Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to Tysabri® in Patients With Relapsing-Remitting Multiple Sclerosis (RRMS)
Phase: PHASE3
Conditions: Relapsing-Remitting Multiple Sclerosis (RRMS)
Sponsor: Polpharma Biologics S.A.

Property of Polpharma Biologics S.A. 
Confidential 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be used, divulged, published, or otherwise disclosed without the written consent of 
Polpharma Biologics S.A. These restrictions on disclosure will apply equally to all future information supplied 
to you which is indicated as privileged or confidential. 
 
Polpharma Biologics S.A. 
Product PB006 
Protocol No. PB006-03-01 
EudraCT No. 2018-004751-20 
Antelope: Efficacy and Safety of the Biosimilar Natalizumab 
PB006 in Comparison to Tysabri® in Patients with Relapsing-
Remitting Multiple Sclerosis (RRMS) 
Document type: 
Clinical Study Protocol 
Development Phase: 
3 
Release date of original protocol: 05 FEB 2019 
Release date of Version 2.0 
04 SEP 2019 
Release date of Version 3.0 
05 FEB 2020 
Release date of Version 4.0 
15 JUL 2020 
Sponsor 
Polpharma Biologics S.A. 
ul. Trzy Lipy 3 
80-172 Gdansk 
Poland 

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TABLE OF CONTENTS 
Table of Contents ................................................................................................................................... 2 
Contact Information ............................................................................................................................... 6 
Time and Events Schedule ................................................................................................................... 13 
Signature Page for Sponsor .................................................................................................................. 17 
Signature Page for Investigators ........................................................................................................... 18 
List of Abbreviations and Terms .......................................................................................................... 19 
1. 
Ethic Considerations ................................................................................................................... 22 
1.1. 
Statement of Compliance ............................................................................................................. 22 
1.2. 
Independent Ethics Committee ................................................................................................... 22 
1.3. 
Informed Consent and Patient Information ............................................................................... 22 
1.4. 
Patient Confidentiality ................................................................................................................. 23 
2. 
Introduction ................................................................................................................................ 23 
2.1. 
Background Information About Relapsing-Remitting Multiple Sclerosis .............................. 23 
2.2. 
Background Information About PB006 ...................................................................................... 24 
2.3. 
Risks and Benefits ......................................................................................................................... 25 
2.4. 
Risk Management Plan for PML ................................................................................................ 26 
2.4.1. 
Process and Assessments of Early Detection ................................................................................... 26 
2.4.2. 
Action Steps if PML is Suspected ..................................................................................................... 27 
2.4.2.1. Study Drug Interruption ................................................................................................... 27 
2.4.2.2. PML Diagnosis ................................................................................................................ 27 
2.4.3. 
Action Steps if PML is Confirmed .................................................................................................... 28 
2.4.3.1. Study Drug Discontinuation ............................................................................................. 28 
2.4.3.2. Treatment of PML ............................................................................................................ 28 
2.4.4. 
Further Follow-Up for PML ............................................................................................................ 28 
3. 
Study Objectives ......................................................................................................................... 28 
3.1. 
Primary Objective ........................................................................................................................ 28 
3.2. 
Secondary Objectives ................................................................................................................... 28 
4. 
Investigational Plan .................................................................................................................... 29 
4.1. 
Overall Study Design .................................................................................................................... 29 
4.2. 
Rationale for the Study Design .................................................................................................... 32 
4.3. 
Number of Patients ....................................................................................................................... 32 
4.4. 
Replacement of Patients ............................................................................................................... 32 
4.5. 
Randomization .............................................................................................................................. 32 
4.6. 
Blinding and Unblinding Procedures .......................................................................................... 32 
4.7. 
Interruption and Stopping Rules................................................................................................. 33 
4.7.1. 
Interruption and Discontinuation of Study Drug ............................................................................. 33 
4.7.2. 
Withdrawal from the Study .............................................................................................................. 36 
4.8. 
Expected Study Duration ............................................................................................................. 36 
5. 
Study Population Selection ......................................................................................................... 36 
5.1. 
Inclusion Criteria .......................................................................................................................... 36 
5.2. 
Exclusion Criteria ......................................................................................................................... 37 
6. 
Treatment of Patients .................................................................................................................. 39 

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6.1. 
Description of Study Drugs .......................................................................................................... 39 
6.1.1. 
Test Drug – Biosimilar - PB006 ...................................................................................................... 39 
6.1.2. 
Comparator Drug - Tysabri ............................................................................................................. 39 
6.1.3. 
Preparation and Administration ...................................................................................................... 39 
6.1.4. 
Storage, Handling, and Accountability ............................................................................................ 39 
6.2. 
Prior and Concomitant Medications ........................................................................................... 40 
6.2.1. 
Allowed Medications........................................................................................................................ 40 
6.2.2. 
Prohibited Medications .................................................................................................................... 40 
6.3. 
Treatment Compliance ................................................................................................................. 40 
7. 
Study Activities by Visit............................................................................................................. 41 
7.1. 
Screening Phase ............................................................................................................................ 41 
7.2. 
Treatment Phase ........................................................................................................................... 42 
7.3. 
End-of-Study Visit or Early Discontinuation Visit .................................................................... 46 
7.4. 
Unscheduled Relapse Visit ........................................................................................................... 46 
7.4.1. 
Definition of Relapse ....................................................................................................................... 46 
7.4.2. 
Procedures for Evaluation of Suspected Relapse............................................................................. 46 
7.4.3. 
Procedures After a Relapse ............................................................................................................. 47 
7.4.3.1. During Screening ............................................................................................................. 47 
7.4.3.2. After Enrollment .............................................................................................................. 47 
7.5. 
Unscheduled PML Visit ............................................................................................................... 47 
7.6. 
PML Follow-Up visit .................................................................................................................... 47 
8. 
Study Procedures ........................................................................................................................ 47 
8.1. 
Demographics and Medical History ............................................................................................ 48 
8.2. 
Magnetic Resonance Imaging ...................................................................................................... 48 
8.2.1. 
Contrast Agent ................................................................................................................................. 49 
8.2.2. 
Suspected PML ................................................................................................................................ 49 
8.2.3. 
MS Relapses / Corticosteroid Treatment ......................................................................................... 49 
8.3. 
Kurtzke Expanded Disability Status Scale ................................................................................. 49 
8.4. 
Columbia-Suicide Severity Rating Scale .................................................................................... 50 
8.5. 
Physical Examination ................................................................................................................... 50 
8.6. 
Vital Signs ...................................................................................................................................... 50 
8.7. 
12-Lead Electrocardiogram ......................................................................................................... 50 
8.8. 
Pregnancy and Contraception ..................................................................................................... 51 
8.9. 
Previous and Concomitant Medication ....................................................................................... 51 
8.10. Adverse Event Assessments ......................................................................................................... 52 
8.10.1. 
Definitions ....................................................................................................................................... 52 
8.10.2. 
Severity ............................................................................................................................................ 52 
8.10.3. 
Relationship ..................................................................................................................................... 53 
8.10.4. 
Expectedness .................................................................................................................................... 54 
8.10.5. 
Clinical Laboratory Adverse Events ................................................................................................ 54 
8.10.6. 
Serious Adverse Events .................................................................................................................... 54 
8.10.7. 
Adverse Events of Special Interest ................................................................................................... 55 
8.10.7.1. Progressive Multifocal Leukoencephalopathy ................................................................. 55 
8.10.7.2. John Cunningham Virus Granule Cell Neuronopathy ...................................................... 55 
8.10.7.3. Opportunistic Infections ................................................................................................... 55 
8.10.7.4. Liver Injury ...................................................................................................................... 56 
8.10.7.5. Hypersensitivity ............................................................................................................... 56 
8.10.7.6. Encephalitis/Meningitis ................................................................................................... 57 
8.10.7.7. Acute Retinal Necrosis ..................................................................................................... 57 
8.11. Clinical Laboratory Tests ............................................................................................................ 57 
8.11.1. 
Blood Chemistry and Hematology ................................................................................................... 57 
8.11.2. 
Urinalysis ........................................................................................................................................ 58 
8.12. Anti-JCV Antibody Samples ....................................................................................................... 58 
8.13. Anti-Natalizumab Antibody Samples ......................................................................................... 58 
8.14. Natalizumab trough concentration ............................................................................................. 58 

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8.15. Biobank Samples ........................................................................................................................... 58 
8.16. Cerebral Spinal Fluid Lumbar Puncture ................................................................................... 58 
8.17. Data Safety Monitoring Board .................................................................................................... 58 
9. 
Planned Statistical Methods........................................................................................................ 59 
9.1. 
General Considerations ................................................................................................................ 59 
9.2. 
Determination of Sample Size ...................................................................................................... 59 
9.3. 
Analysis Populations ..................................................................................................................... 59 
9.3.1. 
Safety Population ............................................................................................................................. 59 
9.3.2. 
Safety-Switch Population ................................................................................................................. 59 
9.3.3. 
Full Analysis Set Population ............................................................................................................ 59 
9.3.4. 
Per-Protocol Population .................................................................................................................. 60 
9.4. 
Analysis of Demographics and Baseline Characteristics ........................................................... 60 
9.5. 
Analysis of Disposition and Patient Characteristics .................................................................. 60 
9.6. 
Analysis of Endpoints ................................................................................................................... 60 
9.6.1. 
Primary Endpoint ............................................................................................................................ 60 
9.6.2. 
Secondary Endpoints ....................................................................................................................... 60 
9.6.3. 
Analysis of Efficacy Endpoints ......................................................................................................... 61 
9.6.4. 
Analysis of Safety ............................................................................................................................. 61 
9.6.5. 
Analysis of Anti-Natalizumab Antibodies ......................................................................................... 62 
9.6.6. 
Analysis of Natalizumab Trough Concentration .............................................................................. 62 
9.6.7. 
Analysis of Anti-JCV Antibodies ...................................................................................................... 62 
9.7. 
Analyses ......................................................................................................................................... 62 
9.8. 
Handling of Dropouts and Missing Data .................................................................................... 62 
9.9. 
Deviations from the Analysis Plan .............................................................................................. 62 
10. 
Administrative Considerations ................................................................................................... 62 
10.1. Monitoring Procedures ................................................................................................................ 62 
10.2. Protocol Violations/Deviations..................................................................................................... 63 
10.3. Recording of Data and Retention of Documents ........................................................................ 63 
10.4. Data Management ......................................................................................................................... 64 
10.4.1. 
Data Collection ................................................................................................................................ 64 
10.4.2. 
Database Management and Quality Control ................................................................................... 64 
10.5. Compensation, Insurance, and Indemnity.................................................................................. 64 
10.6. Auditing Procedures ..................................................................................................................... 64 
10.7. Publication of Results ................................................................................................................... 64 
10.8. Financial Disclosure ..................................................................................................................... 65 
10.9. Investigator Confidentiality ......................................................................................................... 65 
11. 
References .................................................................................................................................. 66 
Appendix 1: 
2010 Revised McDonald Criteria for Diagnosis of MS....................................... 68 
Appendix 2: 
Liver Safety Monitoring and Assessment ............................................................ 70 
 
TABLE OF TABLES 
Table 1 PML Risk Estimates per 1,000 Patients in Anti-JCV Antibody Positive Patients .................. 25 
Table 2 Diagnosis of MS Relapse vs PML .......................................................................................... 27 
Table 3 Interruption and Discontinuation of Study Drug ..................................................................... 34 
Table 4 Clinical Chemistry, Serology and Hematology Tests ............................................................. 57 
 

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TABLE OF FIGURES 
Figure 1 Overall Study Flowchart ........................................................................................................ 31 

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CONTACT INFORMATION 
Corporate name: 
 
Polpharma Biologics S.A. 
Location: 
 
 
ul. Trzy Lipy 3 
80-172 Gdansk 
Poland 
Medical Monitor:  
Name:  
 
 
 
Company: 
 
 
 
Title:  
 
 
Medical Affairs Manager 
Office Phone Number: 
 
Office Fax Number:  
 
Mobile Phone Number: 
 
Safety Desk Email:  
 
 
Other Appropriate Study Contact Personnel: 
 
Name:  
 
 
  
Company: 
 
 
  
Title:  
 
 
Clinical Trial Lead 
Office Phone Number: 
 
Email:  
 
 
  
 
Name:  
 
 
  
Company: 
 
 
 
S.A. Title: 
 
 
Director Clinical Research and Development 
Office Phone Number: 
 
Email:  
 
 
 
 
Name:  
 
 
  
Company: 
 
 
  
Title:  
 
 
Director Regulatory Affairs  
Office Phone Number: 
 
Email:  
 
 
  
If any contact information is changed during the course of the study, this will be done with 
written notification to the Investigator(s), and will not require (a) protocol amendment(s). 

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Synopsis 
Name of the Sponsor/Company 
Polpharma Biologics S.A. 
Study Number 
PB006-03-01 
Name of Investigational Medicinal 
Product 
PB006 
EudraCT No. 
2018-004751-20 
Development Phase of the Study 
Phase 3 
 
TITLE OF THE STUDY 
Antelope: Efficacy and Safety of the Biosimilar Natalizumab PB006 in Comparison to 
Tysabri® in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS)  
STUDY POPULATION 
Adult patients with Relapsing-Remitting Multiple Sclerosis (RRMS)  
OBJECTIVES 
Primary objective 
• 
Evaluate and compare the cumulative number of new active lesions over 24 weeks 
Secondary objectives 
• 
Evaluate and compare the cumulative number of new active lesions over 48 weeks  
• 
Evaluate and compare the cumulative number of new gadolinium-enhancing (GdE) T1-weighted 
lesions over 24 and 48 weeks  
• 
Evaluate and compare the number of patients without new GdE T1-weighted lesions over 24 and 
48 weeks  
• 
Evaluate and compare the cumulative number of new/enlarging T2-weighted lesions over 24 and 
48 weeks  
• 
Evaluate and compare the number of patients without new/enlarging T2-weighted lesions over 24 
and 48 weeks  
• 
Evaluate and compare the number of persistent lesions after 24 and 48 weeks treatment with 
PB006 or Tysabri 
• 
Evaluate and compare the annualized relapse rates and changes in Expanded Disability Status 
Scale (EDSS) after 24 and 48 weeks 
• 
Evaluate and compare local and systemic adverse events (AEs) and serious adverse events (SAEs) 
after 24 and 48 weeks 
• 
Evaluate and compare the immunogenic profile (incidence rate of anti-drug [natalizumab] 
antibodies [ADA] and persistent antibodies) after 24 and 48 weeks and after switching 
• 
Evaluate and compare the immunogenic profile (incidence rate of neutralizing antibodies) after 
24 and 48 weeks and after switching 
• 
Evaluate and compare natalizumab trough concentration (Ctrough) over time 
• 
Evaluate and compare the safety profile (physical examination, vital sign measurements, and 
clinical laboratory tests) over 24 and 48 weeks 
OVERALL STUDY DESIGN:  
This is a Phase 3 multicenter, double-blind, active-controlled, randomized, parallel-group 
study to assess the equivalence in efficacy and similarity in safety of biosimilar PB006 
compared to Tysabri in patients with RRMS. 

