................62 
13.1.3. 
Other Adverse Event ...................................................................................................63 
13.2. 
Relationship to Study Product ....................................................................................63 
13.3. 
Recording Adverse Events .........................................................................................63 
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13.4. 
Reporting Serious Adverse Events .............................................................................64 
13.5. 
Expedited Safety Reporting to Regulatory Authorities ..............................................64 
14. 
STATISTICS ..............................................................................................................65 
14.1. 
Statistical Methods......................................................................................................65 
14.2. 
General ........................................................................................................................65 
14.3. 
Analysis Populations ..................................................................................................65 
14.3.1. 
Full Analysis Set .........................................................................................................65 
14.3.2. 
Intent-to-Treat .............................................................................................................65 
14.3.3. 
Enrolled Set ................................................................................................................65 
14.3.4. 
Efficacy Completers Analysis Set ..............................................................................65 
14.3.5. 
Safety Analysis Set .....................................................................................................65 
14.4. 
Sample Size Calculation .............................................................................................65 
14.5. 
Demographic and Other Baseline Characteristics ......................................................67 
14.6. 
Efficacy Analysis ........................................................................................................67 
14.6.1. 
Observation Period for Efficacy .................................................................................67 
14.6.2. 
Primary Efficacy Endpoints ........................................................................................67 
14.6.3. 
Secondary Efficacy Endpoint .....................................................................................68 
14.6.4. 
 
14.7. 
Safety Analysis ...........................................................................................................69 
14.7.1. 
Primary Safety Endpoints ...........................................................................................69 
14.7.2. 
Secondary Safety Endpoints .......................................................................................69 
15. 
DATA SAFETY MONITORING BOARD/DATA MONITORING 
COMMITTEE.............................................................................................................70 
15.1. 
DSMB/DMC Interim Safety Review..........................................................................70 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................71 
16.1. 
Study Monitoring ........................................................................................................71 
16.2. 
Audits and Inspections ................................................................................................71 
16.3. 
Institutional Biosafety Committee ..............................................................................72 
16.4. 
Institutional Review Board/Independent Ethics Committee ......................................72 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................73 
18. 
ETHICS ......................................................................................................................74 
18.1. 
Ethics Review .............................................................................................................74 
18.2. 
Ethical Conduct of the Study ......................................................................................74 
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18.3. 
Written Informed Consent ..........................................................................................74 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................75 
19.1. 
Electronic Case Report Forms ....................................................................................75 
19.2. 
Inspection of Records .................................................................................................75 
19.3. 
Retention of Records ..................................................................................................75 
20. 
PUBLICATION POLICY ..........................................................................................76 
21. 
LIST OF REFERENCES ............................................................................................77 
22. 
APPENDICES ............................................................................................................80 
APPENDIX 1. DECLARATION OF HELSINKI ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS ........................81 
APPENDIX 2. HAMMERSMITH FUNCTIONAL MOTOR SCALE- EXPANDED ..............87 
APPENDIX 3. SUMMARY OF CHANGES .............................................................................90 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................17 
Table 2: 
Spinal Muscular Atrophy Classification .....................................................................21 
Table 3: 
Schedule of Assessments1...........................................................................................35 
Table 4: 
Investigational Product ...............................................................................................44 
Table 5: 
Motor Milestone Development Survey ......................................................................51 
Table 6: 
Common Terminology Criteria for Adverse Events ..................................................52 
Table 7: 
Total Blood Volume ...................................................................................................56 
Table 8: 
Schedule of Assessments ............................................................................................99 
 
LIST OF FIGURES 
Figure 1: 
Kaplan-Meier survival curves and survival probabilities for  SMA Type 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 ...............................................................................................................34 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist 
Term 
Definition 
AAP 
American Academy of Pediatrics 
AAV 
adeno-associated virus 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BiPAP 
Bilevel Positive Airway Pressure 
BUN 
blood urea nitrogen 
C 
celsius 
CB 
chicken-β-actin-hybrid 
CDC 
Center for Disease Control 
CFR 
Code of Federal Regulations 
CK-MB 
creatinine kinase-MB (isozyme MB) 
cGMP 
current Good Manufacturing Practice 
CLIA 
Clinical Laboratory Improvement Amendment 
cmm 
cubic millimeter 
CNS 
central nervous system 
CSF 
cerebrospinal fluid 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ddPCR 
droplet digital polymerase chain reaction 
dL 
deciliter 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ELISA 
enzyme-linked immunosorbent assay 
ELISpot 
enzyme-linked ImmunoSpot 
FVB 
friend virus b-type 
GCP 
Good Clinical Practice 
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Abbreviation or Specialist 
Term 
Definition 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
GFP 
green fluorescent protein 
HFMSE 
Hammersmith Functional Motor Scale-Expanded 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
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 
IRB 
Institutional Review Board 
IT 
intrathecal(ly) 
ITR 
inverted terminal repeat 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
L3-L4, L4-L5 
lumbar vertebrae 3, 4, 5 
LP 
lumbar puncture 
mg 
milligrams 
mL 
milliliter 
MMRM 
mixed model with repeat measurement 
MRI 
magnetic resonance imaging 
NOAEL 
no observable adverse effect level 
OAE 
other adverse event 
PBMC 
peripheral blood mononuclear cells 
PI 
principal investigator  
PICU 
Pediatric Intensive Care Unit 
PNCR 
Pediatric Neuromuscular Clinical Research 
PPE 
personal protective equipment 
qPCR 
quantitative polymerase chain reaction 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
scAAV 
self-complimentary adeno-associated virus 
scITR 
self-complimentary inverted terminal repeat 
SMA 
spinal muscular atrophy 
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Abbreviation or Specialist 
Term 
Definition 
SMN 
survival motor neuron 
SMN1 
survival motor neuron 1 gene 
SMN2 
survival motor neuron 2 gene 
SoA 
Schedule of Assessments 
SUSAR 
suspected unexpected serious adverse reaction 
Syneos 
contract research organization for this study 
TMF 
Trial Master File 
µL 
microliter 
ULN 
upper limit of normal 
vg/kg 
vector genome per kilogram 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO-MGRS 
World Health Organization-Multicentre Growth Reference Study 
WT or wt 
wild type 
 
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5. 
INTRODUCTION 
This is the first clinical gene therapy trial investigating intrathecal (IT) delivery for spinal 
muscular atrophy (SMA).  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 SMN-Δ7 mouse model 
for SMA from a median of 15.5 days to over 1 year, following intravenous (IV) delivery to the 
facial vein.  Additionally, an ongoing Phase 1 clinical study of SMA Type 1 patients has 
demonstrated improved muscle function and development milestone achievement, following IV 
delivery to a peripheral vein.  This clinical trial is an open-label single injection ascending dose 
study in which AVXS-101 will be delivered one time through IT injection in non-ambulatory 
patients with SMA with 3 copies of survival motor neuron 2 gene (SMN2). 
5.1. 
Background and Preliminary Data 
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.  SMA is an autosomal recessive, early childhood 
disease with an incidence of 1: 10,000 live births (Sugarman 2012).  SMA is the leading cause of 
infant mortality due to genetic diseases.  Disease severity and clinical prognosis depends on the 
number of copies of 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 by 
6 months of age and then death due to respiratory failure by age two.  SMA Type 1 is the leading 
genetic cause of infant death.  Motor neuron loss in SMA Type 1 is profound in the early 
postnatal period (or may even start in the pre-natal period), whereas motor neurons in Type 2 and 
3 SMA 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 postnatal periods (Swoboda 2005, Le 2011, Farrar 2012). 
From a clinical perspective, these findings emphasized the importance of first targeting the SMA 
Type 1 group for gene transfer of SMN2 in hopes of rescuing neurons at this critical stage.  Our 
goal in continuing the development plan for AVXS-101 is to modify the SMA Type 2 
phenotype, which will hopefully lead to a milder disease course and prolonged survival as seen 
in SMA 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, phenyl 
butyrate, and trichostatin A.  These agents activate the SMN2 promoter, resulting in increased 
full-length SMN protein in SMA animal models (Riessland 2010, Dayangac-Erden 2011). 
However, clinical trials employing several of these agents, most notably phenyl butyrate, 
valproic acid, and hydroxyurea, have not resulted in clinical benefit (www.ClinicalTrials.gov and 
Darbar 2011).  FDA recently approved Nusinersen, an antisense oligonucleotide 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 IT injection, requires a lengthy induction period prior to 
effectiveness, and has safety considerations which require clinical monitoring.  A dose escalation 
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trial of AVXS-101 injected IT will provide information for the potential gene transfer has in 
treating Type 2 and 3 SMA patients and will hopefully show promise for success in modifying 
the disease prognosis.  This will be a dose comparison study that includes up to 51 Type 2/3 
patients with 3 copies of SMN2. 
5.2. 
Rationale for Gene Transfer to SMA Type 2/3 Patients 
We have chosen SMA Type 2/3 as the target for this gene therapy study.  We believe there is a 
strong rationale for this based on studies of the natural history of this disease.  The classification 
of SMA is shown below (Table 2); Type 0 to Type 4 SMA is described.  SMA is conventionally 
classified into four phenotypes on the basis of age of onset and highest motor function achieved, 
with an additional phenotype (Type 0) to describe the severe forms of antenatal-onset SMA 
(Mercuri 2012, Kolb 2011). 
Table 2: 
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. 
SMN2 = survival motor neuron 2 gene 
bold = predominant SMN2 copy number that defines the SMA Type, the other copy numbers represent a small 
percentage of the designated SMA Type 
 
SMA Type 1 patients by definition never attain independent sitting and have hypotonia within 
the first 6 months of life.  SMA Type 1 is the leading genetic cause of infant death.  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.  SMA Type 3 patients attain the 
ability to walk unaided [Type 3a have onset <3yo; Type 3b have onset >3 yo].  SMA 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.  Humans also carry a second nearly identical copy of the 
SMN1 gene called SMN2 (Lefebvre 1995).  Both the SMN1 and SMN2 genes express SMN 
protein, however, the amount of functional full-length protein produced by SMN2 is much less 
(by 10-15%) than that produced by SMN1 (Lefebvre 1995, Lorson 1999, Monani 1999).  
Although SMN2 cannot completely compensate for the loss of the SMN1 gene, patients with 
milder forms of SMA generally have higher SMN2 copy numbers (Lefebvre 1997, Park 2010).  
In a large early study by Feldkotter et al 2002 (Feldkotter 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.  As these percentages 
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do not reflect the possible impact of modifier mutations such as that described by Prior et al 2009 
(Prior 2009), they may understate the relationship between copy number (in the absence of a 
genetic modifier) and clinical phenotype (Feldkotter 2002).  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 33–66 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 2 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 Type 1, 2, and 3 
 
 
In Figure 1, the relative stability of the clinical course of SMA Types 2 and 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 postnatal period (or may even start in the pre-natal period, 
especially for SMA Type 1 patients presenting in first three 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 postnatal periods 
(Swoboda 2005, Le 2011, Farrar 2012).  From a clinical trials perspective these findings 
emphasized the importance of first targeting SMA Type 1 for gene transfer of SMN1 in hopes of 
rescuing neurons at this critical stage, as was the case for the ongoing Phase 1 clinical study with 
IV dosing.  However, the delivery directly into the cerebrospinal fluid (CSF) via IT injection 
allows for reduction of the amount of viral vector by a factor of 10 with equal distribution and 
efficacy throughout the central nervous system (CNS) and reduced viral vector loads in major 
peripheral organs such as the liver, thereby further optimizing its safety profile (Meyer 2015, 
Duque 2015, Passini 2014).  For these reasons, we are convinced that scAAV9 is the optimal 
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vehicle for delivering a functional full-length copy of SMN to SMA Type 2 and Type 3 patients, 
who are diagnosed at a later age and are thus potentially too great in size to receive a safe and 
effective weight-based IV dose.  Ultimately, the goal is to modify the SMA Type 2 and 3 
phenotypes leading to a milder course and improved functional development. 
We also have good reason to believe that there are few safety issues to be concerned about when 
targeting the SMA Type 2 and Type 3 groups for this clinical gene therapy trial.  Overexpression 
of SMN has been shown to be well tolerated in both mice and non-human primates, and in 
human’s high copy number of SMN2 poses no risk (as seen in Type 2, 3, and 4 patients who have 
high SMN2 copy number).  This allows us to utilize robust, ubiquitous expression systems (like 
the chicken β-actin-hybrid [CB]-promoter) to ensure sustained, high-level SMN expression.  
Additionally, it is important to point out that recombinant scAAV can be employed for this trial 
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. 
Our recent studies using scAAV9.CB.SMN show a robust postnatal rescue of SMA mice with 
correction of motor function, neuromuscular electrophysiology and survival after a one-time 
delivery of vector (Foust 2010).  Intravenous scAAV9 is able to transduce neurons, muscle and 
vascular endothelium, all of which have been proposed as target cells for SMA treatment. 
Taken altogether, our preclinical efficacy and toxicology studies in mice and non-human 
primates have increased our confidence that our Phase 1 trial will be safe and will have a high 
potential for success in treating this devastating disease. 
5.3. 
Non-Clinical Studies 
A mouse model was developed by the Arthur Burghes Laboratory after a generation of multiple 
variants.  It was found that the double transgenic, referred to as the SMN-Δ7 mouse, provided the 
most suitable model to study gene transfer (Butchbach 2007).  Studies performed in the Kaspar 
laboratory have shown that injecting 5 × 1011 viral genomes of scAAV9.CB.SMN into the facial 
vein on Day 1 old mice rescues the SMN-Δ7 mouse model (Foust 2010).  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.SMN treated mice.  SMN levels were increased 
as well, in brain, spinal cord, and muscle of scAAV9.CB.SMN-treated animals, compared to 
untreated SMA mice (although lower than wild-type [WT] controls).  SMA animals treated with 
either scAAV9.CB.SMN or scAAV9.CB.green fluorescent protein (GFP) on P1 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 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 SMA animals compared with GFP-treated SMA 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 
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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 
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 Kaspar laboratory.  In the non-Good 
Laboratory Practice (GLP) studies, 24 mice and 4 non-human primates were injected, by way of 
vascular delivery, with scAAV9.CB.SMN.  To assess toxicity and safety scAAV9.CB.SMN was 
injected into P1 WT friend virus b-type (FVB) mice with either vehicle (PBS) (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 Δ7 mouse model of SMA 
(Foust 2010).  P1 mice were used in anticipation of simulating potential clinical studies in 
infants, which is the planned population for the first-in-human clinical trial.  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). 
 
