An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to Previously Treated Adults With Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
Phase: PHASE3
Conditions: ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation
Sponsor: Biogen

COVER PAGE 
Official Title: An Extension Study to Assess the Long-Term Safety, Tolerability, 
Pharmacokinetics, and Effect on Disease Progression of BIIB067 
Administered to Previously Treated Adults with Amyotrophic Lateral Sclerosis 
Caused by Superoxide Dismutase 1 Mutation 
NCT number: 
NCT03070119 
Document Date: 04 Aug 2021

CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
PROTOCOL NUMBER:
233AS102
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
3
PROTOCOL TITLE:
An Extension Study to Assess the Long-Term Safety, 
Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 
Administered to Previously Treated Adults with Amyotrophic Lateral Sclerosis Caused by 
Superoxide Dismutase 1 Mutation
EUDRA CT NO:
2016‐003225‐41
DATE:
04 August 2021
Version 6
FINAL
Supersedes previous Version 5 dated 08 November 2019
 

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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SPONSOR INFORMATION .......................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................10
3.
SYNOPSIS .................................................................................................................12
4.
SCHEDULE OF ACTIVITIES FOR STUDY 233AS102.........................................15
5.
INTRODUCTION......................................................................................................20
5.1.
Overview of Amyotrophic Lateral Sclerosis..............................................................20
5.2.
Current Therapies for Amyotrophic Lateral Sclerosis................................................20
5.3.
Profile of Previous Experience With BIIB067...........................................................21
5.3.1.
Nonclinical Experience...............................................................................................21
5.3.1.1.
Toxicology..................................................................................................................21
5.3.1.2.
Pharmacokinetics........................................................................................................22
5.3.2.
Clinical Experience.....................................................................................................22
5.4.
Study Rationale...........................................................................................................23
5.5.
Rationale for Dosing Regimen ...................................................................................23
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................25
6.1.
Primary Objective and Endpoint ................................................................................25
6.2.
Secondary Objectives and Endpoints .........................................................................25
6.2.1.
Pharmacokinetic Endpoints ........................................................................................25
6.2.2.
Pharmacodynamic Endpoint.......................................................................................25
6.2.3.
Biomarker Endpoint....................................................................................................25
6.2.4.
Efficacy Endpoints......................................................................................................25
26
26
6.3.2.
Additional Efficacy Endpoint.....................................................................................26
6.3.3.
Additional Biomarker Endpoints................................................................................26
7.
STUDY DESIGN .......................................................................................................27
7.1.
Study Overview ..........................................................................................................27
7.2.
Overall Study Duration and Follow-Up .....................................................................27
7.2.1.
Screening ....................................................................................................................27
7.2.1.1.
Participants Who Have Completed Parts A and B of Study 233AS101.....................27

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7.2.1.2.
Participants Who Have Completed Part C of Study 233AS101.................................28
7.2.2.
Dosing.........................................................................................................................28
7.2.2.1.
Loading Dose Period ..................................................................................................28
7.2.2.2.
Maintenance Dose Period...........................................................................................29
7.2.3.
Follow-Up...................................................................................................................29
7.3.
Study Stopping Rules .................................................................................................29
7.4.
End of Study ...............................................................................................................29
8.
SELECTION OF PARTICIPANTS ...........................................................................30
8.1.
Inclusion Criteria ........................................................................................................30
8.2.
Exclusion Criteria.......................................................................................................30
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................33
9.1.
Screening and Enrollment...........................................................................................33
9.2.
Randomization and Registration of Participants ........................................................33
9.3.
Blinding Procedures....................................................................................................33
10.
DISCONTINUATION OF STUDY TREATMENT OR WITHDRAWAL 
OF PARTICIPANTS FROM THE STUDY...............................................................34
10.1.
Discontinuation of Study Treatment...........................................................................34
10.2.
Withdrawal of Participants From Study .....................................................................34
11.
STUDY TREATMENT USE .....................................................................................35
11.1.
Regimen......................................................................................................................35
11.1.1.
Participants Who Have Completed Parts A or B of Study 233AS101.......................35
11.1.2.
Participants Who Have Completed Part C of Study 233AS101.................................35
11.1.3.
All Participants ...........................................................................................................35
11.2.
Modification of Dose and/or Treatment Schedule......................................................35
11.3.
Concomitant Therapy and Procedures........................................................................35
11.3.1.
Concomitant Therapy .................................................................................................35
11.3.1.1.
Allowed Concomitant Therapy...................................................................................36
11.3.1.2.
Disallowed Concomitant Therapy..............................................................................36
11.3.2.
Concomitant Procedures.............................................................................................36
11.4.
Continuation of Treatment..........................................................................................36
12.
STUDY TREATMENT MANAGEMENT................................................................37
12.1.
BIIB067 ......................................................................................................................37

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12.1.1.
BIIB067 Preparation...................................................................................................37
12.1.2.
BIIB067 Storage.........................................................................................................37
12.1.3.
BIIB067 Handling and Disposal.................................................................................38
12.1.4.
BIIB067 Accountability..............................................................................................38
12.2.
Placebo Product ..........................................................................................................38
13.
CLINICAL FUNCTION, PHARMACOKINETIC, AND 
PHARMACODYNAMIC ASSESSMENTS..............................................................39
13.1.
Clinical Function Assessments...................................................................................39
13.1.1.
ALS Functional Rating Scale-Revised.......................................................................39
13.1.2.
Slow Vital Capacity....................................................................................................39
13.1.3.
Participant Diary.........................................................................................................39
39
13.1.5.
Handheld Dynamometry.............................................................................................40
40
40
40
40
41
41
41
13.2.
Pharmacokinetic Assessments....................................................................................41
13.3.
Pharmacodynamic/Biomarker Assessments...............................................................41
42
13.4.
Genomic and Pharmacogenomic Assessments...........................................................42
14.
SAFETY ASSESSMENTS ........................................................................................44
14.1.
Clinical Safety Assessments.......................................................................................44
14.2.
Laboratory Safety Assessments..................................................................................44
14.3.
Product-Specific Safety Assessments.........................................................................45
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................46
15.1.
Definitions ..................................................................................................................46
15.1.1.
Adverse Event.............................................................................................................46
15.1.2.
Serious Adverse Event................................................................................................46

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15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................47
15.2.
Safety Classifications..................................................................................................47
15.2.1.
Investigator Assessment of Events.............................................................................47
15.2.2.
Relationship of Events to Study Treatment and Lumbar Puncture ............................48
15.2.3.
Severity of Events.......................................................................................................48
15.2.4.
Expectedness of Events ..............................................................................................49
15.3.
Monitoring and Recording Events..............................................................................49
15.3.1.
Adverse Events...........................................................................................................49
15.3.2.
Serious Adverse Events..............................................................................................49
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................50
15.3.3.1.
Deaths .........................................................................................................................50
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................50
15.4.
Procedures for Handling Special Situations ...............................................................51
15.4.1.
Pregnancy ...................................................................................................................51
15.4.2.
Overdose.....................................................................................................................51
15.4.3.
Medical Emergency....................................................................................................51
15.4.3.1.
Unblinding for Medical Emergency...........................................................................51
15.5.
Contraception Requirements ......................................................................................52
15.6.
Safety Responsibilities................................................................................................53
15.6.1.
The Investigator..........................................................................................................53
15.6.2.
The Sponsor................................................................................................................53
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........54
16.1.
Analysis Population....................................................................................................54
16.2.
Clinical Function ........................................................................................................54
16.2.1.
Methods of Analysis...................................................................................................54
16.3.
Pharmacokinetics........................................................................................................55
16.3.1.
Analysis Population....................................................................................................55
16.3.2.
Methods of Analysis...................................................................................................55
16.4.
Pharmacodynamics.....................................................................................................55
16.4.1.
Analysis Population....................................................................................................55
16.4.2.
Methods of Analysis...................................................................................................56
56

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16.6.
Safety..........................................................................................................................56
16.6.1.
Analysis Population....................................................................................................56
16.6.2.
Methods of Analysis...................................................................................................56
16.6.2.1.
Adverse Events...........................................................................................................56
16.6.2.2.
Clinical Laboratory Results........................................................................................56
16.6.2.3.
Vital Signs ..................................................................................................................56
16.6.2.4.
Columbia Suicide Severity Rating Scale....................................................................57
16.6.2.5.
Limited Neurological Examinations...........................................................................57
16.6.2.6.
Electrocardiogram.......................................................................................................57
16.6.2.7.
Antigenicity/Immunogenicity.....................................................................................57
16.7.
Interim Analyses.........................................................................................................57
16.8.
Sample Size Considerations .......................................................................................57
17.
ETHICAL REQUIREMENTS ...................................................................................58
17.1.
Declaration of Helsinki...............................................................................................58
17.2.
Ethics Committee........................................................................................................58
17.3.
Participant Information and Consent..........................................................................58
17.4.
Participant Data Protection.........................................................................................59
17.5.
Compensation for Injury.............................................................................................59
17.6.
Conflict of Interest......................................................................................................59
17.7.
Registration of Study and Disclosure of Study Results..............................................60
18.
ADMINISTRATIVE PROCEDURES.......................................................................61
18.1.
Study Site Initiation....................................................................................................61
18.2.
Quality Assurance.......................................................................................................61
18.3.
Monitoring of the Study..............................................................................................61
18.4.
Study Funding.............................................................................................................61
18.5.
Publications.................................................................................................................61
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................62
19.1.
Public Health Emergencies.........................................................................................62
19.2.
External Contract Organizations.................................................................................63
19.2.1.
Contract Research Organization.................................................................................63
19.2.2.
Interactive Response Technology...............................................................................63
19.2.3.
Electronic Data Capture..............................................................................................63

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19.2.4.
Central Laboratories for Laboratory Assessments .....................................................63
19.3.
Study Committees.......................................................................................................64
19.3.1.
Independent Data Monitoring Committee..................................................................64
19.4.
Changes to Final Study Protocol ................................................................................64
19.5.
Ethics Committee Notification of Study Completion or Termination........................64
19.6.
Retention of Study Data..............................................................................................64
19.7.
Study Report Signatory...............................................................................................65
20.
REFERENCES ...........................................................................................................66
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................68
LIST OF TABLES
Table 1:
Schedule of Activities.................................................................................................16

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1.
SPONSOR INFORMATION
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
Biogen Japan Ltd.
Nihonbashi 1-chome Mitsui 
Building 14F
4-1, Nihonbashi 1-chome
Chuo-ku, Tokyo 103-0027
Japan
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization and other third parties; however, Biogen retains overall accountability for these 
activities.

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3.
SYNOPSIS
Protocol Number:
233AS102
Protocol Title:
An Extension Study to Assess the Long-Term Safety, 
Tolerability, Pharmacokinetics, and Effect on Disease 
Progression of BIIB067 Administered to Previously Treated 
Adults with Amyotrophic Lateral Sclerosis Caused by 
Superoxide Dismutase 1 Mutation
Version Number
6
Name of Study Treatment:
BIIB067
Study Indication:
SOD1-ALS
Study Rationale
This study is an extension of Study 233AS101, a 
Phase 1/2/3 study evaluating the benefit/risk of BIIB067.  
This study will evaluate the long-term safety, tolerability, 
PK, PD, biomarker effects, and efficacy of BIIB067 
administered to participants with SOD1-ALS.
Phase of Development:
3
Study Objectives and 
Endpoints:
Primary Objective and Endpoint
The primary objective of the study is to evaluate the 
long-term safety and tolerability of BIIB067 in participants 
with ALS and confirmed SOD1 mutation.
The associated primary endpoint is the incidence of AEs and 
SAEs.
Secondary Objectives and Endpoints 
The secondary objectives are to evaluate the PK, PD, 
biomarker effects, and efficacy of BIIB067 administered to 
participants with ALS and confirmed SOD1 mutation.
The endpoints include the following:

PK endpoints: Plasma and CSF levels of 
BIIB067

PD endpoint: Change from baseline in total 
SOD1 protein in CSF

Biomarker endpoint: Change from baseline in 
NfL concentration in plasma

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
Efficacy endpoints:  

Changes over time in the following:  
oTotal ALSFRS-R score
oSVC
oHHD Megascore and individual muscle 
strength

Time to death or permanent ventilation 
(≥ 22 hours of mechanical ventilation 
[invasive or noninvasive] per day for 
≥ 21 consecutive days)

Time to death
The exploratory objectives and endpoints are listed in 
Section 6.3.
Study Design:
This is a multicenter, long-term extension study of BIIB067.  
The study will include a 29-day Loading Dose Period, 
during which participants will receive 3 IT injections 
approximately every 2 weeks (on Days 1, 15, and 29).
Participants who have completed Parts A or B of 
Study 233AS101 will have an unblinded Loading Dose 
Period, during which they will receive 3 doses of BIIB067.  
Participants who have completed Part C of Study 233AS101 
will have a blinded Loading Dose Period, during which 
participants who received BIIB067 in Study 233AS101 will 
receive 2 doses of BIIB067, on Days 1 and 29, and placebo 
on Day 15, and participants who received placebo in 
Study 233AS101 will receive 3 doses of BIIB067, on 
Days 1, 15, and 29. 
For all participants, the Loading Dose Period will be 
followed by an unblinded maintenance dose portion of the 
study, during which participants will receive up to 90 doses 
of BIIB067, approximately every 4 weeks.  
Study Location:
Approximately 42 sites are planned in approximately 
15 countries globally.
Number of Planned 
Participants:
The sample size of this extension study is based on the 
sample size of the SOD1-ALS population in 

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Study 233AS101.  Up to 183 participants will be dosed in 
Study 233AS101.
Study Population:
This study will be conducted in participants at least 18 years 
of age with SOD1-ALS who have completed 
Study 233AS101.
Detailed criteria are described in Section 8.
Treatment Groups:
BIIB067 100 mg will be administered by IT injection. 
Duration of Study 
Participation:
The total duration of study participation for a single 
participant will vary and be up to 368 weeks, consisting of 
an approximately 4-week screening period; up to a 
360-week treatment period; and a 4-week follow-up period. 

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4.
SCHEDULE OF ACTIVITIES FOR STUDY 233AS102

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Table 1:
Schedule of Activities
Screening 
Visit1
Baseline/1st 
Loading Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit
Final or Early 
Termination Visit
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Weeks 8, 12, 16, and 
every 4 weeks 
thereafter up to 
Week 360 (±3 days)
Assessments
Week -4 
to Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
4 weeks after last 
dose
ICF (main) and Genetic/Future 
Scientific Research Consent 
(optional)2
X
Medical History
X
X
Confirmation of Eligibility 
Criteria3
X
Ventilation Use4
X
X
X
X
X
X
ALSFRS-R
X5
X5
X5
X5, 6
X5
SVC7
X5
X5
X5
X5, 8
X5
HHD
X5
X5
X5
X5, 8
X5
C-SSRS12
X
X
X6
X

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Screening 
Visit1
Baseline/1st 
Loading Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit
Final or Early 
Termination Visit
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Weeks 8, 12, 16, and 
every 4 weeks 
thereafter up to 
Week 360 (±3 days)
Assessments
Week -4 
to Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
4 weeks after last 
dose
Weight
X
X
X
Vital Signs (temperature, blood 
pressure, pulse rate, respiratory 
rate)
X
X
X
X
X
X
X
X
X
X
12-lead ECG13
X
X
X
Physical Examination14
X
X
X
Limited Neurological 
Examination14
X
X
X
Pregnancy Test15
X
X
X
X
X
X
CSF Samples16
X17
X17
X17
X17
Clinical Laboratory Samples for 
Hematology, Coagulation, 
Chemistry, and Urinalysis3
X
X
X
X
X
X
Blood Samples for Plasma 
anti-BIIB067 Antibody
X
X
X
X18
X
Blood Samples for PK
X
X
X
X18
X
Blood Samples for PD and 
Biomarkers
X
X
X
X
X
Blood Samples for DNA19
X
Blood Samples for RNA Analysis 
(optional)20
X
X
X
X
X
Study Treatment Administration
X
X
X
X

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12“Since Last Visit” version of C-SSRS will be used after the Baseline/First Loading Dosing Visit.
13ECGs to be done at Screening, Day 1, Final/Early Termination Visit, and as clinically necessary per the discretion of the Investigator throughout the study. 
ECGs will be obtained after participants have rested in a supine position for at least 10 minutes.
14A physical examination and limited neurological examination will be performed at the specified timepoints (Screening, Day 1, Final/Early Termination Visit). 
At all other visits, the physical and/or limited neurological examination may be performed at the Investigator’s discretion. The components of the limited 
neurological examination are coordination/cerebellar function, reflexes, and motor system.
15To be performed only in women of childbearing potential; results must be negative to continue participation in study.  On dosing days, samples must be 
analyzed before study treatment administration.  To be performed via urine or serum testing. 
16CSF samples will be collected during the LP for PK, PD, safety, and biomarker analysis and will be analyzed to evaluate for blood contamination.  CSF 
samples for safety will be tested at local laboratories.
17Participants will remain under observation in the clinic for ~1 hour after the LP procedure for safety monitoring and can be discharged at the discretion of the 
Investigator and in compliance with the institutional requirements, once the participants have adequately recovered from the procedure.  Participants will 
receive a safety follow-up telephone contact ~24 hours after the procedure.
18Blood samples will be collected on every alternate visit at Week 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148, 156, 164, 172, 
180, 188, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, and 356 (i.e., every 8 weeks) Visits only.  Blood 
samples for anti-BIIB067 antibody and PK assessments will be collected at the same time.
19For participants who did not have the presence or absence of a SOD1 mutation confirmed centrally in Study 233AS101, a one-time blood sample will be 
collected.  For participants who did not have a blood sample collected for testing of other genes related to ALS and/or the response to BIIB067 in Study 
233AS101, an additional blood sample will be collected.  Participants undergoing this sample collection will be asked to sign an optional consent for use of 
DNA for possible future research in all regions where not prohibited by regulatory authorities or ethics committee.
20Participants who agree to provide samples will need to sign separate consent form(s).  RNA sample collection for possible future research will be optional in all 
regions where not prohibited by regulatory authorities or ethics committees.

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5.
INTRODUCTION
BIIB067 is an investigational second-generation ASO inhibitor of SOD1 mRNA, under 
development to reduce levels of SOD1 protein in patients with SOD1-ALS.  ASOs are short 
synthetic strings of nucleotides designed to prevent the expression of a targeted protein by 
selectively binding to the mRNA that encodes the protein with high affinity and selectivity 
through well-characterized Watson-Crick base pairing (hybridization).
5.1.
Overview of Amyotrophic Lateral Sclerosis
ALS is a rare neurodegenerative disease resulting in loss of motor neurons within the cortex, 
brainstem, and spinal cord.  Patients suffer gradual loss of muscle mass, strength, and function in 
bulbar, respiratory, and voluntary muscle.  Decline is inevitable, with death from respiratory 
failure following 2 to 5 years after diagnosis for most patients.  Although the majority of patients 
suffer from sporadic ALS, a smaller fraction of patients, approximately 2%, have an inherited, or 
familial, form of ALS caused by a variety of mutations in SOD1 (referred to as SOD1-ALS) 
[ALSoD 2015; Ferlay 2013].  During the time since SOD1-ALS was first described in 1993, 
more than 180 SOD1 mutations have been reported to cause this form of ALS.  Disease 
progression for individual mutations is variable, with survival of less than 15 months seen with 
the most severe mutations [Cudkowicz 1997].  
Overexpression of mutant SOD1 in mice or rats recapitulates important aspects of ALS in 
humans [Bruijn and Cleveland 1996; Gurney 1994]; however, loss of SOD1, while resulting in 
eventual motor neuron dysfunction, does not result in motor neuron death [Fischer 2012; 
Reaume 1996].  Furthermore, neither loss nor increase of SOD1 activity in mouse models of 
SOD1-ALS alters survival [Bruijn 1998].  In humans, individual disease mutations are associated 
with varying levels of SOD1 activity; some patients with disease-causing mutations have 
apparently normal SOD1 activity [Howlader 2015].  Thus, correlation between disease severity 
and normal SOD1 activity has not been observed [Andersen 1997; Howlader 2015; Ratovitski 
1999].  In contrast, reduction of SOD1 with intracerebroventricular-delivered SOD1 ASO 
extended survival in a rodent model of SOD1-ALS [Smith 2006].  These observations strongly 
suggest that SOD1-ALS is caused by toxic properties of the mutant SOD1 protein.  Reducing 
SOD1 mRNA and, subsequently, toxic SOD1 protein may offer therapeutic benefit for patients 
with SOD1-ALS.  IT delivery of an ASO targeting SOD1 mRNA is a viable method to reduce 
toxic SOD1 protein.
5.2.
Current Therapies for Amyotrophic Lateral Sclerosis 
The only currently approved treatments for ALS are riluzole and edaravone, with approvals 
varying in each region.  Riluzole provides a modest increase in survival (2 to 3 months) without 
noticeable improvement in strength or disability [Miller 2012].  Edaravone lessens functional 
decline as measured by the ALSFRS-R.  The effect of edaravone on survival is unknown 
[Writing Group and Edaravone (MCI-186) ALS 19 Study Group 2017].  No specific treatments 
for SOD1-ALS are available.  