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After obtaining informed consent, screening investigations will begin. Screening will consist 
of the following 2 parts: 
1. Samples for anti-John Cunningham virus (JCV) antibodies and samples for biobanking 
(blood and urine) will be taken. When JCV test results come back: 
a. JCV index >1.5: The patient will be considered a screen failure. 
b. JCV index ≤1.5: Proceed with part 2. 
2. For patients with JCV index ≤1.5, the Investigator or designee will set up a second visit 
for all other screening procedures that will be completed for each patient prior to 
randomization for study treatment. 
Patient eligibility will be determined by the inclusion and exclusion criteria on screening 
evaluations listed in Sections 5.1 and 5.2. 
All eligible patients will be randomly assigned to one of two treatment groups in a 1:1 ratio, 
to receive intravenous (IV) infusions every 4 weeks of either PB006 or Tysabri at a dose of 
300 mg starting at Visit 1 (Week 0) through Visit 12 (Week 44), for a total of 12 infusions. 
In order to evaluate and compare the immunogenic profile between patients treated with 
Tysabri only and those switching from Tysabri to PB006 at Week 24 and in accordance with 
FDA requirements, the 130 patients in the Tysabri group will be re-randomized at Week 24 
(through a re-randomization step). Out of these 130 patients, approximately 34 (to account 
for potential dropouts to reach an approximate minimum of 30) random patients will be 
randomized (switched) to PB006. After re-randomization, the patient groups will be: Tysabri 
group (n= up to 96); Tysabri switch to PB006 group (n=up to 34); and PB006 group (n= up 
to 130). 
The End-of-Study Visit (Visit 13, Week 48) will be performed 4 weeks after the last infusion. 
The evaluations for patients who withdraw prematurely will be the same as for the End-of-
Study Visit. In addition, a progressive multifocal leukoencephalopathy (PML) Follow-Up 
Visit (Visit 14, Week 68) will be performed 24 weeks after the last infusion or earlier in case 
of new signs and symptoms suggestive for PML. All patients who withdraw prematurely 
from the study and received at least 1 infusion of study drug will also be required to return to 
the clinic 24 weeks after the last infusion for the PML Follow-Up Visit or earlier in case of 
symptoms suspicious for PML. 
Magnetic resonance imaging (MRI) will be performed at Screening, prior to treatment at 
Visit 1 (Week 0), and at Weeks 8, 16, 20, 24, 48 and the End-of-Study Visit (Visit 13, Week 
48), at unscheduled visits in case of suspected PML and at the PML Follow-Up Visit if PML 
is suspected (up to 24 weeks after last study drug infusion). Serum samples for ADA and 
neutralizing antibody formation will be collected prior to treatment at Visit 1 (Week 0), and 
at Weeks 4, 8, 16, 24, 28, 32, and 48. Blood samples for natalizumab Ctrough analyses will be 
collected prior to treatment at Visit 1 (Week 0), and at Weeks 8, 16, 24, 32, and 48. Blood 
samples for anti-JCV antibody testing and samples for biobanking (blood and urine) will be 
collected at Screening, Week 24, and 48. Blood samples and urinalysis for safety laboratory 
assessments will be collected at Screening, prior to treatment at Visit 1 (Week 0), and every 
8 weeks through Week 48 and at unscheduled visits in case of a relapse and at unscheduled 
visits if PML is suspected. 
The primary endpoint will be the radiologic response as measured by the cumulative number 
of new active lesions over a 24-week treatment period, starting with the first infusion at Week 
0 to Week 24. Secondary endpoints to be evaluated after 24 and 48 weeks include radiologic 
response criteria using MRI, clinical response as defined by the frequency of relapses, 

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changes in EDSS, safety (AEs, physical examination, vital sign measurements, and clinical 
laboratory tests), natalizumab blood concentration and immunogenicity (ADA).  
The following AEs will be considered as AEs of special interest (AESIs): PML, JCV granule 
cell neuronopathy (GCN), opportunistic infections, liver injury, hypersensitivity, 
encephalitis, meningitis, and acute retinal necrosis (ARN).  
Treatment assignments will be blinded to the Investigator/neurologist, study personnel, and 
the patients.  
The Time and Events Schedule follows this synopsis. 
TEST DRUG – BIOSIMILAR 
PB006 – natalizumab biosimilar, 20 mg/mL concentrate for solution for IV infusion 
COMPARATOR DRUG 
Tysabri (International Nonproprietary Name [INN]: natalizumab), 20 mg/mL concentrate for 
solution for IV infusion 
NUMBER OF PATIENTS 
Approximately 260 patients are planned to be randomized. 
NUMBER OF STUDY CENTERS 
Approximately 55 study sites in 7 countries (Belarus, Croatia, Georgia, Moldova, Poland, 
Serbia, and Ukraine). 
STUDY PERIOD 
The total study period for each patient will be approximately 52 weeks (4 weeks of 
screening and 48 weeks of treatment). In addition, patients are required to come for a PML 
Follow-Up Visit 24 weeks after last study drug infusion. 
INCLUSION AND EXCLUSION CRITERIA 
Inclusion Criteria 
1. Male and female patients (age ≥18 to 60 years), with RRMS defined by the 2010 revised 
McDonald criteria (Appendix 1). 
2. At least 1 documented relapse within the previous year and either ≥1 GdE T1-weighted 
brain lesions or ≥9 T2-weighted brain lesions at Screening. 
3. Kurtzke EDSS score from 0 to 5 (inclusive) at Screening. 
4. At Screening, females of childbearing potential must be non-pregnant and non-lactating; 
or females should be of non-childbearing potential (either surgically sterilized or 
physiologically incapable of becoming pregnant, or at least 1 year post-menopausal 
[amenorrhea duration of 12 consecutive months]); non-pregnancy will be confirmed for 
all females of childbearing potential by a serum pregnancy test conducted at Screening.  
5. Female patients of childbearing potential, with a fertile male sexual partner, must use 
adequate contraception from Screening until 90 days after the last dose of study drug 
(Visit 12, Week 44, or earlier, if treatment is discontinued sooner). Adequate 
contraception is defined as using hormonal contraceptives or an intrauterine device, 
combined with at least one of the following forms of contraception: a diaphragm or 
cervical cap, or a condom. Total abstinence from heterosexual activity, in accordance 
with the lifestyle of the subject, is acceptable. 
6. Male patients who are sexually active with women of childbearing potential agree they 
will use adequate contraception from Screening until 90 days after the last dose of study 

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drug (at Visit 12, Week 44, or earlier, if treatment is discontinued sooner) if not surgically 
sterilized at least 6 months before Screening (with a post-vasectomy semen analysis 
negative for sperm). Male patients must not donate sperm until 90 days after the last dose 
of study drug (Visit 12, Week 44, or earlier, if treatment is discontinued sooner). 
Adequate contraception for the male subject and his female partner of childbearing 
potential is defined as using hormonal contraceptives or an intrauterine device, combined 
with at least one of the following forms of contraception: a diaphragm or cervical cap, or 
a condom. Total abstinence from heterosexual activity, in accordance with the lifestyle 
of the subject, is acceptable. 
7. Signed and dated Informed Consent Form (ICF). 
Exclusion Criteria 
1. Manifestation of multiple sclerosis (MS) other than RRMS. 
2. Relapse within the 30 days prior Screening and until administration of the first dose of 
study drug. 
3. Prior treatment with natalizumab, alemtuzumab, ocrelizumab, daclizumab, rituximab, 
cladribine, or other B- and T-cell targeting therapies. 
4. Prior total lymphoid irradiation or bone marrow or organ transplantation.  
5. Any prior treatment within the following time period prior to Screening: 
• 
30 days: systemic corticosteroids or interferon-β or glatiramer acetate 
• 
2 months:  
 
fingolimod 
 
any other sphingosine-1-phosphate receptor modulator (e.g., siponimod) 
 
any tumor necrosis factor-alpha (TNF-α) inhibitors  
• 
2 months: dimethyl fumarate 
• 
3.5 months: teriflunomide  
• 
12 months: immunosuppressive therapy for indications other than MS (e.g., cytarabine, 
azathioprine, methotrexate, cyclophosphamide, cyclosporine, cladribine)  
6. Any prior treatment with mitoxantrone 
7. Active infections requiring oral or parenteral antibiotic treatment within 2 weeks prior to 
Screening  
8. Increased risk of opportunistic infections; exclusion determination to be made after 
consultation with the Medical Monitor. 
9. Patients with JCV index >1.5 at Screening. 
10. Past or current PML diagnosis. 
11. Presence of malignancies or neoplastic diseases; past history of malignancies within 5 
years prior to Screening (except basal cell and in situ squamous cell carcinomas of the 
skin that have been excised and resolved). 
12. History or known presence of recurrent or chronic infection other than recurring urinary 
tract infections (i.e., hepatitis A, B, or C, human immunodeficiency virus [HIV], 
tuberculosis). 
13. Clinically relevant, severe cardiac or pulmonary diseases, uncontrolled hypertension, or 
poorly controlled diabetes. 
14. Severe renal function impairment as defined by serum creatinine values >120 μmol/L. 

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15. Elevated liver markers:  
• 
Alanine aminotransferase (ALT) >3x upper limit of normal (ULN), 
• 
Aspartate aminotransferase (AST) >3x ULN, or  
• 
Total bilirubin 2x ULN.  
Patients with documented Gilbert syndrome can be enrolled after approval by the Medical 
Monitor. 
16. Decreased white blood cell counts (WBCs) at Screening: 
• 
WBC <3.0 ×109/L, or 
• 
Absolute neutrophil count (ANC) <1.0 ×109/L, or 
• 
Absolute lymphocyte count (ALC) <0.5 ×109/L. 
17. Unable to understand the patient information and ICF. 
18. Unable or unwilling to comply with the protocol requirements. 
19. Alcohol or drug dependence within 1 year prior to study entry. 
20. Self-reported symptoms of depression and/or suicidal thoughts based on the Columbia-
Suicide Severity Rating Scale (C-SSRS) 
21. Any investigational drug within 3 months prior to enrollment or within 5 times of its half-
life, whichever is longer. 
22. Unable to undergo MRI scans due to claustrophobia or metallic implants incompatible 
with MRI. 
23. Unable to receive Gd-based MRI-contrast agents due to history of hypersensitivity to Gd-
based contrast agents or severe renal insufficiency. 
24. Has a known contraindication and (or) hypersensitivity to any of the constituents of the 
study drug or comparator drugs, including their excipients. 
ENDPOINTS 
Primary Endpoint 
• 
Cumulative number of new active lesions over 24 weeks 
Secondary Endpoints 
• 
Cumulative number of new active lesions over 48 weeks 
• 
Cumulative number of new GdE T1-weighted lesions over 24 and 48 weeks 
• 
Number of patients without new GdE T1-weighted lesions over 24 and 48 weeks 
• 
Cumulative number of new/enlarging T2-weighted lesions over 24 and 48 weeks 
• 
Number of patients without new/enlarging T2-weighted lesions over 24 and 48 weeks 
• 
Number of persistent lesions after 24 and 48 weeks 
• 
Annualized relapse rate after 24 and 48 weeks 
• 
Change from baseline in EDSS after 24 and 48 weeks 
• 
Number of local and systemic AEs and SAEs after 24 and 48 weeks 
• 
Incidence rate of ADA and persistent antibodies after 24 and 48 weeks and after switching 
• 
Incidence rate of neutralizing antibodies after 24 and 48 weeks and after switching 
• 
Natalizumab trough concentration (Ctrough) over time 
• 
Safety profile (physical examination, and change from baseline in vital sign measurements and 
clinical laboratory tests) over 24 and 48 weeks 

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STATISTICAL METHODS 
Primary Endpoint 
Equivalence between PB006 and Tysabri will be assessed based on the following set of 
hypotheses: 
 
H0: |µPB006 - µTysabri| > 2.1 vs. H1: | µPB006 - µTysabri | ≤ 2.1,  
where µx denotes the cumulative number of new active lesions over 24 weeks in the 
respective treatment group. Data will be analyzed using a negative binomial model and 
equivalence will be tested based on the corresponding 90% and 95% confidence intervals to 
address different regulatory requirements. 
Secondary Endpoints 
Exact 95% confidence intervals will be calculated for the differences between PB006 and 
Tysabri in the incidence rates of positive, persistent and positive neutralizing ADA over 24 
and 48 weeks and for the 24 weeks after re-randomization between patients who switch to 
PB006 at Week 24 and patients who remain on Tysabri. All other endpoints will only be 
analyzed descriptively using summary statistics or frequency tables depending on the type of 
variable. 
Planned Sample Size 
A total of 230 evaluable patients (115 in each group), i.e., patients who complete the 24-week 
treatment period without relevant major protocol deviations and for whom sufficient post-
baseline MRI data are available, are required to achieve 90% power for the equivalence 
assessment with respect to the cumulative number of new active lesions over 24 weeks 
treatment assuming a common standard deviation of 4.0 lesions and no difference between 
both groups. To account for potential dropouts and non-evaluable patients of up to 10%, 
approximately 260 patients will be randomized to either Tysabri or PB006. At Week 24, the 
130 patients in the Tysabri group will be re-randomized. Out of these 130 patients, 
approximately 34 (to account for potential dropouts to reach an approximate minimum of 30) 
random patients will be randomized (switched) to PB006. After re-randomization, the patient 
groups will be: Tysabri group (n=up to 96); Tysabri switch to PB006 group (n=up to 34); and 
PB006 group (n=up to 130). 
The sample size calculation is based on data published by Miller et al., 2003, which showed 
a mean number of cumulative new active lesions of 1.0 (±2.6) in the pooled natalizumab 
groups (3 mg/kg and 6 mg/kg) versus 9.7 (±27.4) in the placebo group in patients with either 
RRMS or secondary progressive MS. An equivalence margin of 2.1 lesions was chosen to 
ensure that 50% of the treatment effect based on the lower bound of the 95% confidence 
interval of the pooled effect size estimated in Miller et al., 2003 will be preserved. 
 

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TIME AND EVENTS SCHEDULE 
Study Period 
Screeninga 
Treatment 
End-of-Study 
Visit/ 
Early 
Discontinuation 
Visit 
Unscheduled 
Relapse 
Assessment 
Visitb 
Unscheduled 
Suspected 
PML Visitb 
PML 
Follow-Up 
Visitc 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/Subsequent 
to 
discontinuation 
 
 
14 
Week 
-4 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
 
 
68 
Permitted visit 
window (days) 
- 
- 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
 
 
±  
14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
Demographics & 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
Xe 
Xe 
 
Xe 
 
Xe 
Xe 
Xe 
 
 
 
 
 
Xe 
 
Xe,f 
Xg 
EDSS  
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
C-SSRS 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Anti-natalizumab 
antibodiesg 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
Natalizumab 
Ctrough  
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Anti-JCV 
antibodies 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 

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Study Period 
Screeninga 
Treatment 
End-of-Study 
Visit/ 
Early 
Discontinuation 
Visit 
Unscheduled 
Relapse 
Assessment 
Visitb 
Unscheduled 
Suspected 
PML Visitb 
PML 
Follow-Up 
Visitc 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/Subsequent 
to 
discontinuation 
 
 
14 
Week 
-4 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
 
 
68 
Permitted visit 
window (days) 
- 
- 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
 
 
±  
14 
Physical 
examination 
Xi 
Xi 
X 
X 
X 
X 
X 
Xi 
X 
X 
X 
X 
X 
Xi 
 
 
Xj 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum pregnancy 
testk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum chemistryl 
serologym, 
urinalysis 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Lumbar puncture 
for CSF sample 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant 
therapy / 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xn 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xo 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 

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Study Period 
Screeninga 
Treatment 
End-of-Study 
Visit/ 
Early 
Discontinuation 
Visit 
Unscheduled 
Relapse 
Assessment 
Visitb 
Unscheduled 
Suspected 
PML Visitb 
PML 
Follow-Up 
Visitc 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13/Subsequent 
to 
discontinuation 
 
 
14 
Week 
-4 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
 
 
68 
Permitted visit 
window (days) 
- 
- 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
± 
 3 
 
 
±  
14 
Biobank samples 
(blood and urine) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Xp 
 
 
 
ALC=absolute lymphocyte count; CSF=cerebrospinal fluid; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EDSS=expanded disability status scale; 
HIV=human immunodeficiency virus; JCV= John Cunningham virus; MRI=magnetic resonance imaging; PML=progressive multifocal leukoencephalopathy. 
a. 
After obtaining informed consent, Screening will consist of 2 parts:  
1. Samples for anti-John Cunningham virus (JCV) antibodies and biobank samples (blood and urine) will be taken. When JCV test results come back: 
a.  JCV index >1.5: The patient will be considered a screen failure. b. JCV index ≤1.5: Proceed with part 2. 
2. For patients with JCV index ≤1.5, the Investigator or designee will set up a second visit for all other screening procedures that will be completed for each patient 
prior to randomization for study treatment.  
b. Unscheduled Relapse Assessment Visit and Unscheduled Suspected PML Visit are only scheduled from visit 1 through visit 13/Subsequent to discontinuation. 
c. 
In case of symptoms suggestive for PML, a PML Follow-Up visit is scheduled earlier. If PML diagnosis is confirmed, no further PML Follow-Up visit is scheduled. Otherwise, 
the patient will be followed up at week 24 ± 2 weeks after last infusion. 
d. Re-randomization of Tysabri group to either Tysabri or PB006 (automatically through randomization system). 
e. 
Assessed by the central reading center. 
f. 
If PML is suspected based on the MRI scan, the MRI should not be repeated.  
g. If PML is suspected, only. Only locally assessed. 
h. Analysis includes testing for neutralizing antibodies for ADA positive sample. 
i. 
Include height and weight measurement at Screening and weight measurement at other noted visits. 
j. 
For any symptoms suggestive for PML. 
k. Only for females of childbearing potential. Serum pregnancy test to be performed at Screening and if a urine pregnancy test is positive. 
l. 
If ALC is confirmed to be <0.2 ×109/L on 2 consecutive tests within 2 weeks, treatment will be interrupted until ALC is >0.5 ×109/L. 
m. HIV-1 and serology tests only performed at Screening. 
n. Medications for MS treatment, only. 
o. PML or AEs related to or suggestive for PML, only. 

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p. Samples are not taken at an Early Discontinuation Visit scheduled due to withdrawal of informed consent. 