 
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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 
and clinical chemistries assessment (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], alkaline phosphatase, creatinine, blood urea nitrogen [BUN], electrolytes, and creatinine 
kinase).  All were normal except for one variant at the 90-day time point.  This difference 
appeared to be due to a technical problem relating to the site of blood draw, which differed from 
that of all other mice.  For histopathology, 13 mice were necropsied at 120 days post-injection 
and 8 mice at 180 days.  All organs were normal; in particular there was no inflammation seen in 
any section from any organ (heart, liver, kidney, muscle, gonads, brain, lung, lymph nodes, and 
intestines). 
In the safety study for the four male cynomolgus macaques, subjects were injected at 90 days of 
age to closely mimic the likely age of administration of treatment in SMA Type 1 infants.  The 
scAAV9.CB.SMN vector was administered one time by catheterization of the saphenous vein 
with a dose of 6.7 × 1013/kg, which corresponds to the lowest dose tested for which SMN-Δ7 
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. 
In these non-GLP studies, serum chemistry and hematology studies were unremarkable as was 
the histopathology assessment.  The non-human primate subjects 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 (Foust 2010). 
When newborn FVB mice were given a single IV injection of scAAV9.CB.SMN at levels up to 
3.3 × 1014 vg/kg on Day 1, there was neither test article-related mortality nor evidence of toxicity 
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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 
values, were mild effects of treatment, but did not result in toxicity. 
Activity of the scAAV9.CB.SMN was demonstrated by the bio distribution 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. 
In these studies, scAAV9.CB.SMN IT administration to the CSF was safe and well tolerated in 
mice (through Week 12) and macaques (up to 14 months post injection).  CSF delivery in mice 
likely reduced periphery exposure of scAAV9.CB.SMN and qualitative polymerase chain 
reaction (qPCR) results indicate transgene expression was higher in cervical and lumbar regions 
compared to the thoracic region.  Monkeys maintained in the Trendelenburg position for 5 
minutes at injection and were confirmed seronegative for anti-AAV9 antibodies prior to 
injection.  All non-human primates were highly positive for AAV9 antibodies up to 6 months 
post injection.  No cytotoxic T- lymphocyte response to either AAV9 capsid or SMN transgene 
was observed for 6 months post injection.  No tissue degradation or reactive response in the brain 
or spinal cord was observed. 
In pivotal GLP compliant 3-month mouse toxicology studies, the main target organs of toxicity 
were the heart and liver.  Following IV 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. 
These data support moving forward to clinical trials. 
To determine whether CSF delivery can reduce the transduction of peripheral organs compared 
to the IV injections, a detailed bio distribution analysis was performed on the tissue of the 
nonhuman primates that were placed head down in the Trendelenburg position for either 5 or 10 
minutes (n = 5).  These animals were selected over the nonhuman primates that were not placed 
head down because the treatment highly improved distribution in the spinal cord and brain, 
favoring this approach for clinical trials.  Two weeks post-injection, the cynomolgus macaques 
were sacrificed and various tissues were collected to perform detailed Deoxyribonucleic Acid 
(DNA) and RNA bio distribution analyses.  scAAV9.CBA.GFP was lower in most peripheral 
tissues except spleen and liver compared to the high levels in brain and spinal cord.  These 
findings are in line with previous reports from other groups (Dirren 2014, Gray 2013).  In the 
skeletal muscles and the CNS, there is a strong correlation between DNA and RNA levels, while 
in soft tissues and glands, RNA levels are generally lower than expected for the viral genomes 
detected.  In particular, testes, intestines, and spleen show a 1,000 times fewer RNA molecules 
than DNA.  Despite the detection of AAV in peripheral organs (Dirren 2014, Gray 2013), there 
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was a significant decrease in the amount of vector detected peripherally compared to systemic 
injection.  Additionally, similar observations were made when comparing mice that were injected 
either IV or intracerebroventricularly at P1 24 weeks post- treatment.  Thus, CSF delivery is 
adding a significant potential safety component to future clinical trials with AVXS-101. 
5.3.1. 
Trendelenburg Positioning Improves CSF Delivery 
Dosing and efficacy of scAAV9-SMN was evaluated in SMA mice and non-human primates, 
delivered directly to the CSF via single injection.  Widespread transgene expression was 
observed throughout the spinal cord in mice and nonhuman primates when using a 10 times 
lower dose compared to the IV application.  In nonhuman primates, lower doses than in mice can 
be used for similar motor neuron targeting efficiency.  The transduction efficacy was found to be 
further improved when subjects were kept in the Trendelenburg position to facilitate spreading of 
the vector (Meyer 2015).  Tilting the animals significantly improved transduction in the thoracic 
and cervical region of the spinal cord, as demonstrated by immunofluorescence and 
quantification of GFP/ChAT double positive motor neurons.  Tilting for 10 minutes was 
sufficient to increase motor neuron transduction to 55, 62, and 80% in the cervical, thoracic, and 
lumbar region respectively, which implies major benefits for patients according to the rescue 
observed in the mouse model.  The motor neuron counts tightly correlated with GFP transcript 
quantification in each of the spinal cord segments. 
5.4. 
Clinical Studies 
First-in-human trial AVXS-101-CL-101 is a completed 2-year trial which evaluated 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 (Mendell 2017).  After the End of Trial 
visit, patients were invited to participate in a long term follow up study conducted under a 
separate protocol. 
Based on data obtained in Study AVXS 101-CL-101, the following conclusions can be made 
regarding the efficacy of AVXS-101: AVXS-101 administration had a positive effect on 
survival.  All 15 patients were alive and free of permanent ventilation 24 months after dosing and 
all Cohort 2 patients had survived free of permanent ventilation, a statistically significant 
difference compared with the natural history rate of 8% reported by Finkel, 2014 (Finkel 2014). 
5.5. 
Risks 
A full understanding of all risks of AVXS-101 is not known at this time.  Potential risks of 
AVXS-101 are discussed below and further details are provided in the AVXS-101 Investigator’s 
Brochure.  Please note, the risks discussed below are the result of observations with IV 
administration.  The dose for IV therapy is 1- to 3-fold higher than for the IT therapy.  Because 
the IT dose is lower than the IV dose and delivered directly to the CNS, the systemic exposure 
and associated risks are expected to be less. 
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. 
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Some mice affected with a form of SMA Type 1 that were treated with the study vector 
developed localized vascular necrosis around the ear called necrotic pinna.  This is believed to be 
unrelated to the vector, and likely related to an underlying defect that has been observed to occur 
in several SMA mouse models (Narver 2008).  The relevance to humans with SMA is unknown. 
Respiratory tract infections in neonates are very common in the general pediatric population 
(Paes 2001).  In one study, an estimated 338 million new episodes of respiratory syncytial virus 
(RSV)-associated acute lower respiratory infections occurred worldwide in children younger 
than 5 years, with at least 34 million episodes necessitating hospital admission (Nair 2010).  
Respiratory syncytial virus is the primary cause of hospitalization for respiratory tract infection 
in young children (Hall 2001).  It would not be unexpected that infants enrolled in the 
AVXS-101 gene replacement therapy trials might have similar incidences of respiratory 
infections due to these pathogens. 
Patients must be clinically stable before AVXS-101 dosing.  Clinical signs or symptoms of 
infection should not be evident at the time of AVXS-101 administration.  Vaccinations, 
including palivizumab prophylaxis that can prevent RSV infections (Palivizumab SmPC 2019), 
are also recommended (Finkel 2018) and should be up to date.  Added caution is advised 
regarding the timing of AVXS-101 administration in the presence of prodrome or resolving viral 
illness. In the event of a severe viral respiratory infection, the Investigator should be aware of the 
possibility of adrenal insufficiency in the presence of systemic immune response which may 
require longer glucocorticosteroid support at increasing doses to effectively manage the patient 
and prevent serious complications. 
Some mice affected with SMA Type 1 that were treated with AVXS-101 experienced liver 
findings comprised on hepatocellular hypertrophy, Kupffer cell activation, and scattered 
hepatocellular necrosis. 
Adverse events (AEs) of increased transaminases (ALT increased, AST increased, and 
transaminase increased) were reported as related to AVXS-101 in clinical studies.  The 
underlying cause of the transaminase elevations is not known; though, may be related to an 
immune response to AAV9, as indicated by the response to prednisolone.  Though these AEs can 
be serious, in most cases they were clinically asymptomatic, did not meet criteria for Hy's law, 
did not exhibit clinically relevant increases in bilirubin, and generally resolved with prednisolone 
treatment.  A case of acute liver failure (serious unexpected serious adverse reaction [SUSAR]) 
was reported in the US Managed Access Program with AVXS-101.  A 6-month-old male 
concurrently receiving nusinersen with elevations of AST and ALT of > 3 x upper limit of 
normal (ULN) before treatment with AVXS-101 developed acute liver failure approximately 
51 days post AVXS-101 dosing.  The patient recovered with additional steroid therapy. 
Nonclinical cardiovascular toxicity findings that could potentially be relevant to the clinical use 
of AVXS-101 have been reported in 2 mouse toxicology studies of AVXS-101.  Similar findings 
were reported in both studies.  Findings in the ventricles of the heart were comprised of 
inflammation, edema and fibrosis.  Primary findings in the atrium of the heart were thrombosis 
and inflammation.  The underlying mechanism of these findings and the translatability of the 
observed findings in mice to primates are not known at this time. 
The available clinical cardiovascular safety data have not provided evidence for a cardiovascular 
safety problem in humans.  As of the last update to the Investigator’s Brochure (v5), there have 
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been no cardiovascular AEs that have been judged to be related to AVXS-101 in the clinical 
studies.   
A transient decrease in platelet counts has been observed with both IV and less frequently with 
IT administration.  The majority of values remained above the lower limit of normal.  Decreases 
were clinically asymptomatic and transient. 
This risk can be effectively managed through monitoring platelet counts for 1 month following 
dosing, and appropriate prednisolone (or an equivalent corticosteroid in countries where 
prednisolone is not available) use. 
Preclinical data indicate that in most cases, DNA delivered by recombinant AAV vectors 
predominantly persists as extrachromosomal elements (episomes) rather than integrating into 
host cell genomes (McCarty 2004).  Although AVXS-101 is also not anticipated to integrate into 
the host cell genome as described above, the long-term consequences of administering AAV 
viral vectors to humans are not yet fully understood.  This is in contrast to wtAAV, also 
nonpathogenic, which has the ability to stably integrate into the host cell genome at a specific 
site (designated AAVS1) in the human chromosome 19 (Kotin 1990; Surosky ).  Since the 
AVXS-101 product uses AAV9 with all of the wtDNA removed from the capsids, except for the 
inverted terminal repeats (ITRs), the potential risk of incorporation of AVXS-101 into the patient 
chromosomal DNA is thought to be significantly reduced. 
There are conflicting reports that integration of the wtAAV2 genome is associated with induction 
of hepatocellular carcinoma in a small subset of patients; however, there are several studies with 
evidence to contradict these claims including:  a) AAV2 has infected approximately 90% of the 
human population, b) AAV2 has been shown to possess anticancer activity, c) epidemiological 
evidence suggests that AAV2 infection plays a protective role against cervical carcinoma, and d) 
AAV serotypes including recombinant AAV2 and AAV9 have been or are currently used in 162 
clinical trials to date in which no cancer of any type has been observed or reported.  For a review 
of the topic, see Srivastava and Carter, 2017 (Srivastava 2017).  Further support for the 
extremely low potential incorporation into host chromosomal DNA comes from pre-clinical 
studies, which to date have not shown the development of cancer in treated animals including 
mice and non-human primates exposed to AVXS-101. 
It is possible the AAV9 vector containing the SMN gene could interact with other viruses with 
which the patients come in contact, such as rhinoviruses, adenovirus or herpes.  If this happens, 
the AAV9 vector could form a virus that causes infection if the patient and cells for rescue, 
replication, and packaging are also exposed to wtAAV2.  However, the rescue, replication, and 
packaging would stop as the helper viruses, such as rhinoviruses, adenovirus or herpes, were 
cleared by the patient’s immune system.  This unlikely scenario has been studied.  In cell culture, 
the recombinant AAV (rAAV) genome can be rescued and replicated by superinfection with 
wtAAV and a helper virus; however, in vivo rescue experiments have failed to show rescue and 
replication (Favre 2001), except in one case in which very large doses of wtAAV and adenovirus 
were administered in a particular setting (Alfione 1996).  Therefore, AAV9 interaction with 
other viruses to cause infection appears to be a minimal risk for AVXS-101. 
Studies have shown that some vector can be excreted from the body for up to a few weeks after 
injection/infusion; this is called “viral shedding”.  Vector shedding can be found in the blood, 
urine, saliva, and stool for up to a few weeks following injection.  The risks associated with the 
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shed vector are not known at this time; however, because the vector is non-pathogenic and 
cannot replicate, it is believed that shed vector is unlikely to result in clinically significant 
adverse effects.  Regardless, instructions should be provided to patient families and caregivers 
regarding use of protective gloves if/when coming into direct contact with patient bodily fluids 
and/or waste, as well as good hand-hygiene for a minimum of four weeks after the injection.  
Additionally, patients are prohibited from donating blood for two years following the vector 
injection. 
Viral shedding is dependent on a variety of factors including the route of administration of the 
product, the tropism of the virus or bacteria, and the natural route of transmission and shedding 
of the parent virus or bacterium from which the product is derived.  AveXis, Inc. (AveXis) 
collected saliva, urine, and stool samples at weekly timepoints through Day 30 and then monthly 
timepoints through Month 18 after gene transfer during the AVXS-101-CL-101 clinical study 
from five patients for viral shedding analysis.  This analysis detects the number of genome 
copies by droplet digital polymerase chain reaction (ddPCR) in the applicable shed samples. 
After IV administration, AVXS-101 is detectable in the shed samples from Day 1 post injection.  
All five patients analyzed were dosed with 2.0 × 1014 vg/kg.  Concentrations of vector shed in 
saliva and urine are quite low and are below the limits of quantitation by ddPCR in the matrices 
within days post dose.  Shedding of AVXS-101 was reported as a proportion of the initial 
concentration. 
All five patients analyzed for viral shedding were dosed with the proposed therapeutic dose.  
AVXS-101 was detectable in shed samples post-infusion. AVXS-101 concentrations in urine and 
saliva were 0.1% to 0.01% of initial concentration in the body at Day 1 post infusion, after which 
concentrations fell below the limit of quantitation.  In stool, levels 10% to 30% of the initial 
concentration in the body were detectable at Day 1 post-infusion.  One patient showed a peak 
concentration in stool at Day 14 post infusion of 280% of initial concentration in body.  In 
contrast, three patients for whom data were available showed a concentration of <1% of initial 
concentration in body at Day 14 post infusion, with concentrations declining approximately 
4 logs (10,000-fold) over 30 days post infusion.  Overall, AVXS-101 was primarily cleared from 
the body in stool and by Day 60 post infusion was below the limit of quantitation in stool.  Shed 
AAV vectors have been previously shown not to be infectious in urine and saliva excreta 
(Favre 2001).  Together, these data demonstrate rapid decline of shed vector quantities well 
below initial concentrations in patients treated with AVXS-101.  Clearance of AVXS-101 is 
primarily via the feces, and the majority of the dose is cleared within 30 days of dose 
administration. 
The results seen in the IV development program support further clinical investigation of the 
efficacy and safety of AVXS-101 in patients with SMA.   Based on the current available data, 
safety events that appear to be associated with AVXS-101 consist of transient liver enzyme 
elevations, which have resolved following treatment with prednisolone.  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. 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The primary safety objective is to assess the safety and tolerability of IT administration of 
AVXS-101 by the incidence and severity of AEs while determining the optimal dose of AVXS-
101 that demonstrates acceptable safety with maximum preliminary efficacy administered by IT 
injection.  Safety and efficacy will be assessed independently for each age cohort. 
6.1.1. 
Primary Objective: patients ≥ 6 months and < 24 months of age at time of dosing 
The primary objective is to determine the proportion of patients ≥ 6 months and < 24 months of 
age at time of dosing achieving the ability to stand without support for at least three seconds 
(Bayley Scales of Infant and Toddler Development – Gross motor subset item # 40). 
6.1.2. 
Primary Objective: patients ≥ 24 months and < 60 months of age at time of dosing 
The primary objective is to determine the change from baseline in Hammersmith Functional 
Motor Scale- Expanded (HFMSE) for patients ≥ 24 and < 60 months of age at time of dosing. 
6.2. 
Secondary Objective 
The secondary efficacy objective for both age groups is to determine the: 
• Proportion of patients that achieve ability to walk without assistance defined as taking at 
least five steps independently displaying coordination and balance (Bayley Scales of 
Infant and Toddler Development – Gross Motor subset item # 43). 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
The proposed clinical study is a Phase 1, open-label, single-dose administration study of infants 
and children with a genetic diagnosis consistent with SMA, bi-allelic deletion of SMN1 and 3 
copies of SMN2 without the genetic modifier who are able to sit but cannot stand or walk at the 
time of study entry.  Patients will receive AVXS-101 in a dose comparison safety study of up to 
three potential therapeutic doses as described below.  Patients will be stratified in two groups, 
those ≥6 months and < 24 months of age at time of dosing and those ≥ 24 months and 
< 60 months of age at time of dosing.  At least 15 patients ≥6 months and < 24 months will be 
enrolled and 12 patients ≥ 24 and < 60 months will be enrolled. 
The first cohort will enroll three patients (Cohort 1) ≥6 months and < 24 months of age who will 
receive administration of 6.0 × 1013 vg of AVXS-101 (Dose A).  There will be at least a 4-week 
interval between the dosing of each patient within the cohort.  AveXis will confer with the Data 
Safety Monitoring Board/Data Monitoring Committee (DSMB/DMC) on all Grade III or higher 
AEs within approximately 48 hours of awareness that are possibly, probably, or definitely related 
to the study agent before continuing enrollment.  Safety data will be reviewed by the 
DSMB/DMC during quarterly meetings; following enrollment of the first three patients and 
based upon the available safety data a decision will be made whether to: a) stop due to toxicity, 
or b) proceed to Cohort 2 using Dose B. 
Should the determination be made to advance to Dose B, three patients < 60 months of age will 
be enrolled to receive administration of 1.2 × 1014 vg of AVXS-101 (Dose B).  Again, there will 
be at least a 4-week interval between dosing of the three patients within the cohort.  Based on the 
available safety data from the three Cohort 2 patients and all of the Cohort 1 patients, the 
DSMB/DMC may decide and document during quarterly meetings that further 4-week intervals 
between patients dosing is unnecessary.  AveXis will take this recommendation into 
consideration and will make the final determination whether to persist with 4-week intervals 
between patients dosing going forward; the decision will be communicated to sites and 
Institutional Review Boards (IRBs) in a formal sponsor letter.  AveXis will confer with the 
DSMB/DMC on all Grade III or higher AEs within approximately 48 hours that are possibly, 
probably, or definitely related to the study agent before continuing enrollment.  Safety data will 
be reviewed by the DSMB/DMC during quarterly meetings; following enrollment of the first six 
patients and based upon available safety data, a decision will be made whether to a) stop due to 
toxicity, or b) continue to enroll an additional 21 patients until 12 patients ≥6 months and 
< 24 months and 12 patients ≥ 24 months and < 60 months have received Dose B. 
Based upon an ongoing assessment of safety and efficacy data from patients treated with the 
1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on 
all available data, this is judged to be necessary, three patients < 60 months of age will receive 
Dose C, 2.4 × 1014 vg administered IT. A meeting of the DSMB/DMC will be called to obtain 
agreement on the safety of escalating to a higher dose prior to proceeding.  If agreement is 
obtained from the DSMB/DMC, there will again be a four-week interval between dosing of the 
first three patients receiving Dose C, as in Cohorts 1 and 2.  Safety data will be reviewed by the 
DSMB/DMC during quarterly meetings; following enrollment of the first three Dose C patients 
and based upon available safety data, a decision will be made whether to: a) stop due to toxicity, 
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or b) continue to enroll an additional 21 patients until there are a total of 12 patients > 6 months 
and < 24 months and 12 patients ≥ 24 and < 60 months that have received Dose C. 
Selection of the appropriate dose and justification for testing Dose C will be supported by 
ongoing safety and efficacy reviews of clinical findings from the patients receiving Dose B 
(1.2 × 1014 vg).  Dose C will be 2.4 × 1014 vg delivered IT.  Doses up to 1.1 × 1014 vg/kg have 
been safely administered systemically (IV) to children weighing up to 8.4 kg (total dose 9.24 × 
1014 vg).  In addition, in preclinical studies, the IT administration of scAAV9.CB.SMN was safe 
and well tolerated up to 14 months post injection in large non-human primates at a dose of 2 × 
1013 vg/kg (AVXS-101 Investigator’s Brochure). 
The overall study design is summarized in Figure 4. 
Safety will be assessed through monitoring AE reports and concomitant medication usage, and 
by conducting physical examinations, vital sign assessments, cardiovascular evaluations, and 
laboratory evaluations.  Patients will be observed at the hospital for 48 hours post-IT injection.  
Patients will return for follow up according to the Schedule of Assessments (SoA) (Table 3). 
Patients enrolled in Cohort 1 (Dose A) and Cohort 2 (Dose B) will complete 12 months of 
follow-up post IT administration.  Patients enrolled in Cohort 3 (Dose C) will complete 15 
months of follow-up post IT administration. 
An autopsy and tissue collection process will be in place for those patients who consent to 
autopsy/tissue collection for research purposes. 
Once patient completes the study, he or she will be invited to participate in a long-term follow-
up study conducted under a separate protocol. 
 
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Figure 4: Study Design 
  
1 Four week dosing between first three patients within each cohort to allow safety monitoring 
2 Provided no dose related toxicities and DSMB/DMC determines acceptable to escalate/expand during quarterly meeting 
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Table 3: 
Schedule of Assessments1 
Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection (Inpatient) 
Follow-up (Outpatient) 
Notes 
Study Day 
-60 to -2 
-1 
1 
2-3 
7 
14 
21 
30 
44 
60 
72 
Monthly 
Through 
M121 
M15/ 
EOS 
Window 
 
 
 
 
± 2 
± 7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spinal X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
Medical History 
X 
 
X 
(X) 
X 
X 
X 
X 
 
X 
 
X 
X 
Medical history collected at baseline; review of 
systems conducted at each study visit. 
(X): Patients to remain inpatient 48 hours post-
dose for observation and AE monitoring. 
Physical Exam 
(X) 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Includes measuring head circumference. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Vitals/Weight/ 
Length/Height 
(X) 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Vital signs will include BP, respiratory rate, 
pulse, and axillary temperature.  Vitals including 
BP, respiratory rate, pulse axillary temperature, 
pulse oximetry and HR will be monitored and 
recorded every 15 minutes (± 5 minutes) from 
dosing for four hours and every hour (± 15 
minutes) for 24 hours following the AVXS-101 
dosing procedure. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Pulse Oximetry 
(X) 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Pulmonary Exam 
(X) 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
                                                 
1 Patients who reached the Month 12 visit prior to Protocol Amendment 7 had their EOS assessments conducted at Month 12. 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection (Inpatient) 
Follow-up (Outpatient) 
Notes 
Study Day 
-60 to -2 
-1 
1 
2-3 
7 
14 
21 
30 
44 
60 
72 
Monthly 
Through 
M121 
M15/ 
EOS 
Window 
 
 
 
 
± 2 
± 7 
12-Lead ECG 
X 
 
X 
X 
 
 
 
 
 
 
 
(X) 
X 
Irrespective of study schedule, after signing the 
updated informed consent, all patients enrolled 
prior to the Amendment 5 version of the 
protocol should have ECG, 24-hour Holter 
monitoring, and echocardiogram done at the 
next scheduled visit and then in conformity with 
the study SoA. 
(X):  Months 3, 6, 9, and 12 visits. 
12-Lead Holter 
Monitor 
X 
X 
X 
X 
 
 
 
X 
 
(X) 
 
(X) 
X 
ECGs extracted from Holter by central reader in 
triplicate at the following time points: pre-dose, 
2h, 4h, 6h, 8h, 12h, 24h, 36h, and 48h during the 
patient’s inpatient stay. 
(X):  Months 2, 3, 6, 9, and 12 visits. 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
(X) 
X 
Irrespective of study schedule, after signing the 
updated informed consent, all patients enrolled 
prior to the Amendment 5 version of the 
protocol should have echocardiogram done at 
the next scheduled visit and then in conformity 
with the study SoA. 
(X):  Months 3, 6, 9, and 12 visits. 
Capillary Blood 
Gas 
 
X 
 
(X) 
 
 
 
 
 
 
 
 
 
(X):  Laboratory samples collected on Day 2. 
HFMS- Expanded  
(with video) 
(X) 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Will be conducted for patients ≥ 24 months of 
age; patients < 24 months of age at study entry 
will begin HFMS-E at such time that 24 months 
of age is reached. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Bayley III (with 
video) 
(X) 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
Gross and fine motor sections will be performed 
at screening and monthly through 15 months. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection (Inpatient) 
Follow-up (Outpatient) 
Notes 
Study Day 
-60 to -2 
-1 
1 
2-3 
7 
14 
21 
30 
44 
60 
72 
Monthly 
Through 
M121 
M15/ 
EOS 
Window 
 
 
 
 
± 2 
± 7 
Motor Milestone 
Development 
Survey  
(with video) 
(X) 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Hematology / 
Chemistry 
(X) 
(X)* 
 
(X)$ 
X 
X 
X 
X 
(X)† 
X 
(X)† 
X 
X 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
(X)*:  Laboratory samples collected prior to 
dosing are to be processed locally. 
(X)$:  Laboratory samples collected on Day 2. 
(X)† Liver function test (AST, ALT, total 
bilirubin, alkaline phosphatase, GGT) only. 
Coagulation 
(X) 
(X)* 
 
(X)$ 
X 
X 
X 
X 
 
X 
 
X 
X 
Urinalysis 
(X) 
(X)* 
 
(X)$ 
X 
X 
X 
X 
 
X 
 
X 
X 
CK-MB 
X 
 
 
 
X 
 
 
X 
 
X 
 
(X) 
X 
Troponin I will be measured instead of 
CK-MB in new patients who are screened 
and enrolled after amendment 5 (protocol 
version 6.0) goes into effect.  Participants who 
have been screened and enrolled but who 
have not yet received gene replacement therapy 
(visit #2) at the time that amendment 5 (protocol 
version 6.0) goes into effect will have baseline 
troponin I testing prior to treatment with AVXS-
101, and will have troponin I testing in place of 
CK-MB.  CK-MB will be collected from all 
other participants. 
(X):  Months 2, 6, 9, and 12 visits. 
Troponin I 
X 
 
 
 
X 
 
 
X 
 
X 
 
(X) 
X 
Virus Serology 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Blood for 
diagnostic 
confirmation 
testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
To be performed by central laboratory. 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection (Inpatient) 
Follow-up (Outpatient) 
Notes 
Study Day 
-60 to -2 
-1 
1 
2-3 
7 
14 
21 
30 
44 
60 
72 
Monthly 
Through 
M121 
M15/ 
EOS 
Window 
 
 
 
 
± 2 
± 7 
Saliva, Urine, and 
Stool Samples (for 
viral shedding) 
 
X 
 
(X) 
(X) (X) 
 
(X) 
 
 
 
 
 
(X):  Sites participating in the viral shedding 
sub-study will collect 24-hour full volume 
samples for urine and feces through 24 and 
48 hours.  All other sites will collect singular 
urine and feces samples within 24 hours and 
48 hours of dosing.  Full urine and feces samples 
will be collected for patients ≥ 48 months who 
are no longer in diapers. 
Baseline Screening 
of Biological 
Mother (Anti-
AAV9 Ab) 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sample collected at screening for anti-
AAV9 antibodies. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
(X)*:  Additional sampling may be performed at 
subsequent time points if ELISpot value(s) 
continue to be elevated, based on further 
discussion with the PI and Medical Monitor. 
Immunology Labs  
(Anti-AAV9/SMN) 
(X) 
 
 
 
X 
X 
X 
(X) 
 
 
 
 
 
Immunology Labs  
(IFN-y T-cells) 
 
 
 
 
X 
X 
X 
(X) 
 
 
 
 
 
(X):  Additional sampling may be performed at 
subsequent time points if ELISpot value(s) 
continue to be elevated, based on further 
discussion with the PI and Medical Monitor. 
Prophylactic 
Prednisolone  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
See Section 9.2.1.  Daily dosing from 24 hours 
prior to scheduled AVXS-101 dose and 
continued as per protocol. 
Study Product 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Photograph 
Injection Site 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection (Inpatient) 
Follow-up (Outpatient) 
Notes 
Study Day 
-60 to -2 
-1 
1 
2-3 
7 
14 
21 
30 
44 
60 
72 
Monthly 
Through 
M121 
M15/ 
EOS 
Window 
 
 
 
 
± 2 
± 7 
Prior and 
Concomitant 
Medications 
To be collected from 2 weeks before study dosing until final study visit 
 
AE = adverse event, ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK-MB = Creatinine kinase-MB (isozyme MB); 
ECG = electrocardiogram; ELISpot = enzyme-linked ImmunoSpot; GGT = gamma glutamyl transferase; IFN-γ = interferon gamma; PI = Principal 
Investigator; SoA = Schedule of Assessments;  
 