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5.3.
Profile of Previous Experience With BIIB067
5.3.1.
Nonclinical Experience
Four in vivo nonclinical toxicology studies were performed to support the development of 
BIIB067:  a repeated-dose, 12-week, subcutaneous bolus injection study in mice (25 and 
150 mg/kg); a single-dose, IT bolus injection study in rats (0.1, 0.3, 1.0, and 3.0 mg); a 
repeated-dose, 13-week, IT bolus injection study in cynomolgus monkeys (4, 12, and 35 mg); 
and a repeated-dose, 9-month, IT bolus injection study in cynomolgus monkeys (4, 12, and 
35 mg).  
See the BIIB067 Investigator’s Brochure for detailed information on all nonclinical studies.
5.3.1.1.
Toxicology
In mice, subcutaneous administration of BIIB067 was well tolerated, with the highest dose 
evaluated (150 mg/kg) being the NOAEL.  The NOAELs in the toxicology studies in which the 
clinical route of administration (IT) was used were 1 mg (rat) and 35 mg (monkey).  
In rats, a single IT bolus delivery of BIIB067 resulted in 1 early death in a rat receiving the 
highest dose evaluated (3 mg).  Transient acute tactile hypersensitivity was noted approximately 
25 minutes postdose in animals receiving 3 mg.  Decreases in arousal, gait, mobility, respiration, 
and sensorimotor observations were also noted 3 hours postdose in the 3-mg group.
In cynomolgus monkeys, repeated IT administration of BIIB067 for 13 weeks was well tolerated 
up to the highest dose evaluated (35 mg), although 2 animals in the 35-mg group had transient 
clinical signs (reduced locomotor activity).  Cytoplasmic vacuolation in some neurons of the 
hippocampus, and to a lesser degree of the cerebral cortex, was observed at all doses (4, 12, and 
35 mg).  The neuronal vacuolation was not associated with any morphological evidence of cell 
degeneration or necrosis and was fully reversible within a 13-week recovery period.  
Furthermore, IT injection of BIIB067 caused mononuclear inflammatory cell infiltrates in the 
meninges at the lumbar spinal cord injection site, possibly as a local proinflammatory effect 
caused by ribonuclease H-based ASOs.  Remnants of such inflammatory infiltrates were still 
detectable after 13 weeks of recovery, although at a lower magnitude.  In addition, vacuolated 
histiocytes were found in lymph nodes as well as in the Virchow-Robin space of the brain; this 
finding was not fully reversible within 13 weeks.  Neuronal vacuolation in the spinal cord was 
observed in 1 recovery animal but was not observed in any animal at the end of the 13-week 
dosing period.  The relation of this finding to BIIB067 is unknown.  Based on the lack of any 
evidence of cell degeneration or necrosis and absence of clinical or neurological abnormalities 
associated with the vacuolation, it was concluded that the microscopic findings were not adverse.
From the 9-month cynomolgus monkey toxicology study, the NOAEL for repeated, 
IT-administered BIIB067 was 12 mg.  This was based on adverse clinical observations for 
1 female administered 35 mg.  This female exhibited neurological signs after the second dose, 
characterized by transient muscle cramping (seen immediately after dosing on multiple days), 
prolonged recovery from anesthesia, and intermittent tremors (during the last months of the 
dosing phase).  Treatment with diazepam was required on several dosing occasions.  An EEG on 

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this animal revealed altered postdose signals (with effects on high frequency bands) but 
confirmed that muscle cramping during EEG recording was not a seizure and could have been 
related to arousal.  This finding was considered test-article related; however, there were no 
correlates in clinical and anatomic pathology.
5.3.1.2.
Pharmacokinetics
To characterize the PK properties of BIIB067, CSF (monkey only), plasma (monkey and mouse 
only), and tissue (monkey, mouse, and rat) concentrations were assessed following IT (monkey 
and rat) or subcutaneous (mouse) administration.  
Following bolus IT administration in monkeys, BIIB067 concentrations in CSF declined in a 
multiphasic manner with a rapid distribution phase, followed by a slower and longer elimination 
phase.  The rapid distribution phase was due to rapid and broad distribution from CSF to CNS 
tissues and clearance from CSF due to transfer to systemic circulation (including plasma and 
systemic tissues such as kidney and liver).  The estimated CSF t½ was 20 to 37 days.
BIIB067 concentrations in plasma peaked 1 to 4 hours after the IT bolus injection in monkeys 
and then rapidly declined during the first 48 hours postdose, with a much slower elimination 
phase thereafter.  The estimated plasma t½ was 22 to 51 days.  In mice, BIIB067 concentrations 
in plasma peaked 0.5 hour after subcutaneous administration, indicating rapid absorption into the 
systemic circulation and, similar to monkeys, declined rapidly over the next 48 hours due to 
extensive distribution to systemic tissues. 
Dose-dependent tissue distribution of BIIB067 to CNS and peripheral tissues was seen in all 
species studied (monkey, rat, and mouse), with no clear or consistent evidence of a sex 
difference in distribution to tissues.  
Following IT administration, distribution to CNS tissues was broad in both rats and monkeys, 
with the highest CNS concentrations seen in the lumbar spinal cord, consistent with the IT route 
of administration.  In monkeys, relatively higher concentrations were observed in the liver and 
kidney, indicating a significant proportion of the administered dose was distributed from CSF to 
the systemic circulation.  During the recovery period, BIIB067 appeared to be cleared slowly 
from CNS and peripheral tissues.  The estimated tissue t½ was similar to that for CSF and plasma 
(31 to 40 days in CNS tissues, 15 to 20 days in the liver, and 18 to 23 days in the kidney).  
BIIB067 was rapidly and extensively distributed from plasma to liver and kidney following 
subcutaneous administration in mice.  
The long CSF and CNS tissue t½ observed in monkeys support an infrequent clinical dosing 
regimen following IT administration.
5.3.2.
Clinical Experience
This study is an extension of Study 233AS101, a Phase 1/2/3 study evaluating the benefit/risk of 
BIIB067.  In the single and multiple dose escalation parts (Parts A and B) of this study, BIIB067 
at dose levels up to and including 100 mg was generally well tolerated.  Most of the AEs were 

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mild or moderate in severity.  Plasma concentrations of BIIB067 were dose proportional; CSF 
concentrations showed a less-than-dose-proportional response.  Administration of BIIB067 
100 mg for 12 weeks in Part B of Study 233AS101 led to a 36% reduction in total CSF SOD1 
protein compared to a 3% reduction observed in the placebo arm. Administration of BIIB067 
100 mg for 12 weeks also led to an apparent slowing in decline across exploratory clinical 
outcome measures including ALSFRS-R, SVC, and HHD Megascore.
5.4.
Study Rationale
This study will evaluate the long-term safety, tolerability, PK, PD, and efficacy of BIIB067 
administered to participants with SOD1-ALS who have completed Parts A, B, or C of Study 
233AS101 of BIIB067.
5.5.
Rationale for Dosing Regimen
BIIB067 100 mg will be administered via IT bolus over 1 to 3 minutes.
The BIIB067 dosing regimens for Parts A and B of Study 233AS101 were selected based on 
target tissue concentrations from SOD1 transgenic mouse models, and nonclinical toxicology 
and PK observations in repeated dose, IT administration in 13-week and 9-month NHP studies. 
Based on pharmacology and PK results in SOD1 transgenic mice, the estimated tissue 
concentrations of BIIB067 needed to produce a 50%, and the upper 95% CI of an 80%, SOD1 
mRNA reduction within the human spinal cord are 0.9 µg/g and 4.7 µg/g, respectively.  
Evaluations of cortex from the same experiment indicate that the estimated tissue concentration 
of BIIB067 needed to produce a 50% cortical SOD1 mRNA reduction is 8 µg/g.
The lowest dose selected for Study 233AS101 (10 mg in Part A) was predicted to achieve greater 
than 0.9 µg/g tissue concentration in the spinal cord.  The initial highest proposed dose (60 mg, 
multiple doses in Part B) was predicted to achieve greater than 4.7 µg/g steady-state tissue 
concentration in the spinal cord, and approximately 1.5 µg/g steady-state tissue concentration in 
the cortex, which is expected to yield approximately 15% to 20% SOD1 mRNA reduction in that 
tissue.  The addition of a 100-mg cohort is predicted to achieve steady-state exposures in the 
cortex of approximately 2.5 µg/g, which is predicted to be sufficient for a meaningful CSF total 
SOD1 protein reduction of 25% to 30%.  This reduction is expected to be clinically meaningful, 
based on the expectation that the reduction of total SOD1 protein in tissues (spinal cord and 
cortex) would be greater than the 20% to 30% reduction observed in CSF.  This prediction is 
based on observations in NHP studies, where approximately 50% reduction in CSF corresponded 
to approximately 50% or greater reduction in the spinal cord and cortex.  In rodent efficacy 
experiments, doses of BIIB067 that reduced tissue total SOD1 protein by approximately 30% or 
more were found to improve measures of electrophysiology, function, and neurofilament.  
Based on nonclinical PK and pharmacology data, and taking into consideration participant 
safety, the inconvenience of repeated IT injections, and the rapid, fatal nature of ALS, the 
following dose intervals were selected for this extension study:  3 loading doses, once every 
2 weeks, and 22 maintenance doses, administered approximately every 4 weeks from Months 3 

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to 24.  These intervals were selected based on the estimated t½ of BIIB067 (~1 month) in the 
target CNS tissues (spinal cord and brain cortex), to achieve and maintain the target tissue 
concentration of BIIB067 at a steady-state level and within the estimated pharmacologically 
active range and allow collection of PK and PD data during dose interruption and resumption, 
providing information on the dynamic behavior of the system.  
From the 9-month NHP toxicology study, the NOAEL for repeated, IT-administered BIIB067 
was 12 mg.  This NOAEL was converted to a HED based on the NHP to human CSF volume 
scaling (approximately 10-fold difference).  CSF volume scaling conservatively estimates the 
needed scaling factor and has predicted HED with reasonable accuracy.  The HED for the 
9-month, IT NHP toxicology study was calculated to be 120 mg.  This provides a 6-fold safety 
margin for the BIIB067 starting dose (20 mg) of the extension study, and a 2-fold safety margin 
for the 60-mg dose.  The safety margin for a 100-mg clinical dose (highest planned dose) would 
be 1.2-fold.  Preliminary PK data (plasma AUC from time 0 to 24 hours) from the 20 mg MAD 
cohort in Study 233AS101, indicate that the safety margin based on exposure is 2.2-fold relative 
to a 100-mg clinical dose.  The 1.2-fold safety margin based on CSF volume scaling from the 
NHP toxicology study was chosen over the 2.2-fold safety margin calculated from the plasma 
steady-state exposures, since the former provides a more conservative estimate.
For Part C (Pivotal) of Study 233AS101, the dose of BIIB067 100 mg was determined based on 
the interim analyses of data from participants in Part B (MAD) Cohorts 5 to 8 treated for 
85 days.  Safety analyses of these data suggested that all doses through 100 mg had been well 
tolerated, with a safety profile supportive of continued development of BIIB067 in participants 
with ALS.  The selection of the BIIB067 100 mg dose for Part C is supported by PK/PD
 analyses of data from participants in Part A (SAD) and Part B (MAD) [see 
Section 5.3.2].

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6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
Primary Objective and Endpoint
The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 
in participants with ALS and a confirmed SOD1 mutation.
The associated primary endpoint is the incidence of AEs and SAEs.
6.2.
Secondary Objectives and Endpoints
The secondary objectives are to evaluate the PK, PD, biomarker effects, and efficacy of BIIB067 
administered to participants with ALS and a confirmed SOD1 mutation.  
6.2.1.
Pharmacokinetic Endpoints
The PK endpoints are plasma and CSF levels of BIIB067.
6.2.2.
Pharmacodynamic Endpoint
The PD endpoint is the change from baseline in total SOD1 protein in CSF.
6.2.3.
Biomarker Endpoint
The biomarker endpoint is the change from baseline in NfL concentration in plasma.
6.2.4.
Efficacy Endpoints

Efficacy endpoints are changes over time in the following:  

Total ALSFRS-R score

SVC

HHD Megascore and individual muscle strength

Time to death or permanent ventilation (≥ 22 hours of mechanical ventilation 
[invasive or noninvasive] per day for ≥ 21 consecutive days)

Time to death

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7.
STUDY DESIGN
7.1.
Study Overview
This is a multicenter, open-label, long-term extension study to assess the long-term safety, 
tolerability, PK, PD, and efficacy of BIIB067 administered by IT injection to previously treated 
participants with SOD1-ALS who have completed Parts A, B, or C of Study 233AS101.  The 
study will be conducted at approximately 42 sites in approximately 15 countries globally.  
Participants who have completed Parts A or B of Study 233AS101 will have a washout period of 
at least 4 times the t½ (~16 weeks) from the time of their last dose of study treatment in 
Study 233AS101 to their first dose in Study 233AS102.  These participants will receive 
3 loading doses of BIIB067 100 mg, approximately 2 weeks apart, during the first 4 weeks.  
Participants who have completed Part C of Study 233AS101 will not have a washout period.  To 
preserve the blinding used in Study 233AS101 until database lock, participants who enroll in 
Study 233AS102 after completing Part C of Study 233AS101 will have a blinded Loading Dose 
Period.  Participants who received placebo while in Study 233AS101 will receive 3 doses of 
BIIB067 100 mg, approximately once every 2 weeks (Days 1, 15, and 29), while participants 
who received BIIB067 in Study 233AS101 will receive 2 doses of BIIB067 100 mg, on Days 1 
and 29, and placebo on Day 15.  
After the Loading Dose Period, participants will receive up to 90 maintenance doses of BIIB067 
100 mg, approximately every 4 weeks until the last participant enrolled has had the opportunity 
to have their Week 152 Maintenance Dose Visit.  Participants who were not receiving BIIB067 
100 mg (i.e., participants in Parts A and B) will be dosed at BIIB067 100 mg at their next 
scheduled Maintenance Dose Visit. 
7.2.
Overall Study Duration and Follow-Up
The overall duration of study participation for a single participant will be up to 368 weeks, which 
includes an approximately 4-week screening period, up to a 360-week treatment period, and a 
4-week follow-up period.
7.2.1.
Screening
7.2.1.1.
Participants Who Have Completed Parts A and B of Study 233AS101
Participants who have completed Part B (MAD) of Study 233AS101 and participants who have 
completed Part A (SAD) of that study will be eligible for screening.  Participant eligibility for 
the study will be determined from Week -4 through Day -1.  
The Screening Visit assessments may be performed over approximately 2 days, which do not 
need to be consecutive, to minimize participant burden.  All assessments must be completed on 
or before the Baseline/Loading Dose Visit on Day 1.  

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7.2.1.2.
Participants Who Have Completed Part C of Study 233AS101
Participants who have completed the last dosing visit in Part C of Study 233AS101 will be able 
to screen to determine eligibility to participate in Study 233AS102.  A participant’s last dosing 
visit in Part C of Study 233AS101 may be the start of the Screening Visit (Week -4 to Day -1) 
for this extension Study 233AS102.  Results from assessments completed by participants at the 
last dosing visit of Study 233AS101 can be used for the purpose of screening and do not need to 
be repeated as long as they are conducted within 4 weeks of the Baseline/Loading Dose Visit on 
Day 1.
7.2.2.
Dosing
Eligible participants will report to the study site on Day 1 to complete baseline assessments and 
reaffirm eligibility.  Day 1 should occur no earlier than 28 days after the participant’s last dose 
(i.e., Day 169 [Week 24 Visit]) in Study 233AS101.
Assessments collected at the End of Study Visit (i.e., Day 197 [Week 28 Visit]) or at the Safety 
Follow Up (Alternative End of Study Visit) (i.e., Day 225 [Week 32 Visit]) of Part C of 
Study 233AS101 may be used as the Day 1 predose assessments for Study 233AS102 if they are 
collected within 48 hours of the first dose in Study 233AS102.
On dosing days, participants will remain at the study site for at least 1 hour postdose for safety 
monitoring and can be discharged at the discretion of the Investigator and in compliance with the 
institutional requirements, once the participants have adequately recovered from the dosing 
procedure.  Participants will receive a safety follow-up telephone contact approximately 24 hours 
after the procedure.  
7.2.2.1.
Loading Dose Period
The Loading Dose Period of the study will occur from Day 1 to Day 29. 

Participants who have completed Parts A or B of Study 233AS101:  

Participants will receive 3 loading doses of BIIB067 approximately 2 weeks apart 
(Day 1, Day 15, and Day 29).  

Participants who have completed Part C of Study 233AS101:  

Participants randomized to receive placebo during Study 233AS101 will receive 
3 loading doses of BIIB067, approximately 2 weeks apart (Day 1, Day 15, and 
Day 29).  The Investigators, study staff (except for an unblinded designated 
pharmacist/technician), and study participants will be blinded to the study 
treatment during the Loading Dose Period. 

Participants randomized to receive BIIB067 during Study 233AS101 will receive 
2 loading doses of BIIB067, on Days 1 and 29, and 1 dose of placebo on Day 15.  
The Investigators, study staff (except for an unblinded designated 

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pharmacist/technician), and study participants will be blinded to the study 
treatment during the Loading Dose Period.
7.2.2.2.
Maintenance Dose Period
During the maintenance portion of the study, participants will receive up to 90 doses of BIIB067, 
approximately every 4 weeks, during visits at Weeks 8, 12, and 16 and every 4 weeks thereafter 
until the last participant enrolled has had the opportunity to have their Week 152 Maintenance 
Dose Visit.
7.2.3.
Follow-Up
Participants will return for their final visit, which will be 4 weeks after their last dose. 
Participants who withdraw from the study early will return for an Early Termination Visit, which 
will be 4 weeks after their last dose.
7.3.
Study Stopping Rules
The Sponsor may terminate this study at any time, after informing Investigators.  The Sponsor 
will notify Investigators if the study is to be placed on hold, completed, or terminated.
Conditions that may warrant termination of the study include, but are not limited to the 
following: 

The discovery of an unexpected, serious, or unacceptable risk to the participants 
enrolled in the study.  

A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.
7.4.
End of Study
The end of study is last participant, last visit (approximately 4 weeks after their last dose).  The 
last Maintenance Dose Visit for a participant will occur when the last participant enrolled has 
had the opportunity to have their Week 152 Maintenance Dose Visit.

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8.
SELECTION OF PARTICIPANTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening, or at the time point specified in the individual eligibility criterion listed:
1. Ability of the participant to understand the purpose and risks of the study and indicate 
consent, and ability of the participant or his/her legally authorized representative to 
provide signed and dated informed consent and authorization to use PHI in accordance 
with national and local participant privacy regulations.  
2. Must have diagnosis of SOD1-ALS and must have completed the End of Study Visit for 
either Parts A, B, or C of Study 233AS101 (i.e., were not withdrawn). 
3. If taking riluzole, participant must be receiving a stable dose for ≥ 30 days prior to Day 1.
4. If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment 
cycles) prior to Day 1.  Edaravone may not be administered on dosing days during this 
study.
5. Medically able to undergo the study procedures, and to adhere to the visit schedule at the 
time of study entry, as determined by the Investigator.
6. Must have screening values of coagulation parameters including platelet count, INR, PT, 
and aPTT within normal ranges.  Coagulation tests may be repeated at the local 
laboratory once if, in the opinion of the Investigator, values of the initial tests are out of 
range but deemed not clinically significant.  Participants with nonclinically significant 
and stable out-of-range values may be eligible to enroll in the study at the discretion of 
the Investigator.  (For normal ranges, please refer to the Study Reference Guide).
7. Female participants of childbearing potential must agree to practice effective 
contraception during the study and be willing and able to continue contraception for 
5 months after their last dose of study treatment.  For further details of contraceptive 
requirements for this study, please refer to (see Section 15.5).
8. Participants in Parts A and B must have a washout ≥ 16 weeks between the last dose of 
study treatment received in Study 233AS101 and the first dose of BIIB067 received in 
the current Study 233AS102.  Participants in Part C do not require a washout period. 
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening, or at the timepoint specified in the individual criterion listed:

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Medical History
1. History of drug abuse or alcoholism within 6 months before study enrollment that would 
limit participation in the study, as determined by the Investigator.
2. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy, or any other ongoing medical condition during the 
screening period that, according to the Investigator, would interfere with the conduct or 
assessments of the study.  
3. Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, 
including psychosis, suicidal ideation, suicide attempt, or untreated major depression 
≤90 days, as determined by the Investigator.
4. History of allergies to a broad range of anesthetics.
5. Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not 
managed optimally and could place a participant at an increased risk for bleeding during 
or after an LP procedure.  These risks could include, but are not limited to, anatomical 
factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or other 
abnormalities) and underlying disorders of the coagulation cascade, platelet function, or 
platelet count (e.g., hemophilia, Von Willebrand’s disease, liver disease). 
6. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
7. Clinically significant abnormalities in hematology or clinical chemistry parameters, as 
determined by the Investigator, which would render the participant unsuitable for 
enrollment.  
8. Clinically significant, as determined by the Investigator, 12-lead ECG abnormalities, 
including corrected QT interval using Fridericia’s correction method of > 450 ms for 
males and > 470 ms for females.
Medications
9. Prior or current treatment with small interfering RNA, stem cell therapy, or gene therapy.
10. Treatment with another investigational drug, biological agent (excluding BIIB067), or 
device within 1 month or 5 half-lives of study agent, whichever is longer.  
11. Current or anticipated need, in the opinion of the Investigator, of a DPS during the study 
period.
12. Current or recent (within 1 month) use, or anticipated need, in the opinion of the 
Investigator, of copper (II) (diacetyl-bis[N4-methylthiosemicarbazone]) or 
pyrimethamine.

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13. Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet 
or anticoagulant medication that cannot be safely continued or held for an LP procedure, 
if necessary, according to local or institutional guidelines and/or Investigator 
determination. 
Other
14. Female participants who are pregnant or currently breastfeeding.
15. Current enrollment in any other interventional study.
16. Inability to comply with study requirements.
17. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
participant unsuitable for enrollment.

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9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION
9.1.
Screening and Enrollment
Participants (or their legally authorized representative [e.g., spouse], where applicable) must 
provide informed consent before any screening tests are performed (see Section 17.3).  When a 
participant signs the ICF, that participant is considered to be enrolled in the study.  Participating 
study sites are required to document all screened candidates initially considered for inclusion in 
this study.  If a participant is excluded from the study, the reasons for exclusion will be 
documented in the participant’s source documents and on the screening log.
Participants who fail screening can be rescreened once at the discretion of the Investigator.  All 
rescreening must be completed within 56 calendar days after the start of the screening period 
(Study 233AS101 Day 169 [Week 24 Visit]). 
9.2.
Randomization and Registration of Participants
Participants will be registered on Day 1 after all predose assessments have been completed, and 
after the Investigator has verified that the participants are eligible per criteria in Sections 8.1 
and 8.2.  No participant may begin treatment before being assigned a unique identification 
number.  Participant identification numbers that are assigned will not be reused, even if the 
participant does not receive treatment.  Participants will not be randomized.
Refer to the Study Reference Guide for details on registration.
9.3.
Blinding Procedures
This is an open-label, long-term extension study of BIIB067 in participants with SOD1-ALS 
who have completed either Parts A, B, or C of Study 233AS101.  In Study 233AS101, the 
Investigators, study staff (except for an unblinded designated pharmacist/technician), and study 
participants are blinded to the randomized study treatment assignments.  To preserve the blinding 
used in Study 233AS101 until database lock, participants who completed Parts A or B of 
Study 233AS101 will have a washout period of at least 4 times the t½ (~16 weeks) from the time 
of their last dose of study treatment in Study 233AS101 to their first dose in Study 233AS102.  
Participants who completed Part C of Study 233AS101 will have a blinded Loading Dose Period 
(see Section 7.2.2.1 for details). 

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10.
DISCONTINUATION OF STUDY TREATMENT OR 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
A participant must discontinue study treatment for any of the following reasons:

The participant becomes pregnant.  Study treatment must be discontinued 
immediately.  Report the pregnancy according to the instructions in Section 15.4.1.