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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation  
Term 
ADA 
anti-drug (natalizumab) antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALB 
albumin 
ALC 
absolute lymphocyte count 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ARN 
acute retinal necrosis 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
ATC 
anatomical therapeutic chemical 
CNS 
central nervous system 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIS 
dissemination in space 
DIT 
dissemination in time 
DSMB 
Data Safety Monitoring Board 
DW 
diffusion weighted 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDSS 
Expanded Disability Status Scale 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
ePMF 
electronic project master file 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
(United States) Food and Drug Administration 
FLAIR 
fluid attenuation inversion recovery 
GCN 
granule cell neuronopathy 
GCP 
Good Clinical Practice 
Gd 
gadolinium 
GdE 
gadolinium-enhancing 
GGT 
gamma-glutamyl transferase 

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GRAS 
generally recognized as safe 
HDL 
high-density lipoprotein 
Hct 
hematocrit 
HCV 
anti-hepatitis C virus 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRIS 
Immune Reconstitution Inflammatory Syndrome 
IV 
intravenous 
IWRS 
interactive Web response system 
JCV 
John Cunningham virus 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
MAdCAM 
mucosal addressin cell adhesion molecule 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
NCI 
National Cancer Institute 
PCR 
polymerase chain reaction 
PD 
proton density 
PI 
product information 
PML 
progressive multifocal leukoencephalopathy 
PP 
per-protocol population 
RBC 
red blood cell count 
RMP 
Risk Management Plan 
RMS 
relapsing multiple sclerosis 
RRMS 
relapsing-remitting multiple sclerosis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SmPC 
Summary of Product Characteristics 
SPMS 
secondary progressive multiple sclerosis 
TEAE 
treatment-emergent adverse event 

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TNF-α 
tumor necrosis factor-alpha 
ULN 
upper limit of normal 
VCAM 
vascular cell adhesion molecule 
VZV 
varicella zoster virus 
WBC 
white blood cell count 

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1. 
ETHIC CONSIDERATIONS 
1.1. 
STATEMENT OF COMPLIANCE 
The Sponsor conducts its studies according to the highest ethical and scientific standards in 
accordance with International Council for Harmonisation Good Clinical Practice (ICH GCP), 
the Declaration of Helsinki, and any additional relevant ethics committee or regulatory agency-
required procedures, whichever represents the greater protection for the individual. The 
protocol articulates standards to which investigators will be held accountable, as well as matters 
of compliance to document adherence to such standards. 
It is expected that investigators understand and comply with the protocol. This includes but is 
not limited to adhering to diagnostic or other procedures as specified in the protocol. The study 
will be conducted under a protocol reviewed and approved by an IEC and Regulatory Agency, 
where applicable. Investigators will apply due diligence to avoid protocol deviations; no 
waivers will be permitted. 
The protocol, ICF, recruitment materials, and all participant materials will be submitted to the 
IEC for review and approval. Approval of both the protocol and the ICF must be obtained before 
any participant is enrolled and before any study-related tests or evaluations are performed. 
Any amendment to the protocol will require review and approval by the IEC and Regulatory 
Agency, where applicable, before the changes are implemented to the study. However, the 
IEC/Regulatory Agency may be notified for amendments containing only administrative 
changes. 
All changes to the ICF will require review and approval by the IEC and Regulatory Agency, 
where applicable. A determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent using a previously approved ICF. 
The study will be conducted by scientifically and medically qualified persons. All personnel 
involved in the conduct of this study must complete Human Subjects Protection and ICH GCP 
training. 
1.2. 
INDEPENDENT ETHICS COMMITTEE 
Before implementing this study, the protocol, the ICF, and other information that will be given 
to patients must be reviewed by an IEC. 
A signed and dated statement that the protocol and ICF have been approved by the IEC must 
be filed in the electronic project master file (ePMF) before study initiation. 
The IEC as required by local law, will approve any amendments to the protocol, which need 
formal approval. The IEC may be notified for all other amendments (i.e., administrative 
changes). 
The name and occupation of the chairperson and the members of the IEC (preferred) must be 
filed in the ePMF. 
1.3. 
INFORMED CONSENT AND PATIENT INFORMATION  
No patient can enter the study before his/her informed consent has been obtained. 
The Investigator will explain to each patient the nature of the research study, its purpose, the 
procedures involved, the expected duration, alternative treatment, the potential risks and 
benefits involved and any discomfort, which may occur. Each patient will be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 

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superimposed events. A smaller percentage of patients will have a similar onset but with 
occasional MS attacks (progressive-relapsing). 
Patients with relapsing-remitting MS (RRMS) have acute exacerbations or MS attacks with 
subsequent variable recovery (remission). At the onset of MS, 80% to 85% of patients will have 
the relapsing-remitting form of the disease. Expanded Disability Status Scale (EDSS) scores 
are below 4 in most cases of RRMS. Approximately 10% of patients have benign MS, a subset 
of RRMS characterized by the lack of accumulation of significant residual neurological deficit 
over time, with EDSS scores of <3 after 10 to 15 years of disease. 
Fifty percent (50%) of patients with RRMS will convert to secondary progressive MS (SPMS) 
within 10 years of onset (Runmarker and Andersen, 1993), with the peak time of conversion 
being at about 8 years after disease onset (Paty and Ebers, 1998). The proportion of patients 
with RRMS progressing to SPMS approaches 80% at 25 years. SPMS is characterized by the 
steady accumulation of significant and persistent neurological deficit, with or without 
superimposed MS attacks. Response to first-line therapy may differ based on whether MS 
attacks continue to occur in SPMS. The majority of patients with EDSS scores of 6.0 or higher 
has SPMS. Patients at the early stage of SPMS, generally with an EDSS score between 4 and 
6, present normally still relapses, which however are not characterized by a full recovery of the 
previous functionality or a stage of remission. This group of subjects is called Relapsing MS 
(RMS). 
2.2. 
BACKGROUND INFORMATION ABOUT PB006 
PB006 is developed as a natalizumab biosimilar in the same dosing regimen, route of 
administration, and presentation as the reference medicinal product, Tysabri® (Biogen), 
currently approved by the European Medicines Agency (EMA) and the United States Food and 
Drug Administration (FDA) in RRMS and additionally by the FDA for the treatment of 
moderately to severely active Crohn’s disease. 
PB006 has the same amino acid sequence as the reference product Tysabri. The biochemical 
and physicochemical characteristics as well as secondary and tertiary structure of PB006 and 
the reference product Tysabri are comparable; minor differences are not expected to affect 
biological activity, pharmacokinetic and pharmacodynamic properties, or immunogenicity. An 
alternative formulation has been developed for PB006. The alternative formulation contains 
well-characterized generally recognized as safe (GRAS) excipients only. Given the high degree 
of analytical comparability between Tysabri and PB006, no differences in clinical safety and 
efficacy should be expected. 
The clinical development program is designed following the relevant international guidelines 
and following interactions with FDA, EMA, and the Paul-Ehrlich-Institute in Germany. The 
clinical studies will provide final confirmation regarding similarity between the biosimilar 
candidate PB006 and the reference medicinal product Tysabri. 
Natalizumab is a humanized monoclonal IgG4 antibody that selectively binds to the α4-integrin 
component of adhesion molecules found on lymphocytes, monocytes, and eosinophils. The 
α4-integrin is a subunit of the leukocyte adhesion molecules α4β1 and α4β7. Natalizumab 
inhibits the interaction of α4β1 with vascular cell adhesion molecule (VCAM)-1 and of α4β7 
with mucosal addressin cell adhesion molecule (MAdCAM)-1. VCAM-1 and MAdCAM-1 are 
found on endothelial cells and interact with α4β1 and α4β7 on leukocytes for firm adherence of 
leukocytes to endothelial cells, a requisite step for their extravasation into inflamed tissue. As 
VCAM-1 is expressed on inflamed cerebrovascular endothelial cells, α4β1 is considered to be 
the critical target of natalizumab in preventing leukocyte migration into the CNS in MS. Further 
details regarding the mode of action of natalizumab are provided in the PB006 Investigator’s 
Brochure (IB) and in the Tysabri product information (PI) (Tysabri PI, 2018). 

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Natalizumab therapy is to be initiated and continuously supervised by specialized physicians 
experienced in the diagnosis and treatment of neurological conditions, in sites with timely 
access to MRI. Continued therapy must be carefully reconsidered in patients who show no 
evidence of therapeutic benefit beyond 6 months.  
Refer to the current PB006 IB for additional information regarding relevant nonclinical, 
microbiology, pharmacology, and clinical studies. 
2.3. 
RISKS AND BENEFITS 
Tysabri is indicated as monotherapy for the treatment of patients with RRMS to delay the 
progression of physical disability and to reduce the frequency of relapse. 
Progressive multifocal leukoencephalopathy (PML) is a known risk to patients receiving 
Tysabri (Tysabri PI, 2018). PML is a rare, often fatal viral disease, caused by the JCV, with a 
slow onset resulting in inflammation and demyelination in the white matter of the brain. 
Acquired by 60% to 80% of the adult population, JCV is a human DNA polyoma virus 
(papovavirus) that resides latently in tubular epithelial cells of the kidneys and bone marrow. 
Immune system suppression can reactivate the virus and cause PML (Pietropaolo et al., 2018). 
Approximately 50% of the JCV-positive MS population noted above have a JCV antibody index 
>0.9; approximately 30% have a JCV antibody index >1.5. Pooled data from large clinical 
studies suggest that, in patients with no prior immunosuppressant use, the level of anti-JCV 
antibody response (index) relates to the level of risk for PML (EMA, 2016). Risk estimates for 
PML in JCV antibody positive patients treated with Tysabri are shown in Table 1. For JCV 
antibody negative patients the risk is 0.1 per 1000. Based on the inclusion/exclusion criteria 
(e.g., JCV index ≤1.5, Tysabri naïve, no prior treatment with immunosuppressants), the risk for 
patients in this study is minimized. 
 
Table 1 PML Risk Estimates per 1,000 Patients in Anti-JCV Antibody Positive Patients 
Duration of 
Tysabri Use 
No Prior Use of Immunosuppressants 
Prior Use of 
Immunosuppressants 
No Index 
Value 
Index ≤0.9 
Index 0.9 to 1.5 
Index >1.5 
1-12 months 
0.1 
0.1 
0.1 
0.2 
0.3 
13-24 months 
0.6 
0.1 
0.3 
0.9 
0.4 
25-36 months 
2 
0.2 
0.8 
3 
4 
37-48 months 
4 
0.4 
2 
7 
8 
49-60 months 
5 
0.5 
2 
8 
8 
61-72 months 
6 
0.6 
3 
10 
6 
Source: EMA, 2016 (Original source: Tysabri Physician Information and Management Guidelines) 
 
There is no specific screening test for PML. For this study, investigators will use a combination 
of patient history, physical examination, and radiologic evidence using MRI, EDSS, 
hematology results, and results of testing for JCV DNA presence in CSF to determine a 
diagnosis of PML. See details in Section 2.4. 
There is no consistently effective treatment for PML. Treatments include cytarabine, cidofovir, 
topotecan, mefloquine, and interleukin-2. The goals of treatment are to stop Tysabri 
administration and to treat the underlying disease. 
 

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2.4. 
RISK MANAGEMENT PLAN FOR PML 
Use of Tysabri has been associated with an increased risk of PML (EMA, 2019). PML also has 
been reported following discontinuation of Tysabri in patients who did not have findings 
suggestive of PML at the time of discontinuation. Patients and physicians should continue to 
follow the same monitoring protocol and be alert for any new signs or symptoms that may be 
suggestive of PML for approximately 6 months following discontinuation of Tysabri.  
Three factors that are known to increase the risk of PML in natalizumab-treated patients have 
been identified: 
• Presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a 
higher risk for developing PML. 
• Longer treatment duration, especially beyond 2 years. There is a limited experience in 
patients who have received more than 6 years of natalizumab treatment. 
• Either have used an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, 
cyclophosphamide, mycophenolate mofetil) before starting Tysabri, or have not used 
immunosuppressants and have a high JCV antibody index.  
These factors should be considered in the context of expected benefit when initiating and 
continuing treatment with natalizumab. 
Due to the increased risk of developing PML in patients treated with natalizumab, the Sponsor 
has developed a Risk Management Plan (RMP) for PML. There is no prevention or cure for 
PML. Rapid recognition of PML and early discontinuation of natalizumab are key interventions. 
Therefore, the RMP is focused on early clinical detection and management of PML, including 
discontinuation of study drug, if applicable.  
2.4.1. 
PROCESS AND ASSESSMENTS OF EARLY DETECTION 
To ensure success of the RMP program, training will be provided for study personnel prior to 
start of the study to recognize the signs and symptoms of PML.  
The benefits and risks of Tysabri treatment should be individually evaluated by the Investigator 
and discussed with the patient. Patients will receive training, including how to recognize the 
specific neurological signs and symptoms of PML, how to report these without delay, and 
educational materials prior to receiving study drug. The ICF will contain specific information 
on the risk of PML. 
A baseline anti-JCV antibody test and MRI will be performed for comparison to subsequent 
MRI scans. Prior to the administration of each dose of study drug and until the PML Follow-Up 
Visit, each patient will be assessed for signs and symptoms of PML that may be suggestive of 
PML. Any signs and symptoms of PML will be recorded in the eCRF.  
Symptoms associated with PML are diverse, progress over days to weeks, and include 
progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and 
changes in thinking, memory, and orientation leading to confusion and personality changes. 
The progression of deficits usually leads to death or severe disability over weeks or months. 
During the study, patients who suspect they are experiencing new or worsening neurological 
symptoms, including a possible relapse or PML, are required to call the study site neurologist 
as soon as possible (preferably 24 hours) after onset of the symptoms to set up an Unscheduled 
Relapse Assessment Visit (Section 7.4) or an Unscheduled Suspected PML Visit if the 
Investigator feels the patient is in fact experiencing a relapse or suspected PML, respectively. 
If symptoms occur after the End-of-Study Visit or after the Early Discontinuation Visit, a PML 
Follow-Up Visit is scheduled instead of an Unscheduled Relapse Assessment Visit or an 

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Unscheduled Suspected PML Visit. The visits and the PML Follow-Up Visit should be 
performed as soon as possible within the next 3 days.  
Table 2 Diagnosis of MS Relapse vs PML presents certain clinical features that may help 
differentiate between an MS relapse and PML. 
Table 2 Diagnosis of MS Relapse vs PML 
 
MS Relapse 
PML 
Onset 
Acute 
Subacute 
Evolution 
• 
Over hours to days 
• 
Normally stabilize 
• 
Resolve spontaneously or with 
treatment 
• 
Days to weeks 
• 
Progressive 
Clinical presentation 
• 
Diplopia 
• 
Paresthesia 
• 
Paraparesis 
• 
Optic neuritis 
• 
Myelopathy 
• 
Cortical symptoms/signs 
• 
Behavioral and 
neuropsychological 
alteration 
• 
Retrochiasmal visual 
deficits 
• 
Seizures 
• 
Hemiparesis 
Source: Tysabri, 2013. 
In addition to PML and MS, other medical and CNS conditions including other infections 
should be considered when evaluating patients with new neurological symptoms. 
2.4.2. 
ACTION STEPS IF PML IS SUSPECTED 
2.4.2.1. 
Study Drug Interruption 
The study drug must be interrupted immediately in all cases when PML is suspected. 
Natalizumab dosing should only be resumed if the diagnosis of PML is excluded. 
2.4.2.2. 
PML Diagnosis 
To determine a diagnosis of PML, investigators will use a combination of the following test 
from Visit 1 through the End-of-Study Visit or Early Discontinuation Visit:  
• Patient history  
• EDSS 
• Serum chemistry, hematology, and urinalysis  
• MRI will be performed (FLAIR, T1- and T2-weighted sequences, with or without Gd); if 
findings during a scheduled MRI suggest PML, the MRI may not be repeated  
• Local radiologist will alert the site, CRO, and central MRI reader 
• Central MRI reader will alert the site, Sponsor representative, and CRO 
• The CRO and Sponsor will inform the Data Safety Monitoring Board (DSMB) 
• Lumbar puncture with evaluation of CSF for detection of JCV DNA 
If clinical suspicion of PML remains despite the negative evaluation, then CSF assessment 
should be repeated to exclude the diagnosis of PML. 
If diagnosis remain uncertain and suspicion of PML remains high, further investigations will be 
performed according to the local standards. Cases of PML diagnosed based on MRI findings 
and the detection of JCV DNA in the CSF in absence of clinical signs and symptoms have been 
reported (Tysabri, 2016). Many of these patients become subsequently symptomatic. Periodic 
monitoring for radiologic signs consistent with PML should be considered to allow for an early 