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7.2. 
Number of Patients 
At least 27 patients will be enrolled; up to 51 patients may be enrolled if escalation to Dose C is 
determined necessary. 
7.3. 
Treatment Assignment 
This is an open-label comparative single-dose study.  Treatment will be assigned in accord with 
the dose escalation schedule specified in Section 10.6. 
7.4. 
Dose Adjustment Criteria 
The study investigates a one-time IT injection of AVXS-101; therefore, no dose adjustments are 
possible. 
7.5. 
Criteria for Study Termination 
An independent DSMB/DMC and medical monitor will monitor safety data on a continual basis 
throughout the trial.  The DSMB/DMC can recommend early termination of the trial for reasons 
of safety.  Study enrollment may be halted when any patient experiences a Grade III, or higher 
AE toxicity that is unanticipated and possibly, probably or definitely related to the study product 
that presents with clinical symptoms and requires medical treatment.  This will include any 
patient death, important clinical laboratory finding or any severe local complication in the 
injected area related to administration of the study agent.  If after review by the DSMB/DMC the 
decision is made to continue, the study will proceed according to the dose escalation schedule. 
The trial may be terminated for the following reasons: 
• Development of unacceptable toxicity, defined as the occurrence of any unanticipated 
Common Terminology for Adverse Events (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/DMC can recommend early termination of the study for safety reasons 
• Study is terminated by sponsor 
• Regulatory Authority recommendation 
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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients with a genetic diagnosis consistent with SMA, bi-allelic deletion of SMN1 and 3 copies 
of SMN2 without the genetic modifier who demonstrate the ability to sit unassisted for 10 or 
more seconds but cannot stand or walk at the time of study entry will be enrolled in this clinical 
trial.  Patients will be of any racial, ethnic, or gender background.  Enrollment will be staggered 
with at least four weeks between patient injections for all patients in Cohort 1 and at least the 
first three patients in Cohort 2 and Cohort 3. 
8.1. 
Patient Inclusion Criteria 
Patients must meet all of the following inclusion criteria: 
1. Patients ≥6 months of age and ≤60 months (1800 days) of age at time of dosing following 
diagnostic confirmation during screening period by genotype who demonstrate the ability 
to sit unassisted for 10 or more seconds but cannot stand or walk 
− Diagnostic confirmation by genotype includes lab documentation of homozygous 
absence of SMN1 exon 7; with exactly three copies of SMN2 
2. Negative gene testing for SMN2 gene modifier mutation (c.859G>C) 
3. Onset of clinical signs and symptoms consistent with SMA at < 12 months of age 
4. Able to sit independently and not standing or walking independently.  Definition of 
sitting independently is defined by the World Health Organization- Multicentre Growth 
Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head 
erect for at least 10 seconds.  Child should not use arms or hands to balance body or 
support position (Wijnhoven 2004) 
5. Meet age-appropriate institutional criteria for use of anesthesia and sedation, as 
determined necessary by the Investigator 
6. Be up-to-date on childhood vaccines, including palivizumab prophylaxis (also known as 
Synagis) to prevent RSV infections, in accordance with the recommendations of the 
American Academy of Pediatrics (AAP 2009) 
7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process 
8.2. 
Patient Exclusion Criteria 
Patients must not meet any of the following exclusion criteria: 
1. Current or historical ability to stand or walk independently 
2. Contraindications for spinal tap procedure or administration of IT therapy (e.g., spina 
bifida, meningitis, impairment, clotting abnormalities, or obstructive spinal hardware 
preventing effective access to CSF space) or presence of an implanted shunt for the 
drainage of CSF or an implanted CNS catheter 
3. Severe contractures as determined by designated Physical Therapist(s) at screening that 
interfere with either the ability to attain/demonstrate functional measures (e.g., standing, 
walking) or interferes with ability to receive IT dosing 
4. Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination 
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5. Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose 
administration 
6. Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse 
oximetry < 95% saturation at screening while the patient is awake, or for high altitudes 
> 1000 m, oxygen saturation < 92% while the patient is awake 
− Pulse oximetry saturation must not decrease ≥ four percentage points between 
screening and highest value on day of dosing 
7. Use or requirement of non-invasive ventilatory support for 12 or more hours daily in the 
two weeks prior to dosing 
8. Medical necessity for a gastric feeding tube, where the majority of feedings are given by 
non- oral methods (i.e., nasogastric tube or nasojejunal tube) or patients whose weight-
for-age falls below the 3rd percentile based on World Health Organization (WHO) Child 
Growth Standards (Onis 2006).  Placement of a permanent gastrostomy prior to screening 
is not an exclusion. 
9. Active viral infection (includes human immunodeficiency virus [HIV] or serology 
positive for hepatitis B or C, or Zika virus) 
10. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization 
within two weeks prior to study entry 
11. Respiratory infection requiring medical attention, medical intervention or increase in 
supportive care of any manner within four weeks prior to study entry 
12. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis or meningitis) 
within four weeks before study dosing or concomitant illness that in the opinion of the 
Principal Investigator creates unnecessary risks for gene transfer such as: 
− Major renal or hepatic impairment 
− Known seizure disorder 
− Diabetes mellitus 
− Idiopathic hypocalciuria 
− Symptomatic cardiomyopathy 
13. History of bacterial meningitis or brain or spinal cord disease, including tumors, or 
abnormalities by magnetic resonance imaging (MRI) or computed tomography (CT) that 
would interfere with the lumbar puncture (LP) procedures or CSF circulation 
14. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their 
excipients 
15. Known allergy or hypersensitivity to iodine or iodine-containing products 
16. 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, or immunosuppressive therapy 
within 3 months of study dosing (e.g., corticosteroids, cyclosporine, tacrolimus, 
methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) 
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17. Inability to withhold use of laxatives or diuretics in the 24 hours prior to dose 
administration 
18. Anti-AAV9 antibody titers >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 
19. Clinically significant abnormal laboratory values (gamma glutamyl transferase [GGT], 
ALT, and AST, or total bilirubin > 2 × ULN, 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.  Patients with an elevated bilirubin level that is unequivocally the result of 
neonatal jaundice shall not be excluded. 
20. Participation in recent SMA treatment clinical trial or receipt of an investigational or 
approved compound product or therapy received with the intent to treat SMA (e.g., 
valproic acid, nusinersen) at any time prior to screening for this study 
− Oral beta agonists must be discontinued 30 days prior to 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 
21. Expectation of major surgical procedures during the 1-year study assessment period (e.g., 
spinal surgery or tracheostomy) 
22. Inability or unwillingness to comply with study procedures or inability to travel for repeat 
visits 
23. Unwillingness to keep study results/observations confidential or to refrain from posting 
confidential study results/observations on social media sites 
24. Refusal to sign consent form 
8.3. 
Patient Withdrawal Criteria and Discontinuation 
Patients meeting the following criteria will be withdrawn: 
• Death 
− Autopsies will be requested of any patients, with the exception of untreated patients, 
that expire following participation in a gene transfer study 
• 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. Patients who terminate the study early for 
reasons other than death will be offered enrollment in a long-term follow-up study. 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Description of Study Product 
The biological product is a non-replicating recombinant self-complementary adeno-associated 
virus serotype 9 (AAV9) containing the cDNA of the human SMN gene under the control of the 
cytomegalovirus enhancer/chicken-β-actin-hybrid promoter (CB).  The AAV 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.  Cells transduced with AVXS-101 (formerly scAAV9.CB.hSMN) 
express the human SMN protein. 
Table 4: 
Investigational Product 
 
Investigational Product 
Product Name 
AVXS-101 
Unit Dose 
6.0 × 1013 vg (Dose A)  
1.2 × 1014 vg (Dose B)  
2.4 × 1014 vg (Dose C) 
Route of Administration 
Intrathecal Injection 
Physical Description 
Once thawed, AVXS-101 is a clear to slightly opaque, colorless to faint 
white solution, free of visible particulates 
9.2. 
Prior and Concomitant Medications 
Prior and concomitant medications will be captured in the electronic Case Report Form (eCRF) 
from two weeks prior to study dosing until the End of 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 investigating AVXS-101 treatment via IV infusion.  This is an expected response 
between 2-4 weeks following gene transfer.  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, patients will 
receive prophylactic prednisolone (glucocorticoid) (approximately 1 mg/kg/day) 24 hours prior 
to AVXS-101 dosing.  Treatment will continue for approximately 30 days in accord with the 
following treatment guideline: 
• Until at least 30 days post-injection: 1 mg/kg/day 
• Weeks 5 and 6 post-injection: 0.5 mg/kg/day 
• Weeks 7 and 8 post-injection: 0.25 mg/kg/day 
• Week 9 post-injection prednisolone discontinued 
Liver function testing should guide each step of the taper, and liver function tests should be 
checked prior to prednisolone discontinuation.  If the GGT, AST or ALT values are ≥ 2 × ULN, 
then the present dose of prednisolone will be adjusted as needed until the GGT, AST, and ALT 
values decrease below threshold, at which point the taper may continue.  Liver function tests 
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should also be checked approximately 2 weeks after the taper has concluded and prednisolone 
has been discontinued to evaluate for rebound elevation of GGT, AST or ALT levels.  Variance 
from these recommendations will be at the discretion of the Investigator based on potential safety 
issues for each patient.  If another glucocorticoid is used in place of prednisolone by the 
Investigator, similar considerations should be taken into account after 30 days and tapered as 
appropriate and at the discretion of the Investigator. 
9.2.2. 
Prohibited Medications 
Concomitant use of any of the following medications is prohibited: 
• Drugs for treatment of myopathy or neuropathy 
• Agents used to treat diabetes mellitus 
• Therapy received with the intent to treat SMA (e.g., valproic acid, nusinersen). 
- Oral beta-agonists must be discontinued at least 30 days prior to gene therapy dosing. 
- Inhaled beta agonists may be used to treat respiratory complications of SMA provided 
such medications are dosed at clinically appropriate levels 
• Ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as 
adalimumab, or immunosuppressive therapy within 3 months of starting the trial (e.g., 
corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV 
immunoglobulin, rituximab) 
Corticosteroid usage following completion of the prednisolone taper is permissible at the 
discretion of the managing physician as part of routine clinical management.  The use of 
prednisone in such circumstances should be documented appropriately as a concomitant 
medication, and the event precipitating its usage should be appropriately documented as an AE. 
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 AveXis medical monitor, who will be responsible for any indicated 
medication adjustments related to the taper. 
9.2.3. 
Vaccinations 
Where feasible, the vaccination schedule should be adjusted appropriately to accommodate 
prednisolone use.  When avoiding vaccination while on steroids represents an undue delay or 
interruption of a vaccination schedule, vaccination should continue at the discretion and 
judgment of the treating physician given 1) the importance of maintaining childhood vaccination 
in this population and 2) the published literature that indicates that vaccination while on steroid 
doses 1 mg/kg/day or below is safe and effective (Mendell 2017; Kroger 2018). 
9.3. 
Treatment Compliance 
AVXS-101 will be administered as a one-time IT injection. 
9.4. 
Randomization and Blinding 
This is an open-label study.  See Section 10.7 for a description of the dosing cohorts. 
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10. 
STUDY PRODUCT MATERIALS AND MANAGEMENT 
AVXS-101 was manufactured in accordance with current Good Manufacturing Practice (cGMP).   
10.1. 
Study Product 
AVXS-101 
10.2. 
Study Product Dose and Dose Justification 
Patients will receive a one-time dose of AVXS-101 6.0 × 1013 vg, 1.2 × 1014 vg or a third dose of 
2.4 × 1014 vg, if determined necessary via IT injection.  The delivery directly into the CSF via IT 
injection allows for reduction of the amount of viral vector approximately by a factor of 10 with 
equal distribution and efficacy throughout the CNS, reducing viral vector loads and further 
optimizing safety (see Section 5.2) for additional details).  Selection of the appropriate dose and 
justification for studying all dose escalations are further supported by ongoing safety and 
efficacy reviews of clinical findings from the patients receiving previous doses as described (see 
Section 7.1).  The highest selected dose will be 2.4 × 1014 vg delivered IT.  Doses up to 1.1 × 
1014 vg/kg have been safely administered systemically (IV) to children weighing up to 8.4 kg 
(total dose 9.24 × 1014 vg).  In addition, in preclinical studies, the IT administration of 
scAAV9.CB.SMN was safe and well tolerated up to 14 months post injection in large non-
human primates at a dose of 2 × 1013 vg/kg (AVXS-101 Investigator’s Brochure). 
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 and Destruction 
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 and processed for destruction in 
accord with 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. 
AVXS-101 will be pre-mixed with an appropriate 
 approved and labeled for 
pediatric use for radiographic monitoring of the injection via lumbar IT injection.  The total 
volume of AVXS-101 
 will NOT exceed 8 mL, as outlined in the Pharmacy 
Manual. 
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 
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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 
Patients will receive AVXS-101 IT injection under sterile conditions in a PICU patient room or 
other appropriate setting (e.g., interventional suite, operating room, dedicated procedure room) 
with immediate access to acute critical care management.  After patients are admitted, vitals will 
be monitored immediately after dosing and every 15 (± 5) minutes for four hours and every hour 
(± 15 minutes) for 24 hours following the AVXS-101 dosing procedure. 
Sites are instructed to use an atraumatic needle inserted with the bevel parallel to the dura fibers; 
this has been shown to considerably reduce damage to the dura and consequently decrease the 
risk for CSF leak after lumbar puncture including in children (Kiechl-Kohlendorfer 2003; 
Ebinger 2004). 
Sedation/anesthesia is required for all patients receiving AVXS-101.  Method and medications 
will be at the discretion of the local anesthesiologist but should incorporate a sufficient degree of 
sedation or anxiolysis to ensure analgesia and lack of movement for the procedure and post-
procedure Trendelenburg positioning placement.  Patients will be placed in the Trendelenburg 
position, tilted head-down at 30° for 15 minutes following administration of vector to enhance 
distribution to cervical and brain regions. 
AVXS-101 will be administered by an Investigator 
 
 
 Patients will be placed in the 
lateral decubitus position and a catheter with stylet will be inserted by a lumbar puncture into the 
L3-L4 or L4-L5 interspinous space into the subarachnoid space.  Subarachnoid cannulation will 
be confirmed with the flow of clear CSF from the catheter.  Approximately 4 mL CSF will be 
removed for Dose A and Dose B, a volume of CSF closely approximating the volume of AVXS-
101 plus contrast injected (up to 7 mL) will be removed for Dose C and disposed of as per 
institutional guidelines.  AVXS-101 in the pre-mixed contrast solution will be injected directly 
into the subarachnoid space.  Flushing of the injection needles with 0.5 mL saline will be 
allowed as per institutional standards/guidelines. 
10.6.1. 
Post-Administration Procedures 
Following AVXS-101 administration patients will return to a designated PICU bed, or other 
appropriate setting, with close monitoring of vital signs.  Concomitant medications and all 
AEs/serious adverse events (SAEs) will also be monitored and documented following dosing 
procedures. 
Patients will be kept in the PICU patient room or other appropriate setting (e.g., interventional 
suite, operating room, dedicated procedure room) with immediate access to acute critical care 
management for 48 hours for closer monitoring of mental status.  During the inpatient stay, 
personnel are required to follow appropriate safety precautions as per institutional standards for 
infection control; standards should require personal protective equipment (PPE) such as gowns, 
gloves, masks, glasses, and closed-toe shoes.  Patients’ families will be provided standardized, 
IRB-approved handouts regarding monitoring for mental status changes which includes 
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monitoring for severe headache, fever, irritability, neck pain or stiffness, light sensitivity, 
vomiting, and lethargy (tiredness).  Patients may be discharged from the hospital when the 
following criteria are met: 
• Afebrile 
• Absence of hypersensitivity reactions 
• Absence of meningismus 
• Absence of abnormal laboratory values suggestive of possible CNS infection or 
complication 
10.7. 
Dose Escalation 
There will be a 4-week dosing interval between all patients within Cohort 1 to allow review of 
the safety analysis from six-time points (Days 1, 2, 7, 14, 21, 30) prior to dosing of the next 
patient. 
AveXis will confer with the DSMB/DMC on all Grade III or higher AEs within approximately 
48 hours of awareness that are possibly, probably or definitely related to the study agent before 
continuing enrollment.  Safety data will be reviewed by the DSMB/DMC during quarterly 
meetings; following enrollment of the first three patients ≥6 months and < 24 months of age at 
the time of dosing and based upon the available safety data a decision will be made whether to: 
a) stop due to toxicity, or b) proceed to Cohort 2 using Dose B. 
Should the determination be made to advance to Cohort 2 (Dose B), again there will be at least a 
4-week interval between dosing of the first three patients < 60 months of age at the time of 
dosing within the cohort.  Based on the available safety data from the first three Cohort 2 patients 
and all of the Cohort 1 patients, the DSMB/DMC may decide and document during quarterly 
meetings that further 4-week intervals between patients dosing is unnecessary.  AveXis will take 
this recommendation into consideration and will make the final determination whether to persist 
with 4-week intervals between patients dosing going forward.  The decision will be 
communicated to sites and IRBs in a formal sponsor letter.  AveXis will confer with the 
DSMB/DMC on all Grade III or higher AEs within approximately 48 hours that are possibly, 
probably or definitely related to the study agent before continuing enrollment.  Safety data will 
be reviewed by the DSMB/DMC during quarterly meetings; following enrollment of the first six 
patients and based upon available safety data, a decision will be made whether to a) stop due to 
toxicity or b) continue to enroll an additional 21 patients until 12 patients ≥6 months and 
< 24 months of age at time of dosing and 12 patients > 24 < 60 months of age at time of dosing 
have received Dose B. 
Based upon an ongoing assessment of safety and efficacy data from patients treated with the 
1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on 
all available data, this is judged to be safe and necessary, three patients < 60 months of age will 
receive Dose C, 2.4 × 1014 vg administered IT.  A meeting of the DSMB/DMC will be called to 
obtain a recommendation on the safety of escalating to a higher dose prior to proceeding.  If a 
decision is made to proceed to testing a higher dose, there will again be a four-week interval 
between dosing of the first three patients receiving Dose C, as in Cohorts 1 and 2.  Safety data 
will be reviewed by the DSMB/DMC during quarterly meetings.  Following enrollment of the 
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first three Dose C patients and based upon available safety data, the DSMB/DMC will be 
consulted and a decision will be made whether to: a) stop dosing Dose C due to safety concern, 
or b) continue to enroll an additional 21 patients until there are a total of 12 patients ≥6 months 
and < 24 months and 12 patients ≥ 24 and < 60 months that have received Dose C. 
10.8. 
Study Product Accountability 
This is an open-label study.  Eligible patients will be assigned a unique patient identification 
number once informed consent is obtained and all eligibility criteria are met. 
The pharmacist or designee will maintain accurate records of the quantities of AVXS-101 
received, dispensed, and destroyed.  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 
prepared for destruction 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 PPE, 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 AveXis 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. 
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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Physical Assessments 
11.1.1. 
Hammersmith Functional Motor Scale- Expanded 
The HFMSE was devised for use in children with SMA Type 2 and Type 3, to give objective 
information on motor ability and clinical progression. 
The HFMSE will be administered by a qualified clinical evaluator (e.g., licensed physical or 
occupational therapist, or national equivalent) in accord with Table 3 for all patients ≥ 24 months 
of age.  Patients < 24 months of age at time of dosing will begin having HFMSE assessments at 
such time that 24 months of age is reached. 
The HFMSE sessions will be videotaped in accord with the AVXS-101-CL-102 Videotaping 
Manual. 
11.1.2. 
Bayley Scales of Infant and Toddler Development 
Bayley Scales of Infant and Toddler Development© version 3 is a standardized, norm-referenced 
infant assessment and will be administered by a qualified clinical evaluator (e.g., licensed 
physical or occupational therapist, or national equivalent).  The gross and fine motor subtests 
will be completed in accordance with Table 3.  See AVXS-101-CL-102 Physical Assessments 
Manual. 
Bayley Scales assessments will be videotaped in accordance with the AVXS-101-CL-102 
Videotaping Manual. 
11.2. 
Motor Milestone Development Survey 
The achievement of significant motor milestones will be assessed by the qualified clinical 
evaluator (e.g., licensed physical or occupational therapist, or national equivalent) using a 
standard Motor Milestone Development Survey shown in Table 5 with definitions of each 
milestone driven by the Bayley Scales of Infant and Toddler Development (see AVXS-101-
CL-102 Physical Assessments Manual).  The clinical evaluator will record whether the patient 
has attained each of the milestones on the Motor Milestone Development Survey in accordance 
with Table 3.  Once observed, a motor milestone is considered attained.  The date of attainment 
of each motor milestone will be determined by the date of the visit in which the milestone is 
observed. 
During the screening visit, the clinical evaluator will complete an assessment of baseline 
milestone achievement in accordance with Table 3; this assessment must be recorded on video 
and the findings must be documented in the source. 
As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each milestone be captured on video.  Development milestone 
assessment sessions will be videotaped in accord with the AVXS-101-CL-102 Videotaping 
Manual. 
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Table 5: 
Motor Milestone Development Survey 
Developmental Milestone- Bayley 
Scale Item Number 
Performance Criteria 
Head Control – Gross Motor Subtest 
Item #4  
Child holds head erect for at least 3 seconds without support 
Rolls from Back to Sides – Gross 
Motor Subtest Item #20 
Child turns from back to both right and left sides 
Sits Without Support – Gross Motor 
Subtest Item #26 
Child sits alone without support for at least 30 seconds 
Stands with Assistance - Gross Motor 
Subtest Item #33 
Child supports own weight for at least 2 seconds 
Crawls – Gross Motor Subtest 
Item #34 
Child makes forward progress of at least 5 feet by crawling on hands and 
knees 
Pulls to Stand – Gross Motor Subtest 
Item #35 
Child raises self to standing position using chair or other convenient 
object for support 
Walks with Assistance – Gross Motor 
Subtest Item #37 
Child walks by making coordinated, alternated stepping movements 
Stands Alone – Gross Motor Subtest 
Item #40 
Child stands alone for at least 3 seconds after you release his or her hands 
Walks Alone – Gross Motor Subtest 
Item #43 
Child takes at least five steps independently, displaying coordination and 
balance 
11.3. 
Video Evidence 
Clinical assessments required at each study visit will be videotaped in an effort to produce 
compelling, demonstrable, documented evidence of efficacy, as determined by changes in 
functional abilities.  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 and/or the medical community, and/or in appropriate venues 
to discuss the results of this clinical trial. 
Videos will be provided to an independent, centralized reviewer for unbiased assessment of 
milestone achievement.  The independent central reviewer will document whether the video 
displays evidence of having achieved each developmental milestone. The date of motor 
milestone achievement will be computed as the earliest date on which video evidence 
demonstrates the achievement of the specified developmental milestone. 
Additionally, the parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the trial. These videos will be 
handled in the same manner in which the trial-derived videos are handled. 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
The primary outcome for this clinical trial is safety.  Study discontinuation rules are based on the 
development of unacceptable toxicity, defined as the occurrence of any one Grade III or higher 
treatment-related toxicity. 
12.1.1. 
Dose Limiting Toxicity 
Dose limiting toxicity is defined as any grade III AE, according to the CTCAE version 4.03 that 
is possibly, probably or definitely related to the study agent.  The CTCAE version 4.03 
classifications are outlined in Table 6. 
Table 6: 
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) 
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 by the Investigators when any patient experiences a Grade 
III, or higher AE toxicity that is unanticipated and possibly, probably, or definitely related to the 
study product.  The event will then be reviewed by the DSMB/DMC and an evaluation will be 
made as to whether the trial should be terminated early following the discontinuation rules. 
Dose limiting toxicities must be immediately reported as per study safety reporting guidelines to 
ensure timely escalation to the DSMB/DMC. 
12.1.2. 
Discontinuation Rules 
An independent DSMB/DMC and medical monitor will monitor safety data on a continual basis 
throughout the trial.  The DSMB/DMC can recommend early termination of the trial for reasons 
of safety.  Study enrollment will be halted by the Investigators when any patient experiences a 
Grade III, or higher AE toxicity that is unanticipated and possibly, probably, or definitely related 
to the study product that presents with clinical symptoms and requires medical treatment.  This 
will include any patient death, important clinical laboratory finding, or any severe local 
complication in the injected area related to administration of the study agent.  If after review by 
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the DSMB/DMC the decision is made to continue, the study will proceed according to 
Section 7.1 of this protocol. 
12.2. 
Demographic/Medical History 
Patient demographics and medical history information will be collected at baseline and captured 
in the eCRF.  Medical history throughout the study will be collected as a Review of Systems at 
each visit. 
Medical History information will include: 
• 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 
12.3. 
Vital Signs 
Vital signs will include blood pressure, respiratory rate, pulse, and axillary temperature within 
30 days of dosing and at the time points specified in Table 3. 
Vitals including pulse oximetry and heart rate will be continuously monitored and recorded by a 
team member during the injection. 
After patients are admitted, vitals including blood pressure, respiratory rate, pulse axillary 
temperature, pulse oximetry, and heart rate will be monitored and recorded every 15 minutes 
(± 5 minutes) after dosing for four hours and every hour (± 15 minutes) for 24 hours following 
the AVXS-101 dosing procedure. 
12.4. 
Weight and Length/Height 
Weight and length and/or height, as appropriate, will be measured as per the time points 
specified in Table 3. 
12.5. 
Physical Examination 
Physical examination will include review of the following systems: head, eyes, ears, nose and 
throat, lungs/thorax, cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, 
lymphatic, and genitourinary. 
The head circumference shall be measured with each physical examination.  To measure head 
circumference, the examiner should securely wrap a flexible measuring tape around the 
circumference of the head, above the eyebrows over the broadest part of the forehead, above the 
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ears, and over the most prominent part of the occiput.  The measurement should be taken 3 times, 
and the largest measurement should be recorded to an accuracy of 0.1 centimeters. 
Baseline physical examinations must be completed within 30 days of dosing, and in accord with 
the time points specified in Table 3. 
12.6. 
Vaccination Recommendations 
Patients are encouraged to follow all routinely scheduled immunizations as recommended by the 
Center for Disease Control (CDC) including palivizumab prophylaxis (also known as Synagis) to 
prevent RSV infections in accordance with the recommendations of the American Academy of 
Pediatrics (AAP 2009). 
12.7. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed as specified in the SoA (Table 3).  For 
patients enrolled in the study prior to Amendment 5 and irrespective of 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 SoA (Table 3).   
The ECG will be interpreted locally by a cardiologist or designee for immediate safety 
evaluation.  The ECG tracings or ECG machine data will also be collected for centralized review 
and interpretation by a cardiologist. 
A 12-Lead ECG will be performed (concurrent with Holter Monitor) as specified in the SoA 
(Table 3).  Additional electrophysiological monitoring will be at the discretion of the Investigator 
as per local institutional guidelines. 
12.8. 
12-Lead Holter Monitor 
Patients will have a 12-lead continuous Holter monitor attached 24 hours prior to dose 
administration on Day -1.  The Holter monitor will remain through 48 hours (Day 3).  Serial 
ECG data will be pulled in triplicate from the Holter monitor data at the following time points: 
• pre-dose 
• 2 hour 
• 4 hour 
• 6 hour 
• 8 hour 
• 12 hour 
• 24 hour 
• 36 hour 
• 48 hour 
 