The participant withdraws consent to continue study treatment.  

The participant experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.

The participant is unwilling or unable to comply with the protocol.

At the discretion of the Investigator or Sponsor.
The reason for discontinuation of study treatment must be recorded in the participant’s CRF.
Participants who discontinue study treatment will be encouraged to remain in the study and 
complete all applicable protocol-specified tests and assessments.  In circumstances when onsite 
visits are not possible, these assessments may be conducted by telephone.  
Participants who terminate from the study early (i.e., discontinue both study treatment and study 
assessments) should complete the Final or Early Termination Visit.  Home assessments will be 
allowed with Investigator approval for participants who are unable to complete the Final or Early 
Termination Visit at the site.
10.2.
Withdrawal of Participants From Study
Participants must be withdrawn from the study for any one of the following reasons:

The participant withdraws consent.  

The participant enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered.

The participant is unwilling or unable to comply with the protocol.
The reason for the participant’s withdrawal from the study must be recorded in the participant’s 
CRF.

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11.
STUDY TREATMENT USE
11.1.
Regimen
11.1.1.
Participants Who Have Completed Parts A or B of Study 233AS101
Participants will receive 3 loading doses of BIIB067, approximately 2 weeks apart, during the 
first 4 weeks, and up to 90 maintenance doses of BIIB067, approximately every 4 weeks, by IT 
injection.  
All participants who were not receiving the 100 mg dose of BIIB067 will be dosed at BIIB067 
100 mg at their next scheduled Maintenance Dose Visit.
11.1.2.
Participants Who Have Completed Part C of Study 233AS101
Participants will not have a washout period.  Participants who received placebo while in Part C 
of Study 233AS101 will receive 3 loading doses of BIIB067 100 mg approximately once every 
2 weeks (Days 1, 15, and 29), while participants who received BIIB067 in Part C of 
Study 233AS101 will receive 2 doses of BIIB067 100 mg, on Days 1 and 29, and placebo on 
Day 15.  All participants will receive BIIB067 100 mg at each Maintenance Dose Visit (up to 
58 doses) thereafter.  Study treatment administered to participants during the Loading Dose 
Period is to be blinded.
11.1.3.
All Participants
Prior to injection, approximately 10 mL of CSF will be collected for analyses.  Depending on 
institutional guidelines, anesthesia or sedation may be used for the LP procedure.  On dosing 
days, participants will remain at the study site for at least 1 hour postdose for safety monitoring 
and can be discharged at the discretion of the Investigator and in compliance with the 
institutional requirements, once the participants have adequately recovered from the dosing 
procedure.  Participants will receive a safety follow-up telephone contact approximately 24 hours 
after the procedure.  During the follow-up periods, participants will remain under observation in 
the clinic for approximately 1 hour after the LP procedure and will receive a safety follow-up 
telephone contact approximately 24 hours after the procedure.  Refer to and follow the DHA. 
11.2.
Modification of Dose and/or Treatment Schedule
The dosage should not be modified, other than as stated in Section 7.2.2.  Any change in the 
planned dose or dosing regimen would require a protocol amendment.
11.3.
Concomitant Therapy and Procedures
11.3.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between Day 1 and the Final or 
Early Termination Visit.

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11.3.1.1.
Allowed Concomitant Therapy
Participants taking concomitant riluzole at study entry must be receiving a stable dose for 
≥30 days prior to the first dose of study treatment (Day 1).  These participants should remain on 
this stable dose of riluzole until the completion of the Week 12 Visit, unless riluzole use must be 
discontinued in the judgment of the Investigator, in which case it should not be restarted until the 
completion of the Week 12 Visit.  If participants are not receiving riluzole at Day 1, they should 
not initiate it until the completion of the Week 12 Visit.
Participants taking concomitant edaravone at study entry must have initiated edaravone ≥60 days 
(2 treatment cycles) prior to the first dose of study treatment (Day 1).  Edaravone may not be 
administered on dosing days of this study.  These participants should remain on this stable dose 
of edaravone until the completion of the Week 12 Visit, unless edaravone use must be 
discontinued in the judgment of the Investigator, in which case it should not be restarted until the 
completion of the Week 12 Visit.  If participants are not receiving edaravone at Day 1, they 
should not initiate it until the completion of the Week 12 Visit.
Concomitant medication for symptom management during the study is at the discretion of the 
Investigator.  Participants with questions about allowed concomitant therapy should seek medical 
guidance from the Investigator.
11.3.1.2.
Disallowed Concomitant Therapy
Any antiplatelet or anticoagulant medication that cannot be safely continued or held for an LP 
procedure, if necessary, according to local or institutional guidelines and/or Investigator 
determination is prohibited for the duration of the study.
Use of DPS, copper (II) (diacetyl-bis[N4-methylthiosemicarbazone]), or pyrimethamine is 
prohibited for the duration of the study.  
Treatment with small interfering RNA, stem cell therapy, or gene therapy is prohibited.
Off-label use of any disease-modifying treatment for ALS is prohibited for the duration of the 
study.
Participants should be instructed to contact their Investigator before taking any new medications, 
including nonprescription drugs and herbal preparations.  
11.3.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the participant is enrolled in the study and the final study visit.
11.4.
Continuation of Treatment 
There is no provision to provide study treatment after the study.

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12.
STUDY TREATMENT MANAGEMENT
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA aligns with all other references, 
including the protocol.
Study treatment must be dispensed only by a Pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to participants enrolled in this study.  Once study treatment is 
prepared for a participant, it can be administered only to that participant.  Study treatments are 
for one-time use only; do not use any study treatment remaining in the vial for another 
participant.
12.1.
BIIB067
The Sponsor will supply BIIB067 as a liquid in vials containing approximately 16.4 mL per vial, 
to ensure 15.0 mL deliverable volume after withdrawal from vial and dose preparation.  The drug 
product is a sterile, parenteral solution formulation that contains BIIB067 drug product 
6.7 mg/mL, sodium dihydrogen phosphate dihydrate 
mg/mL, sodium phosphate dibasic 
anhydrous 
mg/mL, sodium chloride
mg/mL, potassium chloride 
mg/mL, calcium 
chloride dihydrate
 mg/mL, and magnesium chloride hexahydrate in water for injection 
 mg/mL, pH 7.2.
The contents of the BIIB067 label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, study treatment 
identifier, quantity of dosage units, lot number, and other pertinent information in accordance 
with local law.  The expiry or use-by date will be stored in the IRT system, and printable 
assignment reports will be available to site personnel.  BIIB067 should not be used after the 
expiration date.  
12.1.1.
BIIB067 Preparation
The individual preparing BIIB067 should carefully review the instructions provided in the DHA.
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or study treatment, then the study treatment should not be used.  The vial in question 
should be saved at the study site, and the problem should be reported to the Sponsor 
immediately.
12.1.2.
BIIB067 Storage
Study treatment must be stored in a secure location.  

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BIIB067 is to be protected from light and stored at 2C to 8C (36F to 46F), in a monitored, 
locked refrigerator, with limited access.  For the most up-to-date storage requirements, follow the 
instructions provided in the DHA.
12.1.3.
BIIB067 Handling and Disposal
The Investigator must return all used and unused vials of BIIB067 as instructed by the Sponsor, 
unless approved for onsite destruction.
If any BIIB067 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from the Sponsor, by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, the Sponsor must be 
notified, in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, 
quantities), the date of destruction, and proof of destruction.
12.1.4.
BIIB067 Accountability
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (participant-by-participant accounting), and accounts of any study treatment 
accidentally or deliberately destroyed or lost.  
Unless otherwise notified, the study site must save all vials, both used and unused, for study 
treatment accountability.  At the end of the study, reconciliation must be made between the 
amount of BIIB067 supplied, dispensed, and subsequently destroyed, lost, or returned to the 
Sponsor.  A written explanation must be provided for any discrepancies.
12.2.
Placebo Product
Placebo is to be stored at 2°C to 8°C (36°F to 46°F), in a monitored, locked cabinet with limited 
access.
The Sponsor manufactures the matching placebo (artificial CSF), supplied as a liquid in vials 
containing approximately 21 mL per vial for use during the blinded Loading Dose Period in 
participants who enrolled after completing Part C of Study 233AS101.  The drug supply label 
will include conditions for storage, lot number, and other pertinent information.

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Approximately 10% of ALS is known to be caused by genetic mutations; to date, at least 
20 genes have been identified as causative of or highly associated with ALS, including SOD1.  
The DNA sample will be analyzed for genetic variation in the SOD1 gene to determine the 
spectrum of likely pathogenic mutations in the gene and to assess if SOD1 polymorphisms affect 
response to treatment.  In addition, samples collected during the study may be analyzed for 
genetic variation in other genes of known and probable relevance for the pathogenesis of ALS 
and neurodegeneration, including but not limited to TAR DNA-binding protein, fused in 
sarcoma, chromosome 9 open reading frame 72, optineurin, valosin-containing protein, 
ubiquilin 2, profilin 1, and ataxin.
In the event of an unusual response or observation of unexplained AEs, DNA samples may be 
used to determine if there are any pharmacogenomics associations with drug response.
In the future, as the understanding of ALS and BIIB067 increases, additional genomic analyses 
may be warranted to refine the knowledge of the molecular basis of the disease and the drug 
response as well as to advance the development of novel therapeutics.  The sample will only be 
used in genetic analyses to understand ALS, neurodegeneration, and response to BIIB067.
The DNA samples will be coded with the participant’s identification number and may be stored 
for up to 25 years after the end of the main study or a duration dictated by local, national, or 
regional laws or regulations.  No genotyping or genomic data will be provided back to the 
participant.  Participants may withdraw consent and request to have their samples destroyed at 
any time, and no further genetic data will be generated; any data already generated will not be 
destroyed. 

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14.
SAFETY ASSESSMENTS
Refer to Section 4 for the timing of all safety assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BIIB067:

Medical history

Physical examinations

Limited neurological examinations (to be assessed by a trained specialist) of 
coordination/cerebellar function, reflexes, and motor system

Vital sign measurements:  temperature, systolic and diastolic blood pressure, pulse 
rate, and respiratory rate will be measured after the participant has rested in a sitting 
position for at least 5 minutes

Weight measurements

12-lead ECGs (paper; as applicable) 

C-SSRS

Concomitant therapy and procedure recording

AE and SAE recording
14.2.
Laboratory Safety Assessments
The following laboratory assessments will be performed to evaluate the safety profile of 
BIIB067:

Hematology:  Complete blood count with differential and platelet count.  Platelet 
count will also be measured for all participants at Screening and at all dosing and 
final/early termination visits

Coagulation:  INR, PT, and aPTT (all of which will also be measured for all 
participants at Screening and at all dosing and final/early termination visits)

Blood chemistry:  total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, 
bicarbonate, chloride, sodium, and potassium

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
Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal)

Pregnancy tests

CSF:  red and white blood cell count, protein, and glucose
The majority of clinical laboratory samples will be collected at the clinic and analyzed by a 
central laboratory external to the clinic.  Pregnancy tests will be collected and analyzed at the 
clinic.  CSF will be collected in the clinic and analyzed at the local laboratory.  At each CSF 
collection, 2 sample tubes will be sent to the local laboratories for routine cell count, differential 
count, and for protein and glucose analysis.  In addition, should repeat coagulation or 
hematology tests be required, these may be collected in the clinic and sent to the local laboratory 
for analysis to facilitate timely review.
14.3.
Product-Specific Safety Assessments
If performed, anti-BIIB067 antibody assessments will be performed according to the schedule 
provided in Section 4.

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15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the participant.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each participant or his/her legally authorized representative and/or 
main caregiver must be given the names and telephone numbers of study site staff for reporting 
AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Although abnormal laboratory values are typically not considered 
AEs, the following considerations may result in an abnormal laboratory value being considered 
an AE:

A laboratory test result that meets the criteria for an SAE

A laboratory test result that requires the participant to receive specific corrective 
therapy

A laboratory abnormality that the Investigator considers to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the participant at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

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
Results in persistent or significant disability/incapacity

Results in a congenital anomaly/birth defect

Is a medically important event
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the participant or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.)
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment, including 
hospitalization that is part of the study design (e.g., admission to the clinic for the purposes of 
dosing or post-LP observation) will not be considered an SAE, even if the participant is 
hospitalized.  The study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the 
participant’s consent to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the participant’s consent to participate in the study and the time 
of the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.

If a participant is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless one 
of the requirements in Section 15.1.2 is met.
15.2.
Safety Classifications
15.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.2.

The relationship of the event to study treatment as defined in Section 15.2.2.

The severity of the event as defined in Section 15.2.3.

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15.2.2.
Relationship of Events to Study Treatment and Lumbar Puncture
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment and LP.
Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to:  
the lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and 
the AE, or the presence of a more likely alternative explanation for the AE.
Related
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to:  
a positive rechallenge, a reasonable temporal sequence between administration of the 
drug and the event, a known response pattern of the suspected drug, improvement 
following discontinuation or dose reduction, a biologically plausible relationship 
between the drug and the AE, or a lack of an alternative explanation for the AE.
Relationship of Event to Lumbar Puncture
Not related
An AE will be considered “not related” to the LP procedure if there is not a reasonable 
possibility that the event has been caused by the LP procedure.  Factors pointing toward 
this assessment include but are not limited to:  the lack of reasonable temporal 
relationship between the LP procedure and the event, the presence of a biologically 
implausible relationship between the LP procedure and the AE, or the presence of a 
more likely alternative explanation for the AE.
Related
An AE will be considered “related” to the LP procedure if there is a reasonable 
possibility that the event may have been caused by the LP procedure.  Factors that point 
toward this assessment include but are not limited to:  a reasonable temporal sequence 
between the LP procedure and the event, a known response pattern of the LP procedure 
(e.g., bleeding from the puncture site), a biologically plausible relationship between the 
LP procedure and the AE, or a lack of an alternative explanation for the AE.
15.2.3.
Severity of Events
The severity of AEs and SAEs will be graded using the National Cancer Institute CTCAE 
(version 4).  Any AE not listed in the CTCAE will be graded as follows:

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Severity of Event
Grade
Definition
1
Mild AE
2
Moderate AE
3
Severe or medically significant AE
4
Life-threatening AE
5
Death related to AE
15.2.4.
Expectedness of Events
Expectedness of all AEs will be determined by the Sponsor according to the Investigator’s 
Brochure.  
15.3.
Monitoring and Recording Events
15.3.1.
Adverse Events
Any AE experienced by the participant between the time of first dose of study treatment and the 
last study visit is to be recorded on the CRF, regardless of the severity of the event or its 
relationship to study treatment.  At each study visit, post-LP telephone contact, and the Final or 
Early Termination Visit, the Investigator will assess the participant for AEs and will record any 
new AEs or updates to previously reported AEs on the CRF.
AEs that are ongoing when the participant completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status. AE 
outcome will not be recorded on the CRF.
15.3.2.
Serious Adverse Events
Any SAE experienced by the participant between the time of the signing of the ICF and the final 
study visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to the Sponsor within 24 hours or 
according to national law as described in Section 15.3.3.  Follow-up information regarding an 
SAE also must be reported with 24 hours. 
Participants will be followed for all SAEs until the final study visit.  Thereafter, the event should 
be reported to the Sponsor only if the Investigator considers the SAE to be related to study 
treatment.
Any SAE that is ongoing when the participant completes or discontinues the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status.

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15.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify the Sponsor within 24 hours of the study site staff becoming aware of the SAE or 
according to national law.  It is the Investigator’s responsibility to ensure that the SAE reporting 
information and procedures are used and followed appropriately.
Reporting Information for SAEs
A report must be submitted to the Sponsor regardless of the following:

Whether or not the participant has undergone study-related procedures

Whether or not the participant has received study treatment

The severity of the event

The relationship of the event to study treatment
To report initial or follow-up information on an SAE, fax a completed SAE form; refer to the 
Study Reference Guide for complete contact information.
15.3.3.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event or according to national law.  The Investigator should make every 
effort to obtain and send death certificates and autopsy reports to the Sponsor.  The term death 
should be reported as an SAE only if the cause of death is not known and cannot be determined.
15.3.4.
Suspected Unexpected Serious Adverse Reactions
SUSARs are SAEs that are unexpected and judged by the Investigator or the Sponsor to be 
related to the study treatment administered.
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting. The Sponsor will submit SUSARs (in blinded or unblinded fashion) to regulatory 
agencies according to local law. The Sponsor will submit SUSARs to Investigators in a blinded 
fashion.
The Sponsor will report SUSARs to the appropriate regulatory authorities and Investigators as 
required, according to local law.

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15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
Participants should not become pregnant during the study and for 5 months after their last 
dose of study treatment.  If a female participant becomes pregnant, study treatment must be 
discontinued immediately.
The Investigator must report a pregnancy occurring in a female participant by faxing or emailing 
the appropriate form to the Sponsor within 24 hours of the study site staff becoming aware of the 
pregnancy; refer to the Study Reference Guide for complete contact information.  The 
Investigator or study site staff must report the outcome of the pregnancy to the Sponsor.  A 
pregnancy is not considered an AE and should not be recorded on the AE CRF. 
Congenital abnormalities and birth defects in the offspring of male or female participants should 
be reported as an SAE if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a participant or taken by a participant 
that exceeds the dose assigned to the participant according to the protocol.  Overdoses are not 
considered AEs and should not be recorded as an AE on the CRF; however, all overdoses must 
be recorded on an Overdose form and faxed or emailed to the Sponsor within 24 hours of the site 
becoming aware of the overdose.  An overdose must be reported to the Sponsor even if the 
overdose does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  If 
an overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed 
to the Sponsor; refer to the Study Reference Guide for complete contact information.  All study 
treatment-related dosing information must be recorded on the dosing CRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information.
15.4.3.1.
Unblinding for Medical Emergency
In a medical emergency during the Loading Dose Period, when knowledge of the participant’s 
study treatment assignment may influence the participant’s clinical care, the Investigator and, if 
applicable, designated site personnel at the Sponsor, may access the participant’s study treatment 
assignment by IRT.  The Investigator must document the reasons for unblinding in the 
participant’s source documents.  The Investigator is strongly advised not to divulge the 
participant’s study treatment assignment to any individuals who are not directly involved in 
managing the medical emergency or to site personnel who are involved with the analysis and 
conduct of the study.  The Investigator can contact the Sponsor or designee to discuss such 
situations.

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15.5.
Contraception Requirements
All women of childbearing potential must ensure that effective contraception is used during the 
study and for 5 months, whichever is longer, after their last dose of study treatment.  In addition, 
female participants should not donate eggs for the duration of the study and for at least 5 months 
after their last dose of study treatment.
For the purposes of this study, women who do not meet one of the following criteria are 
considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential:

Postmenopausal

12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum FSH level >40 mIU/mL 

6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation) 
For the purposes of the study, effective contraception is defined as use of at least 1 of the 
following:
For females:

Established use of oral, injected, implanted, intravaginal, or transdermal hormonal 
methods of contraception.

Placement of an intrauterine device or intrauterine hormone-releasing system.

Barrier methods of contraception with use of a spermicide:  condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository.  
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide.

Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate).  

True abstinence, when this is consistent with the preferred and usual lifestyle of the 
participant, can be considered an acceptable method of contraception based on the 
evaluation of the Investigator who should also take into consideration the duration of 
the clinical trial.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not considered acceptable methods of 
contraception.

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Pregnancy reporting is described in Section 15.4.1.
15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies and follow up on the outcome of the pregnancy in 
female participants.

Complete an SAE form for each SAE and fax or email it to the Sponsor within 
24 hours of the study site staff becoming aware of the event or according to national 
law.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to the Sponsor within 24 hours of the study site staff becoming 
aware of new information or according to national law.

Ensure all AE and SAE reports are supported by documentation in the participants’ 
medical records.

Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
The Sponsor 
The Sponsor’s responsibilities include the following:

Before study site activation and participant enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definitions of AE and SAE, as well 
as the instructions for monitoring, recording, and reporting AEs and SAEs.

The Sponsor is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames.

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16.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
16.1.
Analysis Population
The safety population is defined as participants who enrolled and have received at least 1 dose of 
study treatment in the extension study. The analyses of clinical function and safety for 
233AS102 will be performed for the safety population. Integrated analyses of 233AS101 and 
233AS102 will be performed for the populations defined in 233AS101 protocol for mITT and 
non-mITT.
For participants from Part C of 233AS101 who enrolled in 233AS102, summaries for clinical 
function, PK, PD/biomarker endpoints, and safety evaluations will also be presented by disease 
progression subgroup (i.e., those who met prognostic enrichment criteria for rapid disease 
progression in 233AS101 Part C [labelled as "enriched" for analyses] and all other eligible 
participants in 233AS101 Part C [labelled as "other"]). Summaries of data collected during 
233AS102 for participants from Part C of 233AS101 will be presented by prior treatment group 
from 233AS101. Integrated summaries of 233AS101 and 233AS102 will be presented by 
treatment group during 233AS101 for each of the mITT and non-mITT populations, with some 
limited summaries for overall intention-to-treat population.
Generally, data for participants from 233AS101 Part C will be analyzed separately from that of 
participants from Parts A and B, but there may be some analyses where all participants in the 
extension study will be pooled, particularly for safety summaries. Participants from Parts A and 
B will generally be pooled together; the data in these participants will mainly be grouped overall 
rather than by dose level, but there may be limited summaries based on individual dose level. 
Further details will be provided in the interim and/or final statistical analysis plan.
Some of the analyses specified will be more relevant for integrated efficacy, safety, and 
immunogenicity plans where data from both 233AS101 and 233AS102 will be pooled.
16.2.
Clinical Function
16.2.1.
Methods of Analysis
As this is an open-label, long-term extension study, analyses will be exploratory and descriptive 
in nature.
Data will be summarized using descriptive statistics for continuous variables and using 
frequency and percentage for discrete variables.  For participants who have completed Parts A or 
B of Study 233AS101, the time trajectory of each clinical function may be summarized at 
selected timepoints and presented in plots.  For participants who have completed Part C of 
Study 233AS101, the time trajectory will be summarized by the prespecified subgroup (enriched 
population versus other eligible participants) and the prior treatment received during Study 

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233AS101 from the baseline of Study 233AS101 (including data from Studies 233AS101 and 
233AS102), from the baseline of Study 233AS102 (including data from Study 233AS102 only), 
and from the start of BIIB067 100 mg dosing.
Efficacy will be measured based on changes in ALSFRS-R, percent predicted SVC, HHD 
Megascore and individual muscle strength, 
.  Changes from baseline (using 
definitions outlined above) will be summarized over time for each of these endpoints.
Analysis of covariance using multiple imputation will be performed at selected timepoints, based 
on level of data available at interim and final analysis.
Time to death or permanent ventilation (i.e., ≥ 22 hours of mechanical ventilation [invasive or 
noninvasive] per day for ≥ 21 consecutive days) and time to death will be summarized using 
Kaplan-Meier curves based on the starting time using the following:
1. Entry into Study 233AS101
2. Entry into Study 233AS102
3. The start of BIIB067 100 mg dosing
4. Time of symptom onset
The relationship between PK or PD endpoints and the clinical function endpoints will also be 
explored.
16.3.
Pharmacokinetics
16.3.1.
Analysis Population
The PK population is defined as participants who have received at least 1 dose of study treatment 
and have at least 1 available postdosing evaluation of PK endpoints in the extension study.
16.3.2.
Methods of Analysis
Plasma and CSF BIIB067 concentrations will be summarized using descriptive statistics and, 
where warranted, presented graphically.
16.4.
Pharmacodynamics
16.4.1.
Analysis Population
The PD population is defined as participants who have received at least 1 dose of study treatment 
and have at least 1 available postdosing evaluation of the respective PD endpoint in the extension 
study.