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diagnosis of PML. Lower PML-related mortality and morbidity have been reported following 
natalizumab discontinuation in patients with PML who are initially asymptomatic at diagnosis.  
2.4.3. 
ACTION STEPS IF PML IS CONFIRMED  
2.4.3.1. 
Study Drug Discontinuation 
The study drug must be discontinued immediately in all cases when PML is confirmed. 
Confirmed PML cases should be reported as SAEs/AESIs to the CRO/Sponsor immediately 
(within 24 hours). 
2.4.3.2. 
Treatment of PML 
Plasma exchange may be considered as a means to accelerate the clearance of natalizumab. 
Three sessions of plasma exchange over 5 to 8 days were shown to accelerate natalizumab 
clearance in clinical studies. Additional plasma exchanges (up to a total of 5 over a 10-day 
period) may more consistently reduce natalizumab plasma concentration. 
AEs that may occur during plasma exchange include clearance of other medications and volume 
shift, which have the potential to lead to hypotension or pulmonary edema. 
Immune Reconstitution Inflammatory Syndrome (IRIS) has been reported in the majority of 
patients who developed PML and subsequently discontinued natalizumab. In almost all cases, 
IRIS occurred within days to several weeks after plasma exchange was used to accelerate 
natalizumab clearance. However, natalizumab has not been associated with IRIS in patients 
discontinuing treatment with natalizumab for reasons unrelated to PML.  
IRIS usually presents as an unanticipated clinical decline that may be rapid and severe, can lead 
to serious neurological complications, and may be fatal. IRIS is often associated with 
characteristic changes in the MRI. 
IRIS should be reported as an SAE to CRO/Sponsor immediately (within 24 hours). 
2.4.4. 
FURTHER FOLLOW-UP FOR PML 
After the End-of-Study Visit or after the Early Discontinuation Visit, patients are further 
followed up for PML. 
Physicians should monitor patients for approximately 6 months after discontinuing natalizumab 
and patients should be instructed to contact the study site any time in case they experience new 
signals or symptoms suggestive for PML. A PML Follow-Up Visit is performed 24 weeks 
(± 2  weeks) after the last study drug infusion or earlier in case of new symptoms suggestive for 
PML. If PML diagnosis is confirmed, no additional PML Follow-Up Visit will be scheduled.  
Outcomes of the PML Follow-Up Visit will be recorded in the source data and on an extra eCRF 
page. Data on the extra eCRF page will be kept separately from data in the clinical database. 
Cases of confirmed PML will be included as an addendum to the clinical study report. 
3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate and compare the cumulative number of new 
active lesions over 24 weeks. 
3.2. 
SECONDARY OBJECTIVES 
The secondary objectives of this study are to: 

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• Evaluate and compare the cumulative number of new active lesions over 48 weeks 
• Evaluate and compare the cumulative number of new gadolinium-enhancing (GdE) 
T1-weighted lesions over 24 and 48 weeks 
• Evaluate and compare the number of patients without new GdE T1-weighted lesions over 
24 and 48 weeks 
• Evaluate and compare the cumulative number of new/enlarging T2-weighted lesions over 
24 and 48 weeks 
• Evaluate and compare the number of patients without new/enlarging T2-weighted lesions 
over 24 and 48 weeks 
• Evaluate and compare the number of persistent lesions after 24 and 48 weeks treatment 
with PB006 or Tysabri 
• Evaluate and compare the annualized relapse rates and changes in EDSS after 24 and 
48 weeks 
• Evaluate and compare local and systemic adverse events (AEs) and serious adverse events 
(SAEs) after 24 and 48 weeks 
• Evaluate and compare the immunogenic profile (incidence rate of anti-drug [natalizumab] 
antibodies [ADA] and persistent antibodies) after 24 and 48 weeks and after switching 
• Evaluate and compare the immunogenic profile (incidence rate of neutralizing antibodies) 
after 24 and 48 weeks and after switching 
• Evaluate and compare natalizumab trough concentration (Ctrough) over time 
• Evaluate and compare the safety profile (physical examination, vital sign measurements, 
and clinical laboratory tests) over 24 and 48 weeks 
4. 
INVESTIGATIONAL PLAN 
4.1. 
OVERALL STUDY DESIGN 
This is a Phase 3 multicenter, double-blind, active-controlled, randomized, parallel-group study 
to assess the equivalence in efficacy and similarity in safety of biosimilar PB006 compared to 
Tysabri in patients with RRMS. 
After obtaining informed consent, screening investigations will begin. Screening will consist of 
the following 2 parts: 
1. Samples for anti-JCV antibodies and samples for biobanking (blood and urine) will be 
taken. When JCV test results come back: 
a) JCV index >1.5: The patient will be considered a screen failure. 
b) JCV index ≤1.5: Proceed with part 2. 
2. For patients with JCV index ≤1.5, the Investigator or designee will set up a second visit 
for all other screening procedures that will be completed for each patient prior to 
randomization for study treatment (see the Time and Events Schedule).  
Patient eligibility will be determined by the inclusion and exclusion criteria on screening 
evaluations listed in Sections 5.1 and 5.2. 
All eligible patients will be randomly assigned to one of two treatment groups in a 1:1 ratio, to 
receive intravenous (IV) infusions every 4 weeks of either PB006 or Tysabri at a dose of 300 mg 
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In order to evaluate and compare the immunogenic profile between patients treated with Tysabri 
only and those switching from Tysabri to PB006 at Week 24 and in accordance with FDA 
requirements, the 130 patients in the Tysabri group will be re-randomized at Week 24 (through 
a re-randomization step). Out of these 130 patients, approximately 34 (to account for potential 
dropouts to reach an approximate minimum of 30) random patients will be randomized 
(switched) to PB006. After re-randomization, the patient groups will be: Tysabri group (n=up 
to 96); Tysabri switch to PB006 group (n=34); and PB006 group (n=up to 130). 
The End-of-Study Visit (Visit 13, Week 48) will be performed 4 weeks after the last infusion. 
The evaluations for patients who withdraw prematurely will be the same as for the End-of-
Study Visit. 
Physicians should monitor patients who received at least 1 dose of study drug (including 
prematurely withdrawn patients) for approximately 6 months after discontinuing natalizumab 
and patients should be instructed to contact the study site any time in case they experience new 
signals or symptoms suggestive for PML. A PML Follow-Up Visit is performed 24 weeks 
(± 2 weeks) after the last study drug infusion or earlier in case of new symptoms suggestive for 
PML. If PML diagnosis is confirmed, no additional PML Follow-Up Visit will be scheduled. 
MRI will be performed at Screening, prior to treatment at Visit 1 (Week 0), and at Weeks 8, 16, 
20, 24, 48, at any unscheduled visit in case of a suspected PML, and at a PML Follow-Up Visit 
if PML is suspected. Serum samples for ADA and neutralizing antibody formation will be 
collected prior to treatment at Visit 1 (Week 0), and at Weeks 4, 8, 16, 24, 28, 32, and 48. Blood 
samples for natalizumab Ctrough analyses will be collected prior to treatment at Visit 1 (Week 0), 
and at Weeks 8, 16, 24, 32, and 48. Blood samples for anti-JCV antibody testing and samples 
for biobanking (blood and urine) will be collected at Screening, Week 24, and Week 48. Blood 
samples and urinalysis for safety laboratory assessments will be collected at Screening, prior to 
treatment at Visit 1 (Week 0), and every 8 weeks through the End-of-Study Visit and at 
unscheduled visits in case of a relapse and at unscheduled visits if PML is suspected. 
The primary endpoint will be the radiologic response as measured by the cumulative number of 
new active lesions over a 24-week treatment period, starting with the first infusion at Week 0 
to Week 24. Secondary endpoints to be evaluated after 24 and 48 weeks include radiologic 
response criteria, clinical response as defined by the frequency of relapses, changes in EDSS, 
safety (AEs, physical examination, vital sign measurements, and clinical laboratory tests), 
natalizumab blood concentration and immunogenicity (ADA). 
The following AEs will be considered as AEs of special interest (AESI): PML, JCV granule 
cell neuronopathy (GCN), opportunistic infections, liver injury, hypersensitivity, encephalitis, 
meningitis, and acute retinal necrosis (ARN) (Section 8.10.7). 
Treatment assignments will be blinded to the Investigator/neurologist, study personnel, and the 
patients. 
The overall study flowchart is presented in Figure 1. The Time and Events Schedule for all of 
the study visits follows the synopsis. 

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4.2. 
RATIONALE FOR THE STUDY DESIGN 
The goal of the study is to support the demonstration of biosimilarity between PB006 and 
Tysabri. In particular, the study aims to confirm that there are no clinically meaningful 
differences between PB006 and Tysabri. Therefore, an equivalence design has been chosen in 
line with the applicable biosimilar guidelines. 
4.3. 
NUMBER OF PATIENTS 
Approximately two hundred sixty (260) patients will be randomized in this study. 
4.4. 
REPLACEMENT OF PATIENTS 
Randomized patients who prematurely discontinue study treatment for any reason prior to the 
Week 48 visit will not be replaced. 
4.5. 
 RANDOMIZATION 
Investigators are required to register all patients who sign the ICF in the eCRF with the date the 
ICF is signed. The Investigator/designee will obtain a patient number using an electronic data 
capture (EDC) system. Patients who are screened will be entered into a screening log. Patients 
who do not meet eligibility criteria will be registered as screen failures in the eCRF along with 
the date and reason for screen failure. Patients who meet all eligibility requirements and who 
have signed an ICF will be randomly assigned (using the eCRF Randomization Form) to one 
of the two treatment groups in a 1:1 ratio. Randomization will be used to avoid bias in assigning 
patients to treatment, to increase the likelihood that known and unknown patient attributes (e.g., 
demographics and baseline characteristics) are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across treatment groups. 
Randomization will be stratified by the following factors at Screening: 
• Absence/presence of GdE lesions (0, >0) 
• Presence of T2 lesions (≤15, >15) 
• JCV status for safety (negative, positive) 
Once assigned, patient numbers for any screening failures, non-treated, non-evaluable, or 
discontinued patients will not be re-used. 
If a patient experiences a relapse during screening, re-screening will be allowed and the patient 
will receive a new patient number. 
At Week 24, the 130 patients in the Tysabri group will be re-randomized (through a re-
randomization step). Out of these 130 patients, approximately 34 (to account for potential 
dropouts to reach an approximate minimum of 30) random patients will be randomized 
(switched) to PB006. After re-randomization, the patient groups will be: Tysabri group (n=up 
to 96); Tysabri switch to PB006 group (n=up to 34); and PB006 group (n=up to 130). 
4.6. 
BLINDING AND UNBLINDING PROCEDURES 
This study will be double-blinded with regard to the study drug. The unblinded 
pharmacist/designee will be responsible for maintaining accountability, blinding, and 
dispensing the study drugs according to the handling instructions. Study center personnel, with 
the exception of the unblinded pharmacist/designee, will remain blinded to the identity of the 
study drug until the database has been locked and the study has been unblinded. 

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Individual patient numbers, indicating the treatment for each randomized patient, will be 
available to the investigators or pharmacists from the IWRS. Procedures will be described in 
the IWRS user manual that will be provided to each center. 
To maintain Investigator blinding, the treatment code should not be broken except in medical 
emergencies when the appropriate management of the patient requires knowledge of the 
treatment randomization. In such a case, the patient should receive all appropriate medical care. 
Prior to any unblinding, the Investigator should contact the Medical Monitor (see Contact 
Information) to discuss options. The unblinding procedure will be done through the IWRS 
system. As soon as possible and without revealing the patient’s study drug assignment (unless 
important to the safety of patients remaining in the study), the Investigator must notify the 
Sponsor if the blind is broken for any reason and the Investigator was unable to contact the 
Sponsor prior to unblinding. The Investigator will record in the source documentation the date 
and reason for revealing the blinded treatment assignment for that patient; the treatment 
assignment itself should not be entered into source documentation. 
The Sponsor may break the code for SAEs that are unexpected and are believed to be causally 
related to study drug and that potentially require expedited reporting to regulatory authorities. 
In such cases, the minimum number of Sponsor personnel will be unblinded. Treatment codes 
will not be broken for the planned analyses of data until all decisions on the evaluability of the 
data from each individual patient have been made and documented and databases have been 
locked. 
4.7. 
INTERRUPTION AND STOPPING RULES 
4.7.1. 
INTERRUPTION AND DISCONTINUATION OF STUDY DRUG 
Table 3 presents when to interrupt or discontinue treatment.  

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Table 3 Interruption and Discontinuation of Study Drug 
Disease/Condition 
Diagnosis Stage/Labs 
Treatment 
Interruption 
Testing Required 
Resume 
Treatment 
Withdrawal From Study 
Drug and Early 
Discontinuation Visit 
PML 
Suspected 
X 
Schedule confirmatory testing 
within 3 days (i.e., patient history, 
physical examination, MRI, EDSS, 
hematology, test for JCV DNA  
presence in CSF) 
 
 
Not diagnosed during confirmatory 
testing 
 
 
X 
 
Confirmed  
 
 
 
X 
JCV GCN  
Suspected 
(same symptoms as PML) 
X 
 
 
 
Confirmed 
 
 
 
X 
Opportunistic infections (as 
defined in Section 8.10.7.3) 
 
 
 
 
X 
 
Liver injury 
Jaundice  
ALT or AST >5x ULN (until 
confirmation) 
X 
 
Perform repeat lab tests 
 
 
 
Normal lab results 
 
 
X 
 
ALT or AST >8x ULN (not confirmed)  
ALT or AST >5x ULN (confirmed, 
retest required within 14 days) 
ALT or AST >3x ULN (confirmed) in 
conjunction with elevated total bilirubin 
>2x ULN or international normalized 
ratio (INR) >1.5, or 
 
 
 
X 
 

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Disease/Condition 
Diagnosis Stage/Labs 
Treatment 
Interruption 
Testing Required 
Resume 
Treatment 
Withdrawal From Study 
Drug and Early 
Discontinuation Visit 
ALT or AST >3 × ULN with appearance 
of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, 
and / or eosinophilia 
Hypersensitivity  
(not including infusion-related 
reactions) 
 
 
 
 
X 
Encephalitis 
 
 
 
 
X 
Meningitis 
 
 
 
 
X 
ARN 
Suspected (Patients presenting with eye 
symptoms such as decreased visual 
acuity, redness and painful eye) 
X 
 
Refer for retinal screening for ARN 
 
 
Confirmed 
 
 
 
X 
Low lymphocyte count 
ALC <0.2 ×109/L on 2 consecutive tests 
within 2 weeks  
X 
 
 
 
 
ALC returns to >0.5 ×109/L 
 
 
X 
 
Suicidal ideation/suicidal 
behaviors 
At any C-SSRS test post screening, the 
score is “yes” on any item of the Suicidal 
Ideation section or “yes” on any item of 
the Suicidal Behavior section. 
 
 
Refer patient to a mental health 
professional for further assessment 
and/or treatment. The decision on 
whether the study drug should be 
discontinued is to be taken by the 
Investigator in consultation with the 
mental health professional 
 
To be determined 
ALC=absolute lymphocyte count; ALT= alanine aminotransferase; ARN=acute retinal necrosis; AST= aspartate aminotransferase; CSF=cerebrospinal fluid; C-SSRS=Columbia-
Suicide Severity Rating Scale; EDSS=expanded disability status scale; GCN=granule cell neuronopathy; JCV= John Cunningham virus; MRI=magnetic resonance imaging; 
PML=progressive multifocal leukoencephalopathy; ULN=upper limit of normal. 
 

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4.7.2. 
WITHDRAWAL FROM THE STUDY 
Every reasonable effort should be made to encourage retention of patients in the study, 
maximize compliance with the study protocol requirements, and facilitate attendance at all 
scheduled study visits. 
All patients have the right to refuse further participation in the study at any time and for any 
reason. A patient’s participation must, therefore, be terminated immediately upon his/her 
request. 
The Investigator will make every attempt to ascertain the reason(s) for withdrawal and to 
document this in detail in the source documentation and the appropriate sections of the eCRF. 
Patients should be withdrawn from the study due to any of the following reasons: 
• Patient withdraws consent 
• Patient is noncompliant, defined as refusal or inability to adhere to the study procedures 
• Patient becomes pregnant 
• Unacceptable or intolerable treatment-related AEs 
• Use of any other investigational treatment 
• Any illness or circumstance (e.g., incarceration) that would substantially impact the study 
procedures or outcome measures 
• At the request of the Sponsor, regulatory agencies, or IEC 
• Loss to follow-up, i.e., the patient did not return to the clinic and attempts to contact the 
patient were unsuccessful; three attempts to contact the patient must be documented (i.e., 
2 attempts by phone and 1 attempt by registered letter) 
• Patients who discontinue study drug treatment permanently as listed in Table 3 
In case of premature withdrawal of the patient from the study, he/she will be asked to perform 
the Early Discontinuation Visit assessments (Time and Events Schedule). Withdrawn patients 
who received at least 1 dose of study drug will be followed up for PML for 24 weeks 
(+/- 2 weeks). 
4.8. 
EXPECTED STUDY DURATION 
The total study period for each patient will be approximately 52 weeks (4 weeks of screening 
and 48 weeks of treatment). In addition, patients are required to come for a PML Follow-Up 
Visit 24 weeks after last study drug infusion. 
5. 
STUDY POPULATION SELECTION 
The specific inclusion and exclusion criteria for enrolling patients in this study are described in 
the following sections. 
5.1. 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible to participate in the study: 
1. Male and female patients (age ≥18 to 60 years), with RRMS, defined by the 2010 
revised McDonald criteria (Appendix 1). 
2. At least 1 documented relapse within the previous year and either ≥1 GdE 
T1-weighted brain lesions or ≥9 T2-weighted brain lesions at Screening. 