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Twenty-four-hour Holter monitoring will also be performed as specified in the SoA (Table 3).  
For patients enrolled in the study prior to Amendment 5 and irrespective of study schedule, after 
signing an updated informed consent, patients should have a 24-hour Holter monitor at their next 
scheduled visit and then in conformity with the SoA. 
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.  AveXis will be notified of any safety concerns from the centralized review. 
12.9. 
Echocardiogram 
An echocardiogram will be performed as specified in the SoA (Table 3).  For patients enrolled in 
the study prior to Amendment 5 and irrespective of study schedule, after signing an updated 
informed consent, all patients should have a transthoracic echocardiogram at their next scheduled 
visit and then in conformity with the SoA (Table 3). 
The echocardiogram will be interpreted locally by a cardiologist or designee for immediate 
safety evaluation.  The echocardiograms will also be collected for centralized review and 
interpretation by a cardiologist. 
12.10. Spinal X-ray 
A spinal X-ray will be performed at screening/baseline to rule out patients with severe scoliosis 
or those that would require major spinal surgical procedures during the 1-year study assessment 
period. 
12.11. Pulmonary Exam 
Pulmonary examinations will be performed by a pulmonologist (or appropriate individual as per 
standard institutional practice) at the time points specified in the SoA (Table 3).  Prior to trial 
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 a non-invasive positive pressure ventilator (e.g., bilevel positive 
airway pressure [BiPAP]) at the discretion of the pulmonologist and/or Investigator.  Non-
invasive ventilatory support equipment will be provided by AveXis through a third-party vendor 
if not covered by the patient’s insurance. 
Should the patient require non-invasive ventilator support at any time during the trial, the 
equipment to be provided must be approved by AveXis in order to ensure ability to upload usage 
data. 
Patients requiring non-invasive ventilatory support will be asked to bring the machine to each 
study visit such that the study staff can remove the storage device 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. 
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12.13. Photographs of Injection Site 
Photographs will be taken of the injection site at the time points specified in Table 3 to monitor 
healing of the injection wound.  The Day 1 injection site photograph will be performed prior to 
the start of gene replacement therapy injection.  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 trial. 
12.14. Laboratory Assessments 
Biological samples will be collected throughout the trial at the time points specified in Table 3.  
Biological samples will be collected and shipped to a central laboratory.  Samples for laboratory 
tests required on the day prior to dosing (Day -1) will be collected prior to dosing and will be 
processed locally by the site’s Clinical Laboratory Improvement Amendment (CLIA) -certified 
local laboratory.  In some cases, samples may be collected locally due to a need for immediate 
results or other safety or logistical concerns. 
Table 7: 
Total Blood Volume 
Visit 
Tests1, 3 
Total Volume (mL)2 
Screening 
Hematology, chemistry/CK-MB3 or Troponin I, coagulation, virus 
serology, immunology sample (AAV9/SMN Ab only), diagnostic 
confirmation sample 
19.3-19.6 
Day -1 
Hematology, chemistry, coagulation, capillary blood gas 
6.0 
Day 2 
Hematology, chemistry, coagulation, capillary blood gas 
6.0 
Day 7 
Hematology, chemistry/CK-MB or Troponin I, coagulation, 
immunology sample 
10.0-12.3 
Day 14 
Hematology, chemistry, coagulation immunology sample 
9.0-11.0 
Day 21 
Hematology, chemistry, coagulation immunology sample 
9.0-11.0 
Day 30 
Hematology, chemistry/CK-MB or Troponin I, coagulation, 
immunology sample 
11.0-12.3 
Day 44 
Chemistry 
1.3 
Day 60 
Hematology, chemistry/CK-MB or Troponin I, coagulation 
6.0-6.3 
Day 72 
Chemistry 
1.3 
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Visit 
Tests1, 3 
Total Volume (mL)2 
Month 3 
Hematology, chemistry, coagulation 
5 
Month 4 
Hematology, chemistry, coagulation 
5 
Month 5 
Hematology, chemistry, coagulation 
5 
Month 6 
Hematology, chemistry/CK-MB or Troponin I, coagulation 
6.0-6.3 
Month 7 
Hematology, chemistry, coagulation 
5 
Month 8 
Hematology, chemistry, coagulation 
5 
Month 9 
Hematology, chemistry/CK-MB or Troponin I, coagulation 
6.0-6.3 
Month 10 
Hematology, chemistry, coagulation 
5 
Month 11 
Hematology, chemistry, coagulation 
5 
Month 12 
Hematology, chemistry/CK-MB or Troponin I, coagulation 
6.0-6.3 
Last Study Visit 
(Month 15)4 
Hematology, chemistry/CK-MB or Troponin I, coagulation 
6.0-6.3 
Total Volume for Study 1-Year Duration 
137.9-147.3 
Immunology = Serum antibody to AAV9 and SMN, IFN-γ ELISpot to detect T-cell responses to AAV9 and SMN 
1 Immunology sample requires 4-6 mL of whole blood 
2 Maximum total blood volume specified for each visit; in cases where tests can be combined, lower blood volumes may be 
sufficient.  Positive serology samples at screening and elevated T-cell responses at Day 30 may require additional surveillance 
samples not reflected in the table. 
3 Troponin I will be measured instead of CK-MB in new patients who are screened and enrolled after amendment 5 (protocol 
version 6.0) goes into effect.  Participants who have been screened and enrolled but who have not yet received gene 
replacement therapy (visit #2) at the time that amendment 5 (protocol version 6.0) goes into effect will have baseline troponin I 
testing prior to treatment with AVXS-101, and will have troponin I testing in place of CK-MB.  CK-MB will be collected from 
all other participants. 
4 Only patients enrolled in Cohort 3 will have a month 15 visit.  Patients enrolled in Cohorts 1 and 2 will complete 
the study or have EOS visit at Month 12 
 
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 blood labs: chemistry  hematology  coagulation  creatinine kinase isozyme-
MB (CK-MB) or troponin 
2. Interferon gamma (IFN-γ) ELISpot to detect T-cell responses 
3. Serum antibody to AAV9 and SMN 
4. Genetic re-confirmation testing 
If there is not sufficient blood volume to include the genetic reconfirmation testing sample at the 
screening visit, the patient must return before the inpatient period.  All patients must have 
genetic reconfirmation testing completed. 
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12.14.1. 
Hematology 
Hematology analysis will include a CBC with differential and platelet count with smear.  
Samples will be collected and shipped in accord with the laboratory manual provided by the 
central laboratory as per the time points specified in Table 3. 
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. 
12.14.2. 
Serum Chemistry 
Samples will be collected and shipped in accord with the laboratory manual provided by the 
central laboratory as per the time points specified in Table 3. 
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 
CK-MB or troponin I will be collected as specified in the SoA (Table 3).  Troponin I will be 
measured instead of CK-MB in new patients who are screened and enrolled after amendment 5 
(protocol version 6.0) goes into effect.  Participants who have been screened and enrolled but 
who have not yet received gene replacement therapy at the time that amendment 5 (protocol 
version 6.0) goes into effect will have baseline troponin I testing prior to treatment with AVXS-
101 and will have troponin I testing in place of CK-MB.  CK-MB will be collected from all other 
participants. 
Investigators will receive laboratory results from all study visits from the central laboratory 
(except Day -1). 
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12.14.3. 
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 and shipped in 
accord with the laboratory manual provided by the central laboratory. 
12.14.4. 
Coagulation Studies 
Coagulation studies include prothrombin time, partial prothrombin time, and international 
normalized ratio will be collected in accordance with the laboratory manual provided by the 
central laboratory.  Coagulation studies will be performed as per the timepoints specified in 
Table 3. 
12.14.5. 
Urinalysis 
Urine samples will be collected in accord with the laboratory manual provided by the central 
laboratory as per the time points specified in Table 3. 
Day -1 and immediate/same-day urinalyses required during in-patient dosing, as determined by 
the Investigator, 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 Cells 
• WBCs 
• Squamous epithelial cells 
• Casts 
• Crystals 
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• Bacteria 
• Yeast 
12.14.6. 
Capillary Blood Gas 
Capillary blood gas will be completed as per the time points specified in Table 3.  A puncture or 
small incision will be made with a lancet or similar device into the cutaneous layer of the 
patients’ 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 capillary tube. 
12.14.7. 
Research Immunology Blood 
12.14.7.1. ELISA:  Anti-AAV9 Ab 
Blood samples will be collected and shipped to the central laboratory in accord with the 
laboratory manual to test for serum antibodies to AAV9 as per the timepoints specified in 
Table 3. 
12.14.7.2. ELISA:  Anti-SMN Ab 
Blood samples will be collected and shipped to the central laboratory in accord with the 
laboratory manual to test for serum antibodies to SMN as per the timepoints specified in Table 3. 
12.14.7.3. IFN-γ ELISpot 
Blood will be collected and shipped to the central laboratory in accord with the laboratory 
manual to perform IFN-γ ELISpot to detect T-cell responses to AAV9 and SMN as per the 
timepoints specified in Table 3. 
12.14.8. 
Baseline Screening of Biological Mother 
There is potential that the biological mother of the enrolled patient may have pre-existing 
antibodies to AAV9 that may be transferred to the patient via placental transfer in utero or 
theoretically through breast milk.  Informed consent will be requested from the biological mother 
of the patient to screen the biological mother for circulating antibodies to AAV9.  Once informed 
consent has been obtained, the biological mother will have her blood drawn from a peripheral 
vein and shipped to the central laboratory for screening of anti-AAV9 antibodies. 
If AAV9 antibodies are identified, the Investigator should discuss with the biological mother 
whether to continue or to stop breastfeeding. 
Patients consuming banked breast milk from donor sources that cannot be tested for anti-AAV9 
antibodies must be transitioned to formula prior to participation. 
12.14.9. 
Blood for Diagnostic Confirmation Testing 
A blood sample will be collected during the screening visit and shipped to the central laboratory 
in accord with the laboratory manual for re-confirmation of SMN1 deletions, SMN2 copy 
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number, and absence of exon 7 gene modifier mutation (c.859G>C).  This will be done to ensure 
consistency in diagnostic testing practices. 
12.14.10. 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 a week following injection.  The risks associated with the shed vector 
are not known at this time; however, it is unlikely as the vector is non-infectious and cannot 
replicate.  Regardless, IRB-approved instructions should be provided to patient families and care 
givers regarding use of protective gloves if/when coming into direct contact with patient bodily 
fluids and/or waste as well as good hand-hygiene for a minimum of four weeks after the 
injection. 
Additionally, patients are prohibited from donating blood for two years following the vector 
injection. 
Saliva, urine, and stool samples will be collected in accord with the laboratory manual for viral 
shedding studies in accord with Table 3.  Patients at all sites ≥ 48 months of age who are no 
longer in diapers will provide full volume urine and full volume feces samples at the timepoints 
specified in the SoA (Table 3) for at least one void and one defecation.  Samples will be prepared 
as per the laboratory manual, stored in a -80 freezer, and shipped to the central laboratory in 
accord with 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 
48 hours-post dose (to include all excretions in those time periods). 
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13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
13.1. 
Definition of Adverse Events 
13.1.1. 
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 causally 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 AEs that occur after any patient has received treatment, during treatment or up through the 
last study visit, whether or not they are related to the study, must be recorded on forms provided 
by Syneos Health, formerly INC (a Contract Research Organization responsible for managing 
specific aspects of the study, as designated by AveXis). 
All AEs will be classified in accordance with the CTCAE version 4.03 outlined in Table 6. 
Study enrollment will be interrupted should any patient experience an unanticipated CTCAE 
Grade 3, or higher AE toxicity that is possibly, probably or definitely related to the product.  The 
event will then be reviewed by the DSMB/DMC 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 AEs that are possibly, probably or definitely related to 
gene replacement therapy must be reported within 24 hours to AveXis and/or designee to ensure 
timely escalation to the DSMB/DMC. 
13.1.2. 
Serious Adverse Event 
An SAE is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, comparator or placebo, 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 
• It 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 any patient has been enrolled, before treatment, during treatment, or up 
through the last study visit, whether or not they are related to the study, must be recorded on 
forms provided by Syneos Health. 
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13.1.3. 
Other Adverse Event  
The following specific treatment-emergent AEs of special interest (AESIs), which may be 
searched using Standardized MedDRA queries, will be summarized: 
• Elevated liver enzymes 
Grade 3 or higher elevated liver enzyme events related to AVXS-101 must be collected and 
recorded on forms provided by the Contract Research Organization.  These events should be 
reported within 24 hours of occurrence, whether or not they are deemed to be an SAE. 
Other adverse events (OAEs) could be identified by the Drug Safety Physician and, if applicable, 
also by the Clinical Trial Team Physician during the evaluation of safety data for the Clinical 
Study Report.  Examples of AESIs include hepatotoxicity, cardiac toxicity, and 
thrombocytopenia. Significant AEs 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/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” the event will be considered to be related to 
the investigational product for the purposes of expedited regulatory reporting. 
13.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the patient or family 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.  However, abnormal values that constitute an SAE or lead to 
discontinuation of administration of study product must be reported and recorded as an AE.  
Information about AEs will be collected from the time of IT injection 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 start date 
during inpatient period), resolution (date and time, if start date during inpatient period), intensity, 
causality, action taken, serious outcome (if applicable), and whether or not it caused the patient 
to discontinue the study. 
Intensity will be assessed according to Table 6 in Section 13.1.1. 
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 13.1.2.  An AE of severe intensity 
may not be considered serious. 
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13.4. 
Reporting Serious Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of consent form through the last 
study visit.  Any SAEs considered possibly, probably, or definitely 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 via Syneos Health 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 email to Syneos Health. 
Additional follow-up information, if required or available, should all be faxed or emailed to 
Syneos Health 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/IEC of all SAEs that occur at his/her site, 
as per IRB/IEC reporting guidelines.  Investigators will also be notified of all unexpected, 
serious, drug-related events (7/15 Day Safety Reports) that occur during the clinical trial.  Each 
site is responsible for notifying its IRB/IEC of these additional SAEs. 
13.5. 
Expedited Safety Reporting to Regulatory Authorities 
All unexpected, serious, drug-related events which are fatal or life-threatening will be reported to 
relevant regulatory authorities in an expeditious manner.  All other unexpected, serious, 
drug-related events will be reported to relevant regulatory authorities within 15 days. 
 