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16.6.2.4.
Columbia Suicide Severity Rating Scale
C-SSRS data will be listed and summarized using descriptive statistics.
16.6.2.5.
Limited Neurological Examinations
The changes from baseline in the limited neurological examination (coordination/cerebellar 
function, reflexes, and motor system) will be summarized by visit.
16.6.2.6.
Electrocardiogram
The changes from baseline will be summarized using shift tables.  The number and percentage of 
participants with shifts to the categorical values (abnormal, not AE; or abnormal and AE) will 
also be summarized.
16.6.2.7.
Antigenicity/Immunogenicity 
Anti-BIIB067 antibody results will be summarized by prior treatment groups for participants 
from 233AS101 Part C and will also be summarized for participants from 233AS101 Parts A and 
B.
16.7.
Interim Analyses
Interim analyses may be performed periodically to provide content for regulatory submissions 
and safety updates and to support drug development planning and business activities.
16.8.
Sample Size Considerations
The sample size for this study is based on the number of the SOD1-ALS participants in 
Study 233AS101 who consent to participate.  Up to 183 participants will be dosed in 
Study 233AS101.

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17.
ETHICAL REQUIREMENTS
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and applicable ICH and GCP guidelines and conduct the study according to local 
regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  The Sponsor will submit documents on behalf of the 
investigational sites.  
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
the Sponsor.  After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and the Sponsor.
17.3.
Participant Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the 
participant or participant’s legally authorized representative (e.g., spouse), as applicable, in 
accordance with local practice and regulations.  

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The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the participant must be explained to the participant (or 
the participant’s legally authorized representative).  The participant must be given sufficient time 
to consider whether to participate in the study.
Participants will be informed that their race and ethnicity will not be collected for the purposes of 
data analysis during the extension study.  However, this information was collected in 
Study 233AS101, where applicable and after participant consent, unless the collection was not 
permitted by applicable law or not approved by the governing ethics committee, and the data will 
be used during analysis of the results of that study.  
A copy of the signed and dated ICF must be given to the participant or the participant’s legally 
authorized representative.  The signed and dated ICF will be retained with the study records.  
Local regulations must be complied with in respect to the final disposition of the original (wet 
signature) and copies of the signed and dated ICFs.
Confirmation of informed consent must also be documented in the participant’s medical record.
17.4.
Participant Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., PHI authorization in North 
America).
During the study, participants’ race and ethnicity will not be collected for the purposes of data 
analysis.
Study reports will be used for research purposes only.  The participant will not be identified by 
name in CRFs, study-related forms, study reports, or any related publications.  The Sponsor, its 
partners and designees, ethics committees, and various government health agencies may inspect 
the records of this study.  Every effort will be made to keep the participant’s personal medical 
data confidential.
17.5.
Compensation for Injury
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor or partnering companies) with the participant before the participant makes a decision to 
participate in the study.

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17.7.
Registration of Study and Disclosure of Study Results
The Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.

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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any participants prior to completion of a study initiation visit, 
conducted by the Sponsor or designee.  This initiation visit will include a detailed review of the 
protocol and study procedures.
18.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the participants’ medical histories.  Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete.  Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail).  The 
Investigator should maintain a record of the location(s) of essential documents.
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate.  During these visits, CRFs and supporting documentation 
related to the study will be reviewed and any discrepancies or omissions will be resolved.
Remote evaluation of data (centralized monitoring) and remote verification of source 
documentation may also be conducted and reported as defined in the Monitoring Plan.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.  
18.5.
Publications
Details are included in the clinical trial agreement for this study.

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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
Public Health Emergencies
In the event of a public health emergency that results in site closure, travel restrictions, and/or the 
study being deprioritized at the site such that clinic visit(s) cannot occur, a protocol deviation 
would be incurred for any deviation from the protocol-specified visits and assessments, with 
additional notation that this protocol deviation is due to the public health emergency.  If a 
protocol-specified clinical visit cannot occur because of a public health emergency, the following 
mitigating options should be pursued, in order of preference (in which the highest preference 
option that is feasible should be done): 1) transfer to another active study site that is open, 2) 
home visit, 3) telemedicine visit (e.g., by telephone or web conference), and 4) local laboratory 
visit.  These mitigating options only apply in the setting of a public health emergency in which a 
protocol-specified clinic visit cannot occur and should not be pursued solely because of a 
participant’s preference.  If the participant does not participate in one of these options, a Safety 
Telephone call must be conducted within 14 days of the last dosing visit.
A third-party vendor has been engaged to perform the following assessments at the study 
participant’s home:

Limited neurological examination

Physical examination

Vital signs

Height and body weight collection

Health outcome measures

C-SSRS

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
SVC

Biological sample collection

Pregnancy test (if applicable)

HHD

Collection/shipment of ventilation diary records
The following assessments will be performed via telephone (telemedicine) by the site staff:

ALSFRS-R

Assessing changes in signs and symptoms as well as review of concomitant 
medications and AEs
19.2.
External Contract Organizations
19.2.1.
Contract Research Organization 
The Sponsor will be responsible for administrative aspects of the study including, but not limited 
to, study initiation, monitoring, management of SAE reports, and data management.  Before 
participants are screened at each study site, the Sponsor will review study responsibilities with 
the Investigators and other study site staff, as appropriate.
19.2.2.
Interactive Response Technology
IRT will be used in this study.  Before participants are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
19.2.3.
Electronic Data Capture
Participant information will be captured and managed by study sites on electronic CRFs by a 
Web-based electronic data capture tool developed and supported by 
 and configured by 
the Sponsor.  Ventilation use information will be recorded on paper initially and then via 
eDiaries developed (as applicable) and supported by 
19.2.4.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by the Sponsor to analyze all samples collected for the 
assessment of safety in this study except urine and, where applicable, serum pregnancy tests and 
CSF, which will be analyzed by a local laboratory; repeat coagulation tests will be analyzed by 
either the local laboratory or the central laboratory.

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19.3.
Study Committees
19.3.1.
Independent Data Monitoring Committee
An IDMC will be formed to review ongoing safety and tolerability data.  Members of the IDMC 
will not be allowed to participate as Investigators in this study.  The IDMC will review safety 
data on an ongoing basis to ensure the safe and proper treatment of participants.  Regular IDMC 
meetings will occur approximately every 3 months after the first meeting until the blinded Study 
233AS101 is completed.  An IDMC charter will provide full guidance on the function and 
practices to be followed by the IDMC.
19.4.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect participant safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a participant.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 17).
19.5.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.6.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations.  Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records.  
In addition, the Investigator must notify the Sponsor of any changes in the archival 
arrangements, including but not limited to, archival at an offsite facility or transfer of ownership 
if the Investigator leaves the site.

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19.7.
Study Report Signatory
The Sponsor will designate one of the participating Study Investigators as a signatory for the 
study report.  This determination will be made by several factors, including but not limited to, 
the Investigator's experience and reputation in the studied indication; the Investigator's 
contribution to the study in terms of design, management, and/or participant enrollment; or by 
other factors determined to be relevant by the Sponsor.

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Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur 
Respir J. 2005;26(5):948-68.
Ratovitski T, Corson LB, Strain J, et al. Variation in the biochemical/biophysical properties of 
mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial 
amyotrophic lateral sclerosis kindreds. Hum Mol Genet. 1999;8(8):1451-60.
Reaume AG, Elliott JL, Hoffman EK, et al. Motor neurons in Cu/Zn superoxide dismutase-
deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet. 
1996;13(1):43-7.
Smith RA, Miller TM, Yamanaka K, et al. Antisense oligonucleotide therapy for 
neurodegenerative disease. J Clin Invest. 2006;116(8):2290-6.
Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur 
Respir J. 2005;26(3):511-22.
Writing Group, Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in 
well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-
controlled trial. Lancet Neurol. 2017;16(7):505-512. Epub 2017/05/15.

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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “An Extension Study to Assess the Long-Term Safety, 
Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to 
Previously Treated Adults with Amyotrophic Lateral Sclerosis Caused by Superoxide 
Dismutase 1 Mutation,” and agree to conduct the study according to the protocol and the 
applicable ICH guidelines and GCP regulations, and to inform all who assist me in the conduct 
of this study of their responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)

CONFIDENTIAL
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1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS102
An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect 
on Disease Progression of BIIB067 Administered to Previously Treated Adults with 
Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
Version 6
Date: 04 August 2021
EUDRA CT Number: 2016‐003225‐41
Version 6 of the protocol has been prepared for this amendment, which supersedes Version 5.

Amendment Summary for Protocol 233AS102, Version 6
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2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 233AS102 is to extend the maintenance 
dosing portion of the treatment period of the study by up to 124 weeks while minimizing the 
burden on participants. Maintenance dosing will continue for all participants until the LPI has 
had the opportunity to reach Week 152 of the maintenance dosing period, which for the first 
participant in is Week 360. The maintenance dosing period will be followed by a Final Visit at 4 
weeks after the last dose. This extends the study until the LPI reaches Week 156. Changes to the 
study visits include the following:

The Follow-Up Visits before the Final/Early Termination visit will be eliminated.

The Final or Early Termination Visit will now be held 4 weeks after the last dose.

SVC and HHD will be completed every 12 weeks instead of every 4 weeks during the 
maintenance dosing period.

ECGs, physical examinations, and limited neurological examinations will be removed 
from all dosing visits (except for predose at Baseline and as clinically indicated per 
the discretion of the Investigator). Triplicate ECGs will be reduced to single ECGs.

The MMSE will be removed as a safety assessment.

Diary/eDiary use will only be required for days when the participant uses mechanical 
ventilation.

Additional days for individual assessments were clarified in the footnotes of the 
Schedule of Activities table.
New text is shown in bold type; deleted text is shown with a strikethrough.

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3
Section 4, Schedule of Activities for Study 233AS102
Note: The table and footnotes below have been truncated to only shown rows and columns that are affected by the changes.
Now reads:
Screening 
Visit1
Baseline/1st Loading 
Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit
Follow-Up 
Visits
Final or Early 
Termination 
Visit
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Weeks 8, 12, 16, and 
every 4 weeks 
thereafter up to Week 
236 360 (±3 days)
Assessments
Week -4 
to Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Weeks 240 
and 244 
(±7 days) 
(4 and 8 
weeks after 
last dose)
Week 248 (±7 
days) or 12 
4 weeks after 
last dose 
[Early 
Termination 
Visit]
Ventilation Use4
X
X
X
X
X
X
X
ALSFRS-R
X5
X5
X5
X5, 6
X
X5
SVC7
X5
X5
X5
X5, 
68
X
X5
HHD
X5
X5
X5
X5, 
68
X
X5
C-SSRS12
X
X
X6
X
X
Vital Signs (temperature, blood 
pressure, pulse rate, respiratory 
rate)
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG13
X
X
X
X
X
X

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4
Screening 
Visit1
Baseline/1st Loading 
Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit
Follow-Up 
Visits
Final or Early 
Termination 
Visit
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Weeks 8, 12, 16, and 
every 4 weeks 
thereafter up to Week 
236 360 (±3 days)
Assessments
Week -4 
to Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Weeks 240 
and 244 
(±7 days) 
(4 and 8 
weeks after 
last dose)
Week 248 (±7 
days) or 12 
4 weeks after 
last dose 
[Early 
Termination 
Visit]
Physical Examination14
X
X
X
X
X
X
X
Limited Neurological 
Examination14
X
X
X
X
X
X
X
X
X
X
X
MMSE
X
X
X
X11
X11
X
Clinical Laboratory Samples for 
Hematology, Coagulation, 
Chemistry, and Urinalysis3
X
X
X
X
X
X
X
AE/Concomitant Therapy and 
Procedures Recording
------------------------------------------------------------------X (ongoing)---------------------------------------------------
SAE Recording
-----------------------------------------------------------------------X (ongoing)--------------------------------------------------------
4Participants will use a diary/eDiary to record ventilation use.  The diary/eDiary should be completed only for days when the participant uses mechanical 
ventilation.  This diary will be reviewed with study site staff at each visit.  Refer to the Study Reference Guide for details.   
5May be performed at any time on the day prior to study treatment administration, predose on the day of study treatment administration, or over 2 days at the 
Follow-up Visits (Weeks 240 and 244) andat the Final or Early Termination Visit.
6To be performed at Week 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 
140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, and 236 (i.e., every 4 weeks) Visits only 
236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 356, and 
360 (i.e., every 4 weeks).
8To be performed at Week 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, and 228 228, 240, 252, 264, 276, 288, 300, 312, 324, 
336, 348, and 360 (i.e., every 12 weeks) Visits only.
11To be performed at Week 12, 24, 36, and 48 Visits (i.e., every 12 weeks); Week 72, 96, 120, 144, 168, 192, and 216 216, 240, 264, 288, 312, 336, and 360 
Visits (i.e., every 24 weeks); and Week 228 Visit.
13ECGs to be done at Screening, Day 1, Final/Early Termination Visit, and as clinically necessary per the discretion of the Investigator throughout the 
study. Triplicate 12-lead (paper) ECGs will be obtained after subjectparticipants have rested in a supine position for at least 10 minutes.  The first ECG will be 
interpreted, and the last 2 ECGs will be checked for consistency and quality.

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14A physical examination and limited neurological examination will be performed at the specified timepoints (Screening, Day 1, Final/Early 
Termination Visit). At all other visits, the physical and/or neurological examination may be performed at the Investigator’s discretion. The components 
of the limited neurological examination are coordination/cerebellar function, reflexes, and motor system.
18Blood samples will be collected on every alternate visit at Week 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148, 156, 164, 172, 
180, 188, 196, 204, 212, 220, 228, and 236 236, 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, and 356 (i.e., every 8 weeks) Visits only.  
Blood samples for anti-BIIB067 Ab antibody and PK assessments will be collected at the same time.
Rationale:
Extension in study duration:
The extension in study duration is intended to enable generation of longer-term safety and efficacy data and continued access to study 
drug for study participants through anticipated commercial availability.
Reduced duration of follow-up after the last dose of study drug:
With this amendment, all participants will complete maintenance dosing when the LPI has had the opportunity to complete Week 152 
of maintenance dosing, before completing their Final Visit at 4 weeks after their last dose. The reduced duration (28-day) of follow-up 
after the last dose of study drug is supported by data from the Phase 1 single ascending dose and multiple ascending dose portions of 
Study 233AS101, which incorporated a 3-to-5-month follow-up period after the last dose of study drug. Since no new safety signals 
were identified during this follow-up period, a 28-day follow-up period after the last dose of study drug will allow for adequate 
monitoring of study participants.
Reduced frequency of assessments:
The frequency of SVC and HHD assessments was reduced to once every 12 weeks during the maintenance dosing period to reduce the 
burden of efficacy assessments and support participant retention. The requirement to enter ventilation data in the diary/eDiary was 
refined to only apply to days when ventilation assistance was used to minimize burden for participants in line with Study 233AS101. 
MMSE assessments were eliminated, and the frequency of the ECG, physical examination, and limited neurological examination was 
reduced to minimize the burden on participants while still maintaining appropriate safety monitoring. The changes in the frequency of 
safety assessments reflect the increased understanding of the safety profile of BIIB067based on the totality of data across the program.
This change also affects Section 7.1, Study Overview; Section 7.2, Overall Study Duration and Follow-Up; Section 7.2.2.2, 
Maintenance Dose Period; Section 7.2.3, Follow-Up; Section 7.4, End of Study; Section 11.1, Regimen; Section 11.3, 

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Concomitant Therapy and Procedures; Section 14.1, Clinical Safety Assessments; Section 15.3.1, Adverse Events; Section 
15.3.2, Serious Adverse Events; and Section 16.6.2.5, Limited Neurological Examinations.

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 3, Synopsis
The synopsis was revised to reflect changes made throughout the protocol.
Section 4, Schedule of Activities for Study 233AS102
Change: The procedures for reviewing coagulation tests and/or platelet counts prior to LP were 
clarified.Now reads:3Coagulation and/or platelet tests may be repeated at the local laboratory if, 
in the opinion of the Investigator, values of the initial tests are out of range but deemed not 
clinically significant.  The results of the most recent (i.e., obtained at previous visit) centrally 
read coagulation tests and platelet count must be reviewed before LP can be performed.The 
results of the most recent centrally read coagulation tests and platelet count (i.e., those 
obtained at the previous visit) must be reviewed before LP is performed. Should these 
results suggest, in the opinion of the Investigator, that LP may be safely performed, then no 
further review of coagulation tests and platelet counts would be required before 
performing the LP. However, should repeat coagulation and platelet tests be clinically 
indicated in the opinion of the Investigator, then these tests may be done locally, to 
facilitate timely review.
Rationale: This revision was provided to avoid confusion regarding study procedures for 
reviewing coagulation tests and/or platelet counts prior to LP.
Section 4, Schedule of Activities for Study 233AS102
Change: Footnote 7 was revised to clarify the procedures for participants who begin the study 
not using a facemask but later develop the need to use one.
Now reads:7If a facemask is used in Study 233AS101 or at screening and/or baseline of this 
study, it should be used for all SVC assessments for the duration of the study.  If a facemask is 
not used during Study 233AS101 or at screening and/or baseline of this study, it should not be 
used for the duration of the study, if possible. If the participant begins the 233AS102 study 
not using a facemask, but develops the need to use a facemask to complete the SVC during 
the study, then the facemask should be used for all subsequent SVC assessments for the 
duration of the study.  Upright SVC will be determined by performing 3 to 5 measures.  The 
results will be overread by a central reader to confirm that these criteria (at least 3 acceptable 
tests with the 2 highest acceptable [largest and next largest] efforts within 150 mL of vital 
capacity) have been achieved.

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Rationale: This change was included to provide flexibility for participants with progressive 
disease who need to transition to using facemasks for SVC during the study.
Section 5.3.2, Clinical Experience
Change: The description of clinical data from Study 233AS101 was expanded.
Now reads:
This study is an extension of Study 233AS101, a Phase 1/2/3 study evaluating the benefit/risk of 
BIIB067.  In the single and multiple dose escalation parts (Parts A and B) of this study, BIIB067 
at dose levels up to and including 100 mg was generally well tolerated.  Most of the AEs were 
mild or moderate in severity.  Plasma concentrations of BIIB067 were dose proportional; CSF 
concentrations showed a less-than-dose-proportional response.  A statistically significant 
Administration of BIIB067 100 mg for 12 weeks in Part B of Study 233AS101 led to a 36% 
reduction in CSF total CSF SOD1 protein concentration was compared to a 3% reduction 
observed in the BIIB067 100 mg group (37% reduction) compared with the placebo group (no 
reduction).  
 Administration of decline 
BIIB067 100 mg for 12 weeks also led to an apparent slowing in functional (decline across 
exploratory clinical outcome measures including ALSFRS-R), respiratory (SVC)SVC, and 
strength measures (HHD Megascore)HHD Megascore.  These data support the continued 
development of BIIB067 for the treatment of SOD1-ALS.
Rationale: This change was included to reflect the final analyses from the multiple ascending 
dose portion of Study 233AS101.
Section 5.5, Rationale for Dosing Regimen
Change: Information on the duration of BIIB067 administration was added.
Now reads:
BIIB067 100 mg will be administered via IT bolus at 100 mgover 1 to 3 minutes.
Rationale: This change was included to clarify study procedures for how BIIB067 is to be 
administered.
Section 6.2, Secondary Objectives and Endpoints
Change: Consistent with Study 233AS101, the protocol was revised to reflect that plasma NfL 
will be evaluated as a secondary biomarker endpoint 
 
 The time-to-event endpoints were renamed so that VAFS 

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was relabeled as time to death or permanent ventilation and so that overall survival was renamed 
to time to death.Now reads:
The secondary objectives are to evaluate the PK, PD, biomarker effects, and efficacy of 
BIIB067 administered to subjectsparticipants with ALS and a confirmed SOD1 mutation.  
6.2.1. Pharmacokinetic Endpoints
The PK endpoints are plasma and CSF levels of BIIB067.
6.2.2. Pharmacodynamic Endpoints
The PD endpoints are changes is the change from baseline in total CSF SOD1 protein in CSF 
6.2.3
Biomarker Endpoint
The biomarker endpoint is the change from baseline in NfL concentration in plasma.
6.2.36.2.4.
Efficacy Endpoints

Efficacy endpoints are changes over time in the following:

Total ALSFRS-R scores

Slow vital capacity (SVC)

Handheld dynamometry (HHD) Megascore and individual muscle strength

Ventilation assistance-free survival (VAFS), which is defined as the time to the 
earliest occurrence of one of the following events:Time to death or permanent 
ventilation (≥ 22 hours of mechanical ventilation [invasive or noninvasive] per 
day for ≥ 21 consecutive days)

Death.

Permanent ventilation (≥ 22 hours of mechanical ventilation [invasive or 
noninvasive] per day for ≥ 21 consecutive days).