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3. Kurtzke EDSS score from 0 to 5 (inclusive) at Screening. 
4. At Screening, females of childbearing potential must be non-pregnant and non-
lactating; or females should be of non-childbearing potential (either surgically 
sterilized or physiologically incapable of becoming pregnant, or at least 1 year post-
menopausal [amenorrhea duration of 12 consecutive months]); non-pregnancy will be 
confirmed for all females of childbearing potential by a serum pregnancy test 
conducted at Screening. 
5. Female patients of childbearing potential, with a fertile male sexual partner, must use 
adequate contraception from Screening until 90 days after the last dose of study drug 
(Visit 12, Week 44, or earlier, if treatment is discontinued sooner). Adequate 
contraception is defined as using hormonal contraceptives or an intrauterine device, 
combined with at least one of the following forms of contraception: a diaphragm or 
cervical cap, or a condom. Total abstinence from heterosexual activity, in accordance 
with the lifestyle of the subject, is acceptable. 
6. Male patients who are sexually active with women of childbearing potential agree they 
will use adequate contraception from Screening until 90 days after the last dose of 
study drug (at Visit 12, Week 44, or earlier, if treatment is discontinued sooner) if not 
surgically sterilized at least 6 months before Screening (with a post-vasectomy semen 
analysis negative for sperm). Male patients must not donate sperm until 90 days after 
the last dose of study drug (Visit 12, Week 44, or earlier, if treatment is discontinued 
sooner). Adequate contraception for the male subject and his female partner of 
childbearing potential is defined as using hormonal contraceptives or an intrauterine 
device, combined with at least one of the following forms of contraception: a 
diaphragm or cervical cap, or a condom. Total abstinence from heterosexual activity, 
in accordance with the lifestyle of the subject, is acceptable. 
7. Signed and dated ICF. 
5.2. 
EXCLUSION CRITERIA 
Patients who exhibit any of the following exclusion criteria will not be eligible for admission 
into the study: 
1. Manifestation of MS other than RRMS. 
2. Relapse within the 30 days prior Screening and until administration of the first dose of 
study drug. 
3. Prior treatment with natalizumab, alemtuzumab, ocrelizumab, daclizumab, rituximab, 
cladribine, or other B- and T-cell targeting therapies. 
4. Prior total lymphoid irradiation or bone marrow or organ transplantation.  
5. Any prior treatment within the following time period prior to Screening: 
• 30 days: systemic corticosteroids or interferon-β or glatiramer acetate 
• 2 months:  
 fingolimod 
 any other sphingosine-1-phosphate receptor modulator (e.g., 
siponimod) 

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 any tumor necrosis factor-alpha (TNF-α) inhibitors  
• 2 months: dimethyl fumarate 
• 3.5 months: teriflunomide  
• 2 months: dimethyl fumarate 
• 12 months: immunosuppressive therapy for indications other than MS (e.g., 
cytarabine, azathioprine, methotrexate, cyclophosphamide, cyclosporine, 
cladribine)  
6. Any prior treatment with mitoxantrone. 
7. Active infections requiring oral or parenteral antibiotic treatment within 2 weeks prior 
to Screening.  
8. Increased risk of opportunistic infections; exclusion determination to be made after 
consultation with the Medical Monitor. 
9. Patients with JCV index >1.5 at Screening. 
10. Past or current PML diagnosis. 
11. Presence of malignancies or neoplastic diseases; past history of malignancies within 
5 years prior to Screening (except basal cell and in situ squamous cell carcinomas of 
the skin that have been excised and resolved). 
12. History or known presence of recurrent or chronic infection other than recurring 
urinary tract infections (i.e., hepatitis A, B, or C, human immunodeficiency virus 
[HIV], tuberculosis). 
13. Clinically relevant, severe cardiac or pulmonary diseases, uncontrolled hypertension, 
or poorly controlled diabetes. 
14. Severe renal function impairment as defined by serum creatinine values >120 μmol/L. 
15. Elevated liver markers:  
• Alanine aminotransferase (ALT) >3x upper limit of normal (ULN) 
• Aspartate aminotransferase (AST) >3x ULN, or  
• Total bilirubin 2x ULN 
Patients with documented Gilbert syndrome can be enrolled after approval by the Medical 
Monitor. 
16. Decreased white blood cell counts (WBCs) at Screening: 
• WBC <3.0 ×109/L 
• Absolute neutrophil count (ANC) <1.0 ×109/L, or 
• Absolute lymphocyte count (ALC) <0.5 ×109/L. 
17. Unable to understand the patient information and ICF. 
18. Unable or unwilling to comply with the protocol requirements. 

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19. Alcohol or drug dependence within 1 year prior to study entry. 
20. Self-reported symptoms of depression and/or suicidal thoughts based on the 
Columbia-Suicide Severity Rating Scale (C-SSRS). 
21. Any investigational drug within 3 months prior to enrollment or within 5 times of its 
half-life, whichever is longer. 
22. Unable to undergo MRI scans due to claustrophobia or metallic implants incompatible 
with MRI. 
23. Unable to receive Gd-based MRI-contrast agents due to history of hypersensitivity to 
Gd-based contrast agents or severe renal insufficiency. 
24. Has a known contraindication and (or) hypersensitivity to any of the constituents of 
the study drug or comparator drugs, including their excipients. 
6. 
TREATMENT OF PATIENTS 
6.1. 
DESCRIPTION OF STUDY DRUGS 
6.1.1. 
TEST DRUG – BIOSIMILAR - PB006 
The test drug, PB006, natalizumab biosimilar, is a concentrate for solution for IV infusion. 
PB006 is provided in an alternative formulation to Tysabri, based on well-established excipients 
and containing the same concentration of natalizumab as the reference (comparator) product. 
The detailed composition is: 20 mg/mL natalizumab, 10 mM L-histidine/L-histidine 
hydrochloride, 150 mM sodium chloride, 0.02% (w/v) polysorbate 80, pH 5.7. 
6.1.2. 
COMPARATOR DRUG - TYSABRI 
Tysabri (International Nonproprietary Name [INN]: natalizumab), European Union (EU)-
sourced, is a concentrate for solution for IV infusion. The detailed composition is: 20 mg/mL 
natalizumab, 10 mM sodium phosphate, 140 mM sodium chloride, 0.02% (w/v) polysorbate 80, 
pH 6.1. 
6.1.3. 
PREPARATION AND ADMINISTRATION 
Both study drugs will be diluted with 100 mL sodium chloride solution (0.9%), resulting in a 
natalizumab concentration of approx. 2.6 mg/mL for administration. 
After dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, immediate use is 
recommended. If not used immediately, the diluted solution must be stored at 2˚C to 8˚C and 
infused within 8 hours of dilution. If the diluted study drug is stored at 2˚C to 8˚C (do not 
freeze), allow the solution to warm to room temperature prior to infusion. 
The diluted solution is to be infused intravenously over 1 hour at a rate of approximately 
2 mL/minute. After the infusion is complete, flush the intravenous line with sodium chloride 
9 mg/mL (0.9%) solution for injection. 
For further details regarding preparation and administration, consult the Pharmacy Manual. 
6.1.4. 
STORAGE, HANDLING, AND ACCOUNTABILITY  
All study drug(s) and preparation/administration materials (infusion sets, catheters, transfer 
syringes, needles and isotonic saline bottles) will be supplied to the investigators. The 
Investigator or designee must confirm appropriate temperature conditions have been maintained 

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during transit for all study intervention received and any discrepancies are reported and resolved 
before use of the study intervention. 
Only participants enrolled in the study may receive the study drug and only authorized site staff 
may supply or administer study intervention. All study drugs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
For details of storage and handling, please refer to the Pharmacy Manual. 
6.2. 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications taken within 30 days prior to Screening, and all concomitant therapy 
administered during the study, should be recorded on the relevant eCRF page(s), along with the 
reason for, and details of, therapy use. 
The patient’s complete MS medication history should be recorded on the relevant eCRF page(s), 
along with the reason for, and details of, therapy use. 
6.2.1. 
ALLOWED MEDICATIONS  
The following medications are allowed during this study: 
• Corticosteroids (IV methylprednisolone 1g once daily) for 3 to 5 days for treatment of 
relapses 
• Symptomatic MS treatments, if they are stable for at least 3 months prior to Screening 
6.2.2. 
PROHIBITED MEDICATIONS  
The use of medications is restricted from Screening through the End-of-Study Visit/ Early 
Discontinuation Visit. 
Study drug (PB006 or Tysabri) should not be administered in combination with other disease-
modifying agents, including natalizumab, alemtuzumab, ocrelizumab, daclizumab, rituximab, 
cladribine, and other B- and T-cell targeting therapies, interferons, glatiramer acetate, 
fingolimod, any other sphingosine-1-phosphate receptor modulator (e.g., siponimod), any TNF-
α inhibitors, teriflunomide, dimethyl fumarate, immunosuppressive therapy (e.g., cytarabine, 
azathioprine, methotrexate, cyclophosphamide, cyclosporine, cladribine), mitoxantrone, or any 
other investigational treatment. 
Systemic corticosteroid therapy or adrenocorticotropic hormone, except for treatment of 
relapses as defined in 6.2.1. 
Corticosteroids that are by non-systemic routes (e.g., topical, inhaled, intra-articular) are 
allowed. 
6.3. 
TREATMENT COMPLIANCE 
Treatment compliance will be documented by recording the infusion time in the eCRF (start/end 
time plus any complications during the infusion) and by drug accountability. 

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7. 
STUDY ACTIVITIES BY VISIT 
The study is divided into phases with associated evaluations and procedures that must be 
performed at specific time points, as described in the following sections. The Time and Events 
Schedule summarizes the frequency and timing of study events. 
As soon as the patient is considered for this study, and prior to any other study procedures, the 
patient will have the nature of the study explained to them, and will be asked to give written 
informed consent (Section 1.3). Informed consent must be obtained prior to any procedures that 
do not form a part of the patient’s normal care. 
All patients (withdrawn or completed) will have evaluations and procedures performed as 
described for the End-of-Study Visit. 
7.1. 
SCREENING PHASE  
Written informed consent must be obtained before any study-related procedures are performed.  
Patients will be evaluated for entry criteria during the screening period within 4 weeks prior to 
administration of study drug. 
Screening will consist of the following 2 parts: 
1. Samples for anti-JCV antibodies and samples for biobanking (blood and urine) will be 
taken. When JCV test results come back: 
a. JCV index >1.5: The patient will be considered a screen failure. 
b. JCV index ≤1.5: Proceed with part 2. 
2. For patients with JCV index ≤1.5, the Investigator or designee will set up a second 
visit for the following screening procedures that will be completed for each patient 
prior to randomization for study treatment: 
• Assessment of eligibility 
• Demographics and baseline characteristics 
• Medical history 
• MRI 
• EDSS 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Physical examination, including height and weight 
• Vital signs (heart rate, body temperature, blood pressure) 
• Serum pregnancy test for females of childbearing potential only 
• Clinical laboratory tests (serum chemistry, serology, hematology, and urinalysis) 
• Review and documentation of prior (within the previous 30 days) medications, any 
medications used for MS treatment,  and concomitant medications 
• Assessment of AEs 
• 12-lead electrocardiogram (ECG) 
If a patient relapses during the screening process, re-screen after 30 days of the relapse and 
provide a new patient number. 

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7.2. 
TREATMENT PHASE 
This period begins with randomization (Section 4.4) of the patients found to be eligible for the 
study during the Screening Phase. 
The first administration of study drug (either PB006 or Tysabri, 300 mg dose) will be given at 
Visit 1, Week 0 and continues through the end-of-visit 12, Week 44 (±3 days). Each patient 
should remain at the site for 1 hour after the first infusion is complete to monitor for any 
infusion/hypersensitivity reactions (Section 8.10.7). 
During the Treatment Phase, the following evaluations will be conducted and the data will be 
collected and recorded on the eCRF at each scheduled visit (or as indicated). 
Visit 1 Week 0 
• MRI 
• EDSS 
• ADA 
• Physical examination, including weight 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Samples to determine natalizumab trough concentration (Ctrough) 
• Assessment of concomitant medications 
• Assessment of AEs (including infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 2 Week 4 (±3 days) 
• ADA 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 3 Week 8 (±3 days) 
• MRI 
• ADA 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 

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• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Samples to determine natalizumab trough concentration (Ctrough) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 4 Week 12 (±3 days) 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 5 Week 16 (±3 days) 
• MRI  
• ADA 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Samples to determine natalizumab trough concentration (Ctrough) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 6 Week 20 (±3 days) 
• MRI  
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 

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Visit 7 Week 24 (±3 days) 
At Week 24, patients previously receiving Tysabri will be re-randomized and may be switched 
to receive PB006 for the remaining treatment period (Approximately 34 out of the 130 patients 
in the Tysabri group will be switched to PB006). The switching of patients to the PB006 group 
will be done automatically by the randomization system in a blinded manner. 
In addition, the following evaluations will be performed at Week 24: 
• MRI 
• EDSS 
• C-SSRS 
• ADA 
• Anti-JCV antibodies (should the JCV index value be >1.5 the Investigator should re-
evaluate the risk and benefits of continuing natalizumab treatment) 
• Physical examination, including weight 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Samples to determine natalizumab trough concentration (Ctrough) 
• Biobank samples (blood and urine) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 8 Week 28 (±3 days) 
• ADA 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 9 Week 32 (±3 days) 
• ADA  
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 

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• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Samples to determine natalizumab trough concentration (Ctrough) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 10 Week 36 (±3 days) 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 11 Week 40 (±3 days) 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 
Visit 12 Week 44 (±3 days) 
• Physical examination 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
• Study drug administration 

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7.3. 
END-OF-STUDY VISIT OR EARLY DISCONTINUATION VISIT 
The End-of-Study Visit will be scheduled at Visit 13 Week 48 (±3 days) for all patients treated 
in the study. 
All patients who withdraw or who are withdrawn must be asked to attend an Early 
Discontinuation Visit as soon as possible after withdrawal. 
• MRI 
• EDSS  
• C-SSRS 
• ADA 
• Anti-JCV antibodies 
• Physical examination, including weight 
• Vital signs (heart rate, body temperature, blood pressure) 
• Urine pregnancy test for females of childbearing potential only (serum test to be 
performed if urine test is positive) 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Samples to determine natalizumab trough concentration (Ctrough) 
• Biobank samples (blood and urine, except in case of patients’ withdrawal of informed 
consent) 
• Assessment of concomitant medications 
• Assessment of AEs (including assessing for new neurological signs/symptoms of PML 
and infusion/hypersensitivity reactions 1 hour post infusion) 
7.4. 
UNSCHEDULED RELAPSE VISIT 
7.4.1. 
DEFINITION OF RELAPSE 
The general definition of relapse is the appearance of a new neurological abnormality or 
worsening of previously stable or improving pre-existing neurological abnormality, separated 
by at least 30 days from onset of a preceding clinical demyelinating event (National Clinical 
Guidelines Center, 2014). The abnormality must be present for at least 24 hours and have 
occurred in the absence of fever (<37.5° C) or infection. 
7.4.2. 
PROCEDURES FOR EVALUATION OF SUSPECTED RELAPSE 
In case of suspected relapse from Visit 1 through the End-of-Study Visit or Early 
Discontinuation Visit, patients are required to contact the site to be evaluated for relapse and 
need to have easy access to schedule an appointment. The study coordinator must be able to 
coordinate patient and physician assessments for unscheduled relapse visits. The visit must be 
scheduled as soon as possible within 3 days. 
A relapse must be confirmed by the blinded rater (examining neurologist; see Section 8.3). It is 
recommended that this occurs within 3 days of the onset of symptoms. A relapse is confirmed 
when it is accompanied by an increase of at least half a step (0.5) on the EDSS or an increase 
of 1 point on two different Functional Systems of the EDSS or 2 points on one of the Functional 
Systems (excluding Bowel/Bladder or Cerebral Functional System). 
After the relapse is confirmed, a post-baseline EDSS should be conducted 4 weeks after 
confirmation. 