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14. 
STATISTICS 
14.1. 
Statistical Methods 
A Statistical Analysis Plan (SAP) will be developed that describes in detail the statistical 
methods to be used for analysis of this study and will be finalized prior to study enrollment. 
14.2. 
General 
Binary endpoints (e.g., standing without support) will be compared between AVXS-101 and 
natural history control groups using a 2-sided Fisher’s Exact Test at level of 0.05.  A 95% exact 
unconditional confidence interval for the true population difference in response rates will be 
computed. 
Results involving continuous endpoints (e.g., change in HFMSE) will be compared between 
AVXS-101 and natural history control groups at 2-sided significance level α=0.05 using analysis 
of variance (ANOVA), or non-parametric Wilcoxon Rank Sum test, as appropriate. 
All statistical tests will be conducted at a significance level of 0.05. 
14.3. 
Analysis Populations 
14.3.1. 
Full Analysis Set 
The full analysis set consists of all patients who receive the AVXS-101 injection. 
14.3.2. 
Intent-to-Treat 
The Intent-to-Treat (ITT) Set will include all enrolled patients who receive AVXS-101 IT 
injection treatment.  Patients will be analyzed according to the assigned dose.  All efficacy 
analyses will be conducted using the ITT Set as the primary population, unless specified 
otherwise. 
14.3.3. 
Enrolled Set 
The Enrolled Set will include all patients enrolled (i.e., completed the informed consent process). 
Unless specified otherwise, this set will be used for patient listings and for summaries of patient 
disposition. 
14.3.4. 
Efficacy Completers Analysis Set 
The Efficacy Completers Analysis Set consists of all treated patients who complete 12 months 
following AVXS-101 dose procedure. 
14.3.5. 
Safety Analysis Set 
The safety analysis set consists of all patients who receive the AVXS-101 injection. 
14.4. 
Sample Size Calculation 
This is a Phase 1 trial with determination of optimal dose as primary objective, using both safety 
and efficacy measures on motor function assessments.  Secondary outcomes include the 
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achievement of milestones and change from baseline on HFMSE and fine and gross motor 
portions of the Bayley Scales of Infant and Toddler Development. 
This study is designed to assess the impact of AVXS-101 on non-ambulatory young children 
with SMA who have 3 copies of SMN2, with efficacy outcomes specifically assessing 
improvement in motor function from that expected in the natural history of non-ambulatory 
children with SMA.  Data will be compared with patient-level data drawn from a widely (peer-
reviewed) published natural history dataset collected by the Pediatric Neuromuscular Clinical 
Research (PNCR) network. 
Although patients with SMA Type 2 and 3 are easily differentiated in a retrospective manner by 
best clinical function, given the clinical overlap between the two phenotypes it is difficult at the 
time of diagnosis to predict the ultimate clinical course for a given individual patient at the time 
of initial diagnosis.  From the published literature from a large natural history study 
(Kaufman 2012), we believe that a significant majority of the patients eligible for this study will, 
in fact, have SMA Type 2.  However, it is also expected based upon this literature that a small 
percentage of children eligible for this study (3 copies of SMN2, age of symptom onset less than 
12 months, sitting but not standing or walking independently) will, in fact, be children who 
would ultimately walk independently as part of the normal course of their disease (and therefore 
would be ultimately re-classified as SMA Type 3).  The study design, statistical considerations, 
and study size are based upon this presumption. 
Patients will be stratified into 2 groups based upon age at dosing.  Between Dose A and Dose B 
15 patients will be enrolled aged ≥6 months and < 24 months at dosing, and 12 patients will be 
enrolled who are aged 24 months to < 60 months at the time of dosing.  Up to an additional 24 
patients may be enrolled and receive a higher dose (Dose C) if deemed appropriate and necessary 
by AveXis and approved by the DSMB/DMC (see Section 15). 
The primary efficacy endpoint for the group of patients ≥6 months and < 24 months of age at 
time of dosing will be the proportion of treated patients who achieve the ability to stand without 
support up to the 12-month study visit.  Twelve children aged ≥6 months and < 24 months will 
be enrolled who receive Dose B.  The proportion of patients developing the ability to stand 
without support will be compared with a cohort of eligibility-matched patients from the PNCR 
natural history study of SMA.  Based upon a review of eligibility-matched patients from the 
PNCR, 14% of patients who meet the study criteria for patients ≥6 months and < 24 months of 
age achieved the ability to stand without support, and 10% achieved the ability to walk without 
assistance.  We expect 85% of treated patients ≥6 months and < 24 months of age to achieve the 
ability to stand alone and 60% to achieve the ability to walk without support.  With this efficacy 
a sample size of 12 patients would provide power of > 90% to detect a significant difference 
compared with the matched control cohort with α = 0.05 using a two-sample 2-sided superiority 
Fisher exact test. 
The primary efficacy endpoint will be the change in HFMSE in treated patients between 
24 months and < 60 months of age at time of dosing.  Twelve children aged ≥ 24 months and 
< 60 months will be enrolled.  Change in HFMSE score at 12 months will be compared with a 
cohort of eligibility-matched patients from the PNCR natural history study of SMA.  Based upon 
a review of eligibility-matched patients from the PNCR, a mean change of -1.33 points (standard 
deviation = 4.32 points) is seen at 12 months from baseline among patients aged 2-5 years at first 
evaluation with 3 copies of SMN2 in the PNCR dataset.  We expect to observe a mean increase 
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of 8 points from baseline on the HFMSE with equivalent variance.  Based upon these 
assumptions, 12 patients between 24 and <60 months at enrollment will have >90% power to 
detect a significant difference with α = 0.05 when compared to patient-level data available from 
the PNCR dataset using two-sample ANOVA. 
14.5. 
Demographic and Other Baseline Characteristics 
Continuous demographic and other baseline characteristics (age, months since symptom onset, 
etc.) will be summarized by dosing cohort using n, mean, SD, median, minimum, and maximum.  
Qualitative characteristics (such as gender and race) will be summarized by counts and 
percentages. 
14.6. 
Efficacy Analysis 
14.6.1. 
Observation Period for Efficacy 
Efficacy comparisons will be made once all patients have either completed 15 months of follow- 
up or withdrawn prior to 15 months of follow-up. The primary analysis of efficacy data will be 
based on data collected through the 12-month time point; a supportive analysis of efficacy data 
will be based on data collected through the 15-month time point. 
14.6.2. 
Primary Efficacy Endpoints 
Primary efficacy endpoints are assessed independently for each age group. 
14.6.2.1. Primary Efficacy Endpoint: patients ≥6 months and < 24 months at time of 
dosing 
The primary efficacy endpoint is the proportion of patients ≥6 months and < 24 months at time 
of dosing that achieve the ability to stand alone, without support for at least 3 seconds (Bayley 
Scales of Infant and Toddler Motor Development – Gross Motor subset item # 40) up to the 
12-month study visit.  A Responder for the primary endpoint of standing alone will be defined as 
per the Bayley Scales of Infant and Toddler Motor Development – Gross Motor subset item #40 
– the child stands alone for at least 3 seconds after you release his or her hands. 
The proportion of patients ≥6 months and < 24 months of age at time of dosing achieving the 
ability to stand without support up to the 12-month study visit will be compared between AVXS-
101 and natural history control groups using a two-sample 2-sided superiority Fisher exact test.  
A 95% exact conditional confidence interval for the difference in response rates will be 
computed. 
The primary analyses will be based on the Full Analysis Set for patients ≥6 months and 
< 24 months of age at the time of dosing. 
A sensitivity analysis will be conducted by repeating each primary efficacy analysis on the 
Efficacy Completers Analysis Set for patients ≥ 6 months and < 24 months of age at the time of 
dosing. 
A supportive analysis will be conducted by repeating the analysis of the primary efficacy 
endpoint for patients ≥ 6 months and < 24 months of age considering data through the 15-month 
visit. 
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14.6.2.2. Primary Efficacy Endpoint: patients ≥ 24 months and < 60 months at time of 
dosing 
The primary endpoint is the change from baseline in HFMSE for patients ≥ 24 months and 
< 60 months of age at time dosing. 
The primary efficacy analysis performed amongst patients aged between 24 months and 
< 60 months of age at time of dosing will be the change from baseline in HFMSE at the 
12-month study visit using a two-sample ANOVA at significance level of 0.05 (2-sided).  A 95% 
confidence interval will be computed. 
The primary analyses will be based on the Full Analysis Set for patients ≥ 24 months of age and 
< 60 months of age at the time of dosing. 
A sensitivity analysis will be conducted by repeating each primary efficacy analysis on the 
Efficacy Completers Analysis Set for patients ≥ 24 months of age and < 60 months of age at the 
time of dosing. 
A supportive analysis will be conducted by repeating the analysis of the primary efficacy 
endpoint for patients ≥ 24 months of age and < 60 months of age considering data through the 
15-month visit. 
14.6.3. 
Secondary Efficacy Endpoint 
The secondary endpoint for both patient strata (aged ≥6 months and < 24 months at dosing, aged 
≥ 24 and < 60 months at dosing) will be the proportion achieving the ability to walk without 
assistance, defined as per the Bayley Scales of Infant and Toddler Motor Development – Gross 
Motor subset item # 43) up to the 12-month study visit.  A Responder will be defined as a patient 
demonstrating achievement of the ability to walk without assistance at any post-procedure visit 
up to Month 12. 
The proportion of patients ≥6 months and < 24 months or ≥ 24 and < 60 months at time of dosing 
who achieve the ability to walk without assistance will be compared separately between 
AVXS 101 and natural history control groups using two-sample Fisher’s 2-sided exact test.   
A 95% exact confidence interval for the differences in response rates will be computed. 
A supportive analysis will be conducted by repeating the analysis of the secondary efficacy 
endpoint considering data through the 15-month visit. 
 
 
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14.7. 
Safety Analysis 
Safety will be assessed through monitoring AE reports and concomitant medication usage, and 
by conducting physical examinations, vital sign assessments, cardiovascular evaluations, and 
laboratory evaluations (chemistry, hematology, coagulation, immunology).  Patients will be 
observed at the hospital for 48 hours post IT injection.  Patients will return for follow-up visits in 
accordance with the SoA.  Adverse events will be coded in accord with the most current version 
of the MedDRA coding dictionary. 
14.7.1. 
Primary Safety Endpoints 
14.7.1.1. Safety and Tolerability of AVXS-101 IT Administration 
The safety and tolerability of IT administration of AVXS-101 will be assessed through the 
incidence, severity, and relatedness of AEs up to the time of data lock. 
The proportion of patients with any AE, any SAE; any AE related to study product, and any 
Grade III or higher AE will be summarized overall, and by Body System and Preferred Term.  
Incidence rates will also be reported by cohort. 
14.7.1.2. Determination of Optimal Dose 
Up to 3 IT doses of AVXS-101 are examined in this dose escalation study.  The DSMB/DMC’s 
recommendation to escalate from Dose A to Dose B will be based on safety data as of the first 
quarterly DSMB/DMC meeting following enrollment of the third patient in Cohort 1.  The 
recommendation to proceed to Cohort 2 signals the DSMB/DMC’s evaluation that Dose A has 
acceptable safety. 
Similarly, at the first quarterly DSMB/DMC meeting following enrollment of the third patient in 
Cohort 2, the DSMB/DMC will again evaluate safety data.  The recommendation to expand 
Cohort 2 signals the DSMB/DMC’s evaluation that the Dose B also has acceptable safety. 
Based upon an ongoing assessment of safety and efficacy data from patients treated with Dose B, 
an option for testing of a third dose (Dose C), will be considered.  If AveXis decides to proceed 
with testing of a third dose, a meeting of the DSMB/DMC will be convened to make 
recommendations regarding dose escalation.  The DSMB/DMC’s recommendation to escalate 
from Dose B to Dose C will be based on safety and efficacy.  The recommendation to proceed to 
Cohort 3 signals the DSMB/DMC’s evaluation that Dose B has acceptable safety. 
14.7.2. 
Secondary Safety Endpoints 
14.7.2.1. Ventilatory Support 
The number of hours per day of non-invasive ventilatory support will be captured continuously 
by the device.  The n, mean, median, range of number of hours per day of non-invasive 
ventilatory support will be summarized by visit and cohort.  At each visit and within cohort, the 
daily non-invasive ventilatory support use will be summarized for AVXS- 101. 
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15. 
DATA SAFETY MONITORING BOARD/DATA MONITORING 
COMMITTEE 
The DSMB/DMC 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/DMC will be chartered to oversee the safety of patients during the 
conduct of the trial and will act in an advisory capacity to AveXis.  A detailed description of the 
DSMB/DMC, its role in this trial, and the timing of the scheduled reviews will be described in a 
DSMB/DMC Charter. 
The DSMB/DMC will routinely convene on a quarterly basis to review emerging safety data 
from the trial.  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/DMC will make a 
recommendation as to whether or not the accumulated safety data warrants a suspension or 
discontinuation of the trial, a modification to the trial, or any additional comments or 
recommendations related to safety.  The DSMB/DMC will prepare and provide minutes of their 
meetings to AveXis who will provide copies to the regulatory authorities as appropriate. 
The DSMB/DMC will also convene on an ad hoc basis within approximately 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/DMC will review the safety information and provide its 
recommendation.  Based upon the DSMB/DMC’s review, the DSMB/DMC can recommend 
continuing enrollment, halting enrollment or early termination of the trial for safety reasons. 
15.1. 
DSMB/DMC Interim Safety Review 
Up to three interim safety reviews will be conducted by the DSMB/DMC.  The first 
DSMB/DMC interim safety review will take place after three patients have been enrolled in 
Cohort 1.  The consideration for this review is terminating the study for safety.  In the absence of 
a termination recommendation, a recommendation to escalate enrollment to the higher dose is 
made. 
The second DSMB/DMC interim safety review will take place after three patients have been 
enrolled in Cohort 2 (six total enrolled).  The consideration for this review is terminating 
enrollment in Cohort 2 due to safety concerns.  In the absence of a termination recommendation, 
a recommendation to expand the current Cohort 2 is made. 
The third DSMB/DMC interim safety review may take place after three patients have been 
enrolled in Cohort 3.  The consideration for this review is terminating enrollment in Cohort 3 due 
to safety concerns.  In the absence of a termination recommendation, a recommendation to 
expand the current Cohort 3 is made. 
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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 eCRFs, and that investigational product accountability checks 
are being performed 
• Perform source data verification.  This includes a comparison of the data in the eCRFs 
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) 
• 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, Inc. and those SAEs that met criteria for reporting 
have been forwarded to the IRB. 
 
The monitor will be available between visits if the Investigator(s) or other staff need information 
or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of AveXis regulatory authorities, an IRB/IEC 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 Harmonisation (ICH), and any applicable regulatory 
requirements.  The Investigator should contact AveXis immediately if contacted by a regulatory 
agency about an inspection. 
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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 accord with institutional requirements and/or guidelines. 
16.4. 
Institutional Review Board/Independent Ethics Committee 
The Principal Investigator must obtain IRB/IEC approval for the investigation.  Initial IRB/IEC 
approval, and all materials approved by the IRB/IEC for this study including the patient / subject 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Qualified individuals designated by AveXis 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 AveXis representatives direct access to the clinical data 
and supplies, dispensing and storage areas and if requested, agrees to cooperate fully or assist the 
AveXis representative.  The Investigator and staff are responsible for being present or available 
for consultation during routinely scheduled site visits conducted by AveXis or its designees. 
Noncompliance with the protocol, ICH, GCP or local regulatory requirements by an Investigator, 
site staff, or representatives of AveXis will lead to prompt action by the AveXis 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. 
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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/IEC as appropriate.  The Investigator 
must submit written approval to AveXis before he/she can enroll any patient into the study. 
The Principal Investigator is responsible for informing the IRB/IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB/IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the 
IRB/IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB 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/IEC according to local regulations and guidelines. 
Initial IRB 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 (please see Appendix 1) and are consistent with ICH GCP, and 
applicable regulatory requirements. 
18.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient/parent(s)/legal guardian(s) 
is given full and adequate oral and written information about the nature, purpose, possible risk 
and benefit of the study.  Patients/parent(s)/legal guardian(s) must also be notified that they are 
free to discontinue from the study at any time.  The patient/parent(s)/legal guardian(s) should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The patients’ 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 patient. 
There will be three Informed Consent Forms: 
• Parent/Guardian Informed Consent Form 
• Biological Mother Baseline AAV9 Antibody Screening Informed Consent Form  
• Autopsy Informed Consent Form (optional) 
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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, urinary drugs of abuse screening, 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 his 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 (e.g., 25 years in Canada) 
included in ICH shall be followed. 
The site will maintain essential documents as required by ICH-GCP. The site must keep these 
documents available for review by AveXis, IRB/IEC, and/or regulatory bodies. 
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20. 
PUBLICATION POLICY 
The Investigator is obliged to provide AveXis with complete test results and all data derived by 
the Investigator from the study.  During the study, only AveXis 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 AveXis. 
AveXis 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 AveXis or the AveXis 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/her site. 
The Investigator will provide the AveXis 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.  AveXis shall inform the Investigator in writing of any changes or deletions in 
such presentation or publication required to protect AveXis 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 AveXis has 
notified the institution or the Investigator in writing that such proposed publication or 
presentation discloses AveXis confidential and proprietary technical information.  Further, upon 
the request of AveXis, the Investigator will delay the publication or presentation for an 
additional 90 days to permit AveXis to take necessary actions to protect its intellectual property 
interests. 
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21. 
LIST OF REFERENCES 
Afione SA, Conrad CK, Kearns WG, et al. In vivo model of adeno-associated virus vector persistence and 
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for prevention of respiratory syncytial virus infections. Committee on Infectious Diseases. Pediatrics. 
2009 Dec;124(6):1694-701. 
AVXS-101 Investigator’s Brochure, version 5 addendum 3.  08 April 2019. 
Butchbach ME, Edwards JD, Burghes AH. Abnormal motor phenotype in the SMNDelta7 mouse model 
of spinal muscular atrophy. Neurobiology of disease 2007; 27(2): 207-19. 
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. 
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 
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Dirren, E, Towne, CL, Setola, V, Redmond, DE Jr, Schneider, BL and Aebischer, P (2014). 
Intracerebroventricular injection of adeno-associated virus 6 and 9 vectors for cell type specific transgene 
expression in the spinal cord. Hum Gene Ther 25: 109–120. 
Duque, S.I. et al. A large animal model of spinal muscular atrophy and correction of phenotype. Annals of 
neurology 77, 399-414 (2015). 
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and adolescents: a prospective study. Pediatrics. 113:1588–1592. 
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muscular atrophy. Archives of neurology 2012; 69(4): 467-73. 
Favre D, Provost N, Blouin V, et al. Immediate and long-term safety of recombinant adeno-associated 
virus injection into the nonhuman primate muscle. Mol Ther. 2001; 4(6):559-566. 
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. American journal of human genetics 2002; 70(2): 358-68. 
Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ et al. Diagnosis and 
management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and 
immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018; 28(3):197-207. 
Finkel RS, McDermott MP, Kaufmann P, et al. Observational trial of spinal muscular atrophy Type I and 
implications for clinical trials. Neurol. 2014; 83(9):810-817. 
Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM et al. Rescue of the spinal muscular 
atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nature biotechnology 2010; 
28(3): 271-4. 
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Gray, SJ, Nagabhushan Kalburgi, S, McCown, TJ and Jude Samulski, R (2013). Global CNS gene 
delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-
human primates. Gene Ther 20: 450–459. 
Hall CB. Respiratory syncytial virus and parainfluenza virus. New Eng J Med, 2001;344:1917-1928. 
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30; 79(18): 1889–1897. 
Kiechl-Kohlendorfer U, Unsinn KM, Schlenck B, Trawöger R, Gassner I. 2003. Cerebrospinal fluid 
leakage after lumbar puncture in neonates: incidence and sonographic appearance. AJR Am J Roentgenol. 
181:231–234. 
Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Archives of neurology 2011; 68(8): 979-84. 
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Acad Sci USA. 1990; 87(6):2211-2215. 
Kroger A, Duchin J, Vazquez M. General Best Practice Guidelines for Immunization (ACIP). 
[www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf]. Accessed on 2018. 
Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM et al. Temporal requirement 
for high SMN expression in SMA mice. Human molecular genetics 2011; 20(18): 3578-91. 
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): 155-64. 
Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A etal. Correlation between severity & 
SMN protein level in spinal muscular atrophy. Nature genetics 1997;16(3):264-9. 
Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing 
and is responsible for spinal muscular atrophy. Proceedings of the National Academy of Sciences of the 
United States of America 1999; 96(11): 6307-11 
McCarty DM, Young Jr SM, Samulski RJ. Integration of adeno-associated virus (AAV) and recombinant 
AAV vectors. Annu Rev Genet. 2004; 38:819-845. 
Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular 
atrophy. N Engl J Med. 2017;377(18):1713-1722. 
Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. 
Lancet neurology 2012; 11(5): 443-52. 
Meyer, K. et al. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a 
dose-response study in mice and nonhuman primates. Molecular therapy: the journal of the American 
Society of Gene Therapy 23, 477-487 (2015). 
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. 
Human molecular genetics 1999; 8(7): 1177-83. 
Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to 
respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010; 
375:1545–55. 
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Narver HL, Kong L, Burnett BG, et al., 2008. Sustained improvement of spinal muscular atrophy mice 
treated with trichostatin A plus nutrition. Annuals of neurology, 64(4), pp.465-470. 
Onis, M. "WHO Child Growth Standards based on length/height, weight and age." Acta paediatrica 
95.S450 (2006): 76-85. 
Paes BA, Mitchell I, Banerji A, Lanctot KL, Langley JM. A decade of respiratory syncytial virus 
epidemiology and prophylaxis: translating evidence into everyday practice. Can Respir J, 2001;18(2): 
e10-9. 
Park GH, Kariya S, Monani UR. Spinal muscular atrophy: new and emerging insights from model mice. 
Current neurology and neuroscience reports 2010; 10(2): 108-17. 
Passini, M.A. et al. Translational fidelity of intrathecal delivery of self-complementary AAV9- survival 
motor neuron 1 for spinal muscular atrophy. Human gene therapy 25, 619-630 (2014). 
Palivizumab SmPC. www.ema.europa.eu/en/documents/product-information/synagis-epar-product-
information_en.pdf, April 6, 2019. 
Prior TW, Krainer AR, Yimin H, Swoboda KJ, Snyder PC, et al. A Positive Modifier of Spinal Muscular 
Atrophy in the SMN2 Gene. American Journal of Human Genetics 2009; 85, 408-413. 
Riessland M, Ackermann B, Forster A, Jakubik M, Hauke J, Garbes L et al. SAHA ameliorates the SMA 
phenotype in two mouse models for spinal muscular atrophy. Human molecular genetics 2010; 19(8): 
1492-506. 
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28(4):323-327 
Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM et al. Pan-ethnic carrier screening and 
prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. 
European journal of human genetics: EJHG 2012; 20(1): 27-32. 
Surosky RT, Urabe M, Godwin SG, et al. Adeno-associated virus Rep proteins target DNA sequences to a 
unique locus in the human genome. J Virol. 1997; 71(10):7951-7959. 
Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP et al. Natural history of 
denervation in SMA: relation to age, SMN2 copy number, and function. Annals of neurology 2005; 57(5): 
704-12. 
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22. 
APPENDICES 
Appendix 1  
Declaration of Helsinki Ethical Principles for Medical Research Involving 
Human Subjects  
Appendix 2  
Hammersmith Functional Motor Scale- Expanded  
Appendix 3  
Summary of Changes  
 
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APPENDIX 1. 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 subjects. 
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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 subjects.  The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, 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 subjects 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 
subjects. 
15. Appropriate compensation and treatment for subjects 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 subjects. 
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. 
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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 subjects and information regarding provisions for treating and/or 
compensating subjects 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 subjects 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 SAEs.  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 subjects and the 
confidentiality of their personal information. 
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Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects 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 subjects 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 subjects 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 subjects 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 subjects 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 
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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 participants who still need an intervention 
identified as beneficial in the trial.  This information must also be disclosed to participants 
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. 
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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. 
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APPENDIX 2. HAMMERSMITH FUNCTIONAL MOTOR SCALE- 
EXPANDED 
 
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APPENDIX 3. SUMMARY OF CHANGES 
The section below highlights content changes represented in this version of the protocol.  
Language deleted from Protocol version 7.0 appears in red strike through.  Language added to 
Protocol version 8.0 appears in bold. 
Administrative changes have been made throughout the entire protocol, including updated 
references and minor editorial edits (minor changes in formatting, spelling, punctuation, 
grammar, order of first appearance of abbreviations, etc.).  Time points for procedures within 
text of the protocol were deleted and replaced with a statement referencing Schedule of 
Assessments. 
The Amendment 7 version of the protocol (Protocol version 8.0) is updated to include more 
stringent eligibility criteria for liver function tests and additional visits for monitoring liver 
function, following the acute liver failure case reported in the US Managed Assess Program.   
General 
References updated throughout the protocol. 
General 
Minor editorial edits throughout the protocol. 
Rationale for change 
Updated references as part of administrative changes. 
 
Section 1.1. 
Approval 
This study will be conducted with the highest respect for the individual patients in 
accordance with the requirements of this clinical study protocol and in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council for Harmonisation and Harmonised Tripartite, Integrated Addendum 
to ICH E6(R1): Guideline for Good Clinical Practice E6 (R2) 
• 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): 
________________________________________________ 
__________________ 
 
Date 
Vice President of Clinical Development 
AveXis, Inc. 
 