Overall survivalTime to death
Rationale: The secondary endpoints were updated to reflect that plasma NfL concentration will 
be classified as a biomarker endpoint to align with the 233AS101 protocol and to reflect 
emerging data that neurofilaments are potential biomarkers of ALS disease activity and treatment 
response. Plasma NfL was selected given the potential utility of a blood-based biomarker in the 
future, along with assay characteristics. Plasma NfL will be evaluated on the Siemens 

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Healthineers NfL assay, which has good analytical performance and utilizes a fully automated 
instrument.
The names of the efficacy endpoints "ventilation assistance-free survival (VAFS)" and "overall 
survival" were updated to "time to death or permanent ventilation" and "time to death" to more 
accurately reflect the intended analyses that are being performed for each of these endpoints, and 
the statistics that will be estimated from the Kaplan-Meier analysis. No change has been made to 
the intended analysis.
This change also affects Section 6.3.3, Additional Biomarker Endpoints; and Section 13.3, 
Pharmacodynamic/Biomarker Assessments.
Section 7.2.2, Dosing
Change: References to the last study visit from Part C of Study 233AS101 were updated since 
either Week 28 or Week 32 Visit could be considered the End of Study Visit.Now reads:
Assessments collected at the End of Study Visit (i.e., Day 197 [Week 28 Visit]) or at the 
Safety Follow -Up Visit (4 weeks after last dose)(Alternative End  of Study Visit) (i.e., Day 
225 [Week 32 Visit]) of Part C of Study 233AS101 willmay be used as the Day 1 predose 
assessments for Study 233AS102 if they are collected within 48 hours of the first dose in Study 
233AS102.
Rationale: This change was made to align with updates from the 233AS101 protocol.
This change also affects Section 7.2.1.2, Participants Who Have Completed Part C of Study 
233AS101.
Section 13.2, Pharmacokinetic Assessments
Change: The list of PK parameters for assessment was removed.
Now reads:
BIIB067 concentrations in plasma and CSF will be determined using validated assays.
Samples for analysis of BIIB067 concentrations in plasma and CSF will be collected from each 
participant at the timepoints specified in Section 4.
The following PK parameters will be assessed in plasma, when feasible: 

Maximum observed concentration 

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
Time to reach the maximum observed concentration  

AUC from time 0 to infinity 

AUC from time 0 to time of the last measurable concentration 

Apparent terminal t½
The t½ will be assessed in CSF, when feasible. 
Additional PK parameters may be calculated at the discretion of the study Pharmacokineticist.
Rationale: This change was made to align with the current Schedule of Activities. Blood and 
CSF samples for PK will only be taken at troughs, so these PK parameters cannot be calculated. 
This is an error from the previous version.
This change also affects Section 16.3.2, Methods of Analysis.
Section 13.4, Genomic and Pharmacogenomic Assessments
Change: Details on DNA samples were added to specify that the participant’s identification 
number will be used for coding and the samples may be stored for up to 25 years (or a duration 
dictated by regulations specific to the location) instead of 15 years.
Now reads:
The DNA samples will be coded with the participant’s identification number and may be 
stored for up to 15 25 years after the end of the main study or a duration dictated by local, 
national, or regional laws or regulations.
Rationale: These changes were made to clarify the precautions taken to protect participant 
privacy as well as reflect Biogen’s current standard storage time.
Section 15.3.1, Adverse Events
Change: A clarification was added to describe procedures for AEs that are ongoing when the 
participant completes or discontinues the study.
AEs that are ongoing when the participant completes or discontinues the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. AE outcome will not be recorded on the CRF.
Rationale: This change was made to reflect current best practices for follow-up of AEs.

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Section 15.3.2, Serious Adverse Events
Change: A clarification was added to state that SAEs are to be recorded on an SAE form 
(instead of the CRF) and must be reported to the Sponsor according to national law (in addition 
to the prespecified timeframe).
Now reads:
Any SAE experienced by the subjectparticipant between the time of the signing of the ICF and 
the last Follow Up Visit, including the last telephone contact (approximately 24 hours after the 
Final or Early Termination Visit),final study visit is to be recorded on the CRFan SAE form, 
regardless of the severity of the event or its relationship to study treatment.  SAEs must be 
reported to Biogenthe Sponsor within 24 hours or according to national law as described in 
Section 15.3.3.  Follow-up information regarding an SAE also must be reported with 24 hours. 
SubjectsParticipants will be followed for all SAEs until the final study visit, including the last 
telephone contact (approximately 24 hours after the Final or Early Termination Visit).  
Thereafter, the event should be reported to Biogenthe Sponsor only if the Investigator considers 
the SAE to be related to study treatment.
Rationale: This change was made to clarify the safety reporting process and accurately reflect 
safety reporting requirements.
This change also affects Section 15.3.3, Immediate Reporting of Serious Adverse Events and 
Section 15.6, Safety Responsibilities.
Section 15.3.4, Suspected Unexpected Serious Adverse Reactions
Change: Guidance text was added regarding unblinding for the purpose of reporting SUSARs.
Now reads:
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting. The Sponsor will submit SUSARs (in blinded or unblinded fashion) to 
regulatory agencies according to local law. The Sponsor will submit SUSARs to 
Investigators in a blinded fashion.
Rationale: This change was made to reflect the process of unblinding for regulatory reporting 
purposes.
Section 15.4.3, Medical Emergency
Change: Information was included to clarify the procedures for unblinding of a participant’s 
study treatment assignment during a medical emergency.Now reads:

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15.4.3.1.
Unblinding for Medical Emergency
In a medical emergency during the Loading Dose Period, when knowledge of the 
participant’s study treatment assignment may influence the participant’s clinical care, the 
Investigator and, if applicable, designated site personnel at the Sponsor, may access the 
participant’s study treatment assignment by IRT.  The Investigator must document the 
reasons for unblinding in the participant’s source documents.  The Investigator is strongly 
advised not to divulge the participant’s study treatment assignment to any individuals who 
are not directly involved in managing the medical emergency or to site personnel who are 
involved with the analysis and conduct of the study.  The Investigator can contact the 
Sponsor or designee to discuss such situations.
Rationale: This update was made to clarify and expand upon the process of unblinding of site 
personnel for medical emergencies.
Section 16.1, Analysis Population
Change: Details on the analysis population were expanded to include relevant information on 
the integrated analyses of the 233AS101 and 233AS102 studies, as well as clarification on the 
subgroup analysis for 233AS102 alone.Now reads:
The clinical function safety population is defined as subjectsparticipants who enrolled and 
have received at least 1 dose of study treatment in the extension study. The analyses of clinical 
function and safety for 233AS102 will be performed for the safety population. Integrated 
analyses of 233AS101 and 233AS102 will be performed for the populations defined in 
233AS101 protocol for mITT and non-mITT.
For participants from Part C of 233AS101 who enrolled in 233AS102, summaries for 
clinical function, PK, PD/biomarker endpoints, and safety evaluations will also be 
presented by disease progression subgroup (i.e., those who met prognostic enrichment 
criteria for rapid disease progression in 233AS101 Part C [labelled as "enriched" for 
analyses] and all other eligible participants in 233AS101 Part C [labelled as "other"]). 
Summaries of data collected during 233AS102 for participants from Part C of 233AS101 
will be presented by prior treatment group from 233AS101. Integrated summaries of 
233AS101 and 233AS102 will be presented by treatment group during 233AS101 for each 
of the mITT and non-mITT populations, with some limited summaries for overall 
intention-to-treat population.
Generally, data for participants from 233AS101 Part C will be analyzed separately from 
that of participants from Parts A and B, but there may be some analyses where all 
participants in the extension study will be pooled, particularly for safety summaries. 
Participants from Parts A and B will generally be pooled together; the data in these 
participants will mainly be grouped overall rather than by dose level, but there may be 

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limited summaries based on individual dose level. Further details will be provided in the 
interim and/or final statistical analysis plan.
Some of the analyses specified will be more relevant for integrated efficacy, safety, and 
immunogenicity plans where data from both 233AS101 and 233AS102 will be pooled.
Rationale: This update was made to reflect analyses described in the 233AS102 and 
233AS101/102 integrated statistical analysis plans.
Section 16.2.1, Methods of Analysis
Change: The terminology of participant populations for statistical analyses was changed from 
“fast progressors” and “non-fast progressors” to “enriched population” and “other eligible 
participants,” respectively. Details on the analysis of covariance and Kaplan-Meier curves were 
clarified.Now reads:
Data will be summarized using descriptive statistics for continuous variables and using 
frequency and percentage for discrete variables.  For subjectsparticipants who have completed 
Parts A or B of Study 233AS101, the time trajectory of each clinical function may be 
summarized for the period of each dose level.  For subjectsat selected timepoints and 
presented in plots.  For participants who have completed Part C of Study 233AS101, the time 
trajectory will be summarized by the prespecified mutation/progressing group (fast-
progressingsubgroup (enriched population versus non-fast progressingother eligible 
participants) and the prior treatment received during Study 233AS101 from the baseline of 
Study 233AS101 (including data from Studies 233AS101 and 233AS102), from the baseline of 
Study 233AS101233AS102 (including data from Study 233AS102 only), and from the start of 
BIIB067 100 mg dosing.
Efficacy will be measured based on changes in ALSFRS-R, percent predicted SVC, HHD 
Megascore and individual muscle strength, 
.  Changes from baseline (using 
definitions outlined above) will be summarized over time for each of these endpoints.  
VAFSAnalysis of covariance using multiple imputation will be performed at selected 
timepoints, based on level of data available at interim and overall survivalfinal analysis.
Time to death or permanent ventilation (i.e., ≥ 22 hours of mechanical ventilation [invasive 
or noninvasive] per day for ≥ 21 consecutive days) and time to death will be summarized 
using Kaplan-Meier curves based on the starting time using the following: 
1.
Entry into Study 233AS101
2.
Entry into Study 233AS102
3.
The start of BIIB067 100 mg dosing

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4.
Time of symptom onset
Rationale: The change in terminology from "fast progressing" and "non-fast progressing" 
subgroups to "enriched" and "other" populations in the 233AS102 protocol was made to align 
with language in the 233AS101 protocol. The primary analysis population for Study 233AS101 
was enriched, based on SOD1 mutation type and prerandomization ALSFRS-R slope decline, for 
participants more likely to have rapid disease progression during the study. The terminology 
used to describe this population in Study 233AS101 was thus changed from "fast progressors" to 
"participants who met prognostic enrichment criteria for rapid disease progression" to more 
accurately reflect the population enrolled. Consistently, the terminology for the broader 
population enrolled (previously "non-fast progressors") was updated to "other eligible 
participants." No changes have been made to the criteria to define either subgroup.
Multiple imputation for the analysis of covariance will be utilized to increase the robustness of 
the analysis in the context of varying lengths of follow-up in the extension study. This analysis 
will also help address problems with missing data due to the COVID-19 pandemic. Other 
revisions were made to align with the statistical analysis plans.
Section 16.6.2.1, Adverse Events
Change: References to “dose level” in the descriptions of analyses were removed and replaced 
with more general identifiers such as “treatment group” or removed entirely. The summary of the 
analyses was also revised to reflect the key statistical estimates.
Now reads:
The incidence of all AEs, SAEs, deaths (all causes and ALS-related), and AEs leading to 
discontinuation will be summarized by system organ class and preferred term by time interval on 
a given dose leveltreatment group. The incidence rate per person year may also be determined 
when long-term dosing follow-up is accrued.  Kaplan Meier estimates of survival will also be 
derived.
Rationale: These changes were made to more accurately reflect the analyses described in the 
final statistical analysis plan.
This change also affects Section 16.6.2.2, Clinical Laboratory Results; Section 16.6.2.3, Vital 
Signs; Section 16.6.2.4, Columbia Suicide Severity Rating Scale; Section 16.6.2.5, Limited 
Neurological Examinations; Section 16.6.2.6, Electrocardiogram; and Section 16.6.2.7, 
Antigenicity/Immunogenicity.Section 18.3, Monitoring of the Study
Change: Implemented remote evaluation of data and source documents.
Now reads:
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical historiesparticipants’ medical histories.  Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete.  Changes to 
source data must be traceable, not obscure the original entry, and be explained if necessary 

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(e.g., with an audit trail).  The Investigator should maintain a record of the location(s) of 
essential documents.
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate.  During these visits, CRFs and supporting documentation 
related to the study will be reviewed and any discrepancies or omissions will be resolved.
Remote evaluation of data (centralized monitoring) and remote verification of source 
documentation may also be conducted and reported as defined in the Monitoring Plan.
Rationale: Remote evaluation of data and source documents is being implemented to allow the 
Sponsor and CRO to continue to provide oversight of site performance and ensure overall patient 
safety and data integrity. This process is being implemented because several sites/institutions 
have restricted on-site access for the CRO monitors during this ongoing COVID-19 pandemic.
Section 19, Further Requirements and General Information
Change: Details on contingency plans were added for potential site closure, travel restrictions, 
or other events resulting from a public health emergency.Now reads:
19.1
Public Health Emergencies
In the event of a public health emergency that results in site closure, travel restrictions, 
and/or the study being deprioritized at the site such that clinic visit(s) cannot occur, a 
protocol deviation would be incurred for any deviation from the protocol-specified visits 
and assessments, with additional notation that this protocol deviation is due to the public 
health emergency.  If a protocol-specified clinical visit cannot occur because of a public 
health emergency, the following mitigating options should be pursued, in order of 
preference (in which the highest preference option that is feasible should be done): 1) 
transfer to another active study site that is open, 2) home visit, 3) telemedicine visit (e.g., by 
telephone or web conference), and 4) local laboratory visit.  These mitigating options only 
apply in the setting of a public health emergency in which a protocol-specified clinic visit 
cannot occur and should not be pursued solely because of a participant’s preference.  If the 
participant does not participate in one of these options, a Safety Telephone call must be 
conducted within 14 days of the last dosing visit.
A third-party vendor has been engaged to perform the following assessments at the study 
participant’s home:

Limited neurological examination

Physical examination

Vital signs

Height and body weight collection

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
Health outcome measures

C-SSRS

SVC

Biological sample collection

Pregnancy test (if applicable)

HHD

Collection/shipment of ventilation diary records
The following assessments will be performed via telephone (telemedicine) by the site staff:

ALSFRS-R


Assessing changes in signs and symptoms as well as review of concomitant 
medications and AEs
Rationale: In the event of a public health emergency, mitigating options provide flexibility with 
respect to the collection of data in the interest of participant safety and to protect the integrity of 
the data when participants are unable to attend a clinic visit.
Section 19.3.1, Independent Data Monitoring Committee
Change: Added information on the end date for the regular IDMC meetings.Now reads:

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An independent data monitoring committee (IDMC) will be formed to review ongoing safety and 
tolerability data.  Members of the IDMC will not be allowed to participate as Investigators in this 
study.  The IDMC will review safety data on an ongoing basis to ensure the safe and proper 
treatment of subjectparticipants.  Regular IDMC meetings will occur approximately every 3 
months after the first meeting until the blinded Study 233AS101 is completed.  An IDMC 
charter will provide full guidance on the function and practices to be followed by the IDMC.
Rationale: This update was provided for clarification that the IDMC will not continue to meet 
regularly after the blinded Study 233AS101 has completed.

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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

Sponsor information was updated.

References to “SOD1” that refer to the PD endpoint were changed to “total SOD1 
protein” for clarity.

Section 2, List of Abbreviations, was updated.

Abbreviation format and preferred usage of terms were updated throughout to reflect 
revisions to the Biogen Style Guide.

Section 20, References, was updated.

Typographical errors and formatting were corrected.

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______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS102
An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect 
on Disease Progression of BIIB067 Administered to Previously Treated Adults with 
Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
Version 5
Date: 08 November 2019
EUDRA CT Number: 2016-003225-41
Version 5 of the protocol has been prepared for this amendment, which supersedes Version 4.

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 3, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 4, Schedule of Activities for Study 233AS102, Table 1 
Change: The frequency of the 
 and Mini-Mental State 
Examination (MMSE) assessments were reduced. Examination of the cranial nerve was removed 
as a component of the limited neurological examination. Pregnancy testing was changed to allow 
testing to be done on either urine or serum.

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Now reads:
Assessments
Screening 
Visit1
Baseline/1st
Loading Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit
Follow-Up 
Visits
Final or 
Early 
Termination 
Visit
Week -4 
to Day -1
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Weeks 8, 12, 16, and 
every 4 weeks 
thereafter up to 
Week 236 (±3 days)
Weeks 240 
and 244 
(±7 days)
(4 and 
8 weeks 
after last 
dose)
Week 248 
(±7 days) or
12 weeks 
after last 
dose [Early 
Termination 
Visit]
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Limited Neurological Examination 
(including MMSE)1214
X
X10
X
X10
X
X10
X
X10
X
X
X
MMSE
X
X
X
X11
X11
X
Urine Pregnancy Test1315
X
X10
X10
X10
X10
X
5 May be performed at any time on the day prior to study treatment administration, or predose on the day of study treatment administration, or over 2 days at the 
Follow-up Visits (Weeks 240 and 244) and Final or Early Termination Visit.
10To be collected/performed predose.
11To be performed at Week 12, 24, 36, and 48 Visits (i.e., every 12 weeks); Week 72, 96, 120, 144, 168, 192, and 216 Visits (i.e., every 24 weeks); and 
Week 228 Visit.
1214
The components of the limited neurological examination are cranial nerves, coordination/cerebellar function, reflexes, and motor system, and MMSE.
1315
To be performed only in women of childbearing potential; results must be negative to continue participation in study.  On dosing days, samples must be 
analyzed before study treatment administration.  To be performed via urine or serum testing.

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Rationale:
 
No findings of concern have been noted on the MMSE during Study 233AS101 or 
233AS102, so the frequency of the MMSE assessment was reduced to every 3 months during the 
treatment period. Likewise, no findings of concern have been seen in the cranial nerve 
examination, so this was removed to align with Part C of Study 233AS101 and to reduce subject 
burden. Changes to pregnancy testing were made to allow flexibility at the site and to align with 
Part C of Study 233AS101.
These changes also affect Section 14.1, Clinical Safety Assessments, Section 14.2, Laboratory 
Safety Assessments, Section 16.5.2.5, Limited Neurological Examination, and Section 19.1.4, 
Central Laboratories for Laboratory Assessments.
Section 8.2, Exclusion Criteria
Change: Exclusion criterion 1 excluding subjects with current or prior hepatitis B infection and 
exclusion criterion 8 excluding the presence of an implanted intravenous port/catheter were 
removed. Exclusion criterion 15 was updated. All subsequent exclusion criteria were renumbered 
accordingly.
Now reads:
1.
Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] 
and/or hepatitis B core antibody [anti HBc]).  Subjects with immunity to hepatitis B from 
previous natural infection (defined as negative HBsAg, positive IgM anti HBc, and 
positive anti HBc) or vaccination (defined as positive anti HBs) are eligible to participate 
in the study.
8.
Presence of an implanted intravenous port/catheter.
1513. Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet 
or anticoagulant medication (e.g., clopidogrel) for 7 days that cannot be safely 
continued or held for before or 48 hours after an LP procedure, if necessary, according 
to local or institutional guidelines and/or Investigator determination.
Rationale: Subjects in Study 233AS102 were previously enrolled in Study 233AS101 and were 
therefore screened for hepatitis B based on the exclusion criteria for Study 233AS101. There is 
no requirement in Study 233AS101 that a subject must discontinue study treatment if they 
acquire hepatitis B during the course of the study.  The requirement for repeat screening is 
therefore not necessary for subjects to roll into Study 233AS102.
Exclusion criterion 8 excluding the presence of an implanted intravenous port/catheter was 
removed for subjects who entered this study from Parts A or B of Study 233AS101 because its 
use is not precluded in Study 233AS101.

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Because study treatment administration will occur via lumbar puncture, care must be exercised in 
the use of antiplatelet or anticoagulant medication. Exclusion criterion 13 (previously exclusion 
criterion 15) has been updated to allow for the Investigator’s clinical judgement and local 
standard of care to be used, accounting for the many different indications, medications, and 
individual subject situations that may be relevant.
This change also affects Section 4, Schedule of Activities, Table 1 and Section 11.3.1.2, 
Disallowed Concomitant Therapy.
Section 9.1, Screening and Enrollment
Change: Language was added to allow rescreening of subjects.
Now reads:
Eligible subjects who are not able to complete the Day 1 Visit within 28 days of starting their 
screening assessments may be rescreened. Subjects who fail screening can be rescreened once 
at the discretion of the Investigator.  All rescreening must be completed within 56 calendar 
days after the start of the screening period (Study 233AS101 Day 169 [Week 24 Visit]). 
Rationale: This was done to prevent the exclusion of subjects due to a transitory issue with a 
screening result.
Section 13.1.3, Subject Diaries
Change: Section 13.1.3, Subject Dairies was added.
Now reads:
At Screening, subjects will be given diaries to record the date and time of ventilation use.  This 
diary will be reviewed with study site staff at each visit.  Refer to the Study Reference Guide for 
details.
Rationale: This was added to align with Section 4, Schedule of Activities for Study 233AS102, 
Table 1 and Biogen template.
This change affects all subsequent header numbering within Section 13.1, Clinical Function 
Assessments.

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Section 13.4, Genomic and Pharmacogenomic Assessments
Change: Section 13.4, Genomic and Pharmacogenomic Assessments, was added.
Now reads:
For subjects who did not have the presence or absence of a SOD1 mutation confirmed 
centrally in Study 233AS101, a one-time blood sample will be collected. For subjects who 
did not have a blood sample collected for testing of other genes related to ALS and/or the 
response to BIIB067 in Study 233AS101, an additional blood sample will be collected. The 
main ICF will govern use of these samples in genetic analyses to understand ALS and the 
response to BIIB067 in the context of this clinical program.
In addition, where not prohibited by regulatory authorities or ethics committees, an 
optional genetic consent will be offered to these subjects to allow samples to be stored for 
future unspecified genetic research related to other diseases and traits of interest to Biogen.
Approximately 10% of ALS is known to be caused by genetic mutations; to date, at least 
20 genes have been identified as causative of or highly associated with ALS, including 
SOD1.  The DNA sample will be analyzed for genetic variation in the SOD1 gene to 
determine the spectrum of likely pathogenic mutations in the gene and to assess if SOD1 
polymorphisms affect response to treatment.  In addition, samples collected during the 
study may be analyzed for genetic variation in other genes of known and probable 
relevance for the pathogenesis of ALS and neurodegeneration, including but not limited to 
TAR DNA binding protein (TARDBP), FUS (fused in sarcoma), C9ORF72, optineurin 
(OPTN), valosin-containing protein (VCP), ubiquilin 2 (UBQLN2), profilin 1 (PFN1), and 
ataxin (ATXN2).
In the event of an unusual response or observation of unexplained AEs, DNA samples may 
be used to determine if there are any pharmacogenomics associations with drug response.
In the future, as our understanding of ALS and BIIB067 increases, additional genomic 
analyses may be warranted to refine the knowledge of the molecular basis of the disease 
and the drug response as well as to advance the development of novel therapeutics.  The 
sample will only be used in genetic analyses to understand ALS, neurodegeneration, and 
response to BIIB067.
The DNA samples will be coded and may be stored for up to 15 years.  No genotyping or 
genomic data will be provided back to the subject.  Subjects may withdraw consent and 
request to have their samples destroyed at any time and no further genetic data will be 
generated; any data already generated will not be destroyed.