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Relapses should be managed according to usual clinical practice. If treating a relapse with 
corticosteroids: 
• A single short course of methylprednisolone can be considered for cases in which PML is 
unlikely on clinical grounds 
• Progression of symptoms, despite treatment with corticosteroids, should trigger further 
investigations 
If a corticosteroid is used to treat the relapse, the study-related MRI scans should be obtained 
before corticosteroid therapy is initiated. If this cannot be done, the MRI scan is to be taken 
14 days or more after the last corticosteroid dose. 
7.4.3. 
PROCEDURES AFTER A RELAPSE 
7.4.3.1. 
During Screening 
In case of relapse during screening, the patient can be re-screened and will receive a new patient 
number. Prior to re-screening the patient will sign again the currently approved version of the 
ICF. In case some of the screening procedures will not need to be repeated, this will be explained 
to the patient. 
7.4.3.2. 
After Enrollment 
The Investigator must discuss with the patient the risk/benefit of continuing participation in the 
study post relapse. This discussion and the decision of the patient regarding further study 
participation must be noted in the source documents. 
7.5. 
UNSCHEDULED PML VISIT 
If PML is suspected, from Visit 1 through the End-of-Study Visit or Early Discontinuation 
Visit, study drug will be interrupted and the Investigator will schedule confirmatory testing as 
soon as possible within 3 days. For more details, see the RMP for PML (Section 2.4). 
7.6. 
PML FOLLOW-UP VISIT 
Upon completion of, or early termination from the study, all patients (also those withdrawn due 
to other reasons than PML) who have received at least 1 infusion of study drug will be required 
to return to the clinic for a PML Follow-Up Visit 24 weeks ± 2 weeks after the last infusion of 
study drug. Patients should contact the study site in case they experience symptoms suggestive 
for PML. If patients experience symptoms suggestive for PML after the End-of-Study or Early 
Discontinuation Visit but before 24 ± 2 weeks after the last infusion, a PML Follow-Up Visit 
is scheduled as soon as possible within 3 days. If during a PML Follow-Up Visit PML diagnosis 
is confirmed, no further PML Follow-Up Visit is scheduled. Otherwise, patients will be 
followed up further until 24 ± 2 weeks after last infusion. 
• Physical examination for any symptoms suggestive for PML 
• MRI (only in case of symptoms suggestive for PML). MRI to be assessed locally, only 
• Assessment for medications for MS treatment 
• PML or AEs related to or suggestive for PML, only 
8. 
STUDY PROCEDURES 
The Time and Events Schedule summarizes the frequency and timing of the study events listed 
in this section. 

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8.1. 
DEMOGRAPHICS AND MEDICAL HISTORY 
Once the signed ICF (Section 1.3) is obtained, the inclusion/exclusion criteria have been 
assessed (Sections 5.1 and 5.2), and the patient has been randomized, the Investigator or 
designee will collect the demographic information (e.g., age, gender) and enter it into the eCRF. 
Relevant medical findings will be collected from the patient’s medical history, which may 
include age at initial diagnosis of MS, and specific information concerning prior or existing 
medical conditions. 
8.2. 
MAGNETIC RESONANCE IMAGING 
Brain MRI scans to provide radiologic response data for assessing lesions will be done at each 
site. Identification of GdE T1-weighted lesions and T2-weighted lesions will be done by a 
trained and certified radiology reviewer according to standard procedures at the MRI central 
reading center. 
Before any site can screen patients, they will be required to perform test (“dummy”) scans. The 
purpose of the dummy scan is to ensure that adequate image quality, consistent patient 
positioning, and measurements reproducibility are obtained through the use of appropriate MRI 
pulse sequence parameters. 
Patients undergoing these test scans will have to sign a separate Dummy MRI ICF after being 
instructed carefully by the local MRI staff on the purpose, risks, and procedures of the test scan. 
For appropriate and safe conduct of the test scans, the MRI staff is to follow the procedures in 
the MRI Manual. The test scans will be prepared and filed at the MRI site and in the ePMF.  
The image quality of each scan (test scans and trial scans) will be reviewed at the MRI central 
reading center with predetermined criteria; unsatisfactory images will be rejected and, in such 
cases, a repeat scan will be requested. If a repeat scan is necessary for the Screening visit, it is 
imperative that it is acquired as soon as possible and before the first study dose, as applicable. 
For each patient evaluated in this study, scans will be performed using the same machine and 
similar operational parameters throughout the trial, if possible. 
To preserve patient confidentiality, the full name of the patient must not appear on the images. 
The scans should contain at least the following identifiers: patient number, study site number, 
date of investigation, and visit number. A comment line should specify the name and the volume 
of the contrast agent delivered. 
Baseline (Visit 1) MRI must be conducted on the day of dosing (randomization date) and prior 
to study drug administration. MRI scans for Week 8 to Week 48 should be planned as per the 
dosing date from the Baseline visit (Visit 1) of each patient. 
MRI for each of these visits must be performed before dosing and within the visit window. 
Early Discontinuation Visit (Visit 13) MRI must be performed as soon as possible after 
withdrawal. 
Unscheduled visits for suspected PML MRI must be performed within 3 days of suspected 
PML. If PML is clinically suspected from Visit 1 through the End-of-Study Visit or the Early 
Discontinuation Visit, the local radiologist should alert the Investigator who will schedule an 
Unscheduled Suspected PML Visit with the patient within 3 days. If PML was suspected 
based on a scheduled MRI scan, a new MRI should not be acquired for the unscheduled visit. 
For further details regarding MRI acquisition windows, consult the Central MRI Reader 
Manual. 
Brain MRI scans performed at a PML Follow-Up Visit will be assessed locally, only. 

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8.2.1. 
CONTRAST AGENT 
The EMA has provided recommendations on restriction of use of linear Gd agents in body scans 
based on a scientific review that found Gd deposition in the brain and other tissues (EMA, 2017) 
following use of gadolinium contrast agents. The EMA has stated that there is currently no 
evidence that Gd deposition in the brain has caused any harm to patients; however, EMA has 
recommended restrictions for some IV linear agents in order to prevent any risks that could 
potentially be associated with Gd brain deposition. The EMA recommended that use of the IV 
linear products gadodiamide, gadopentetic acid, and gadoversetamide be suspended in the EU. 
Another class of Gd agents known as macrocyclic agents (gadobutrol, gadoteric acid, and 
gadoteridol) are more stable and have a lower propensity to release Gd than linear agents. The 
EMA recommended that these products can continue to be used in their current indications but 
at the lowest doses that enhance images sufficiently and only when unenhanced body scans are 
not suitable (EMA, 2017). 
Based on the EMA recommendations, a macrocyclic Gd-based contrast agent (gadobutrol, 
gadoteric acid, or gadoteridol) will be administered as an IV infusion of 0.1 mmol/kg. The 
administration of Gd, including the brand used and the dose given will be documented in the 
eCRF. 
Creatinine/estimated glomerular filtration rate (eGFR) values should be available during 
screening visit and within 3 months prior to each MRI scan with contrast agent to allow safe 
administration of contrast agent in accordance with patient’s renal function. 
For patients with acceptable eGFR values (i.e., eGFR values ≥50 mL/min/1.73m2) obtained at 
the baseline (Visit 1) and subsequent Visits 3, 5, 6 and 7, the eGFR value obtained at Visit 7 
remains valid until EOS MRI assessment. 
For patients without stable eGFR values throughout the previous period (i.e., any eGFR value 
<50 mL/min/1.73m2), an additional (local) creatinine test and eGFR value needs to be obtained 
in order to ensure the MRI with contrast agent can safely be taken at EOS Visit. 
8.2.2. 
SUSPECTED PML 
If PML is clinically suspected from Visit 1 through the End-of-Study Visit or Early 
Discontinuation Visit, the local radiologist will alert the Investigator who will schedule an 
Unscheduled Suspected PML Visit with the patient within 3 days. MRI scans will immediately 
be reviewed by the central reading center. The results of the review will be communicated to 
the site, Sponsor, and CRO immediately. For more details, see the RMP for PML (Section 2.4). 
If PML is suspected after the End-of-Study Visit or Early Discontinuation Visit, a PML 
Follow-Up Visit is scheduled. 
8.2.3. 
MS RELAPSES / CORTICOSTEROID TREATMENT 
In the event of a relapse, the study-related MRI scans should be obtained before corticosteroid 
therapy is initiated. If this cannot be done, the MRI scan is to be taken 14 days or more after the 
last corticosteroid dose. 
8.3. 
KURTZKE EXPANDED DISABILITY STATUS SCALE 
The Kurtzke EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic 
examination) to 10 (death due to MS) in half-point increments. Based on a standard neurological 
examination, the 7 functional systems (plus "other") are rated. These ratings are then used in 
conjunction with observations and information concerning gait and use of assistive devices to 
rate the EDSS. 

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EDSS ratings will be performed by independent examining neurologists. The independent 
neurologists have no access to other patient data. Training (through Neurostatus, level C 
certification) must be documented in the ePMF. Preferably, and if feasible, the same rater 
should examine the same patient throughout the course of the study. The examining physician 
should have a back-up if the primary physician is unavailable. 
8.4. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
The rater/clinician-administered versions of the C-SSRS assess severity and intensity of suicidal 
ideation, types of suicidal behaviors, and lethality of suicide attempts. There are 11 categories 
defined in the C-SSRS (5 subtypes of suicidal ideation, 5 subtypes of suicidal behavior, and 
self-injurious behavior without suicidal intent). The ratings will be assessed per the instructions. 
At Screening, the C-SSRS result will be used to determine study eligibility. 
After randomization, a positive outcome on the C-SSRS would require that the patient be 
referred to a mental health professional for further assessment and/or treatment. The decision 
on whether the study drug should be discontinued is to be taken by the Investigator in 
consultation with the mental health professional and should be documented in the eCRF. 
8.5. 
PHYSICAL EXAMINATION 
Physical examinations will include the following assessments: 
• Weight (kg) (to be collected at Screening, and Weeks 0, 24, 48) and height (cm) (to be 
collected at the Screening visit only) 
• Examination of the injection site and draining nodes (at all visits except screening visit) 
• Head/ears/eyes/nose/throat examination 
• Auscultation of lungs 
• Abdominal examination (liver, spleen, and lower abdomen) 
• Assessment for neurological deficits 
• Musculoskeletal assessment 
Any abnormalities will be recorded in the eCRF. 
8.6. 
VITAL SIGNS 
Vital signs (heart rate, body temperature, and blood pressure) will be measured in the sitting 
position after resting for at least 5 minutes. 
If blood samples are scheduled at the same time, vital signs should be measured before the 
blood draw. 
Blood pressure may be measured manually or with an automated device, preferably in the non-
dominant arm. The same measurement technique should be used throughout the study for each 
patient. 
Body temperature will be measured with an electronic device. 
8.7. 
12-LEAD ELECTROCARDIOGRAM 
For the Screening 12-lead ECG, the patient should be in a supine position (lying down) for at 
least 5 minutes prior to and during the recording. The ECG will be assessed as normal or 
abnormal by the Investigator; any abnormal findings will be described in the eCRF and the 
Investigator will assess clinical significance. The ECG recording strip will be signed and dated 
by the Investigator and stored in the medical records. 

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The ECG should be performed prior to the blood draws. 
8.8. 
PREGNANCY AND CONTRACEPTION 
During Screening, one criterion of the patient’s eligibility to be included in the study is if they 
are willing to practice contraception from Screening until 90 days after the last dose of study 
drug at Visit 12, Week 44 (or earlier, if treatment is discontinued sooner). 
Female patients are to be: 
• Post-menopausal (12 consecutive months of spontaneous amenorrhea), or 
• Surgically sterilized or physiologically incapable of becoming pregnant  and at least 
6 weeks post-sterilization, or 
• Of childbearing potential with a negative pregnancy test at Screening, and using or 
agreeing to use adequate methods of contraception (see description below) from Screening 
until 90 days after the last dose of study drug at Visit 12, Week 44 (or earlier, if treatment 
is discontinued sooner), if they have a fertile male sexual partner. 
Male patients are to be: 
• Surgically sterilized at least 6 months before Screening (with a post-vasectomy semen 
analysis negative for sperm), or 
• Using or agreeing to use adequate methods of contraception (see description below) from 
Screening until 90 days after the last dose of study drug at Visit 12, Week 44 (or earlier, if 
treatment is discontinued sooner), if they have a fertile female sexual partner. 
Male patients must not donate sperm until 90 days after the last dose of study drug (Visit 12, 
Week 44 or earlier, if treatment is discontinued sooner). 
Adequate contraception is defined as using hormonal contraceptives or an intrauterine device, 
combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, 
or a condom. Also, total abstinence from heterosexual activity, in accordance with the lifestyle 
of the subject, is acceptable. 
Also, female patients must not be lactating. 
A serum pregnancy test for human chorionic gonadotropin will be performed on female patients 
of childbearing potential at Screening. 
A urine dipstick pregnancy test for human chorionic gonadotropin will be performed on female 
patients of childbearing potential at all visits during the Treatment Phase, and at the End-of- 
Study/Early Discontinuation Visit. A serum pregnancy test will be performed if the urine 
pregnancy test is positive. 
In case of pregnancy of the patient or the patient’s partner, the Investigator or designee will 
need to submit it via the Pregnancy Report Form and then follow-up to determine outcome of 
the pregnancy and condition of the infant. In case of pregnancy of the patient’s partner, the 
partner will be asked to complete an ICF allowing the Investigator to collect information about 
the course of the pregnancy and the birth and health of the infant, or until the pregnancy is 
terminated. 
A female patient who becomes pregnant during study participation will be withdrawn from the 
study. 
8.9. 
PREVIOUS AND CONCOMITANT MEDICATION 
At Screening, all medications (including nonprescription medications, and complementary and 
alternative medications) taken within 30 days before Screening are to be reviewed and recorded 

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in the eCRF. However, any medications used for MS treatment should be recorded. At each 
visit after Screening, any medication taken by the patient is to be recorded in the eCRF. 
8.10. 
ADVERSE EVENT ASSESSMENTS 
Clinical events occurring before starting study treatment but after signing the ICF are recorded 
on the Medical History/Current Medical Conditions eCRF page. 
8.10.1. 
DEFINITIONS 
An AE is any untoward medical occurrence which can be any undesirable sign, symptom, 
clinically significant laboratory abnormality if associated with clinical symptoms or require 
therapy, or medical condition occurring after starting study treatment, even if the event is not 
considered to be treatment-related. 
Information about all AEs, whether reported by the patient, discovered by Investigator 
questioning, or detected through physical examination, laboratory testing, or other means, will 
be collected and recorded on the adverse event eCRF page and followed as appropriate. 
Monitoring, collection and recording of AEs should continue until the End-of-Study Visit or 
Early Discontinuation Visit. PML, AEs related to or suggestive for PML are monitored, 
collected and recorded until 24 weeks (+/- 2 weeks) after the last infusion of the study drug or 
until PML is diagnosed, whatever comes earlier. 
AEs will be graded using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.03 (National Cancer Institute, 2010). If CTCAE 
grading does not exist for an AE, the intensity of mild (1), moderate (2), severe (3), and life-
threatening (4) will be used. 
Medical conditions/diseases present prior to the ICF being signed are only considered AEs if 
they worsen after the ICF is signed.  
As far as possible, each AE will also be described by: 
1. Description 
2. Duration (start and end dates) 
3. CTCAE grade 1-4 or intensity 
4. Relationship to the study drug – attribution (by categories below) and actions taken 
regarding the study drug 
5. Action(s) taken to treat the AE 
6. Outcome 
Insufficient clinical response, i.e., lack of therapeutic efficacy should NOT be recorded as an 
AE. 
Relapses are to be documented on the specific eCRF page(s). 
8.10.2. 
SEVERITY 
The Investigator, or qualified designee, responsible for the care of the patient will assess an AE 
for severity and seriousness. Severity is not equivalent to seriousness, which is based on 
patient/reaction outcome or action criteria usually associated with reactions that pose a threat 
to a patient’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. The Investigator will determine the severity of each AE using 