________________________________________________ 
__________________ 
  
Date 
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Sr. Medical Director, Clinical Development 
AveXis, Inc. 
________________________________________________ 
__________________ 
 
Date 
Interim Head Senior Director of Clinical Operations 
AveXis, Inc. 
________________________________________________ 
__________________ 
 
Date 
Head of Biostatistics 
AveXis, Inc. 
________________________________________________ 
__________________ 
 
VP & Head, Global Patient Safety 
AveXis, Inc. 
 
Rationale for change: 
Updated signatures of representatives from Avexis as part of administrative changes. 
 
Section 1.4  
Key Contact Information 
Responsible Physician 
 Medical Director, Clinical Development, 
 
Serious Adverse Event 
Reporting 
 
 
Additional study contact information is provided in the Study Contact List. 
Table 1: 
Important Study Contact Information 
Role in Study 
Name/ Address and Telephone Number 
Clinical Study Leaders  
Please see INC Project Communication Plan in Trial Master File (TMF) or Study 
Contact list in the Investigator Site File (ISF) 
Responsible Physician 
Please see INC Project Communication Plan in Trial Master File (TMF) or Study 
Contact list in the Investigator Site File (ISF) 
Drug Safety Physician 
24-Hour Emergency Contact 
Please see INC Project Communication Plan in Trial Master File (TMF) or Study 
Contact list in the Investigator Site File (ISF) 
SAE Reporting 
INC 
 
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Table 2: 
Study Vendor Listing 
Role in Study 
Name/Address 
Clinical Research Organization 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
Central Laboratories 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
Video 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
IP Shipment 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
Non-invasive ventilatory support 
device 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
Independent Video Review 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
Holter Monitor 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
Autopsy 
Please see INC Project Management Plan in TMF or Study Contact list in ISF 
 
Rationale for change 
Updated key contact information and removed other specific contact information as part of 
administrative changes. 
 
Section 2 
SYNOPSIS 
Section 2 was updated as per changes throughout the document. 
 
Section 5.2. 
Rationale for Gene Transfer to SMA Type 2/3 Patients 
Table 2 Footnote 
Source: Adapted from Kolb 2011. 
SMN2 = survival motor neuron 2 gene 
bold = predominant SMN2 copy number that defines the SMA Type, the other copy numbers represent a small 
percentage of the designated SMA Type. 
Rationale for change 
Updated to include footnote specifying the most frequent presentation of the SMA copy number. 
 
Section 5.3 
Non-Clinical Studies 
Activity of the scAAV9.CB.SMN was demonstrated by the bio distribution 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 scAAV9.CB.SMN in newborn male and female mice is 
considered to be 3.3 × 1014 vg/kg. 
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Rationale for change 
Updated to remove redundancy within the protocol. 
 
Section 5.4 
Clinical Studies 
First-in-human trial AVXS-101-CL-101 is a completed 2-year trial which evaluated the 
efficacy and safety of AVXS-101 in 15 SMA Type 1 patients with 2 copies of SMN2.  All 
patients received a single IV dose of AVXS-101 in 2 cohorts (Mendell, 2017).  After the End 
of Trial visit, patients were invited to participate in a long term follow up study conducted 
under a separate protocol. 
Based on data obtained in Study AVXS 101-CL-101, the following conclusions can be made 
regarding the efficacy of AVXS-101:  AVXS-101 administration had a positive effect on 
survival.  Twenty-four months after dosing, all 15 patients were alive and free of 
permanent ventilation and all Cohort 2 patients had survived free of permanent 
ventilation, a statistically significant difference compared with the natural history rate of 
8% reported by Finkel, 2014 (Finkel et al 2014).  
Rationale for change 
Added information based on current studies  
 
Section 5.5  
Risks 
A full understanding of all risks of AVXS-101 is not known at this time.  Potential risks of 
AVXS-101 are discussed below and further details are provided in the Investigator’s 
Brochure. Please note, the risks discussed below are the result of observations with IV 
administration.  The dose for IV therapy is 1- to 3-fold higher than for the IT therapy.  
Because the IT dose is lower than the IV dose and delivered directly to the CNS, the 
systemic exposure and associated risks are expected to be less. 
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. 
Some mice affected with a form of SMA Type 1 that were treated with the study vector 
developed localized vascular necrosis around the ear called necrotic pinna.  This is believed 
to be unrelated to the vector, and likely related to an underlying defect that has been 
observed to occur in several SMA mouse models (Narver et al 2008).  The relevance to 
humans with SMA is unknown. 
Respiratory tract infections in neonates are very common in the general pediatric 
population (Paes, 2001).  In one study, an estimated 338 million new episodes of RSV-
associated acute lower respiratory infections occurred worldwide in children younger than 
5 years, with at least 34 million episodes necessitating hospital admission (Nair, 2010).  
Respiratory syncytial virus is the primary cause of hospitalization for respiratory tract 
infection in young children (Hall, 2001).  It would not be unexpected that infants enrolled 
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in the AVXS-101 gene replacement therapy trials might have similar incidences of 
respiratory infections due to these pathogens. 
Patients must be clinically stable before AVXS-101 dosing.  Clinical signs or symptoms of 
infection should not be evident at the time of AVXS-101 administration.  Vaccinations, 
including palivizumab prophylaxis that can prevent RSV infections (Palivizumab SmPC, 
April 2019), are also recommended (Finkel et al 2017) and should be up to date.  Added 
caution is advised regarding the timing of AVXS-101 administration in the presence of 
prodrome or resolving viral illness. In the event of a severe viral respiratory infection, the 
Investigator should be aware of the possibility of adrenal insufficiency in the presence of 
systemic immune response which may require longer glucocorticosteroid support at 
increasing doses to effectively manage the patient and prevent serious complications.   
Some mice affected with SMA Type 1 that were treated with AVXS-101 experienced liver 
findings comprised on hepatocellular hypertrophy, Kupffer cell activation, and scattered 
hepatocellular necrosis. 
Adverse events (AEs) of increased transaminases (ALT increased, AST increased, and 
transaminase increased) were reported as related to AVXS-101 in clinical studies.  The 
underlying cause of the transaminase elevations is not known; though, may be related to an 
immune response to AAV9, as indicated by the response to prednisolone.  Though these 
AEs can be serious, in most cases they were clinically asymptomatic, did not meet criteria 
for Hy's law, did not exhibit clinically relevant increases in bilirubin, and generally 
resolved with prednisolone treatment.  A case of acute liver failure (serious unexpected 
serious adverse reaction [SUSAR]) was reported in the US Managed Access Program with 
AVXS-101.  A 6-month-old male concurrently receiving nusinersen with elevations of AST 
and ALT of > 3 x upper limit of normal (ULN) before treatment with AVXS-101 developed 
acute liver failure approximately 51 days post AVXS-101 dosing.  The patient recovered 
with additional steroid therapy. 
Nonclinical cardiovascular toxicity findings that could potentially be relevant to the clinical 
use of AVXS-101 have been reported in 2 mouse toxicology studies of AVXS-101.  Similar 
findings were reported in both studies.  Findings in the ventricles of the heart were 
comprised of inflammation, edema and fibrosis.  Primary findings in the atrium of the 
heart were thrombosis and inflammation.  The underlying mechanism of these findings and 
the translatability of the observed findings in mice to primates are not known at this time.  
The available clinical cardiovascular safety data have not provided evidence for a 
cardiovascular safety problem in humans.  As of the last update to the Investigator’s Brochure 
(v5), there have been no cardiovascular AEs that have been judged to be related to AVXS-101 
in the clinical studies.   
A transient decrease in platelet counts has been observed in both IV and less frequently 
with IT administration. The majority of values remained above the lower limit of normal.  
Decreases were clinically asymptomatic and transient.  
This risk can be effectively managed through monitoring platelet counts for 1 month 
following dosing, and appropriate prednisolone (or an equivalent corticosteroid in 
countries where prednisolone is not available) use. 
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Preclinical data indicate that in most cases, DNA delivered by recombinant AAV vectors 
predominantly persists as extrachromosomal elements (episomes) rather than integrating 
into host cell genomes (McCarty et al 2004).  Although AVXS-101 is also not anticipated to 
integrate into the host cell genome as described above, the long-term consequences of 
administering AAV viral vectors to humans are not yet fully understood.  This is in 
contrast to wtAAV, also non-pathogenic, which has the ability to stably integrate into the 
host cell genome at a specific site (designated AAVS1) in the human chromosome 19 (Kotin 
et al 1990, Surosky et al 1997).  Since the AVXS-101 product uses AAV9 with all of the 
wtDNA removed from the capsids, except for the inverted terminal repeats (ITRs), the 
potential risk of incorporation of AVXS-101 into the patient chromosomal DNA is thought 
to be significantly reduced. 
There are conflicting reports that integration of the wtAAV2 genome is associated with 
induction of hepatocellular carcinoma in a small subset of patients; however, there are 
several studies with evidence to contradict these claims including:  a) AAV2 has infected 
approximately 90% of the human population, b) AAV2 has been shown to possess 
anticancer activity, c) epidemiological evidence suggests that AAV2 infection plays a 
protective role against cervical carcinoma, and d) AAV serotypes including recombinant 
AAV2 and AAV9 have been or are currently used in 162 clinical trials to date in which no 
cancer of any type has been observed or reported.  For a review of the topic, see Srivastava 
and Carter, 2017 (Srivastava and Carter 2017).  Further support for the extremely low 
potential incorporation into host chromosomal DNA comes from pre-clinical studies, which 
to date have not shown the development of cancer in treated animals including mice and 
non-human primates exposed to AVXS-101. 
It is possible the AAV9 vector containing the SMN gene could interact with other viruses 
with which the patients come in contact, such as rhinoviruses, adenovirus or herpes.  If this 
happens, the AAV9 vector could form a virus that causes infection if the patient and cells 
for rescue, replication, and packaging are also exposed to wtAAV2.  However, the rescue, 
replication, and packaging would stop as the helper viruses, such as rhinoviruses, 
adenovirus or herpes, were cleared by the patient’s immune system.  This unlikely scenario 
has been studied.  In cell culture, the recombinant AAV (rAAV) genome can be rescued 
and replicated by superinfection with wwtAAV and a helper virus; however, in vivo rescue 
experiments have failed to show rescue and replication (Favre et al 2001), except in one 
case in which very large doses of wtAAV and adenovirus were administered in a particular 
setting (Afione et al 1996).  Therefore, AAV9 interaction with other viruses to cause 
infection appears to be a minimal risk for AVXS-101. 
Studies have shown that some vector can be excreted from the body for up to a few weeks 
after injection/infusion; this is called “viral shedding”.  Vector shedding can be found in 
the blood, urine, saliva, and stool for up to a few weeks following injection.  The risks 
associated with the shed vector are not known at this time; however, because the vector is 
non-pathogenic and cannot replicate, it is believed that shed vector is unlikely to result in 
clinically significant adverse effects.  Regardless, instructions should be provided to patient 
families and caregivers regarding use of protective gloves if/when coming into direct 
contact with patient bodily fluids and/or waste, as well as good hand-hygiene for a 
minimum of four weeks after the injection.  Additionally, patients are prohibited from 
donating blood for two years following the vector injection. 
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Viral shedding is dependent on a variety of factors including the route of administration of 
the product, the tropism of the virus or bacteria, and the natural route of transmission and 
shedding of the parent virus or bacterium from which the product is derived.  AveXis 
collected saliva, urine, and stool samples at weekly timepoints through Day 30 and then 
monthly timepoints through Month 18 after gene transfer during the AVXS-101-CL-101 
clinical study from five patients for viral shedding analysis.  This analysis detects the 
number of genome copies by droplet digital polymerase chain reaction (ddPCR) in the 
applicable shed samples. 
After IV administration, AVXS-101 is detectable in the shed samples from Day 1 post 
injection.  All five patients analyzed were dosed with 2.0 × 1014 vg/kg.  Concentrations of 
vector shed in saliva and urine are quite low and are below the limits of quantitation by 
ddPCR in the matrices within days post dose.  Shedding of AVXS-101 was reported as a 
proportion of the initial concentration.  All five patients analyzed for viral shedding were 
dosed with the proposed therapeutic dose.  AVXS 101 was detectable in shed samples post-
infusion.  AVXS-101 concentrations in urine and saliva were 0.1% to 0.01% of initial 
concentration in the body at day 1 post infusion, after which concentrations fell below the 
limit of quantitation.  In stool, levels 10% to 30% of the initial concentration in the body 
were detectable at day 1 post-infusion.  One patient showed a peak concentration in stool at 
day 14 post infusion of 280% of initial concentration in body.  In contrast, three patients 
for whom data were available showed a concentration of <1% of initial concentration in 
body at day 14 post infusion, with concentrations declining approximately 4 logs (10,000-
fold) over 30 days post infusion.  Overall, AVXS-101 was primarily cleared from the body 
in stool and by day 60 post infusion was below the limit of quantitation in stool.  Shed AAV 
vectors have been previously shown not to be infectious in urine and saliva excreta (Favre, 
2001).  Together, these data demonstrate rapid decline of shed vector quantities well below 
initial concentrations in patients treated with AVXS-101.  Clearance of AVXS-101 is 
primarily via the feces and the majority of the dose is cleared within 30 days of dose 
administration. 
The results seen in the IV development program support further clinical investigation of 
the efficacy and safety of AVXS-101 in patients with SMA.  Based on the current available 
data, safety events that appear to be associated with AVXS-101 consist of transient liver 
enzyme elevations, which have resolved following treatment with prednisolone.   
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. 
Rationale for change 
Added section to include description of recent adverse events and to include benefit/risk 
language from the IB and the Clinical Overview and also to include information on the acute 
liver failure case reported in the US Managed Access Program. 
 
Section 7.1 
Overall Study Design 
The first cohort will enroll three (3) patients (Cohort 1) ≥6 months and < 24 months of age who 
will receive administration of 6.0 × 1013 vg of AVXS-101 (Dose A).  There will be at least a four 
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(4) week interval between the dosing of each patient within the cohort.  The investigatorsAveXis 
will confer with the Data Safety Monitoring Board (DSMB) on all Grade III or higher AEs 
within approximately 48 hours of awareness that are possibly, probably, or definitely related to 
the study agent before continuing enrollment.  Safety data will be reviewed by the DSMB during 
quarterly meetings; following enrollment of the first three patients and based upon the available 
safety data a decision will be made whether to: a) stop due to toxicity, or b) proceed to Cohort 2 
using Dose B. 
Should the determination be made to advance to Dose B, three (3) patients < 60 months of age 
will be enrolled to receive administration of 1.2 × 1014 vg of AVXS-101 (Dose B).  Again, there 
will be at least a 4-week interval between dosing of the three patients within the cohort.  Based 
on the available safety data from the three Cohort 2 patients and all of the Cohort 1 patients, the 
DSMB may decide and document during quarterly meetings that further 4-week intervals 
between patients dosing is unnecessary.  AveXis, Inc. will take this recommendation into 
consideration and will make the final determination whether to persist with 4-week intervals 
between patients dosing going forward; the decision will be communicated to sites and 
Institutional Review Board (IRBs) in a formal sponsor letter.  The investigatorsAveXis will 
confer with the DSMB on all Grade III or higher AEs within approximately 48 hours that are 
possibly, probably, or definitely related to the study agent before continuing enrollment.  Safety 
data will be reviewed by the DSMB during quarterly meetings; following enrollment of the first 
six (6) patients and based upon available safety data, a decision will be made whether to a) stop 
due to toxicity, or b) continue to enroll an additional 21 patients until twelve (12) patients 
≥6 months and < 24 months and twelve (12) patients ≥ 24 months and < 60 months have 
received Dose B. 
Based upon an ongoing assessment of safety and efficacy data from patients treated with the 
1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on 
all available data, this is judged to be necessary, three (3) patients < 60 months of age will 
receive Dose C, which will be no greater than 2.4 × 1014 vg administered IT. A meeting of the 
DSMB will be called to obtain agreement on the safety of escalating to a higher dose prior to 
proceeding.  If agreement is obtained from the DSMB, there will again be a four-week interval 
between dosing of the first three patients receiving Dose C, as in Cohorts 1 and 2.  Safety data 
will be reviewed by the DSMB during quarterly meetings; following enrollment of the first three 
(3) Dose C patients and based upon available safety data, a decision will be made whether to: a) 
stop due to toxicity, or b) continue to enroll an additional 21 patients until there are a total of 
twelve (12) patients > 6 months and < 24 months and twelve (12) patients ≥ 24 and < 60 months 
that have received Dose C. 
Selection of the appropriate dose and justification for testing Dose C will be supported by 
ongoing safety and efficacy reviews of clinical findings from the patients receiving Dose B 
(1.2 × 1014 vg).  The selected dose will be no greater thanDose C will be 2.4 × 1014 vg delivered 
IT.  Doses up to 1.1 × 1014 vg/kg have been safely administered systemically (IV) to children 
weighing up to 8.4 kg (total dose 9.24 × 1014 vg).  In addition, in preclinical studies, the IT 
administration of scAAV9.CB.SMN was safe and well tolerated up to 14 months post injection 
in large non-human primates at a dose of 2 × 1013 vg/kg (AveXis AVXS-101 Investigator’s 
Brochure, Edition 4, page 19). 
The overall study design is summarized in Figure 4. 
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Safety will be assessed through monitoring AE reports and concomitant medication usage, and 
by conducting physical examinations, vital sign assessments, cardiovascular evaluations, and 
laboratory evaluations.  Patients will be observed at the hospital for 48 hours post IT injection.  
Patients will return for follow up visits on Days 7, 14, 21, and 30.  Patients will return monthly 
thereafter, following the Day 30 visit, for 12 months from dose administrationaccording to the 
Schedule of Assessments (SoA) (Table 3). 
Patients enrolled in Cohort 1 (Dose A) and Cohort 2 (Dose B) will complete 12 months of 
follow-up post IT administration.  Patients enrolled in Cohort 3 (Dose C) will complete 15 
months of follow-up post IT administration. 
An autopsy and tissue collection process will be in place for those patients who consent to 
autopsy/tissue collection for research purposes. 
Once patient completes the study, he or she will be invited to participate in a long-term 
follow-up study examining the lasting safety of AVXS-101 up to 15 years conducted under a 
separate protocol. 
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Table 8: 
Schedule of Assessments 
Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection 
(Inpatient) 
Follow-up (Outpatient) 
Notes 
Visit # 
1 
2 
3 
4 
5 
6 
 
 
 
Monthly 
(7-16) 
Month 
12/ EOS 
(17) 
# of Days/Months 
in Study Day 
-60 to -2 
-1 
1 
2-31 
7 
14 
21 
30 374
4 
60 
517
2 
Monthly 
Through 
MonthM
114 
Month1
25/EOS 
Window 
 
 
 
 
±+/- 2 
±+/- 7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spinal X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
Medical History12 
X 
 
X 
(X) 
X 
X 
X 
X 
 
X 
 
X 
X 
Medical history collected at baseline; review 
of systems conducted at each study visit. 
(X): Patients to remain inpatient 48 hours 
post-dose for observation and AE  
monitoring. 
Physical Exam20 
(X)
3 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Includes measuring head circumference. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Vitals/Weight/ 
Length/Height4 
(X)
3 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Vital signs will include BP, respiratory rate, 
pulse, and axillary temperature.  Vitals 
including BP, respiratory rate, pulse axillary 
temperature, pulse oximetry and HR will be 
monitored and recorded every 15 minutes (± 
5 minutes) from dosing for four hours and 
every hour (± 15 minutes) for 24 hours 
following the AVXS-101 dosing procedure. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Pulse Oximetry 
(X)
3 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Pulmonary Exam 
(X)
3 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection 
(Inpatient) 
Follow-up (Outpatient) 
Notes 
Visit # 
1 
2 
3 
4 
5 
6 
 
 
 
Monthly 
(7-16) 
Month 
12/ EOS 
(17) 
# of Days/Months 
in Study Day 
-60 to -2 
-1 
1 
2-31 
7 
14 
21 
30 374
4 
60 
517
2 
Monthly 
Through 
MonthM
114 
Month1
25/EOS 
Window 
 
 
 
 
±+/- 2 
±+/- 7 
12-Lead ECG18 
X 
 
X 
X 
 
 
 
 
 
 
 
(X)
2 
X 
Irrespective of study schedule, after signing 
the updated informed consent, all patients 
enrolled prior to the Amendment 5 version of 
the protocol should have ECG, 24-hour 
Holter monitoring, and echocardiogram done 
at the next scheduled visit and then in 
conformity with the study schedule of 
assessmentsSoA. 
(X):  Months 3, 6, and 9 visits. 
12-Lead Holter 
Monitor5 
X 
X 
X 
X 
 
 
 
X 
 
(X) 
 
(X)17 
X 
ECGs extracted from Holter by central 
reader in triplicate at the following time 
points: pre-dose, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 
and 48h during the patient’s inpatient stay. 
(X):  Months 2, 3, 6, 9 visits. 
Echocardiogram18 
X 
 
 
 
 
 
 
 
 
 
 
(X)
2 
X 
Irrespective of study schedule, after signing 
the updated informed consent, all patients 
enrolled prior to the Amendment 5 version of 
the protocol should have echocardiogram 
done at the next scheduled visit and then in 
conformity with the study schedule of 
assessmentsSoA. 
(X):  Months 3, 6, and 9 visits. 
Capillary Blood 
Gas 
 
X 
 
(X)15 
 
 
 
 
 
 
 
 
 
(X):  Laboratory samples collected on Day 2. 
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Page 101 of 124 
Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection 
(Inpatient) 
Follow-up (Outpatient) 
Notes 
Visit # 
1 
2 
3 
4 
5 
6 
 
 
 
Monthly 
(7-16) 
Month 
12/ EOS 
(17) 
# of Days/Months 
in Study Day 
-60 to -2 
-1 
1 
2-31 
7 
14 
21 
30 374
4 
60 
517
2 
Monthly 
Through 
MonthM
114 
Month1
25/EOS 
Window 
 
 
 
 
±+/- 2 
±+/- 7 
HFMS- Expanded10  
(with video) 
(X)
3 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Will be conducted for patients ≥ 24 months of 
age; patients < 24 months of age at study 
entry will begin HFMS-E at such time that 
24 months of age is reached. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Bayley III (with 
video)6 
(X)
3 
 
 
 
 
 
 
X 
 
X 
 
X
6 
X 
Gross and fine motor sections will be 
performed at screening and monthly through 
15 months. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Motor Milestone 
Development 
Survey  
(with video) 
(X)
3 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Hematology / 
Chemistry 
(X)
3 
(X)*
11 
 