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Rationale: Genetic polymorphisms affecting genes encoding drug targets or relevant biological 
pathways, as well as proteins that affect drug absorption, distribution, metabolism, and 
elimination, may affect the safety and efficacy of the study treatment. To assess this, samples 
will be collected for testing genes related to amyotrophic lateral sclerosis and/or the response to 
BIIB067.  Samples will only be collected from subjects who had not previously provided them in 
Study 233AS101.
This change also affects Section 4, Schedule of Activities for Study 233AS102, Table 1.

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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

Sponsor Signature Page was updated to reflect the signatory’s current title.

The abbreviation 
 was 
updated throughout. 

Editorial change describing the “effects on disease progression of BIIB067” was 
updated throughout to “efficacy of BIIB067.”

Language describing the study as an “open-label, long-term extension study” was 
clarified throughout.

Telephone call was updated to telephone contact throughout the protocol to allow 
contact via text messaging.

Clarification was added throughout the protocol that home visit/assessments may be 
allowed at the discretion of the Investigator.

Typographical errors and formatting were corrected.

Section 2, List of Abbreviations, was updated.

Section 4, Schedule of Activities for Study 233AS102, Table 1, the following minor 
changes were made to reduce redundancies and/or for clarity:

“Clinical Laboratory Samples to Verify Eligibility Criteria” was changed to now 
read “Confirmation of Eligibility Criteria” for clarity, since laboratory samples 
were already being collected during the Screening Visit.

Footnote 3 (previously footnote 2) was reworded for clarity. This change also 
affects Section 8.1 Inclusion Criteria, criterion 6.

Footnote 4 was updated to reference the Study Reference Guide for details. This 
change also affects Section 13.1.3, Subject Diary.

Footnote 5 was updated to include the Follow-up Visits such that assessments at 
the Follow-up Visits may be collected over 2 days similar to the Final or Early 
Termination Visit.

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
Footnote 10 were removed due to redundancy.

Footnote 16 (previously footnote 14) was updated with additional details 
regarding CSF collection during LP, evaluation for contamination, and safety 
testing at local labs.

The numbering of the footnotes and the abbreviations were adjusted accordingly.

Section 5.2, Current Therapies for Amyotrophic Lateral Sclerosis, information was 
generalized to include only the generic names riluzole and edaravone, and details on 
approval status in different countries were removed.

Section 5.3.2, Clinical Experience, was updated to include interim analysis results for 
Part A (single ascending dose) and Part B (multiple ascending dose) of this study. 
This change also affects Section 5.5, Rationale for Dosing Regimen.

Section 5.4, Study Rationale, editorial changes were made for clarity. 

Section 7.1, Study Overview, was updated with the total number of countries and 
number of planned sites globally and to clarify that the last Maintenance Dose Visit 
for subjects will occur at Week 236 OR when the last subject enrolled has had his or 
her Week 92 Maintenance Dose Visit, whichever occurs first.

Section 7.2.2, Dosing, was updated to clarify that Day 1 of this study should occur no 
earlier than 28 days after the subject’s last dose (i.e., Day 169 [Week 24 Visit]) in 
Study 233AS101 to prevent subjects from being dosed too soon.

Section 8.1, Inclusion Criteria, criterion 7 was updated to clarify that this applied only 
to female subjects of childbearing potential. 

Section 13.1, Clinical Function, Pharmacokinetic, and Pharmacodynamic 
Assessments, was updated to clarify that all study visits are expected to occur at the 
site, unless the subject is unable to travel to the site; then, a home visit may be 
possible at the discretion of the Investigator.

Section 13.1.1, ALS Functional Rating Scale-Revised, was updated to include for 
each site that the same qualified and trained study site staff member will consistently 
perform the ALSFRS-R for a subject and that a qualified and trained backup 
ALSFRS-R rater will be identified in case the primary rater is unavailable.

Section 13.1.2, Slow Vital Capacity, was updated to note that at least 3 acceptable 
tests with the 2 highest acceptable (largest and next largest) efforts within 150 mL of 
vital capacity are required for slow vital capacity (SVC) testing. This change also 
affects Section 4, Schedule of Activities for Study 233AS102, Table 1 (the addition 
of footnote 7). Additionally, a statement was added to clarify that the SVC would be 
performed according to the study Pulmonary Procedure Manual. 

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1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS102
An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect 
on Disease Progression of BIIB067 Administered to Previously Treated Adults with 
Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
Version 4
Date: 11 January 2019
EUDRA CT:  2016-003225-41
Version 4 of the protocol has been prepared for this amendment, which supersedes Version 3.

Protocol 233AS102, Version 4
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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 233AS102 is to further extend the study 
duration that will allow any and all subjects to receive treatment until either the subject’s Final 
Visit at Week 248 or until the last subject randomized has had his or her Week 92 Visit, 
whichever occurs first. 
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7.2, Overall Study Duration and Follow-Up (previously Section 7.3 in Protocol 
Version 3)
Now reads:
7.3.7.2.
Overall Study Duration and Follow-Up
The overall duration of study participation for a single subject will be approximately 757 days 
(i.e., 27 months),up to 252 weeks, which includes an approximately 28 day4-week screening 
period, up to a 645 day (i.e., 23 month)236-week treatment period, and an 84 day (i.e., 3 month)
a 12-week follow-up period.
7.3.1.7.2.1.
Screening
7.2.1.1.
Subjects Who Have Completed Parts A and B of Study 233AS101
Subjects who complete have completed Part B (MAD) of Study 233AS101 (up to 48 and 
subjects) and subjects with SOD1 ALS who complete have completed Part A (single ascending 
dose) [SAD],) of that study will be eligible for screening.  Subject eligibility for the study will be 
determined from Day 28 Week -4 through Day -1.  
The Screening Visit assessments may be performed over approximately 2 days, which do not 
need to be consecutive, to minimize subject burden.  All assessments must be completed on or
before the baseline/loading dose visit Baseline/Loading Dose Visit on Day 1.  
7.2.1.2.
Subjects Who Have Completed Part C of Study 233AS101
Subjects who have completed the last dosing visit in Part C of Study 233AS101 will be able 
to screen to determine eligibility to participate in Study 233AS102.  A subject’s last dosing 
visit in Part C of Study 233AS101 will be the start of the Screening Visit (Week -4 to 
Day -1) for this open-label extension Study 233AS102.  Results from assessments completed 
by subjects at the last dosing visit of Study 233AS101 can be used for the purpose of 
screening and do not need to be repeated as long as they are conducted within 4 weeks of 
the Baseline/Loading Dose Visit on Day 1.
7.3.2.7.2.2.
Dosing
Eligible subjects will report to the study site on Day 1 to complete baseline assessments and 
reaffirm eligibility.  Subjects will receive 3 loading doses of BIIB067 approximately 2 weeks 
apart (Day 1, Day 15, and Day 29), during the 29 day loading dose period.

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During the maintenance portion of the study, subjects will receive 22 doses of BIIB067 
approximately every 4 weeks, during visits on Days 57, 85, 113, 141, 169, 197, 225, 253, 281, 
309, 337, 365, 393, 421, 449, 477, 505, 533, 561, 589, 617, and 645 (i.e., Month 3 to Month 24).
Assessments collected at the Follow-up Visit (4 weeks after last dose) of Part C of 
Study 233AS101 will be used as the Day 1 predose assessments for Study 233AS102 if they 
are collected within 48 hours of the first dose in Study 233AS102.
On dosing days, subjects will remain under observation for approximately 6 hours after the 
lumbar puncture (LP) at the study site for at least 1 hour postdose for safety monitoring and 
can be discharged at the discretion of the Investigator and in compliance with the 
institutional requirements, once the subjects have adequately recovered from the dosing 
procedure.  Subjects will receive a safety follow-up telephone call approximately 24 hours after 
the procedure.  
7.2.2.1.
Loading Dose Period
The Loading Dose Period of the study will occur from Day 1 to Day 29. 

Subjects who have completed Parts A or B of Study 233AS101:  

Subjects will receive 3 loading doses of BIIB067 approximately 2 weeks apart 
(Day 1, Day 15, and Day 29), during the 29 day loading dose period. ).  

Subjects who have completed Part C of Study 233AS101:

Subjects randomized to receive placebo during Study 233AS101 will receive 
3 loading doses of BIIB067, approximately 2 weeks apart (Day 1, Day 15, and 
Day 29).  The Investigators, study staff (except for an unblinded designated 
pharmacist/technician), and study subjects will be blinded to the study 
treatment during the Loading Dose Period. 

Subjects randomized to receive BIIB067 during Study 233AS101 will receive 
2 loading doses of BIIB067, on Days 1 and 29, and 1 dose of placebo, on 
Day 15.  The Investigators, study staff (except for an unblinded designated 
pharmacist/technician), and study subjects will be blinded to the study 
treatment during the Loading Dose Period.
7.2.2.2.
Maintenance Dose Period
During the maintenance portion of the study, subjects will receive 22 up to 58 doses of BIIB067,
approximately every 4 weeks, during visits on Days 57, 85, 113, 141, 169, 197, 225, 253, 281, 
309, 337, 365, 393, 421, 449, 477, 505, 533, 561, 589, 617, and 645 (i.e., Month 3 to Month 
24).at Weeks 8, 12, 16, and every 4 weeks thereafter up to Week 236, OR when the last 
subject enrolled has had their Week 92 Maintenance Dose Visit, whichever occurs first.
On dosing days, subjects will remain under observation for approximately 6 hours after the 
lumbar puncture (LP) procedure and will receive a safety follow-up telephone call approximately 
24 hours after the procedure.  
7.3.3.7.2.3.
Follow-Up

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Subjects will return for Follow-Up Visits on Day 673, Day 701at Weeks 240 and 244, and Day 
729 (i.e., Month 25, Month 26, and Month 27 [for the Final Visit at Week 248 OR for early 
withdrawals at 4, 8, and 12 weeks (Final/Early Termination Visit]).) after their last dose.  
CSF sampling will be performed on at either Day 673 (i.e., Month 25) Week 240 or Day 701 
(i.e., Month 26), and on Day 729 (i.e., Month 27).Week 244 or for early withdrawals 4 or 
8 weeks after their last dose.  On the day of CSF sampling during the follow-up periods period, 
subjects will remain under observation in the clinic for approximately 1 hour after the LP 
procedure and will receive a safety follow-up telephone call approximately 24 hours after the 
procedure.
Rationale: The primary reason for extending the study is to allow the collection of additional 
data beyond 2 years to evaluate the long-term efficacy and safety of BIIB067.
This change also affects Section 3, Synopsis; Section 4, Study Schematic and Schedule of 
Activities for Study 233AS102; Section 7.4, Study Stopping Rules; Section 7.5, End of Study; 
Section 11, Study Treatment Use; Section 15.3, Monitoring and Recording Events; and 
Section 16.3, Pharmacodynamics.

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7
Table 1:
Schedule of Activities
Assessments
Screening 
Visit1
Baseline/1st
Loading Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit Visits
Follow-Up 
Visit Visits
Final/ or 
Early 
Termination 
Visit
Day 
28Week -
4 to Day -
1
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Days 57, 85, 113, 
141, 169, 197, 225, 
253, 281, 309, 337, 
365, 393, 421, 449, 
477, 505, 533, 561, 
589, 617, & 645 (i.e., 
Months 3 24)Weeks
8, 12, 16, and every 
4 weeks thereafter 
up to Week 236 
(±3 days)
Days 673 
& 701 
(i.e., 
Months 25 
& 26)
Weeks 240 
and 244 
(±7 days)
(4 and 
8 weeks 
after last 
dose)
Day 729
(i.e., Month 
27)Week 248 
(±7 days)
12 weeks 
after last 
dose [Early 
Termination 
Visit]
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Informed Consent Form (main) 
and Genetic/Future Scientific 
Research Consent (optional)
X
Medical History
X
X
Clinical Laboratory Samples to 
Verify Eligibility2,3
X
Ventilation Use4
X
X
X
X
X
X
ALSFRS-R
X95
X995
X995
X995,6
X
X995
SVC
X995
X995
X995
X995,
X
X995
HHD
X995
X995
X995
X995,6
X
X995

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8
Assessments
Screening 
Visit1
Baseline/1st
Loading Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit Visits
Follow-Up 
Visit Visits
Final/ or 
Early 
Termination 
Visit
Day 
28Week -
4 to Day -
1
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Days 57, 85, 113, 
141, 169, 197, 225, 
253, 281, 309, 337, 
365, 393, 421, 449, 
477, 505, 533, 561, 
589, 617, & 645 (i.e., 
Months 3 24)Weeks
8, 12, 16, and every 
4 weeks thereafter 
up to Week 236 
(±3 days)
Days 673 
& 701 
(i.e., 
Months 25 
& 26)
Weeks 240 
and 244 
(±7 days)
(4 and 
8 weeks 
after last 
dose)
Day 729
(i.e., Month 
27)Week 248 
(±7 days)
12 weeks 
after last 
dose [Early 
Termination 
Visit]
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
C-SSRS9
X
X
X6
X
X
Weight
X
X510
X
Vital Signs (temperature, blood 
pressure, pulse rate, respiratory 
rate)
X
X511
X
X
X
X512
X
X513
X
X
X
12-lead EC14
X
X515
X516
X517
X
X
Physical Examination
X
X518
X519
X520
X521
X
X
Limited Neurological 
Examination (including 
MMSE)422
X
X523
X
X524
X
X525
X
X526
X
X
X

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9
Assessments
Screening 
Visit1
Baseline/1st
Loading Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit Visits
Follow-Up 
Visit Visits
Final/ or 
Early 
Termination 
Visit
Day 
28Week -
4 to Day -
1
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Days 57, 85, 113, 
141, 169, 197, 225, 
253, 281, 309, 337, 
365, 393, 421, 449, 
477, 505, 533, 561, 
589, 617, & 645 (i.e., 
Months 3 24)Weeks
8, 12, 16, and every 
4 weeks thereafter 
up to Week 236 
(±3 days)
Days 673 
& 701 
(i.e., 
Months 25 
& 26)
Weeks 240 
and 244 
(±7 days)
(4 and 
8 weeks 
after last 
dose)
Day 729
(i.e., Month 
27)Week 248 
(±7 days)
12 weeks 
after last 
dose [Early 
Termination 
Visit]
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Urine Pregnancy Test27
X
X528
X529
X530
X531
X
CSF Samples32
X5,13 
33,34
X5,13 
35,36
X5,13 
37,38
X5,13 
39,40
X5,13
X5,13
Clinical Laboratory Samples for 
Hematology, Coagulation, 
Chemistry, and Urinalysis
X
X
X
X
X
X
X
Blood Samples for Plasma 
anti-BIIB067 Ab
X545
X546
X547
X5
48,49
X
Blood Samples for PK
X550
X551
X552
X5
53,54
X
Blood Samples for PD and 
Biomarkers
X555
X556
X557
X558
X
Study Treatment Administration
X
X
X
X
Adverse Event AE/Concomitant 
Therapy and Procedures 
Recording
------------------------------------------------------------------X (ongoing)---------------------------------------------------

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10
Assessments
Screening 
Visit1
Baseline/1st
Loading Dose Visit
2nd Loading Dose 
Visit
3rd Loading Dose 
Visit
Maintenance Dose 
Visit Visits
Follow-Up 
Visit Visits
Final/ or 
Early 
Termination 
Visit
Day 
28Week -
4 to Day -
1
Day 1
Day 15 (±3 days)
(Week 2)
Day 29 (±3 days)
(Week 4)
Days 57, 85, 113, 
141, 169, 197, 225, 
253, 281, 309, 337, 
365, 393, 421, 449, 
477, 505, 533, 561, 
589, 617, & 645 (i.e., 
Months 3 24)Weeks
8, 12, 16, and every 
4 weeks thereafter 
up to Week 236 
(±3 days)
Days 673 
& 701 
(i.e., 
Months 25 
& 26)
Weeks 240 
and 244 
(±7 days)
(4 and 
8 weeks 
after last 
dose)
Day 729
(i.e., Month 
27)Week 248 
(±7 days)
12 weeks 
after last 
dose [Early 
Termination 
Visit]
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
SAE Recording
-----------------------------------------------------------------------X (ongoing)--------------------------------------------------------
Ab = antibody; AE = adverse event;
; ALSFRS-R = Amyotrophic Lateral Sclerosis 
Functional Rating Scale - Revised; CSF = cerebrospinal fluid; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram, EIM = electrical 
impedance myography;
 HHD = handheld 
dynamometry; LP = lumbar puncture; MMSE = Mini-mentalMental State Examination; 
 PD = pharmacodynamics; PK = 
pharmacokinetics; RNA = ribonucleic acid; SAE = serious adverse event;
SVC = slow vital capacity;
.
1 Screening assessments can be performed over ~2 days (need not be consecutive) to minimize subject burden.
2 Including blood samples for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus tests, and platelet and coagulation tests.  Platelet and 
coagulation tests may be repeated at the local laboratory once if, in the opinion of the Investigator, the values of the initial tests are only slightly out of range.
3 Results of coagulation tests and platelet count must be reviewed before a lumbar puncture can be performed.  Should the results obtained at a prior screening, 
dosing, or Follow-Up Visit suggest, in the opinion of the Investigator, that a tap may be safely performed then no additional laboratory values would require 
review before performing the lumbar puncture.  However, should repeat coagulation and platelet tests be clinically indicated in the opinion of the Investigator, 
then these tests may be done locally to facilitate timely review.
4 The components of the limited neurological examination are cranial nerves, coordination/cerebellar function, reflexes, motor, and MMSE.
54Subjects will use a diary to record ventilation use.  This diary will be reviewed with study site staff at each visit.
5 May be performed at any time on the day prior to study treatment administration or predose on the day of study treatment administration, or over 
2 days at the Final or /Early Termination Visit.
6 To be performed at Week 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 
136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, and 236 (i.e., every 4 weeks) 
Visits only.

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9 “Since Last Visit” version of C-SSRS will be used after the Baseline/First Loading Dosing Visit.
10To be collected/performed predose.
611
Triplicate 12-lead (paper) ECGs will be obtained after subjects have rested in a supine position for at least 10 minutes.  The first ECG will be 
interpreted, and the last 2 ECGs will be checked for consistency and quality.
7 “Since Last Visit” version of C SSRS will be used after the Baseline/1st Dosing Visit.
812
The components of the limited neurological examination are cranial nerves, coordination/cerebellar function, reflexes, motor, and MMSE.
13
To be performed only in women of childbearing potential; results must be negative to continue participation in study.  On dosing days, samples must be 
analyzed before study treatment administration.
9 May be performed at any time on the day prior to study treatment administration or predose on the day of study treatment administration, or over 2 days at the 
Final/Early Termination Visit.
10To be performed at Days 141, 309, 477, and 645 (i.e., Months 6, 12, 18 and 24) Visits only.
11To be performed at Days 85, 141, 197, 253, 309, 365, 421, 477, 533, 589, and 645 (i.e., Months 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) Visits only.
1214
Lumbar puncture will be performed to collect CSF samples for PK, PD, safety, and biomarker analysis.
13Subjects will remain under observation in the clinic for ~6 hours after the lumbar puncture procedure and will receive a safety follow up telephone call ~24 
hours after the procedure.
1415
Subjects will remain under observation in the clinic for ~1 hour after the lumbar puncture procedure and for safety monitoring and can be discharged 
at the discretion of the Investigator and in compliance with the institutional requirements once the subjects have adequately recovered from the 
procedure.  Subjects will receive a safety follow-up telephone call ~24 hours after the procedure.  The procedure at the Follow up Visits may be performed at 
the Day 673 (i.e., Month 25) or Day 701 (i.e., Month 26) Visit.
1516
Blood samples will be collected on every alternate visit at Week 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, 140, 148, 156, 
164, 172, 180, 188, 196, 204, 212, 220, 228, and 236 (i.e., every 8 weeks) Visits only.  Blood samples for anti-BIIB067 Ab and PK assessments will be 
collected at the same time.
17
Subjects who agree to provide samples will need to sign separate consent form(s).  RNA sample collection for possible future research will be optional 
in all regions where not prohibited by regulatory authorities or ethics committees.

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Rationale:  These changes were made to align the assessments of this study with those in Part C 
of Study 233AS101, to provide clarity (days to weeks and relation to LP), and to minimize the 
burden to the subject while preserving data and study integrity (changes to assessment 
frequency).
This change also affects 
 
; Section 7.3, Overall Study Duration and Follow-up; Section 13.1, Clinical 
Function Assessments; and Section 16.1.2, Methods of Analysis. 
Section 5.4, Study Rationale
Change: Study rationale text was updated with the evaluation of PD, PK, and effect of disease 
progression of BIIB067.
Now reads:
This study will evaluate the long-term safety, tolerability, PD, PK, and PK effect of disease 
progression of BIIB067 in administered to subjects with SOD1-ALS who have completed Part 
Parts A and/or B, or C of the FIH study (233AS101) of BIIB067.
The study will also characterize the effects of BIIB067 on disease progression by examining 
changes over time in clinical, electrophysiologic, 
 assessments of individual 
subjects
The extension study will allow collection of PK and pharmacodynamics (PD) data during dose 
interruption and resumption, thereby providing valuable information on the dynamic behavior of 
the system.  This information will augment the PK and PD data collected in the FIH Study 
233AS101 for the purpose of creating models of the exposure response relationship.  These 
models will be used to simulate and assess PD profiles under various dosing regimens and will 
inform the dose levels of BIIB067 and frequencies to be tested in future studies.
Rationale: This change was made to align the rationale with Study 233AS101 and for clarity.
This change also affects Section 6, Study Objectives and Endpoints.
Section 5.5, Rationale for Dosing Regimen
Change: All subjects in Study 233AS102 will now be dosed at 100 mg BIIB067.
Now reads:
Doses in this extension studyBIIB067 will be the same as in Part B of Study 233AS101 
administered via IT bolus at 100 mg.
The BIIB067 dosing regimens for Parts A and B of Study 233AS101 were selected based on 
target tissue concentrations from SOD1 transgenic mouse models, and nonclinical toxicology 
and PK observations in repeated dose, IT administration in 13 week and 9 month nonhuman 
primate (NHP) studies.