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the CTCAE Version 4.03. AEs that do not have a corresponding CTCAE term will be assessed 
according to the general guidelines for grading used in the CTCAE Version 4.03 as stated below 
(National Cancer Institute, 2010). 
Grade Descriptions: 
1. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only 
2. Grade 2: moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (e.g., preparing meals, shopping for 
groceries or clothes, using the telephone, managing money) 
3. Grade 3: severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living (eg, bathing, dressing and undressing, feeding self, using 
the toilet, taking medications and not bedridden) 
4. Grade 4: life-threatening consequences; urgent intervention indicated 
5. Grade 5: death related to AE 
8.10.3. 
RELATIONSHIP 
The relationship of each AE to study drug will be defined as “not related,” “unlikely related,” 
“possibly related,” “probably related,” or “related.” The Investigator is responsible for 
determining the study drug relationship for each AE that occurs during the study. Assessments 
are to be recorded on the appropriate eCRF page. 
Not Related 
AEs that are clearly and incontrovertibly due to extraneous causes (concurrent drugs, 
environment, etc.) and do not meet the criteria for drug relationship listed under Unlikely, 
Possibly, Probably, or Related. 
Unlikely Related 
An AE may be considered unlikely related if it includes at least the first 2 features: 
• It does not follow a reasonable temporal sequence from administration of the drug. 
• It could readily have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
• It does not follow a known pattern to the suspected drug. 
• It does not reappear or worsen when the drug is re-administered. 
Possibly Related 
An AE may be considered possibly related if it includes at least the first 2 features: 
• It follows a reasonable temporal sequence from administration of the drug. 
• It could readily have been produced by the patient’s clinical state, environment or toxic 
factors, or other modes of therapy administered to the patient. 
• It follows a known response pattern to the suspected drug. 
Probably Related 
An AE may be considered probably related if it includes at least the first 3 features: 

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• It follows a reasonable temporal sequence from administration of the drug. 
• It could not be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental, or toxic factors or other modes of therapy administered to the 
subject. 
• It disappears or decreased on cessation or reduction in dose. There are exceptions when an 
AE does not disappear upon discontinuation of the drug (e.g., bone marrow depression, 
fixed drug eruptions, tardive dyskinesia). 
• It follows a known pattern of response to the suspected drug. 
Related 
An AE may be considered related if it includes all of the following features: 
• It follows a reasonable temporal sequence from administration of the drug. 
• It could not be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the patient. 
• It disappears or decreases on cessation or reduction in dose. There are exceptions when an 
AE does not disappear upon discontinuation of the drug. For example: bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc. 
• It follows a known pattern of response to the suspected drug. 
• It reappears or worsens if the drug is re-administered. 
The actions taken in response to an AE are described in the following way. One or more of 
these are to be selected: 
1. No action taken 
2. Study drug temporarily interrupted 
3. Study drug permanently discontinued due to this AE 
4. Withdrawal from the study 
8.10.4. 
EXPECTEDNESS 
An adverse reaction, the nature or severity of which is not consistent with the applicable PI (IB 
or Tysabri SmPC) should be considered as unexpected. 
8.10.5. 
CLINICAL LABORATORY ADVERSE EVENTS 
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms or require therapy, in which case they should be recorded on the adverse events eCRF 
page and should include the signs, symptoms, or diagnosis associated with them. 
8.10.6. 
SERIOUS ADVERSE EVENTS 
An SAE is defined by federal regulation as any AE occurring at any dose that results in any of 
the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent one 

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of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
Pre-planned surgeries or other pre-planned measures requiring hospitalization will not be 
considered SAEs for this study unless hospitalization is longer than planned. 
Instructions for Expedited Notification of Serious Adverse Events 
Any SAE occurring in a patient after providing informed consent until the End-of-Study Visit/ 
Early Discontinuation Visit must be reported. 
Each SAE must be reported by the Investigator within 24 hours of learning of its occurrence, 
even if it is not felt to be treatment-related, assessing the causal relationship to study drug 
treatment. 
Follow-up information about a previously reported SAE must also be reported within 24 hours 
of receiving it. The follow-up reporting should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or discontinued study 
participation. 
The 
 may contact the Investigator to obtain further 
information on a reported SAE. If warranted, an Investigator alert may be issued, to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
8.10.7. 
ADVERSE EVENTS OF SPECIAL INTEREST 
The following AEs will be considered as AESI and can lead to withdrawal from the study 
treatment: PML, JCV GCN, opportunistic infections, liver injury, hypersensitivity, encephalitis, 
meningitis, and ARN. 
If an AESI occurs, the Investigator should treat according to the standard of care, report the 
event as an AESI in the format and timelines as for SAEs, and contact the Medical Monitor 
with any further questions. 
If an AESI fulfills the criteria of an SAE (serious criterion) then it should be reported as an 
SAE, only. 
Steps for handling study drug interruption or discontinuation for all AESIs can be found in 
Table 3. 
8.10.7.1. Progressive Multifocal Leukoencephalopathy 
For more details about PML, see the RMP for PML (Section 2.4). 
8.10.7.2. John Cunningham Virus Granule Cell Neuronopathy 
According to the Tysabri PI (2018), “JCV also causes granule cell neuronopathy (GCN) which 
has been reported in patients treated with TYSABRI. Symptoms of JCV GCN are similar to 
symptoms of PML (i.e. cerebellar syndrome, although cerebellar atrophy may be a differential 
feature on MRI), and diagnosis and management of JCV GCN should follow guidance provided 
for PML”. 
8.10.7.3. Opportunistic Infections 
According to the Tysabri PI (2018), “[…] opportunistic infections with use of TYSABRI […] 
cannot currently be excluded.” Certain types of infections, including pneumonias and urinary 
tract infections (including serious cases), gastroenteritis, vaginitis, tooth infections, tonsillitis, 
and herpes infections, occurred more often in Tysabri-treated patients than in placebo-treated 

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patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, 
was observed in a patient who received Tysabri. 
Patients should be informed that natalizumab may lower the ability of their immune system to 
fight infections. Patients should be instructed of the importance of contacting their doctor if 
they develop any symptoms of infection. 
The study drug should be permanently discontinued if the opportunistic infection is confirmed. 
8.10.7.4. Liver Injury 
According to the Tysabri PI (2018), “Spontaneous suspect adverse drug reactions of liver injury, 
including severe liver injury, have been reported from the market. Signs of liver injury, 
including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as 
early as six days after the first dose. Signs of liver injury have also been reported for the first 
time after multiple doses, including cases with rechallenge. In these patients recovery of liver 
function occurred following cessation of therapy. If liver injury occurs during treatment with 
TYSABRI the drug should be discontinued and investigation of cause undertaken. TYSABRI 
should be initiated with caution in patients with a history of liver disease and liver function tests 
should be regularly monitored in these patients.” 
Liver safety monitoring and assessment information can be found in Appendix 2. 
8.10.7.5. Hypersensitivity 
According to the Tysabri PI (2018), “TYSABRI has been associated with hypersensitivity 
reactions, including anaphylactic/ anaphylactoid reactions, which occurred at an incidence of 
<1%. These reactions usually occurred during the infusion or up to 1 hour after completion of 
the infusion, but there have been occasional post-market reports of delays of up to 2 weeks in 
symptom onset. Symptoms associated with these reactions can include urticaria, dizziness, 
fever, rash, rigors, pruritus, nausea, flushing, hypertension, hypotension, dyspnea and chest 
pain. Generally, these reactions are associated with antibodies to TYSABRI. The risk for 
hypersensitivity was greatest with early infusions and in patients re-exposed to TYSABRI 
following an initial short exposure (up to three infusions) and extended period (three months or 
more) without treatment. Neurologists should counsel patients on the importance of 
uninterrupted dosing, particularly in the early months of treatment. However, the risk of 
hypersensitivity reactions should be considered for every infusion administered.” 
Natalizumab IV should be administered by a healthcare provider prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and 
medical support measure should be available for immediate use. Patients should be observed 
during the infusion and for one hour after each infusion. 
Patients and caregivers will be instructed to report the development of rash, hives, pruritus, 
flushing, urticarial, redness and / or swelling, etc. that may represent an administration-related 
reaction (i.e., infusion-related reaction) to study drug. Patients will be asked to report 
administration-related AEs to the sites immediately as they are experienced or after having 
received appropriate medical care. Appropriate treatment and follow-up will be determined by 
the Investigator. If signs or symptoms of an administration-related reaction are observed during 
the administration of study drug, it should be immediately discontinued and the patient treated 
as medically appropriate. 
Patients who have experienced a hypersensitivity reaction to the study drug must be 
permanently discontinued from the study drug. 
In all cases of administration-related reaction, the Medical Monitor must be informed as soon 
as practical. 

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8.10.7.6. Encephalitis/Meningitis 
Natalizumab increases the risk of developing encephalitis and meningitis caused by herpes 
simplex and varicella zoster virus. Serious, life-threatening, and sometimes fatal cases have 
been reported in the post marketing setting in MS patients receiving Tysabri. If herpes 
encephalitis or meningitis occurs, the study drug should be discontinued, and appropriate 
treatment for herpes encephalitis or meningitis should be administered. 
8.10.7.7. Acute Retinal Necrosis 
ARN is a rare fulminant viral infection of the retina caused by the family of herpes virus (e.g., 
varicella zoster). ARN has been observed in patients being administered Tysabri and can be 
potentially blinding. Patients presenting with eye symptoms such as decreased visual acuity, 
redness and painful eye should be referred for retinal screening for ARN. Following clinical 
diagnosis of ARN, study drug discontinuation should be discontinued. 
8.11. 
CLINICAL LABORATORY TESTS 
8.11.1. 
BLOOD CHEMISTRY AND HEMATOLOGY 
All samples will be collected in accordance with acceptable laboratory procedures at the time 
points specified in the Time and Events Schedule. 
Clinical chemistry and hematology tests will include the following and will be carried out by a 
central laboratory as presented in Table 4. 
 
Table 4 Clinical Chemistry, Serology and Hematology Tests 
Hematology: 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Platelet count 
White blood cell (WBC) count full and 
differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils) 
Absolute lymphocyte count (ALC) 
Absolute neutrophil count (ANC) 
Red blood cell (RBC) count 
 
Serology:  
JCV antibodies 
HIV-1 and HIV-2 antibodies (only at 
Screening) 
Varicella zoster virus (VZV) 
immunoglobulin (Ig) (only at Screening) 
Anti-hepatitis A virus  
Hepatitis B surface antigen   
Anti-hepatitis B core antigen  
Anti-hepatitis C virus (HCV) IgG or IgM 
Serum Chemistry: 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Lactate dehydrogenase (LDH) 
Total protein 
Calcium 
Chloride 
Inorganic phosphorus 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Triglycerides 
High-density lipoprotein (HDL) 
Low-density lipoprotein (LDL) 
C-reactive protein (CRP) 
 
Screening labs (outside the requested range) can be repeated (Medical Monitor should be 
contacted). 
Liver safety monitoring and assessment information can be found in Appendix 2. 

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8.11.2. 
URINALYSIS 
A urinalysis will be performed to measure pH, specific gravity, protein (qualitative), glucose 
(qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, occult blood, 
hemoglobin, and cells. A microscopic examination will be performed, if necessary. 
8.12. 
ANTI-JCV ANTIBODY SAMPLES 
Blood samples for anti-JCV antibodies will be collected as specified in the Time and Events 
Schedule. 
Samples will be sent to a central laboratory to determine the presence or absence of JCV 
antibodies using a validated assay. 
Anti-JCV antibody status evaluation will be performed every 6 months. 
Detailed instructions regarding sample collection, processing, and shipping will be provided in 
a separate laboratory manual. 
8.13. 
ANTI-NATALIZUMAB ANTIBODY SAMPLES 
Serum samples for ADA will be collected as specified in the Time and Events Schedule. 
Samples will be sent to a central laboratory to determine the presence or absence of antibodies 
using a validated assay. 
Detailed instructions regarding sample collection, processing, and shipping will be provided in 
a separate laboratory manual. 
8.14. 
NATALIZUMAB TROUGH CONCENTRATION 
Samples to determine natalizumab trough concentrations (Ctrough) over time will be collected as 
specified in the Time and Events Schedule. 
Samples will be sent to a central laboratory. Detailed instructions regarding sample collection, 
processing, and shipping will be provided in a separate laboratory manual. 
If study drug is supposed to be administered at the visit, the samples should be taken before 
study drug administration. 
8.15. 
BIOBANK SAMPLES 
Biobank samples (blood and urine) will be collected as specified in the Time and Events 
Schedule. 
 
Detailed instructions regarding sample collection, processing, and shipping will be provided in 
a separate laboratory manual. 
8.16. 
CEREBRAL SPINAL FLUID LUMBAR PUNCTURE 
If PML is suspected from Visit 1 through the End-of-Study Visit/Early Discontinuation Visit, 
a lumbar puncture will be performed to draw CSF for JCV DNA ultrasensitive polymerase 
chain reaction (PCR). The CSF sample will be sent to the central laboratory. 
Detailed instructions regarding sample collection, processing, and shipping will be provided in 
a separate laboratory manual. 
8.17. 
DATA SAFETY MONITORING BOARD 
Details on the responsibilities, activities, and deliverables of the external DSMB are detailed in 
a separate charter. 

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9. 
PLANNED STATISTICAL METHODS 
9.1. 
GENERAL CONSIDERATIONS 
Prior to unblinding, a detailed statistical analysis plan (SAP) will be completed and approved. 
This will contain a detailed explanation of the methodology used in the statistical analyses and 
provide rules and data handling conventions to perform the analyses and how to handle missing 
data. 
The analysis will be conducted when all patients have completed the End-of-Study Visit 
(Visit 13, Week 48) or have discontinued. 
9.2. 
DETERMINATION OF SAMPLE SIZE  
A total of 230 evaluable patients (115 in each group), i.e., patients who complete the 24-week 
treatment period without relevant major protocol deviations and for whom sufficient post-
baseline MRI data are available, are required to achieve 90% power for the equivalence 
assessment with respect to the cumulative number of new active lesions over 24 weeks 
treatment assuming a common standard deviation of 4.0 lesions and no difference between both 
groups. To account for potential dropouts and non-evaluable patients of up to 10%, 
approximately 260 patients will be randomized to either Tysabri or PB006. 
At Week 24, the 130 patients in the Tysabri group will be re-randomized (through a re-
randomization step). Out of these 130 patients, approximately 34 (to account for potential 
dropouts to reach an approximate minimum of 30) random patients will be randomized 
(switched) to PB006. After re-randomization, the patient groups will be: Tysabri group (n=up 
to 96); Tysabri switch to PB006 group (n=up to 34); and PB006 group (n=up to 130). 
The sample size calculation is based on data published by Miller et al., 2003, which showed a 
mean number of cumulative new active lesions of 1.0 (±2.6) in the pooled natalizumab groups 
(3 mg/kg and 6 mg/kg) versus 9.7 (±27.4) in the placebo group in patients with either relapsing-
remitting or secondary progressive MS. An equivalence margin of 2.1 lesions was chosen to 
ensure that 50% of the treatment effect based on the lower bound of the 95% confidence interval 
of the pooled effect size estimated in Miller et al., 2003 will be preserved. 
9.3. 
ANALYSIS POPULATIONS 
9.3.1. 
SAFETY POPULATION 
Patients participating in this study who receive at least one infusion of the study drug will be 
included in the Safety Population. Patients in this group will be analyzed as treated. 
9.3.2. 
SAFETY-SWITCH POPULATION 
Patients who are included in the Safety Population and receive at least one infusion of the study 
drug after the time point of re-randomization, independent of whether they switch or not, will 
be included in the Safety-Switch Population. Patients in this group will be analyzed as treated 
after re-randomization, also considering treatment before re-randomization. 
9.3.3. 
FULL ANALYSIS SET POPULATION 
The Full Analysis Set (FAS) Population will include all patients who were randomized and 
have received at least one (complete or partial) infusion of the study drug. Patients will be 
analyzed according to the treatment group to which they were randomized. 