(X)$15 
X 
X 
X 
X 
(X)
† 
X 
(X)
† 
X 
X 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
(X)*:  Laboratory samples collected prior to 
dosing are to be processed locally. 
(X)$:  Laboratory samples collected on Day 2. 
(X)†  Liver function test (AST, ALT, total 
bilirubin, alkaline phosphatase, GGT) only. 
Coagulation 
(X)3 
(X)*
11 
 
(X)$15 
X 
X 
X 
X 
 
X 
 
X 
X 
Urinalysis 
(X)
3 
(X)*
11 
 
(X)$15 
X 
X 
X 
X 
 
X 
 
X 
X 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection 
(Inpatient) 
Follow-up (Outpatient) 
Notes 
Visit # 
1 
2 
3 
4 
5 
6 
 
 
 
Monthly 
(7-16) 
Month 
12/ EOS 
(17) 
# of Days/Months 
in Study Day 
-60 to -2 
-1 
1 
2-31 
7 
14 
21 
30 374
4 
60 
517
2 
Monthly 
Through 
MonthM
114 
Month1
25/EOS 
Window 
 
 
 
 
±+/- 2 
±+/- 7 
CK-MB19 
X 
 
 
 
X 
 
 
X 
 
X 
 
(X)16 
X 
Troponin I will be measured instead of 
CK-MB in new patients who are screened 
and enrolled after amendment 5 (protocol 
version 6.0) goes into effect.  Participants who 
have been screened and enrolled but who 
have not yet received gene replacement 
therapy (visit #2) at the time that amendment 
5 (protocol version 6.0) goes into effect will 
have baseline troponin I testing prior to 
treatment with AVXS-101, and will have 
troponin I testing in place of CK-MB.  CK-
MB will be collected from all other 
participants. 
(X):  Months 2, 6, and 9 visits. 
Troponin I19 
X 
 
 
 
X 
 
 
X 
 
X 
 
(X)16 
X 
Coagulation 
X3 
X11 
 
X15 
X 
X 
X 
X 
 
 
 
X 
X 
 
Urinalysis 
X
3 
X11 
 
X15 
X 
X 
X 
X 
 
 
 
X 
X 
 
Virus Serology 
(X)
3 
 
 
 
 
 
 
 
 
 
 
 
 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
Blood for 
diagnostic 
confirmation 
testing7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
To be performed by central laboratory. 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection 
(Inpatient) 
Follow-up (Outpatient) 
Notes 
Visit # 
1 
2 
3 
4 
5 
6 
 
 
 
Monthly 
(7-16) 
Month 
12/ EOS 
(17) 
# of Days/Months 
in Study Day 
-60 to -2 
-1 
1 
2-31 
7 
14 
21 
30 374
4 
60 
517
2 
Monthly 
Through 
MonthM
114 
Month1
25/EOS 
Window 
 
 
 
 
±+/- 2 
±+/- 7 
Saliva, Urine, and 
Stool Samples (for 
viral shedding) 
 
X 
 
(X)13 
(X)13 (X)
13 
 
(X
)13 
 
 
 
 
 
(X):  Sites participating in the viral shedding 
sub-study will collect 24-hour full volume 
samples for urine and feces through 24 and 
48 hours.  All other sites will collect singular 
urine and feces samples within 24 hours and 
48 hours of dosing.  Full urine and feces 
samples will be collected for patients 
≥ 48 months who are no longer in diapers. 
Baseline Screening 
of Biological 
Mother (Anti-
AAV9 Ab)8 
(X)
3 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sample collected at screening for anti-
AAV9 antibodies. 
(X):  Baseline procedure must be completed 
within 30 days of dosing. 
(X)*:  Additional sampling may be performed 
at subsequent time points if ELISpot value(s) 
continue to be elevated, based on further 
discussion with the Principal InvestigatorPI 
and Medical Monitor. 
Immunology Labs  
(Anti-AAV9/SMN)8 
(X)
3 
 
 
 
X 
X 
X 
(X
)14 
 
 
 
 
 
Immunology Labs  
(IFN-y T-cells) 
 
 
 
 
X 
X 
X 
(X
)14 
 
 
 
 
 
(X):  Additional sampling may be performed 
at subsequent time points if ELISpot value(s) 
continue to be elevated, based on further 
discussion with the Principal InvestigatorPI 
and Medical Monitor. 
Prophylactic 
Prednisolone 
dosing9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dosing through Day 30, then follow taper 
scheduleSee Section 9.2.1.  Daily dosing from 
24 hours prior to scheduled AVXS-101 dose 
and continued as per protocol. 
Study Product 
Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
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Study Interval 
Baseline 
Screening 
Vector (AVXS-101) 
Injection 
(Inpatient) 
Follow-up (Outpatient) 
Notes 
Visit # 
1 
2 
3 
4 
5 
6 
 
 
 
Monthly 
(7-16) 
Month 
12/ EOS 
(17) 
# of Days/Months 
in Study Day 
-60 to -2 
-1 
1 
2-31 
7 
14 
21 
30 374
4 
60 
517
2 
Monthly 
Through 
MonthM
114 
Month1
25/EOS 
Window 
 
 
 
 
±+/- 2 
±+/- 7 
Photograph 
Injection Site 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and 
Concomitant 
Medications 
To be collected from 2 weeks before study dosing until final study visit 
 
AE = adverse event, ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK-MB = Creatinine kinase-MB (isozyme MB); 
ECG = electrocardiogram; ELISpot = Enzyme-linked ImmunoSpot; GGT = gamma glutamyl transferase; IFN-γ = interferon gamma; PI = Principal 
Investigator;SoA = Schedule of Assessments;  
1 
Patients to remain inpatient 48 hours post-dose for observation and AE  monitoring. 
2 
To be performed at the Month 3, 6, and 9 visits. 
3 
Baseline procedure must be completed within 30 days of dosing. 
4 
Vital signs will include blood pressure, respiratory rate, pulse, and axillary temperature.  Vitals including blood pressure, respiratory rate, pulse axillary temperature, pulse 
oximetry and heart rate will be monitored and recorded every 15 minutes (+/- 5 minutes) for four hours and every hour (+/- 15 minutes) for 24 hours following the AVXS-
101 dosing procedure. 
5 
ECGs extracted from Holter by central reader in triplicate at the following time points: pre-dose, 2h, 4h, 6h, 8h, 12h, 24h, 36h, and 48h during the patient’s inpatient stay. 
6 
Bayley III gross and fine motor sections will be performed at screening and monthly through 12 months. 
7 
To be performed by central laboratory. 
8 
Serum sample collected at screening for anti-AAV9 antibodies. 
9 
Prednisolone dosing through Day 30, then follow taper schedule. 
10 Hammersmith Functional Motor Scale- Expanded will be conducted for patients ≥ 24 months of age; patients < 24 months of age at study entry will begin HFMS-E at such 
time that 24 months of age is reached. 
11 Laboratory samples collected prior to dosing are to be processed locally. 
12 Medical history collected at baseline; review of systems conducted at each study visit. 
13 Sites participating in the viral shedding sub-study will collect 24-hour full volume samples for urine and feces through 24 and 48 hours.  All other sites will collect singular 
urine and feces samples within 24 hours and 48 hours of dosing.  Full urine and feces samples will be collected for patients ≥48 months who are no longer in diapers. 
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14 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. 
15 Laboratory samples collected on Day 2. 
16 CK-MB or Troponin I sample will be collected at the following visits: Month 2 (Day 60), 6, 9. 
17 Months 2, 3, 6, 9. 
18 Irrespective of study schedule, after signing the updated informed consent, all patients enrolled prior to the Amendment 5 version of the protocol should have ECG, 
24-hour Holter monitoring, and echocardiogram done at the next scheduled visit and then in conformity with the study schedule of assessments. 
19 Troponin I will be measured instead of CK-MB in new patients who are screened and enrolled after amendment 5 (protocol version 6.0) goes into effect.  Participants who 
have been screened and enrolled but who have not yet received gene replacement therapy (visit #2) at the time that amendment 5 (protocol version 6.0) goes into effect will 
have baseline troponin I testing prior to treatment with AVXS-101, and will have troponin I testing in place of CK-MB.  CK-MB will be collected from all other 
participants.  
20 Includes measuring head circumference. 
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Rationale for change 
Reorganized section to include Study Design figure and SoA table in Section 7.1. 
Updated study design to include follow-up for 15 months.  Updated schedule of assessments to 
include Day 44 and Day 72 visits, and to clarify timing of visits.  Footnotes moved to comments 
column for better readability.  Updated to provide additional clarification on the dose level of 
dose C and the timing of the long-term follow-up study and the DSMB scheduling. 
 
Section 7.2 - Section 7.5  
Moved sections below Figure 4, Study Design and Table 3, Schedule of Assessments 
Rationale for change 
Moved sections to more appropriate location. 
 
Section 8.1 
Patient Inclusion Criteria 
6. Be up-to-date on childhood vaccines.  Seasonal vaccinations that include palivizumab 
prophylaxis (also known as Synagis) to prevent RSV infections in accordance with the 
recommendations of the American Academy of Pediatrics (AAP 2009) 
Rationale for change 
Updated to clarify the wording on patient age range and vaccinations. 
Section 8.2 
Patient Exclusion Criteria 
19. Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total 
bilirubin > 2 × ULN, 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.  
Patients with an elevated bilirubin level that is unequivocally the result of neonatal 
jaundice shall not be excluded.Abnormal laboratory values considered to be clinically 
significant (INR > 1.4), GGT > 3X ULN, Bilirubin ≥ 3.0 mg/dL, Creatinine ≥ 1.0 mg/dL, 
Hgb <8 or >18 g/Dl; WBC > 20,000 per cmm) prior to study dosing 
Rationale for change 
Updated text to include more stringent liver function tests further to the recommendations 
following the acute liver failure case reported in the US Managed Assess Program. 
 
Section 8.3 
Patient Withdrawal Criteria and Discontinuation 
Patients may be discontinued from the study for the following reasons: 
• Development of unacceptable toxicity, defined as the occurrence of any unanticipated 
CTCAE Grade 3 or higher Adverse Event/toxicity that is possibly, probably, or definitely 
related to the gene replacement therapy, and is associated with clinical symptoms and/or 
requires medical treatment 
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Patients meeting the following criteria will be withdrawn: 
• Death 
− Autopsies will be requested of any patients, with the exception of untreated patients, 
that expire following participation in a gene transfer study; 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. Patients who terminate the study early for 
reasons other than death will be offered enrollment in a long-term follow-up study. 
Rationale for change 
Updated patient withdrawal and discontinuation criteria and clarified that patients will be offered 
to continue on the long-term follow-up study. 
 
Section 9.1  
Description of Study Product 
Table 4 
Investigational Product 
 
Investigational Product 
Product Name 
AVXS-101 
Unit Dose 
6.0 × 1013 vg (Dose A)  
1.2 × 1014 vg (Dose B)  
No more than 2.4 × 1014 vg (Dose C) 
Route of Administration 
Intrathecal Injection 
Physical Description 
Once thawed, AVXS-101 is a clear to slightly opaque, colorless to faint 
white solution, free of visible particulates 
Rationale for change 
Updated to provide additional clarification on the dose level of Dose C. 
 
Section 9.2.1 Prophylactic Administration of Prednisolone 
In an attempt to dampen the host immune response to the AAV based therapy, patients will 
receive prophylactic prednisolone (glucocorticoid) (approximately 1 mg/kg/day) 24 hours prior 
to AVXS-101 dosing.  Treatment will continue for approximately 30 days in accord with the 
following treatment guideline: 
• Until at least 30 days post-infusioninjection: 1 mg/kg/day 
• Weeks 5 and 6 post-injection: 0.5 mg/kg/day 
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• Weeks 7 and 8 post-injection: 0.25 mg/kg/day 
• Week 9 post-injection prednisolone discontinued 
Liver function testing should guide each step of the taper, and liver function tests should be 
checked prior to prednisolone discontinuation.  If the GGT, AST, or ALT values are ≥ 2 × 
ULN, then the present dose of prednisolone will be adjusted as needed until the GGT, AST, 
and ALT values decrease below threshold, at which point the taper may continue.  Liver 
function tests should also be checked approximately 2 weeks after the taper has concluded 
and prednisolone has been discontinued to evaluate for rebound elevation of GGT, AST, or 
ALT levels.  Variance from these recommendations will be at the discretion of the 
Investigator based on potential safety issues for each patient.  If another glucocorticoid is 
used in place of prednisolone by the Investigator, similar considerations should be taken 
into account after 30 days and tapered as appropriate and at the discretion of the 
Investigator.If the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values 
are > 2 X upper limit of normal (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. 
Rationale for change 
Updated further to the recommendations following the acute liver failure case reported in the US 
Managed Assess Program and to clarify the wording 
 
Section 9.2.3 Vaccinations 
Where feasible, the vaccination schedule should be adjusted appropriately to accommodate 
prednisolone use.  When avoiding vaccination while on steroids represents an undue delay 
or interruption of a vaccination schedule, vaccination should continue at the discretion and 
judgment of the treating physician given 1) the importance of maintaining childhood 
vaccination in this population and 2) the published literature that indicates that 
vaccination while on steroid doses 1 mg/kg/day or below is safe and effective [Mendell, 
2017; Kroger, 2018]. 
Rationale for change 
Added section to include guidance on vaccinations. 
 
Section 10 
Study Product Materials and Management 
AVXS-101 was manufactured in accordance with current Good Manufacturing Practice (cGMP).  
Investigational product accountability logs will be maintained by the clinical pharmacy. 
Rationale for change 
Deleted sentence for accuracy. 
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Section 10.4  Study Product Storage and Destruction 
Rationale for change 
Administrative update to section heading. 
 
Section 10.6 Study Product Administration 
Patients will receive AVXS-101 IT injection under sterile conditions in a PICU patient room or 
other appropriate setting (e.g., interventional suite, operating room, dedicated procedure room) 
with immediate access to acute critical care management.  After pPatients are admitted, and 
vitals will be monitored immediately after dosing and every 15 (± 5) minutes from dosing for 
four hours and every hour (± 15 minutes) for 24 hours following the AVXS-101 dosing 
procedure. 
Rationale for change 
Updated text to clarify timing of vital sign monitoring. 
 
Section 10.6.1 
Post-Administration Procedures 
Patients will be kept in the PICU patient room or other appropriate setting (e.g., interventional 
suite, operating room, dedicated procedure room) with immediate access to acute critical care 
management for 48 hours for closer monitoring of mental status.  During the inpatient stay, 
personnel are required to follow appropriate safety precautions as per institutional standards for 
infection control; standards should require personal protective equipment (PPE) such as gowns, 
gloves, masks, glasses, and closed-toe shoes.  Patients’ families will be provided standardized, 
IRB-approved handouts regarding monitoring for mental status changes which includes 
monitoring for severe headache, fever, irritability, neck pain or stiffness, light sensitivity, and 
vomiting, and lethargy (tiredness).  Patients may be discharged from the hospital when the 
following criteria are met: 
Rationale for change 
Updated text to match the symptoms listed in the patient-facing letter. 
 
Section 10.7 Dose Escalation 
The investigatorsAveXis will confer with the DSMB/DMC on all Grade III or higher AEs within 
approximately 48 hours of awareness that are possibly, probably, or definitely related to the 
study agent before continuing enrollment.  Safety data will be reviewed by the DSMB/DMC 
during quarterly meetings; following enrollment of the first three (3) patients ≥6 months and 
< 24 months of age at the time of dosing and based upon the available safety data a decision will 
be made whether to: a) stop due to toxicity, or b) proceed to Cohort 2 using Dose B. 
Should the determination be made to advance to Cohort 2 (Dose B), again there will be at least a 
4-week interval between dosing of the first three (3) patients < 60 months of age at the time of 
dosing within the cohort.  Based on the available safety data from the first three (3) Cohort 2 
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patients and all of the Cohort 1 patients, the DSMB/DMC may decide and document during 
quarterly meetings that further 4-week intervals between patients dosing is unnecessary.  
AveXis, Inc. will take this recommendation into consideration and will make the final 
determination whether to persist with 4-week intervals between patients dosing going forward.  
The decision will be communicated to sites and IRBs in a formal sponsor letter.  The 
investigatorsAveXis will confer with the DSMB/DMC on all Grade III or higher AEs within 
approximately 48 hours that are possibly, probably, or definitely related to the study agent 
before continuing enrollment.  Safety data will be reviewed by the DSMB/DMC during quarterly 
meetings; following enrollment of the first six (6) patients and based upon available safety data a 
decision will be made whether to a) stop due to toxicity or b) continue to enroll an additional 21 
patients until twelve (12) patients ≥6 months and < 24 months of age at time of dosing and 
twelve (12) patients > 24 < 60 months of age at time of dosing have received Dose B. 
Based upon an ongoing assessment of safety and efficacy data from patients treated with the 
1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on 
all available data, this is judged to be safe and necessary, three (3) patients < 60 months of age 
will receive Dose C which will be no greater than 2.4 × 1014 vg administered IT.  A meeting of 
the DSMB/DMC will be called to obtain a recommendation on the safety of escalating to a 
higher dose prior to proceeding.  If a decision is made to proceed to testing a higher dose, there 
will again be a four-week interval between dosing of the first three patients receiving Dose C, as 
in Cohorts 1 and 2.  Safety data will be reviewed by the DSMB/DMC during quarterly meetings.  
Following enrollment of the first three (3) Dose C patients and based upon available safety data, 
the DSMB/DMC will be consulted and a decision will be made whether to: a) stop dosing Dose 
C due to safety concern, or b) continue to enroll an additional 21 patients until there are a total of 
twelve (12) patients ≥6 months and < 24 months and twelve (12) patients ≥ 24 and < 60 months 
that have received Dose C. 
Rationale for change 
Updated text to clarify the DSMB/DMC meeting and timing, and the dose level of Dose C. 
 
Section 11.1 Physical TherapyPhysical Clinic Assessments 
Rationale for change 
Section title changed for accuracy. 
 
Section 11.1.1 
Hammersmith Functional Motor Scale-Expanded 
The HFMSE will be administered by a qualified physical therapistclinical evaluator (e.g., 
licensed physical or occupational therapist, or national equivalent) in accordance with Table 3 
within 30 days of dosing and monthly through twelve (12) fifteen (15) months for all patients 
≥ 24 months of age.  Patients < 24 months of age at time of dosing will begin having 
Hammersmith Fuctional Motor Scale ExpandedHFMSE assessments at such time that 
24 months of age is reached. 
Rationale for change 
Updated to clarify the roles of the assessors. 
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Section 11.1.2 
Bayley Scales of Infant and Toddler Development 
Bayley Scales of Infant and Toddler Development ©version 3 is a standardized, norm-referenced 
infant assessment and will be administered by a qualified clinical evaluator (e.g., licensed 
physical or occupational therapist, or national equivalent).  The gross and fine motor subtests 
will be completed within 30 days before dosing at baseline in accordance with Table 3 and then 
monthly through Month 12.  See AVXS-101-CL-102 Physical Assessments Therapy Manual. 
Rationale for change 
Updated to clarify the roles of the assessors. 
 
Section 11.2 
Motor Milestone Development Survey 
The achievement of significant motor milestones will be assessed by the qualified physical 
therapistclinical evaluator (e.g., licensed physical or occupational therapist, or national 
equivalent) using a standard Motor Milestone Development Survey shown in Table 5 with 
definitions of each milestone driven by the Bayley Scales of Infant and Toddler Development 
(see AVXS-101-CL-102 Physical Therapy Assessments Manual).  The physical therapistclinical 
evaluator will record whether the patient has attained each of the milestones on the Motor 
Milestone Development Survey in accordance with Table 3.  Once observed, a motor milestone 
is considered attained.  The date of attainment of each motor milestone will be determined by the 
date of the visit in which the milestone is observed. 
During the screening visit, the physical therapistclinical evaluator will complete an assessment 
of baseline milestone achievement in accordance with Table 3; this assessment must be recorded 
on video and the findings must be documented in the source. 
As the Bayley Scales do not necessarily require the child to repeat previously attained 
milestones, it is essential that each milestone be captured on video.  Development milestone 
assessment sessions will be videotaped in accord with the AVXS-101-CL-102 Videotaping 
Manual. 
Rationale for change 
Updated to clarify the roles of the assessors. 
 
Section 11.3 Video Evidence 
Physical therapy Clinical assessments required at each study visit will be videotaped in an effort 
to produce compelling, demonstrable, documented evidence of efficacy, as determined by 
changes in functional abilities.  Parent(s)/legal guardian(s) may also share home videos 
demonstrating achievement of functional abilities with the study site.  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 
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and/or the medical community and/or in appropriate venues to discuss the results of this 
clinical trial. 
Videos will be provided to an independent, centralized reviewer for unbiased assessment of 
milestone achievement.  The independent central reviewer will use the Motor Milestone 
Development Survey to document whether the video displays evidence of having achieved each 
motor developmental milestone.  The date of motor milestone achievement will be computed as 
the earliest date on which video evidence demonstrates the achievement of the video dates in 
which achievement of thespecified developmental milestonehas been demonstrated. 
Additionally, the parent(s)/legal guardian(s) may submit additional videos demonstrating 
achievement of developmental milestones at any time during the trial. These videos will be 
handled in the same manner in which the trial-derived videos are handled. 
Rationale for change 
Updated to clarify the roles and responsibilities of the assessors. 
 
Section 12.3 Vital Signs 
Paragraph 3 
At Visit 2After patients are admitted, vitals including blood pressure, respiratory rate, pulse 
axillary temperature, pulse oximetry and heart rate will be monitored and recorded every 15 
minutes (± 5 minutes) after dosing for four hours and every hour (± 15 minutes) for 24 hours 
following the AVXS-101 dosing procedure. 
Rationale for change 
Updated text to clarify timing of vital signs assessments. 
 