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The lowest dose selected for Study 233AS101 (10 mg in Part A) was predicted to achieve 
greater than 0.9 µg/g tissue concentration in the spinal cord. The initial highest proposed dose 
(60 mg, multiple dose in Part B) was predicted to achieve greater than 4.7 µg/g steady state 
tissue concentration in the spinal cord, and approximately 1.5 µg/g steady state tissue 
concentration in the cortex, which is expected to yield approximately 15% to 20% SOD1 mRNA 
reduction in that tissue.  
Therefore, all For Part C (Pivotal) of Study 233AS101, the dose of 100 mg of BIIB067 was 
determined based on the interim analyses of data from subjects in Part B (MAD) Cohorts 5 
to 8 treated for 85 days.  Safety analyses of these data suggested that all doses planned for 
Studies 233AS101 and 233AS102 are predicted to be pharmacologically active, while 
maintaining sufficient through 100 mg had been well tolerated, with a safety margins 
calculated from the 9 month IT NHP toxicology study. profile supportive of continued 
development of BIIB067 in subjects with ALS.
Rationale: The 100 mg dose of BIIB067 was determined based on the interim analyses of data 
from Study 233AS101.
Section 6, Study Objectives and Endpoints
Change: Clarified that study objectives were being assessed in subjects with ALS and confirmed 
SOD1 mutation. Study secondary and exploratory objectives/endpoints were rearranged and 
segregated using subheadings. The secondary objective was updated to include disease 
progression. As a result, the ALSFRS-R scores, SVC, and HHD scores 
 
were changed to secondary endpoints, and the VAFS and overall survival were added as 
secondary endpoints. 
Now reads:
6.1.
Primary Objective and Endpoints
The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 
in subjects with ALS and confirmed SOD1 ALS mutation.
The associated primary endpoints are the incidence of AEs and serious adverse events (SAEs).
6.2.
Secondary Objectives and Endpoints
The secondary objective is objectives are to evaluate the PK and PD profiles and effects on 
disease progression of BIIB067 in administered to subjects with ALS and confirmed SOD1 
ALS mutation.  
6.2.1. Pharmacokinetic Endpoints
The associated secondary PK endpoints are PK measures, including plasma and CSF levels of 
BIIB067 and CSF levels of the SOD1 protein.
6.2.2. Pharmacodynamic Endpoints
The 
 of this study and the associated PD endpoints are as follows:

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Study 233AS102.  Subjects These subjects will receive 3 loading doses of 100 mg BIIB067, 
approximately 2 weeks apart, during the first 4 weeks and 22 maintenance doses, approximately 
every 4 weeks, by IT injection.  
Initial dose level assignment for each subject who completes Subjects who have completed
Part B C of Study 233AS101 will correspond to their cohort assignment not have a washout 
period.  To preserve the blinding used in Study 233AS101, regardless of whether they until 
database lock, subjects who enroll in Study 233AS102 after completing Part C of 
Study 233AS101 will have a blinded Loading Dose Period.  Subjects who received BIIB067 
or placebo.  All subjects randomized to Cohort 5 (BIIB067 20 mg or placebo) while in 
Study 233AS101 will receive 3 doses of 100 mg BIIB067, approximately once every 2 weeks 
(Days 1, 15, and 29), while subjects who received BIIB067 in Study 233AS101 will receive 
2 doses of 100 mg BIIB067 20 mg;, on Days 1 and 29, and placebo on Day 15.  
After the Loading Dose Period, all subjects who were randomized will receive up to Cohort 6 
(58 maintenance doses of 100 mg BIIB067 40 mg or placebo) will receive, approximately 
every 4 weeks, by IT injection.  Subjects who were not receiving 100 mg BIIB067 40 mg, 
those randomized to Cohort 7 (BIIB067 60 mg or placebo) will receive BIIB067 60 mg, and 
those randomized to Cohort 8 (BIIB067 100 mg or placebo) will receive BIIB067 100 mg.  If the 
highest dose (100 mg) is dropped based on results from the multiple ascending dose (MAD) 
portion (Part B) of Study 233AS101, subjects in Cohort 8, will be placed in the 60 mg cohort in 
this extension study.
Subjects who complete only Part A of Study 233AS101 will be assigned to the dose level of 
whichever cohort in Part B (i.e., Cohort 5, 6, 7, or 8) is enrolling at the time these subjects are 
screened.  Subjects who complete Cohorts 1 through 7 of Study 233AS101 (BIIB067 or placebo) 
will also have the option of switching to a higher dose cohort during or after enrollment in the 
extension Study 233AS102, at the discretion of the Investigator and according to the criteria 
specified in Section 7.2.1. 
7.2.
Study Specifics
7.2.1. Cohort Enrollment
Dose levels will be enrolled sequentially, in an ascending manner, as corresponding dose level 
cohorts complete Part B of Study 233AS101.  
For each cohort in the extension Study 233AS102, before dosing subjects who enroll after 
completing Part B of Study 233AS101, the Safety Surveillance Team (SST) will review safety 
data collected through Day 106 for the corresponding dose level cohort in Study 233AS101.  
Before the start of the higher dose cohorts, the SST will also review available safety data from 
the previous cohorts in Study 233AS102.  The SST will consist of the Biogen Medical Director, 
Safety and Benefit Risk Management (SABR) Physician, and, if required, any ad hoc members.  
Before dosing the first subject enrolling after completing Part B of Study 233AS101 in each 
cohort of the extension study, the SST must agree that the current emerging safety and 
tolerability data support continued exposure for these subjects.  
Subjects who have completed only Part A of Study 233AS101 may be screened for the cohort 
currently open for enrollment in the extension study.  

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Subjects who complete Study 233AS101 (BIIB067 20 60 mg or placebo), may, at the discretion 
of the Investigator, be switched to a higher dose cohort currently open for enrollment in Study 
233AS102.  The opening of a higher dose cohort for enrollment in Study 233AS102 will be 
determined at the planned SST review of emerging safety and tolerability data of the same dose 
cohort for at least 10 subjects through Day 106 in Study 233AS101. Thus, a favorable SST safety 
review of BIIB067 60 mg in Study 233AS101 will allow the opening of the 60 mg cohort for 
those study participants wishing to enroll at this dose in the extension study. Dose switching for 
a subject may continue up to the highest dose (100 mg), but prior to switching at every level, the 
planned Day 106 SST review in Study 233AS101 must support dose escalation in the extension 
study. Furthermore, should a PI wish to escalate the dose level, they must consult with the 
Sponsor to ensure that current emerging safety and tolerability data support continued exposure 
for the subject. will be dosed at 100 mg BIIB067 at their next scheduled Maintenance 
Dosing Visit.
Rationale: All subjects are allowed to receive 100 mg BIIB067 based on the preliminary 
findings from Study 233AS101, which showed that all doses including 100 mg were well 
tolerated and safe; additionally, 100 mg BIIB067 is predicted to be more efficacious than other 
dose levels. Subjects who have completed Part C of Study 233AS101 are allowed to participate 
in Study 233AS102 and to continue receiving BIIB067. Because these subjects are already 
receiving 100 mg BIIB067, they do not need to undergo a washout period and can enter the study 
sooner, with fewer non-dosing days. However, a blinded loading dose period is needed to 
preserve the blind in Study 233AS101. Additionally, the deletion of previous text helps avoid 
confusion about the different dosage forms in Parts A and B of Study 233AS101, as all the 
subjects enrolled from Part C of Study 233AS102 will be dosed at 100 mg.
This change also affects Section 8.1, Inclusion Criteria (inclusion criterion 7) and Section 9.3, 
Blinding Procedures.
Section 8, Selection of Subjects
Inclusion and exclusion criteria were updated to align with Part C of Study 233AS101 and as per 
study requirement.
Section 8.2.1, Inclusion Criteria
Change: Inclusion criterion 1 was updated with text related to signing the informed consent by 
subject or his/her legally authorized representative.
Now reads:
1. Ability of the subject to understand the purpose and risks of the study and indicate 
consent, and ability of the subject or his/her legally authorized representative to
provide signed and dated informed consent and authorization to use protected health 
information (PHI) in accordance with national and local subject privacy regulations.  In 
the case that a subject is physically incapable of providing informed consent, the 
subject’s legally authorized representative must provide the informed consent.

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Rationale: This change was made to clarify that the subject or his/her legally authorized 
representative who provided informed consent should understand the purpose and risks of the 
study and signed the consent according to the requirement of all countries where the study will 
be conducted.
Change: Inclusion criterion 2 was updated to allow subjects who have completed Part C (i.e.,
final clinic visit) of Study 233AS101 to enroll in Study 233AS102.
Now reads:
2. Must have diagnosis of SOD1-ALS, and must have completed Part A and/or Part B the 
End of Study Visit for either Parts A, B, or C of Study 233AS101 (i.e., were not 
withdrawn and did not miss more than 1 dose of study treatment).)
Rationale: This change was made to allow subjects who have completed Part C of 
Study 233AS101 to participate in Study 233AS102 and to clarify the definition of subjects who 
have completed Part C of Study 233AS101.
Change: Inclusion criterion 5, now 6, was updated to remove the requirement that the Sponsor 
be consulted prior to including subjects with nonclinically significant and stable out-of-range 
values.
Now reads:
5.6. Must have screening values of coagulation parameters including platelet count, 
international normalized ratio (INR), prothrombin time (PT), and activated partial 
thromboplastin time (APTT) within normal ranges.  Coagulation tests may be repeated 
at the local laboratory once if, in the opinion of the Investigator, values of the initial tests 
are only slightly out of range.  Subjects with nonclinically significant and stable out of 
range values may be eligible to enroll in the study at the discretion of the Investigator, 
after a consultation with the Sponsor.  (For normal ranges, please refer to the Study 
Reference Guide).
Rationale: This change was made to align the subject’s enrollment requirement with 
Study 233AS101.
Change: Inclusion criterion 6, now 7, was updated with contraception text.
Now reads:
6.7. For subjects of childbearing potential must agree to practice effective contraception 
during the study and be willing and able to continue contraception for 5 months after 
their last dose of study treatment.  For further details of contraceptive requirements for 
this study, please refer to (see Section 15.5).
Rationale: Text was updated to clarify the contraception requirement of a subject of 
childbearing potential to willingly continue contraception during the study.

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Change: Inclusion criterion 8 was updated to clarify that the subjects receiving edaravone as a 
concomitant medication at study entry must be stable for ≥60 days instead of ≥30 days. 
Additionally, this inclusion criterion was renumbered from 8 to 4.
Now reads:
8.4. Subjects taking concomitant edaravone at study entry must be on a stable dose for ≥ 30 
days prior to the first dose of study treatment (Day 1) and must continue with the same 
dose regimen throughout the study, unless the Investigator determines that edaravone 
should be discontinued for medical reasons, in which case it may not be restarted 
during the study.  Edaravone may not be administered on dosing days during this If 
taking edaravone, subject must have initiated edaravone ≥60 days (2 treatment 
cycles) prior to Day 1.  Edaravone may not be administered on dosing days during 
this study.
Rationale: This change was made to align the edaravone requirement as a concomitant 
medication with that in Study 233AS101. 
This change also affects Section 11.3.1.1, Allowed Concomitant Therapy.
Section 8.2.2, Exclusion Criteria
Change: Exclusion criteria 1 and 2, for subjects with a history of human immunodeficiency 
virus and hepatitis C virus antibody, were deleted.
Now reads:
1. History of or positive test result for human immunodeficiency virus. 
2. History of, or positive test result at Screening for hepatitis C virus antibody.
Rationale: Subjects in Study 233AS102 were previously enrolled in Study 233AS101 and were 
therefore screened for HIV and HCV based on the exclusion criteria for Study 233AS101. There 
is no requirement in Study 233AS101 that a subject must discontinue study treatment if they 
acquire HIV or HCV during the course of the study.  The requirement for repeat screening is 
therefore not necessary for patients to roll into Study 233AS102.
Section 11.1, Regimen
Change: This section was restructured to clarify how the dosing regimen, including the loading 
dose, for subjects who have completed Part A or B and subjects who have completed Part C of 
Study 233AS101 will be handled moving forward and that all subjects will now receive 100 mg 
BIIB067. Specifically, it was clarified that the loading dose will occur during the first 4 weeks of 
treatment and that the Maintenance Dose Period will be extended to approximately 58 doses. 
Details of the prior dosing regimen were removed. Additionally, the time that subjects will be
required to stay at the site for safety monitoring following LP was decreased from 6 hours to 
1 hour. 

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Now reads:
11.1.
Regimen
11.1.1. Subjects Who Have Completed Parts A or B of Study 233AS101
Subjects will receive 3 loading doses of BIIB067, approximately 2 weeks apart, and 22 during 
the first 4 weeks, and up to 58 maintenance doses of BIIB067, approximately every 4 weeks, 
by IT injection.  

Group 1:  20 mg

Group 2:  40 mg

Group 3:  60 mg 

Group 4:  100 mg
The number of subjects at each dose level will depend on the available subjects diagnosed with 
SOD1 ALS who complete Part A or Part B of Study 233AS101.  Subjects may also have the 
option of moving to one of the higher dosing cohorts (up to 100 mg) during or after enrollment in 
Study 233AS102, according to the criteria described in Section 7.2.1.
All subjects who were not receiving the 100 mg dose of BIIB067 will be dosed at 100 mg 
BIIB067 at their next scheduled Maintenance Dose Visit.
11.1.2. Subjects Who Have Completed Part C of Study 233AS101
Subjects will not have a washout period.  Subjects who received placebo while in Part C of 
Study 233AS101 will receive 3 loading doses of 100 mg BIIB067 approximately once every 
2 weeks (Days 1, 15, and 29), while subjects who received BIIB067 in Part C of 
Study 233AS101 will receive 2 doses of 100 mg BIIB067, on Days 1 and 29, and placebo on 
Day 15.  All subjects will receive 100 mg BIIB067 at each Maintenance Dose Visit (up to 
58 doses) thereafter.  Study treatment administered to subjects during the Loading Dose 
Period is to be blinded.
11.1.3. All Subjects
Prior to injection, approximately 10 mL of CSF will be collected for analyses.  Depending on 
institutional guidelines, anesthesia or sedation may be used for the LP procedure.  On dosing 
days, subjects will remain under observation in at the clinic study site for approximately 6 hours 
after at least 1 hour postdose for safety monitoring and can be discharged at the LP
discretion of the Investigator and in compliance with the institutional requirements, once 
the subjects have adequately recovered from the dosing procedure and.  Subjects will receive 
a safety follow-up telephone call approximately 24 hours after the procedure.  During the 
follow-up periods, subjects will remain under observation in the clinic for approximately 1 hour 
after the LP procedure and will receive a safety follow-up telephone call approximately 24 hours 
after the procedure.  Refer to and follow the Directions for Handling and Administration (DHA). 
11.2.
Modification of Dose and/or Treatment Schedule
The dosage should not be modified, other than as stated in Section 7.2.2.  However, if necessary 
(e.g., dose is not tolerated), after review of all available data by the Biogen Medical Director, a 

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
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)
For the purposes of the study, highly effective contraception is defined as use of 1 of the 
following:
For females:

Established use of oral, injected, or implanted, intravaginal, or transdermal
hormonal methods of contraception.

Placement of an intrauterine device or intrauterine hormone-releasing system.

Male Barrier methods of contraception with use of a spermicide:  condom or 
occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream suppository.  The use of barrier contraceptives should 
always be supplemented with the use of a spermicide.

Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate).  (For female 
subjects participating in the study, male sexual partners must have undergone surgical 
sterilization.)
For males:

A vasectomy with negative semen analysis at follow up.

True abstinence, when this is consistent with the preferred and usual lifestyle of the 
subject, can be considered an acceptable method of contraception based on the 
evaluation of the Investigator who should also take into consideration the duration of 
the clinical trial.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not considered acceptable methods of 
contraception.
Rationale: Contraception requirements were updated to reflect the availability of reproductive 
toxicology study results.
Section 16.1, Clinical Function
Change: Text related to the method of PD analysis for all subjects was updated, and text for 
subjects who have completed Parts A and B of Study 233AS101 and Part C of Study 233AS101
was clarified.
Now reads:
16.1.
Clinical Function
16.1.1. Analysis Population

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The clinical function/PD population is defined as subjects who have received at least 1 dose of 
study treatment and have at least 1 available postdosing evaluation of the respective clinical 
function or PD endpoint in the extension study.
In the analysis, for subjects who switched dose cohort during the study, an “intent to treat” 
principle will be employed to assign dose cohorts for those subjects; that is, subjects will always 
be assigned to their initial dose cohort when they started the study.  
16.1.2. Methods of Analysis
Because As this is an open-label, uncontrolled study, all clinical function endpoints will be 
evaluated either in reference to historical placebo data or based on observed changes in the 
longitudinal trajectory.  All long-term extension study, analyses will be exploratory and 
descriptive in nature, and no formal statistical testing will be performed. . 
Data will be summarized by dose level using descriptive statistics (N, mean, standard deviation 
[SD], median, minimum, and maximum) for continuous variables and using frequency and 
percentage for discrete variables.  For subjects who have completed Parts A or B of 
Study 233AS101, the time trajectory of each clinical function and PD variable may be 
summarized for the period of each dose level.  For subjects who have completed Part C of 
Study 233AS101, the time trajectory will be summarized by the prespecified 
mutation/progressing group (fast-progressing versus non-fast-progressing) and the 
treatment received during Study 233AS101 from the baseline of Study 233AS101 
(including data from Studies 233AS101 and 233AS102), from the baseline of 
Study 233AS101 (including data from Study 233AS102 only), and from the start of 
BIIB067 100 mg dosing.
Disease progression will be measured based on changes in ALSFRS-R, SVC, 
HHD, 
, HHD, 
.  The improvement in ALSFRS R is 
defined as the positive estimated linear mixed model for repeated measures (MMRM) will be 
used to assess the slope of ALSFRS R change by mutation/progressing group 
(fast-progressing versus non-fast progressing) and the treatment received during 
Study 233AS101.  Baseline characteristics at the start of Study 233AS101 may be included 
as fixed covariates.  The slope of ALSFRS-R score change will be estimated using linear 
MMRM as well as derived using data points from each individual participant, based on 
assumed linear declining of ALSFRS R.  The proportion of positive slope will be estimated and 
presented along with the 95% CI for each 48-week period.  Categorical analysis of slopes in 
different ordered categories may also be performed.  
We postulate that an improvement in disease progression can be demonstrated in subjects with 
an observed PD effect of BIIB067, defined as a reduction in total CSF SOD1 protein by at least 
25%.  The effect of dose level and other covariates including, but not limited to, gender, disease 
onset site, riluzole and edaravone use, and the total number of active doses and the dosing gap 
prior to the extension study, may be explored using statistical modelling.  VAFS and overall 
survival will be summarized using Kaplan-Meier curves based on the starting time using 
the following: 
1. Entry into Study 233AS101

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2. Entry into Study 233AS102
3. The start of BIIB067 100 mg dosing
The relationship between PK or PD endpoints and the clinical function endpoints will also be 
explored.
Rationale: This change was made to clarify that difference between the time trajectories of 
subjects who participated in Parts A and B of Study 233AS101 and those who participated in 
Part C of Study 233AS101. Subjects who completed Parts A and B of Study 233AS101 received 
different dosages prior to Version 4 of Protocol 233AS102, whereas all subjects who completed 
Part C of Study 233AS101 will receive a 100 mg BIIB067 dose in Study 233AS102. Hence, the 
analysis is different among the subjects enrolling from different parts of Study 233AS101 into 
Study 233AS102.
This change also affects Section 16.3.2, Methods of Analysis (for PD endpoints).
Section 16.6, Interim Analyses
Change: Interim analysis was added.
Now reads:
16.5.16.6.
Interim Analyses
No formal interim analysis is planned for this study.
Interim analyses may be performed periodically to provide content for regulatory 
submissions and safety updates and to support drug development planning and business 
activities.
Rationale: Interim analyses were added to support regulatory submissions and further drug 
development planning and business activities.
Section 16.7, Sample Size Considerations
Change: Study’s subject sample size was increased from 84 subject to 144 subjects.
Now reads:
16.6.16.7.
Sample Size Considerations
The sample size for this study is based on the sample size number of the SOD1-ALS population 
subjects in Study 233AS101 who consent to participate.  Up to approximately 84 144 subjects 
will be dosed in Study 233AS101.
Rationale: The study sample size was increased because subjects who participated in Part C of 
Study 233AS101 will be allowed to participate in this open-label extension Study 233AS102.

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Section 19.2, Study Committees
Change: Added an independent data monitoring committee (IDMC) and removed the reference 
to the Safety Surveillance Team (SST).
Now reads:
19.2.1. Safety Surveillance Team
An SST, as described in Section 7.2.1, will monitor dose escalation and the opening of extension 
cohorts.  The SST will meet to review safety data at least every 3 months, and more frequently as 
needed.
19.2.1. Independent Data Monitoring Committee
An IDMC will be formed to review ongoing safety and tolerability data.  Members of the 
IDMC will not be allowed to participate as Investigators in this study.  The IDMC will 
review safety data on an ongoing basis to ensure the safe and proper treatment of subjects.  
Regular IDMC meetings will occur approximately every 3 months after the first meeting.  
An IDMC charter will provide full guidance on the function and practices to be followed by 
the IDMC.
Rationale: The IDMC will review safety data on an ongoing basis to ensure the proper treatment 
of subjects and to maintain the blind in pivotal Study 233AS101 (Part C). The reference to the 
SST was removed because it is no longer applicable.
This change also affects Section 7.4, Study Stopping Rules.

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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

The Sponsor signatory was updated.

Details of Biogen Japan were added as a Sponsor.

Section 2, List of Abbreviations, was updated.

Section 5, Introduction, a description of the mechanism of action information for 
BIIB067 from the Investigator’s Brochure was added.

Section 5.3.2, Clinical Experience, a statement that additional information on the 
preliminary efficacy, safety, pharmacokinetics, and pharmacodynamics for BIIB067 
can be found in the Investigator’s Brochure was added.

Section 7.1, Study Overview, Japan was added as an additional country for potential 
sites in order to enable eventual filing for Japan.

Section 7.3, Study Stopping Rules, previously Section 7.4, and text related to AEs 
were modified with unexpected and serious unacceptable risks. 

Section 7.4, End of Study, previously Section 7.5, and the end of study requirements 
were updated for clarity because the study has been extended to 2 years.

Section 8.2, Exclusion Criteria, criteria 1 previously 3, text updated as per 
Study 233AS101. 

Section 8.2, Exclusion Criteria, and Section 11.3.1.2, Disallowed Concomitant 
Therapy, aspirin was removed as an excluded concomitant medication.

Section 10.1, Discontinuation of Study Treatment, text was updated about the 
subjects who discontinue study treatment and who terminate from the study early. 