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9.3.4. 
PER-PROTOCOL POPULATION 
Only patients participating in this study who complete the 24-week treatment period without 
major protocol deviations, which potentially affect the analysis of the primary endpoint, and for 
whom sufficient post-baseline MRI data are available will be included in the Per-Protocol (PP) 
population. Further details on the definition of the PP Population will be specified in the SAP. 
9.4. 
ANALYSIS OF DEMOGRAPHICS AND BASELINE 
CHARACTERISTICS 
Demographics and baseline characteristics such as age, sex, race, weight, and medical history 
will be summarized by treatment group in all populations using mean, standard deviation, 
median, minimum, and maximum for continuous variables, and counts and percentages for 
categorical variables. Use of prior and concomitant medications will be coded and tabulated by 
treatment group on the Anatomical Therapeutic Chemical (ATC) 2, ATC 4, and preferred name 
level. 
9.5. 
ANALYSIS OF DISPOSITION AND PATIENT CHARACTERISTICS 
Patient disposition (enrollment, discontinuations from the study), study drug administered, 
premature discontinuations from study drug, withdrawals from the study, and major protocol 
deviations will be summarized by treatment group in the FAS population. 
9.6. 
ANALYSIS OF ENDPOINTS 
Generally, analyses will be performed per treatment arm (according to the first and second 
randomization) and overall, using mean, standard deviation, median, minimum, and maximum 
for continuous variables, and counts and percentages for categorical variables, unless specified 
otherwise. 
9.6.1. 
PRIMARY ENDPOINT 
The primary endpoint is the cumulative number of new active lesions over 24 weeks. 
Equivalence between PB006 and Tysabri will be assessed based on the following set of 
hypotheses: 
 
H0: |µPB006 - µTysabri| > 2.1 vs. H1: | µPB006 - µTysabri | ≤ 2.1,  
where µx denotes the cumulative number of new active lesions over 24 weeks in the respective 
treatment group. Data will be analyzed using a negative binomial generalized linear model with 
fixed effects for the treatment group and stratification factors with log link on the PP Population. 
Parameters will be estimated using a maximum likelihood approach. Equivalence will be tested 
based on the corresponding 90% (for FDA) and 95% (for EMA) confidence intervals to address 
different regulatory requirements. This analysis will be repeated for the FAS Population and 
the corresponding 90% and 95% confidence intervals will be derived. 
9.6.2. 
SECONDARY ENDPOINTS 
The secondary endpoints are the: 
• Cumulative number of new active lesions over 48 weeks 
• Cumulative number of new GdE T1-weighted lesions over 24 and 48 weeks 
• Number of patients without new GdE T1-weighted lesions over 24 and 48 weeks 
• Cumulative number of new/enlarging T2-weighted lesions over 24 and 48 weeks 
• Number of patients without new/enlarging T2-weighted lesions over 24 and 48 weeks 

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• Number of persistent lesions after 24 and 48 weeks 
• Annualized relapse rate after 24 and 48 weeks 
• Change from baseline in EDSS after 24 and 48 weeks 
• Number of local and systemic AEs and SAEs after 24 and 48 weeks 
• Incidence rate of ADA and persistent antibodies after 24 and 48 weeks and after switching 
• Incidence rate of neutralizing antibodies after 24 and 48 weeks and after switching 
• Natalizumab trough concentration (Ctrough) over time 
• Safety profile (physical examination, and change from baseline in vital sign measurements 
and clinical laboratory tests) over 24 and 48 weeks 
All secondary endpoints will only be analyzed descriptively without formal comparison 
between treatment groups. Further details will be provided in the SAP. 
9.6.3. 
ANALYSIS OF EFFICACY ENDPOINTS 
Secondary efficacy analysis will be performed on the FAS and PP Populations. 
All lesion numbers will be summarized as continuous measures as well by categories (details 
will be specified in the SAP) per analysis time point. 
The number and percentage of patients without new/enlarging T2-weighted lesions will be 
tabulated. The number and percentage of patients without new GdE T1-weighted lesions will 
be tabulated. 
The annualized relapse rate will be based on a denominator of 365.25 days and summarized as 
a continuous measure. 
Absolute values and change from baseline of EDSS will be tabulated, and categorical 
summaries for each analysis time point will be presented. 
The outcomes and shifts of the C-SSRS will be summarized per time point. 
9.6.4. 
ANALYSIS OF SAFETY 
Safety analysis will be performed using the Safety Population and Safety-Switch Population. 
The number and percentage of patients with treatment-emergent adverse events (TEAEs; 
defined as any AEs starting or worsening after the start of the first infusion of the study drug, 
regardless of relationship to study drug), AESIs (i.e., PML, JVC GCN, opportunistic infections,  
liver injury, hypersensitivity, encephalitis, meningitis,  ARN, see Section 8.10.7), and SAEs 
that occur after the start of the first infusion and through 4 weeks after the last infusion date of 
the study drug (Visit 13, End-of-Study Visit), will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class and Preferred Term overall, by severity, 
and by relationship to study drug for each treatment group. Separate summaries will also be 
generated for treatment-related AEs overall and by severity. In addition to incidence rates, 
exposure adjusted AE rates will be summarized as well. 
Change from baseline in clinical laboratory tests and vital signs will be summarized by 
treatment group. Patients with markedly abnormal values for laboratory tests and vital signs 
will be tabulated. 
Physical examination findings will be presented in data listings. 

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9.6.5. 
ANALYSIS OF ANTI-NATALIZUMAB ANTIBODIES 
The proportions of patients with positive ADA (transient and persistent) persistent ADA and 
positive (transient and persistent) neutralizing ADA during the study will be summarized at 
each visit based on the Safety Population.   
A positive ADA patient is defined as a patient who has at least 1 positive ADA result in any 
post-baseline sample, and is further categorized as: 
• Transiently positive: defined as patient with confirmed positive ADA in 1 sample at a 
post-dose visit. 
• Persistently positive: defined as patient with confirmed positive ADA in 2 or more 
consecutive positive ADA samples at post-dose visits. 
Exact 95% confidence intervals will be calculated for the differences between PB006 and 
Tysabri in the incidence rates of positive, persistent and positive neutralizing ADA over 24 and 
48 weeks and for the 24 weeks after re-randomization between patients who switch to PB006 
at Week 24 and patients who remain on Tysabri. Other ADA incidence rates will be summarized 
descriptively. 
9.6.6. 
ANALYSIS OF NATALIZUMAB TROUGH CONCENTRATION 
Natalizumab trough concentration in serum will be summarized descriptively. 
9.6.7. 
ANALYSIS OF ANTI-JCV ANTIBODIES 
Anti-JCV antibodies incidence rates by JCV index level will be summarized descriptively. 
9.7. 
ANALYSES 
The analysis of all primary and secondary endpoints is planned when all patients have 
completed the End-of-Study Visit (Visit 13, Week 48) or have discontinued. 
9.8. 
HANDLING OF DROPOUTS AND MISSING DATA 
Every effort will be made to collect all data at specified times. A detailed description of the 
handling of dropouts and missing data (including loss to follow-up) for all efficacy and safety 
evaluations will be provided in the SAP. 
9.9. 
DEVIATIONS FROM THE ANALYSIS PLAN 
If any deviations from the planned statistical analysis are deemed necessary, a justification for 
all decisions will be provided in the clinical study report. 
10. 
ADMINISTRATIVE CONSIDERATIONS 
10.1. 
MONITORING PROCEDURES 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative will review the protocol and the eCRF with the investigators and their staff. 
During the study, the site monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to ICH 
GCP, the progress of enrollment, and also to ensure that the study drugs are being stored, 
dispensed, and accounted for according to specifications.  
The Investigator must give the monitor access to relevant hospital or clinical records to confirm 
their consistency with the eCRF entries. No information in these records about the identity of 
the patients will leave the study center. The Sponsor’s monitoring standards require full 

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verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of primary activity and safety variables. Additional 
checks of the consistency of the source data with the eCRFs will be performed according to the 
study-specific monitoring plan. It is important that the Investigator and other study personnel 
are available during the monitoring visits and that sufficient time is devoted to the process. 
10.2. 
PROTOCOL VIOLATIONS/DEVIATIONS 
No waivers for protocol violations or deviations will be granted. 
10.3. 
RECORDING OF DATA AND RETENTION OF DOCUMENTS 
Data on patients collected on eCRFs during the study will be documented in a pseudonymous 
fashion and the patient will only be identified by the patient number. If, as an exception, it is 
necessary for safety or regulatory reasons to identify the patient, both the Sponsor and the 
Investigator are bound to keep this information confidential. 
All the information required by the protocol should be provided; any omissions require 
explanation. All eCRFs should be completed and available for collection within a timely 
manner, preferably no more than 2 days after the patient’s visit, so that the site monitor/clinical 
research associate may check the entries for completeness, accuracy, and legibility, ensure the 
eCRF is signed by the Investigator, and transmit the data to Sponsor. eCRFs must be completed 
in English. 
The Investigator must maintain source documents for each patient in the study. All information 
on eCRFs will be traceable to these source documents, which are generally maintained in the 
patient’s file. 
Essential documents, as listed below, will be retained by the Investigator for as long as needed 
to comply with national and international regulations. Refer to the Clinical Study Site 
Agreement for the Sponsor’s requirement on record retention. The Investigator agrees to adhere 
to the document retention procedures by signing the protocol. Essential documents include: 
1. Signed protocol and all amendments 
2. IB and updates 
3. Copies of regulatory and IEC approvals for the study protocol and all amendments 
(blanks and all signed copies) 
4. All source documents and laboratory record 
5. eCRF copies 
6. Curricula vitae of investigative team members and delegation of responsibilities list 
7. FDA Form 1572 
8. Normal values ranges/values for medical/laboratory/technical procedures 
9. SAE forms and safety updates 
10. Interim reports to ethics committees and authorities in accordance with local 
requirements 
11. Patients’ signed and dated ICF(s) 

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10.8. 
FINANCIAL DISCLOSURE 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
10.9. 
INVESTIGATOR CONFIDENTIALITY 
By signing the protocol, the Investigator agrees to keep all information provided by the Sponsor, 
in strict confidence and to request similar confidentiality from his/her staff and the IEC. Study 
documents provided by the Sponsor (protocols, IBs, eCRFs, and other material) will be stored 
appropriately to ensure their confidentiality. The information provided by the Sponsor to the 
Investigator may not be disclosed to others without direct written authorization from the 
Sponsor, except to the extent necessary to obtain informed consent from patients who wish to 
participate in the study. 
 
 

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11. 
REFERENCES 
 
Acheson ED. Epidemiology of multiple sclerosis. Br Med Bull. 1977; 33(1):9-14. 
Beck J, Rondot P, CAtinot L, Falcoff E, Kirchner H, Wietzerbin J. Increased production of 
interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple 
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Appendix 1: 2010 Revised McDonald Criteria for Diagnosis of MS 
Clinical 
(Attacks) 
Lesions 
Additional Criteria to Make Diagnosis 
≥2 attacksa  
Objective clinical evidence of ≥2 
lesions or objective clinical 
evidence of 1 lesion with 
reasonable historical evidence of a 
prior attackb 
Nonec  
≥2 attacksa 
Objective clinical evidence of 1 
lesion 
DIS, demonstrated by: 
• 
≥1 T2 lesion in at least 2 of 4 MS-typical 
CNS regions (periventricular, juxtacortical, 
infratorial, spinal cord)d; OR 
• 
Await further clinical attacka implicating a 
different CNS site 
1 attacka 
Objective clinical evidence of ≥2 
lesions 
DIT, demonstrated by: 
• 
Simultaneous presence of asymptomatic GdE 
and non-enhancing lesions at any time ; OR 
• 
A new T2 and/or GdE lesions(s) on follow-up 
MRI, irrespective of its timing with reference 
to a baseline scan; OR 
• 
Await a second clinical attacka 
1 attacka 
Objective clinical evidence of 1 
lesion (clinically isolated 
syndrome) 
DIS and DIT, demonstrated by: 
 
For DIS: 
• 
≥1 T2 lesion in at least 2 of 4 MS-typical 
CNS regions (periventricular, juxtacortical, 
infratentorial, spinal cord)d; 
             OR 
• 
Await a second clinical attacka implicating a 
different CNS site AND 
 
DIT, demonstrated by: 
• 
Simultaneous presence of asymptomatic GdE 
and non-enhancing lesions at any time; OR 
• 
A new T2 and/or GdE lesions(s) on follow-up 
MRI, irrespective of its timing with reference 
to a baseline scan; OR 
• 
Await a second clinical attacka 
Insidious 
neurological 
progression 
suggestive of 
MS (PPMS) 
 
1 year of disease progression (retrospectively or 
prospectively determined) plus 2 of 3 of the following 
criteria: 
• 
Evidence for DIS in the brain based on ≥1 T2 
lesion in the MS-characteristic 
(periventricular, juxtacortical, or 
infratentorial) regions; 
• 
Evidence for DIS in the spinal cord based on 
≥2 T2 lesions in the cord;  
• 
Positive CSF (isoelectric focusing evidence of 
oligoclonal bands and/or elevated IgG index) 
Source: Polman, 2011, Table 4 
MS=multiple sclerosis; CNS=central nervous system; CSF=cerebrospinal fluid; DIS=dissemination in space; 
DIT=dissemination in time; GdE=gadolinium-enhancing; IgG=immunoglobulin G; MRI=magnetic resonance 
imaging; PPMS=primary progressive multiple sclerosis. If the criteria are fulfilled and there is no better 
explanation for the clinical presentation, the diagnosis is ‘‘MS’’; if suspicious, but the criteria are not completely 
met, the diagnosis is ‘‘possible MS’’; if another diagnosis arises during the evaluation that better explains the 
clinical presentation, then the diagnosis is ‘‘not MS.’’ 

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a An attack (relapse; exacerbation) is defined as patient-reported or objectively observed events typical of an 
acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in 
the absence of fever or infection. It should be documented by contemporaneous neurological examination, but 
some historical events with symptoms and evolution characteristic for MS, but for which no objective 
neurological findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports 
of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occurring over not 
less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by 
findings on neurological examination, visual evoked potential response in patients reporting prior visual 
disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of 
neurological symptoms. 
b Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical 
evidence for 1 past attack, in the absence of documented objective neurological findings, can include historical 
events with symptoms and evolution characteristics for a prior inflammatory demyelinating event; at least 1 
attack, however, must be supported by objective findings. 
c No additional tests are required. However, it is desirable that any diagnosis of MS be made with access to 
imaging based on these criteria. If imaging or other tests (for instance, CSF) are undertaken and are negative, 
extreme caution needs to be taken before making a diagnosis of MS, and alternative diagnoses must be 
considered. There must be no better explanation for the clinical presentation, and objective evidence must be 
present to support a diagnosis of MS. 
d GdE lesions are not required; symptomatic lesions are excluded from consideration in patients with brainstem 
or spinal cord syndromes. 
 

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Appendix 2: Liver Safety Monitoring and Assessment 
Any patient enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases AT to >3x ULN, or bilirubin >2x ULN, should undergo detailed 
testing for liver enzymes (including at least ALT, AST, and total bilirubin). Testing should be 
repeated within 48 to 72 hours of notification of the test results. Alerts will be generated by the 
central laboratory regarding moderate and severe liver abnormality to inform the site, Sponsor, 
and CRO. Patients should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
 
ALT or AST 
Total Bilirubin 
Moderate 
>3x ULN 
≤2x ULN 
Severe1 
>3x ULN 
>2x ULN 
 
In addition, the patient should be considered to have severe hepatic abnormalities for any of the 
following: 
• ALT or AST >8x ULN (not confirmed) 
• ALT or AST >5x ULN for >2 weeks (confirmed, retest required within 14 days) 
• ALT or AST >3x ULN (confirmed) in conjunction with elevated total bilirubin >2x ULN 
or INR >1.5 
• ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and / or eosinophilia. 
Discontinuation of study drug should be considered for the lab values above. 
In the absence of an explanation for increased liver function tests, such as viral hepatitis, pre-
existing or acute liver disease or exposure to other agents associated with liver injury, the patient 
may require additional monitoring and follow-up or may be discontinued from the study drug.  
In addition, if close monitoring for a patient with moderate or severe hepatic laboratory tests is 
not possible, the study drug should be discontinued. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination, and laboratory tests.  
                                                 
1 Hy’s Law definition (Temple, 2016): Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% mortality (or transplant). 
The two “requirements” for Hy’s Law are: 1) Evidence that a drug can cause hepatocellular-type injury, generally 
shown by an increase in transaminase elevations >3x ULN (“2x ULN elevations are too common in treated and 
untreated patients to be discriminating”). 2) Cases of increased bilirubin (at least 2x ULN) with concurrent 
transaminase elevations at least 3x ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
alkaline phosphatase) or Gilbert’s syndrome.  
 

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Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly 
then weekly or less if abnormalities stabilize or the study drug has been discontinued and the 
patient is asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology, 
should be reported as an AESI. The CRO/Sponsor should be contacted and informed of all 
patients for whom severe hepatic liver function abnormalities possibly attributable to study drug 
are observed. 
To further assess abnormal hepatic laboratory findings, the Investigator is expected to: 
• Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset diseases should be recorded as AEs on the adverse event page of the eCRF. 
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities, should be noted. Non-alcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic and / or diabetic patients and may be 
associated with fluctuating aminotransferase levels. The Investigator should ensure that 
the Medical History eCRF page captures any illness that pre-dated study enrollment that 
may be relevant in assessing hepatic function. 
• Obtain a history of concomitant drug use (including nonprescription medications, 
complementary and alternative medications). 
• Based on the patient’s history, other testing may be appropriate including: 
 acute viral hepatitis (A, B, C, D, E or other infectious agents) 
 ultrasound or other imaging to assess biliary tract disease 
 other laboratory tests including INR and direct bilirubin 
 consider gastroenterology or hepatology consultations