Section 12.6 Vaccine Recommendations 
Patients are encouraged to follow all routinely scheduled immunizations as recommended by the 
Center for Disease Control (CDC).  Seasonal vaccinations that includeincluding palivizumab 
prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are 
also recommended in accordance with the recommendations of the American Academy of 
Pediatrics (AAP 2009). 
Rationale for change 
Added section to include requirement for vaccination per palivizumab prophylaxis  
 
Section 12.7  Electrocardiogram (ECG) 
A 12-lead ECG will be performed at screening/baseline, Day 1, Day 2, Day 3, Month 3, 
Month 6, Month 9, and Month 12as specified in the SoA (or Early Termination) (Table 3).  For 
patients enrolled in the study prior to Amendment 5 and irrespective of 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 AssessmentsSoA (Table 3).   
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The ECG will be interpreted locally by a cardiologist or designee for immediate safety 
evaluation.  The ECG tracings or ECG machine data will also be collected for centralized 
review and interpretation by a cardiologist. 
A 12-Lead ECG will be performed (concurrent with Holter Monitor) on the day of gene delivery 
and on Day 2 and Day 3 post-gene deliveryas specified in the SoA (Table 3).  Additional 
electrophysiological monitoring will be at the discretion of the investigator as per local 
institutional guidelines. 
Rationale for change 
Updated to clarify timing and interpretation of the assessment and deleted text to reduce 
redundancy within the protocol. 
 
Section 12.8  12-Lead Holter Monitor 
Twenty-four-hour Holter monitoring will also be performed at screening and Months 1, 2, 3, 6, 9 
and 12 visits (or Early Termination).as specified in the SoA (Table 3).  For patients enrolled in 
the study prior to Amendment 5 and irrespective of study schedule, after signing an updated 
informed consent, patients should have a 24-hour Holter monitor at their next scheduled visit and 
then in conformity with the schedule of assessmentsSoA. 
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.  AveXisThe sponsor physician will be notified of any safety concerns from the 
centralized review and the safety management plan followed for documenting and reporting of 
AE/Serious Adverse Events (SAEs). 
Rationale for change 
Updated to reduce redundancy within the protocol and to clarify who will be notified with safety 
concerns. 
 
Section 12.9 Echocardiogram 
An echocardiogram will be performed at screening/baseline, and at the Month 3, Month 6, 
Month 9, and Month 12 Visitsas specified in the SoA (or Early Termination) (Table 3).  For 
patients enrolled in the study prior to Amendment 5 and irrespective of study schedule, after 
signing an updated informed consent, all patients should have a transthoracic echocardiogram at 
their next scheduled visit and then in conformity with the SoA (Table 3.). 
The echocardiogram will be interpreted locally by a cardiologist or designee for immediate 
safety evaluation.  The echocardiograms will also be collected for centralized review and 
interpretation by a cardiologist. 
Rationale for change 
Updated to clarify timing and process of interpretation of the assessment and deleted text to 
reduce redundancy within the protocol. 
 
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Section 12.11 Pulmonary Exam 
Pulmonary examinations will be performed by a pulmonologist (or appropriate individual 
as per standard institutional practice)Patients will be assessed by a pulmonologist at the time 
points specified in Table 3. Prior to trial entry, a pulmonologist (or appropriate individual as 
per standard institutional practice) will review and document ventilator usage in the 2 
weeks prior to screening. and  
Patients may be fitted with a non-invasive positive pressure ventilator (e.g., BiPAP) at the 
discretion of the pulmonologist and/or investigator.  Non-invasive ventilatory support equipment 
will be provided by AveXis, Inc. through a third-party vendor if not covered by the patient’s 
insurance. 
Should the patient require non-invasive ventilator support at any time during the trial, the 
equipment to be provided must be approved by AveXis in order to ensure ability to upload 
usage data. 
Patients requiring non-invasive ventilatory support will be asked to bring the machine to each 
study visit such that the study staff can remove an SD cardstorage device which records 
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.This usage data will be transferred to the 
clinical database. 
Patients requiring non-invasive ventilatory support will be asked to remove the SD card and ship 
it to the study site in instances of missed study visits. 
Rationale for change 
Updated with administrative changes and to clarify the roles of the assessors and to clarify 
procedures. 
 
Section 12.13 Photographs of Injection Site 
Photographs will be taken of the injection site through Day 30 at the time points specified in 
Table 3 to monitor healing of the injection wound.  Day 1 injection site photograph will be 
performed prior to the start of gene replacement therapy injection.  AveXis, Inc. 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, Inc. requirements.  Any/all photographs received at AveXis, Inc. or 
the contracted vendor will be treated as confidential study data and will be the sole property of 
AveXis, Inc.  AveXis, Inc. 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, and/or the medical community, and/or in 
appropriate venues to discuss the results of this clinical trial. 
Rationale for change 
Updated with administrative changes to reflect the timing of the assessment and deleted text to 
reduce redundancy within the protocol. 
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Section 12.14 Laboratory Assessments 
Table 7 
Total Blood Volume 
Visit 
Tests1, 3 
Total Volume (mL)2 
Screening 
Hematology, chemistry/CK-MB or Troponin I, coagulation, 
virus serology, immunology sample (AAV9/SMN Ab only),  
diagnostic confirmation sample 
19.3-19.6 mL 
Day -1 
Hematology, chemistry, coagulation, capillary blood gas 
6.0 mL 
Day 2 
Hematology, chemistry, coagulation, capillary blood gas 
6.0 mL 
Day 7 
Hematology, chemistry/CK-MB or Troponin I, coagulation, 
immunology sample 
10.0-12.31 mL 
Day 14 
Hematology, chemistry, coagulation immunology sample 
9.0-11.01 mL 
Day 21 
Hematology, chemistry, coagulation immunology sample 
9.0-11.01 mL 
Day 30 
Hematology, chemistry/CK-MB or Troponin I, coagulation, 
immunology sample 
11.0-12.31 mL 
Day 44 
Hematology, chemistryChemistry 
1.3 
Day 60 
Hematology, chemistry/CK-MB or Troponin I, coagulation 
6.0-6.3 
Day 72 
Hematology, chemistryChemistry 
1.3 
Month 2 
Hematology, chemistry/CK-MB3 or Troponin I, coagulation 
6.0-6.3 mL 
Month 3 
Hematology, chemistry, coagulation 
5. mL 
Month 4 
Hematology, chemistry, coagulation 
5 mL 
Month 5 
Hematology, chemistry, coagulation 
5 mL 
Month 6 
Hematology, chemistry/CK-MB3 or Troponin I, coagulation 
6.0-6.3 mL 
Month 7 
Hematology, chemistry, coagulation 
5 mL 
Month 8 
Hematology, chemistry, coagulation 
5 mL 
Month 9 
Hematology, chemistry/CK-MB3 or Troponin I, coagulation 
6.0-6.3 mL 
Month 10 
Hematology, chemistry, coagulation 
5 mL 
Month 11 
Hematology, chemistry, coagulation 
5 mL 
Month 12 
Hematology, chemistry/CK-MB or Troponin I, coagulation 
6.0-6.35 
Last Study Visit 
(Month 152)4 
Hematology, chemistry/CK-MB3 or Troponin I, coagulation 
6.0-6.3 mL 
Total Volume for Study 1-Year Duration 
137.95-147.337.1 mL2 
Immunology = Serum antibody to AAV9 and SMN, IFN-γ ELISpot to detect T-cell responses to AAV9 and SMN 
1 Immunology sample requires 4-6 mL of whole blood 
2 Maximum total blood volume specified for each visit; in cases where tests can be combined, lower blood volumes may be 
sufficient.  Positive serology samples at screening and elevated T-cell responses at Day 30 may require additional surveillance 
samples not reflected in the table. 
3 Troponin I will be measured instead of CK-MB in new patients who are screened and enrolled after amendment 5 (protocol 
version 6.0) goes into effect.  Participants who have been screened and enrolled but who have not yet received gene 
replacement therapy (visit #2) at the time that amendment 5 (protocol version 6.0) goes into effect will have baseline troponin I 
testing prior to treatment with AVXS-101, and will have troponin I testing in place of CK-MB.  CK-MB will be collected from 
all other participants. 
4 Only patients enrolled in Cohort 3 will have a month 15 visit.  Patients enrolled in Cohorts 1 and 2 will 
complete the study or have EOS visit at Month 12 
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Rationale for change 
Updated blood volume required for additional visits (Day 44, Day 72, Month 15) added for liver 
function tests and additional follow-up visits. 
 
Section 12.14 Laboratory Assessments 
If there is not sufficient blood volume to include the genetic reconfirmation testing sample at the 
screening visit, the patient must return before Visit 2.the inpatient period.  All patients must 
have genetic reconfirmation testing completed. 
Rationale 
Visits are no longer numbered. Updated for SoA clarity. 
 
Section 12.14.1 
Hematology 
Hematology analysis will include a CBC with differential and platelet count with smear.  
Samples will be collected and shipped in accord with the laboratory manual provided by the 
central laboratory as per the time points specified in Table 3. 
Rationale 
To reduce redundancy and direct to SoA. 
 
Section 12.14.2 
Serum Chemistry 
Samples will be collected and shipped in accord with the laboratory manual provided by the 
central laboratory as per the time points specified in Table 3. 
 
CK-MB or Troponin I will be collected as specified in the SoAat screening, Day 7, Day 30, 
Day 60 and at Months 6, 9, and 12/End of Study.   
Rationale 
To reduce redundancy and direct to SoA. 
 
Section 12.14.7.1 
ELISA:  Anti-AAV9-Ab 
Blood samples will be collected and shipped to the central laboratory in accord with the 
laboratory manual to test for serum antibodies to AAV9 at screening and as per the timepoints 
specified in Table 3. 
Rationale 
Updated to reduce redundancy and direct to SoA. 
 
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Section 12.14.8 
Baseline Screening of Biological Mother 
There is potential that the biological mother of the enrolled patient may have pre-existing 
antibodies to AAV9 that may be transferred to the patient via placental transfer in utero or 
theoretically through breast milk.  Informed consent will be requested from the biological 
mother of the patient to screen the biological mother for circulating antibodies to AAV9.  Once 
informed consent has been obtained, the biological mother will have her blood drawn from a 
peripheral vein and shipped to the central laboratory for screening of anti-AAV9 antibodies. 
If AAV9 antibodies are identified, the investigator should discuss with the biological mother 
whether to continue or to stop breastfeeding. 
Rationale for change 
Updated text to reflect that this will only be performed on the biological mother. 
 
Section 12.14.10 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 a week following injection.  The risks associated with the shed vector 
are not known at this time; however, it is unlikely as the vector is non-infectious and cannot 
replicate.  Regardless, IRB-approved instructions should be provided to patient families and care 
givers regarding use of protective gloves if/when coming into direct contact with patient bodily 
fluids and/or waste as well as good hand-hygiene for a minimum of two four weeks after the 
injection. 
Additionally, patients are prohibited from donating blood for two years following the vector 
injection. 
Saliva, urine, and stool samples will be collected in accord with the laboratory manual for viral 
shedding studies in accord with Table 3 including 24 hours and 48 post- doses.  Patients at all 
sites ≥ 48 months of age who are no longer in diapers will provide full volume urine and full 
volume feces samples at Day 7, Day 14, and Day 30at the timepoints specified in the SoA 
(Table 3) for at least one void and one defecation.  Samples will be prepared as per the 
laboratory manual, stored in a -80 freezer, and shipped to the central laboratory in accord with 
the laboratory manual. 
Rationale for change 
Updated to reduce redundancy and direct to SoA. 
 
Section 13.1.1   Adverse Event (AE) 
All AEs that occur after any patient has received treatment, during treatment, or up through the 
last study visit, whether or not they are related to the study, must be recorded on forms provided 
by Syneos Health, formerly INC (a Contract Research Organization responsible for 
managing specific aspects of the study, as designated by AveXis). 
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Unanticipated CTCAE Grade 3 or higher AEs that are possibly, probably, or definitely related to 
the product gene replacement therapy must be reported within 24 hours to Sponsor Avexis 
and/or designee as per trial safety management plan to ensure timely escalation to the 
DSMB/Data Monitoring Committee (DMC). 
Rationale for change 
Administrative change. 
 
Section 13.1.1   Serious Adverse Event 
All SAEs that occur after any patient has been enrolled, before treatment, during treatment, or up 
through the last study visit, whether or not they are related to the study, must be recorded on 
forms provided by Syneos HealthINC. 
Rationale for change 
Administrative change. 
 
Section 13.1.3 
Other Adverse Event (OAE) 
The following specific treatment-emergent AE of special interest (AESI), which may be 
searched using Standardized MedDRA queries, will be summarized: 
• Elevated liver enzymes 
Grade 3 or higher elevated liver enzyme events related to AVXS-101 must be collected and 
recorded on forms provided by the Contract Research Organization.  These events should 
be reported within 24 hours of occurrence whether or not they are deemed to be an SAE.   
Other adverse events (OAEs) may could be identified by the Drug Safety Physician and if 
applicable also by the Medical MonitorClinical Trial Team Physician and/or Drug Safety 
Monitor (DSM) during the evaluation of safety data for the Clinical Study Report.  Examples of 
AESIS include hepatotoxicity, cardiac toxicity and thrombocytopenia. Significant AEs 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. 
Rationale for change 
Updating and clarifying the requirements for reporting elevated liver enzymes accordingly. 
Provided further clarification on other adverse events reporting in the Clinical Trial Report. 
 
Section 13.3  Recording Adverse Events 
AEs spontaneously reported by the patient or family 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.  However, abnormal values that constitute an SAE or lead to discontinuation 
of administration of study product must be reported and recorded as an AE.  Information about 
AEs will be collected from the time of IT injection until the end of the study.  SAE information 
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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 start date during Visit 2inpatient period)), 
resolution (date and time (if start date during Visit 2inpatient period)), intensity, causality, 
action taken, serious outcome (if applicable), and whether or not it caused the patient to 
discontinue the study. 
Rationale for change 
Administrative change 
 
Section 13.4  Reporting Serious Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of consent form through the last 
study visit.  Any SAEs considered possibly, probably, or definitely 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 via Syneos HealthINC 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 email to Syneos HealthINC. 
Additional follow-up information, if required or available, should all be faxed or emailed to 
Syneos HealthINC 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. 
Rationale for change 
Administrative change 
 
Section 13.5 Expedited Safety Reporting to Regulatory Authorities 
All unexpected, serious, drug-related events which are fatal or life-threatening will be 
reported to relevant regulatory authorities in an expeditious manner.  All other 
unexpected, serious, drug-related events will be reported to relevant regulatory authorities 
within 15 days. 
Rationale for change 
Added language to be consistent with protocol template across all studies. 
 
Section 14.6.1 Observation Period for Efficacy 
Efficacy comparisons will be made once all patients have either completed 125 months of 
follow- up or withdrawn prior to 125 months of follow-up.  The primary analysis of efficacy 
data will be based on data collected through the 12-month time point; a supportive analysis 
of efficacy data will be based on data collected through the 15-month time point. 
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Rationale for change 
Included follow-up through 15 months. 
 
Section 14.6.2.1  Primary Efficacy Endpoint: patients ≥6 months and < 24 months at time 
of dosing  
For the cohort regarded as having received the optimal dose, tThe proportion of patients 
≥6 months and < 24 months of age at time of dosing achieving the ability to stand without 
support up to the 12-month study visit will be compared between AVXS-101 and natural history 
control groups using a two-sample 2-sided superiority Fisher exact test.  A 95% exact 
conditional confidence interval for the difference in response rates will be computed. 
The primary analyses will be based on the Full Analysis Set for patients ≥6 months and 
< 24 months of age at the time of dosing. 
A sensitivity analysis will be conducted by repeating each primary efficacy analysis on the 
Efficacy Completers Analysis Set for patients ≥ 6 months and < 24 months of age at the time of 
dosing. 
A supportive analysis will be conducted by repeating the analysis of the primary efficacy 
endpoint for patients ≥ 6 months and < 24 months of age considering data through the 15-
month visit. 
Rationale for change 
Included follow-up through 15 months. 
 
Section 14.6.2.2  Primary Efficacy Endpoint: patients ≥ 24 months and < 60 months at 
time of dosing  
A supportive analysis will be conducted by repeating the analysis of the primary efficacy 
endpoint for patients ≥ 24 months of age and < 60 months of age considering data through 
the 15-month visit. 
Rationale for change 
Included follow-up through 15 months. 
 
Section 14.6.3  
Secondary Efficacy Endpoint  
For the cohort regarded as having received the optimal dose, tThe proportion of patients 
≥6 months and < 24 months or ≥ 24 and < 60 months at time of dosing who achieve the ability to 
walk without assistance will be compared separately between AVXS-101 and natural history 
control groups using two-sample Fisher’s 2-sided exact test.  A 95% exact confidence interval 
for the differences in response rates will be computed. 
A supportive analysis will be conducted by repeating the analysis of the secondary efficacy 
endpoint considering data through the 15-month visit. 
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Rationale for change 
Included follow-up through 15 months. 
 
  
  
Rationale for change 
Included follow-up through 15 months. 
Section 14.7   Safety Analysis 
Safety will be assessed through monitoring AE reports and concomitant medication usage, and 
by conducting physical examinations, vital sign assessments, cardiovascular evaluations, and 
laboratory evaluations (chemistry, hematology, coagulation, immunology).  Patients will be 
observed at the hospital for 48 hours post IT injection.  Patients will return for follow-up visits 
on Days 7, 14, 21, and 30.  Patients will return monthly thereafter, followingin accordance with 
the Day 30 visit, for the first 12 months from dose administrationSoA.  Adverse events will be 
coded in accord with the most current version of the MedDRA coding dictionary. 
Rationale for change 
Administrative change to reduce redundancy within the protocol. 
 
Section 15 
DATA SAFETY MONITORING BOARD/DATA MONITORING 
COMMITTEE 
The DSMB/DMC 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/DMC will be chartered to oversee the safety of 
patients during the conduct of the trial and will act in an advisory capacity to AveXis.  A 
detailed description of the DSMB/DMC, its role in this trial, and the timing of the 
scheduled reviews will be described in a DSMB/DMC Charter. 
The DSMB/DMC will routinely convene on a quarterly basis to review emerging safety 
data from the trial.  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/DMC will make a recommendation as to whether or not the accumulated safety 
data warrants a suspension or discontinuation of the trial, a modification to the trial, or 
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any additional comments or recommendations related to safety.  The DSMB/DMC will 
prepare and provide minutes of their meetings to AveXis who will provide copies to the 
regulatory authorities as appropriate. 
The DSMB/DMC will also convene on an ad hoc basis within approximately 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/DMC will 
review the safety information and provide its recommendation.  Based upon the 
DSMB/DMC’s review, the DSMB/DMC can recommend continuing enrollment, halting 
enrollment or early termination of the trial for safety reasons. 
The DSMB will act in an advisory capacity to review patient safety and study progress for the 
clinical trial.  Responsibilities of the DSMB are to: 
• Review the research protocol, informed consent documents and plans for data and safety 
monitoring 
• Evaluate the progress of the study, including periodic assessments of data quality and 
timeliness, patient recruitment, accrual and retention, patient risk versus benefit, study site 
performance, and other factors that can affect study outcome 
• Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on patient safety or the ethics 
of the study 
• Review study performance, make recommendations and assist in the resolution of problems 
reported by the investigators 
• Protect the safety of the study patients 
• Review safety data to determine whether to recommend dose escalation 
• Review quarterly safety data to determine safety signals or trends 
• Ensure the confidentiality of the study data and the results of monitoring 
Assist by commenting on any problems with study conduct, enrollment, and sample size and/or 
data collection 
Rationale for change 
Administrative updates to DSMB membership, meetings and reporting. 
 
Former Section 15.1 DSMB Reporting and Meeting 
Reports describing the status of the study will be prepared by AveXis, Inc. and sent to the DSMB 
at least quarterly, or at the DSMB’s request.  Reports will be submitted prior to a scheduled 
meeting for review by the DSMB. 
Reports will include the following: 
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• A brief narrative of the study status, including the target enrollment, current and projected 
time to completing enrollment.  Any significant events and/or difficulties should be briefly 
described in this narrative 
• A brief narrative for each patient describing gender, age, race and ethnicity and other relevant 
demographic characteristics.  The narrative for each patient should briefly describe his/her 
study status (i.e., dose level, visit number, AE information) 
• A timeline outlining the study progress relative to visit number for each patient, as well as 
time points for each SAE/Dose Limiting Toxicity.  A total for AEs for each patient should be 
included 
• A summary of AEs by classification 
• A listing of AE details grouped by patient 
• A listing of SAE details grouped by patient 
• A listing of deaths 
• A summary of clinically significant laboratory test results 
• A listing of protocol deviations 
Rationale for change 
Administrative updates to DSMB membership, meetings and reporting. 
 
Former Section 15.3   DSMB Membership 
The DSMB membership will consist of persons completely independent of the investigative sites 
and sponsor who have no financial, scientific, or other conflicts of interest with the trial.  The 
DSMB will include experts in or representatives of the fields of: 
• Neurology and Neuromuscular Diseases 
• Immunology 
• Gene Therapy 
• Spinal Muscular Atrophy Clinical Care 
• Clinical Research and Clinical Trials 
• Statistics (non-voting member) 
Individuals invited to serve on the DSMB as either voting or non-voting members must disclose 
any potential conflicts of interest, whether real or perceived.  Conflicts of interest can include 
professional, proprietary, and miscellaneous interests as described in 45 CFR Part 94.  Potential 
conflicts that develop during a member’s tenure on a DSMB must also be disclosed.   
AveXis, Inc. will employ a third party (e.g. consulting group) to provide planning, organization, 
preparation, and oversight services for the DSMB meetings. 
Rationale for change 
Administrative updates to DSMB membership, meetings and reporting. 
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Section 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 (please see Appendix 1) and are consistent with ICH/GCP, applicable 
regulatory requirements and the AveXis, Inc.’s policies. 
Rationale for Change 
Administrative change. 
 
Section 19.3 Retention of Records 
The site will maintain essential documents as required by ICH-GCPa 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 andthese documents 
available for review by the Sponsor, IRB/IEC, and/or regulatory bodies. 
Rationale for Change 
Administrative change. 
 
Appendix 2  AUTOPSY PLAN 
This was removed to be consistent across protocols.  New sentence added to protocol: An 
autopsy and tissue collection process will be in place for those patients who consent to 
autopsy/tissue collection for research purposes. 
Rationale for change 
Details of autopsy included in manual not in protocol. 
  Effective
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