Section 11.2, Modification of Dose and/or Treatment Schedule, text was added to 
clarify that dose modification requirements are not allowed because there is only one
dose (Cohort) of 100 mg allowed in this study.

Section 11.3.1.1, Allowed Concomitant Medication, text related to concomitant 
medication (riluzole and edaravone) was updated to permit the subjects to remain on 
a stable dose until the completion of Week 12 Visits or as per Investigator’s 
discretion.

Section 12.1, BIIB067, label description was updated to align with Study 233AS101.

Section 12.2 Placebo Product, a new subsection was added to provide details of the 
placebo used in the study during the Loading Dose Period for subjects who are 
enrolling in this study from Part C of Study 233AS101.

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
Typographical errors and formatting were corrected.

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1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS102
An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect 
on Disease Progression of BIIB067 Administered to Previously Treated Adults with 
Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
Version 3
Date:  12 March 2018
EUDRA CT Number:  2016-003225-41
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2.

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PRIMARY REASON FOR AMENDMENT
The primary reasons for this amendment to Protocol 233AS102 are to extend the treatment 
period by 12 months for all patients in the study, and to add a fourth treatment group of BIIB067 
100 mg.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7.1, Study Overview
Now reads:
In Study 233AS101, the Investigators, study staff (except for a designated 
pharmacist/technician), and study subjects are blinded to the randomized study treatment 
assignments.  To preserve the blinding used in Study 233AS101 until database lock, subjects in 
Study 233AS102 will have a washout period of at least 4 times the t½ (~16 weeks) from the time 
of their last dose of study treatment in Study 233AS101 to their first dose in Study 233AS102.  
Subjects will receive 3 loading doses of BIIB067, approximately 2 weeks apart, during the first 
month 4 weeks and 10 22 maintenance doses, approximately monthlyevery 4 weeks, by IT 
injection.
Rationale:  The purpose of extending the treatment period by 12 months is to allow a longer 
period of treatment exposure for studying the long-term effects of exposure to BIIB067.  
This change also affects Sections 4.1, Study Schematic; 4.2, Schedule of Activities; 7.3, Overall 
Study Duration and Follow-Up; and 7.5, End of Study.
Now reads:
Initial Ddose level assignment for each subject thatwho completes Part B of Study 233AS101 
will correspond to their cohort assignment in Study 233AS101, regardless of whether they 
received BIIB067 or placebo.  All subjects randomized to Cohort 5 (BIIB067 20 mg or placebo) 
in Study 233AS101 will receive BIIB067 20 mg; subjects who were randomized to Cohort 6 
(BIIB067 40 mg or placebo) will receive BIIB067 40 mg, and those randomized to Cohort 7 
(BIIB067 60 mg or placebo) will receive BIIB067 60 mg, and those randomized to Cohort 8 
(BIIB067 100 mg or placebo) will receive BIIB067 100 mg.  If the highest dose (60 100 mg) is 
dropped based on results from the multiple ascending dose (MAD) portion (Part B) of 
Study 233AS101, subjects in Cohort 7 8 will be placed in the 40 60 mg cohort (Cohort 6)in this 
extension study.
Rationale: Achieving maximum efficacy in the treatment of superoxide dismutase 1 (SOD1) 
amyotrophic lateral sclerosis (ALS) is likely dependent on reducing the levels of the toxic, 
mutant version of SOD1 throughout the central nervous system (CNS), including the brain 

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(motor cortex) and spinal cord. Emerging preliminary pharmacokinetic data from 
Study 233AS101 indicate that the exposure to BIIB067 was less than that predicted preclinically. 
The purpose of adding a higher-dose cohort (100 mg) to Study 233AS101, and subsequently to 
extension Study 233AS102, was to enable a higher exposure to BIIB067, which would more 
effectively reduce SOD1 in the CNS, and is supported by the safety margins from the 9-month 
nonhuman primate (NHP) study. The extension study aims at studying the long-term effects of 
exposure to BIIB067 100 mg.
This change also affects Sections 7.3.1, Screening; 11.1, Regimen; and 16.6, Sample Size 
Considerations.

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 3, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 4.2, Table 1:  Schedule of Activities
Change:  Visit dates for Maintenance Dose Visits and Follow-Up Visits are now presented as 
days as well as months.  In addition, the second and third loading dose visits were changed to 
take place on Days 15 and 29, and the anti-BIIB067 antibody sampling was removed from the 
Screening Visit.
Now reads:
Screening 
Visit 1
Baseline/1st
Loading 
Dose Visit
2nd
Loading 
Dose Visit
3rd Loading 
Dose Visit
Maintenance 
Dose Visits
Follow-
Up 
Visits
Final/
Early 
Termination 
Visit
Assessments
Day -28
to Day -1
Day 1
Day 1415
(±3 days)
Day 2829
(±3 days)
Days 57, 85, 
113, 141, 169, 
197, 225, 253, 
281, 309, 337, 
365, 393, 421, 
449, 477, 505, 
533, 561, 589, 
617, & 645 
(i.e., Months 
3-1224)
(±3 days)
Days 
673 
& 701 
(i.e.,
Months 
1325 & 
1426)
(±7 
days)
Day 393729
(i.e., Month 
1527)
(±7 days)
Rationale:  These changes permit more precision in scheduling visits.
These changes also affect Sections 4.1, Study Schematic; 7.3.2, Dosing; 7.3.3, Follow-Up; and 
11.3.1, Concomitant Therapy.
Now reads:
Blood Samples for 
Plasma anti-BIIB067 Ab
X
X5
X
X5
X5
X
Rationale:  Removing anti-BIIB067 antibody sampling from the Screening Visit will help 
prevent unnecessary procedures at this visit.
This change also affects Section 4.1, Study Schematic.

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Section 5.2, Current Therapies for Amyotrophic Lateral Sclerosis
Change: Included information on edaravone as a current therapy for ALS.
Now reads:  
The only currently approved treatments for ALS is are Rilutek® (riluzole) (Rilutek®) which is 
marketed globally, and edaravone (Radicava™), which is approved in the United States, 
Japan, and South Korea.  Riluzole which provides a modest increase in survival (2 to 
3 months) without noticeable improvement in strength or disability [Miller 2012].  Edaravone 
lessens functional decline as measured by the Amyotrophic Lateral Sclerosis Functional 
Rating Scale - Revised (ALSFRS-R).  The effect of edaravone on survival is unknown
[Writing Group and Edaravone (MCI-186) ALS 19 Study Group 2017].  No specific 
treatments for SOD1-ALS are available.
Rationale: This change was made because edaravone was recently approved as a treatment for 
ALS.
Section 5.3.1.1, Toxicology
Change:  Added description of a 9-month nonclinical toxicology study in cynomolgus monkeys 
(NHPs).
Now reads:  
From the 9-month cynomolgus monkey toxicology study, the NOAEL for repeated, 
IT-administered BIIB067 was 12 mg.  This was based on adverse clinical observations for 
1 female administered 35 mg.  This female exhibited neurological signs after the second 
dose, characterized by transient muscle cramping (seen immediately after dosing on 
multiple days), prolonged recovery from anesthesia, and intermittent tremors (during the 
last months of the dosing phase).  Treatment with diazepam was required on several dosing
occasions.  An electroencephalogram (EEG) on this animal revealed altered postdose 
signals (with effects on high frequency bands) but confirmed that muscle cramping during 
EEG recording was not a seizure and could have been related to arousal.  This finding was 
considered test-article related; however, there were no correlates in clinical and anatomic 
pathology.
Rationale:  A long-term nonclinical toxicology study was recently completed to support clinical 
development of BIIB067, and the data generated in NHPs were used to update the dosing
rationale in the first-in-human study of BIIB067.
This change also affects Section 5.3.1, Nonclinical Experience.

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Section 5.5, Rationale for Dosing Regimen
Change:  The dosing rationale was updated to include the 100-mg dose of BIIB067.
Now reads:  
The BIIB067 dosing regimens for Study 233AS101 were selected based on target tissue 
concentrations from SOD1 transgenic mouse models, and nonclinical toxicology and PK 
observations in repeated dose, IT administration in 13-week and 9-month nonhuman primate 
(NHP) studies. 
Based on pharmacology and PK results in SOD1 transgenic mice, the estimated tissue 
concentrations of BIIB067 needed to produce a 50%, and the upper 95% confidence 
interval (CI) of an 80%, SOD1 mRNA reduction within the human spinal cord are 0.9 µg/g 
and 4.7 µg/g, respectively.  Evaluations of cortex from the same experiment indicate that 
the estimated tissue concentration of BIIB067 needed to produce a 50% cortical SOD1 
mRNA reduction is 8 µg/g.
The lowest dose selected for Study 233AS101 (10 mg) was predicted to achieve greater than 
0.9 µg/g tissue concentration in the spinal cord. The initial highest proposed dose (60 mg, 
multiple dose) was predicted to achieve greater than 4.7 µg/g steady-state tissue 
concentration in the spinal cord, and approximately 1.5 µg/g steady-state tissue 
concentration in the cortex, which is expected to yield approximately 15% to 20% SOD1 
mRNA reduction in that tissue.  The addition of a 100 mg cohort is predicted to achieve 
steady-state exposures in the cortex of approximately 2.5 µg/g, which is predicted to be 
sufficient for a meaningful CSF SOD1 reduction of 25% to 30%.  This reduction is 
expected to be clinically meaningful, based on the expectation that the reduction of SOD1 
in tissues (spinal cord and cortex) would be greater than the 20% to 30% reduction 
observed in CSF.  This prediction is based on observations in NHP studies, where 
approximately 50% reduction in CSF corresponded to approximately 50% or greater 
reduction in the spinal cord and cortex.  In rodent efficacy experiments, doses of BIIB067 
that reduced tissue SOD1 by approximately 30% or more were found to improve measures 
of electrophysiology, function, and neurofilament.The FIH dose was calculated using the 50% 
of maximum observed biologic effect value for SOD1 mRNA reduction following 
intracerebroventricular administration of BIIB067 in the SOD1 G93A mouse.  The monkey 
whole body physiologically based PK model was scaled to humans using a 10× scaling factor, 
based both on the human:NHP ratio of CSF fluid volumes and on the ratio of the CSF turnover 
rate.   
The highest BIIB067 dose (60 mg) is predicted to achieve greater than the upper 95% confidence 
interval (CI) of an 80% SOD1 mRNA reduction within the human spinal cord.  

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Based on nonclinical PK and pharmacology data, and taking into consideration subject 
safety, the inconvenience of repeated IT injections, and the rapid, fatal nature of ALS, the 
following dose intervals were selected for this extension study:  3 loading doses, once every 
2 weeks, and 22 maintenance doses, administered approximately every 4 weeks from 
Months 3 to 24.  These intervals were selected based on the estimated t½ of BIIB067 
(~1 month) in the target CNS tissues (spinal cord and brain cortex), to achieve and 
maintain the target tissue concentration of BIIB067 at a steady-state level and within the 
estimated pharmacologically active range, and allow collection of PK and 
pharmacodynamic (PD) data during dose interruption and resumption, providing 
information on the dynamic behavior of the system.  
From the 9-month NHP toxicology study, the NOAEL for repeated, intrathecally 
administered BIIB067 was 12 mg.  This NOAEL was converted to a human equivalent dose 
(HED) based on the NHP to human CSF volume scaling (approximately 10-fold difference). 
CSF volume scaling conservatively estimates the needed scaling factor and has predicted 
HED with reasonable accuracy.  The HED for the 9-month, intrathecal NHP toxicology 
study was calculated to be 120 mg.  This provides a 6-fold safety margin for the BIIB067 
starting dose (20 mg) of the extension study, and a 2-fold safety margin for the 60 mg dose. 
The safety margin for a 100 mg clinical dose (highest planned dose) would be 1.2-fold.  
Preliminary PK data (plasma area under the concentration time curve [AUC] from time 0 
to 24 hours) from the 20 mg MAD cohort in Study 233AS101, indicate that the safety 
margin based on exposure is 2.2-fold relative to a 100 mg clinical dose.  The 1.2-fold safety 
margin based on CSF volume scaling from the NHP toxicology study was chosen over the 
2.2-fold safety margin calculated from the plasma steady-state exposures, since the former 
provides a more conservative estimate.
Therefore, all BIIB067 doses planned for Studies 33AS101 and 233AS102 are predicted to 
be pharmacologically active, while maintaining sufficient safety margins calculated from 
the 9-month IT NHP toxicology study.
Rationale:  This change was made based on BIIB067 exposure predictions related both to the 
addition of the 100-mg dose and to updated information from the 9-month NHP toxicology 
study. The human equivalent dose and the safety margin relative to the new highest planned dose 
of 100 mg were also included.
Section 6.1, Primary Objectives and Endpoints
Change:  Deleted laboratory assessments, vital signs, and physical examinations from the 
primary endpoint.
Now reads:  

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The associated primary endpoints are the incidence of AEs and serious adverse events (SAEs), 
and incidence of abnormalities in clinical laboratory assessments, vital signs, physical and 
neurological examinations, and electrocardiograms (ECGs).
Rationale:  Any clinically significant abnormal values collected for the deleted assessments will 
be captured as AEs for reporting purposes, making the inclusion of these assessments as 
endpoints unnecessary. 
Section 7.1, Study Overview
Change:  The number of sites participating in this study was decreased to 16.
Now reads:  
This is a multicenter, open-label, uncontrolled, extension study to assess the long-term safety, 
tolerability, PK, and effect on disease progression of BIIB067 administered by IT injection to 
previously treated subjects with SOD1-ALS who have completed Part A and/or Part B of Study 
233AS101.  The study will be conducted at approximately 17 16 sites in the United States, 
Canada, and Western Europe.  
Rationale:  Italy was removed as one of the participating sites in this study. 
Section 7.2.1, Cohort Enrollment
Change: Changes were made describing the process for subjects switching to a higher-dose
cohort.
Now reads:  
In addition, sSubjects who have completed only Part A of Study 233AS101 may be screened for 
the cohort currently open for enrollment in the extension studyalso be eligible to participate 
in Study 233AS102.  Part A only participants may be screened for inclusion in the currently 
enrolling cohort of Study 233AS102 after at least 3 subjects in the corresponding dose level 
cohort in Part B of Study 233AS101 have received a cumulative dose of BIIB067 greater than or 
equal to the sum of the dose which the subject being screened received in Part A of Study 
233AS101 and the first dose that this subject will receive in Study 233AS102.  (For example, a 
subject who received a 20 mg dose of BIIB067 in Part A of Study 233AS101 may be eligible to 
enroll into the 40 mg dose cohort of Study 233AS102 after at least 3 subjects in the 40 mg dose 
cohort in Part B of Study 233AS101 have received a cumulative dose of at least 60 mg of 
BIIB067.)  Prior to enrollment of the first Part A subject in any 233AS102 cohort, the SABR 
Physician must review the Study 233AS101 Part B exposure up to that time to ensure this 
criterion has been met.  

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Subjects who complete Study 233AS101 (BIIB067 20-60 mg or placebo), may, at the 
discretion of the Investigator, be switched to a higher dose cohort currently open for 
enrollment in Study 233AS102.  The opening of a higher dose cohort for enrollment in 
Study 233AS102 will be determined at the planned SST review of emerging safety and 
tolerability data of the same dose cohort for at least 10 subjects through Day 106 in 
Study 233AS101. Thus, a favorable SST safety review of BIIB067 60 mg in 
Study 233AS101 will allow the opening of the 60-mg cohort for those study participants 
wishing to enroll at this dose in the extension study. Dose switching for a subject may 
continue up to the highest dose (100 mg), but prior to switching at every level, the planned 
Day 106 SST review in Study 233AS101 must support dose escalation in the extension 
study. Furthermore, should a PI wish to escalate the dose level, they must consult with the 
Sponsor to ensure that current emerging safety and tolerability data support continued 
exposure for the subject.
Rationale:  Enabling subjects to switch to a higher dose would allow them to attain higher 
exposure levels of BIIB067 within acceptable safety and tolerability limits, and possibly more 
effective treatment. It would also provide long-term PK and PD data on the exposure-response 
relationship and the dynamic effects of this system.
This change also affects Sections 16.1.1, Analysis Population; 16.1.2, Methods of Analysis
(Clinical Function); and 16.3.2, Methods of Analysis (Pharmacodynamics).
Section 8.1, Inclusion Criteria
Change:  An eligibility criterion was added specifying the 16-week washout prior to the 
subject’s first dose in this study. In addition, an eligibility criterion was updated to permit the use 
of edaravone provided it is not administered on dosing days.
Now reads:  
7.
Must have a washout ≥16 weeks between the last dose of study treatment received in 
Study 233AS101 and the first dose of BIIB067 received in the current Study 233AS102.
Rationale:  This change was made for clarity. Although the current washout period prior to the 
first dose of BIIB067 in Study 233AS102 was already 16 weeks, it was not explicitly stated as an 
inclusion criterion.  The washout period is now noted as an inclusion criterion for the study.
Now reads:  
6.8.
Subjects taking concomitant edaravone at study entry must be on a stable dose for 
≥30 days prior to the first dose of study treatment (Day 1) and must continue with the 
same dose regimen throughout the study, unless the Investigator determines that edaravone
should be discontinued for medical reasons, in which case it may not be restarted during 
the study.  Edaravone may not be administered on dosing days during this study.

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Rationale:  Edaravone was recently approved as a treatment for ALS in the United States, Japan, 
and South Korea, and was added as a permitted medication during this trial.
This change also affects Sections 11.3.1.1, Allowed Concomitant Therapy; and 16.1.2, Methods 
of Analysis (Clinical Function).
Section 8.2, Exclusion Criteria
Change:  Updates were made to the exclusion criteria for hepatitis C- and B.  In addition, 
presence of implanted venous devices was added as an exclusion criterion.
Now reads:  
2.
History of, or positive test result at Screening for hepatitis C virus antibody or hepatitis 
B virus (defined as positive for both hepatitis B surface antigen and hepatitis B core antibody).
2.3.
Current hepatitis B infection (defined as positive for hepatitis B surface antigen 
[HBsAg] and/or hepatitis B core antibody [HBcAb]).  Subjects with immunity to hepatitis B
from previous natural infection (defined as negative HBsAg, positive hepatitis B surface 
antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-
HBs) are eligible to participate in the study.
Rationale:  This update is to clarify the timing for the hepatitis C antibody test and to provide a 
more detailed definition for hepatitis B exclusion criteria.
Now reads:  
8.10.
Presence of an implanted intravenous port/catheter.
Rationale: This change was made to avoid risks associated with implanted venous devices, 
including infection.
Section 14.1, Clinical Safety Assessments
Change: The types of neurological examinations to be conducted at study sites were added.
Now reads:
•
Limited Nneurological examinations, (to be assessed by a trained specialist) of cranial 
nerves, coordination/cerebellar function, reflexes, motor, and including the Mini-
mentalMental State Examination (MMSE; a 30-point questionnaire that is used to measure 
cognitive impairment (to be assessed by a trained specialist)

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Rationale:  This change will eliminate confusion and enable consistency in the type of 
neurological examinations performed across study sites.
This change also affects Sections 4.2, Schedule of Activities; and 16.4.2.6, Limited Neurological 
Examinations.
Section 14.2, Laboratory Safety Assessments
Change: Coagulation assessments were separated from other hematology assessments.
Now reads:
•
Hematology:  Complete blood count withdifferential and platelet count, and absolute 
neutrophil count.  Platelet count, INR, PT, and APTT will also be measured for all subjects at 
Screening and at all dosing and follow-up visits.
•
Coagulation: INR, PT, and APTT (all of which will also be measured for all subjects 
at Screening and at all dosing and follow-up visits)
Rationale:  This change was made for clarity, since coagulation is not part of the standard 
hematology assessments.
This change also affects Sections 4.2, Schedule of Activities; and 16.4.2.2, Clinical Laboratory 
Results.
Section 17.3, Subject Information and Consent
Change: Text was added stating that subjects will be informed about the collection of race and 
ethnicity data.
Now reads:  
Subjects will be informed that their race and ethnicity will not be collected for the purposes of 
data analysis during the extension study.  However, this information was collected in Study 
233AS101, where applicable and after subject consent, unless the collection was not 
permitted by applicable law or not approved by the governing ethics committee, and the 
data will be used during analysis of the results of that study.  In addition, subjects who have 
the capacity should provide their assent to participate in the study.  The level of information 
provided to subjects should match their level of understanding as determined by the Investigator 
and in accordance with applicable regulations and guidelines.

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Rationale:  This update was made to clarify informed consent and the use of race and ethnicity 
data for subjects participating in Studies 233AS101 and 233AS102.

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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

On the title page, the Sponsor address in the United States was updated.

The signatory’s title was updated.

The List of Abbreviations was updated.

In Section 4.1, Figure 1, Study Schematic was replaced to correct minor errors.

In Section 13.2, Pharmacokinetic Assessments the use of abbreviations was corrected 
to include the abbreviation definition.

The 
 assessment was updated to 
 to clarify the version to be used.

The term “monthly” was changed to “every 4 weeks” throughout. 

The term “study drug” was changed to “study treatment” per Biogen style.

A new reference was added to the Reference list.

Formatting and typographical errors were corrected.

CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
250 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS102
An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect 
on Disease Progression of BIIB067 Administered to Previously Treated Adults with 
Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
Version 2
Date:  21 April 2017
EUDRA CT Number:  2016-003225-41
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1.

Protocol 233AS102, Version 2
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Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reasons for this amendment to Protocol 233AS102 are 1) to eliminate the 
requirement to review data from Day 106 through Day 169 of Study 233AS101 before dosing 
the first and second subject enrolling in each cohort of Study 233AS102, and 2) to clarify criteria 
for enrolling subjects who complete only Part A of Study 233AS101.  
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7.2.1, Dose Escalation/Opening of Extension Cohorts
Now reads:
7.2.1
Dose Escalation/Opening of Extension Cohorts Cohort Enrollment
Dose levels will be enrolled sequentially, in an ascending manner, as corresponding dose level
cohorts complete Part B of Study 233AS101 and become eligible for screening into the extension 
study.  
Prior to beginning For each cohort’s dosing in the extension sStudy 233AS102, before dosing 
subjects who enroll after completing Part B of Study 233AS101, the Safety Surveillance 
Team (SST) will review safety data collected through Day 106 for the corresponding dose level 
cohort for all subjects contributing to the dose escalation safety data through Day 106 of in 
Study 233AS101, as well as the additional safety data for the first subject reaching the Day 169 
time point.  Before the start of the higher dose cohorts, the SST will also review available 
safety data from the previous cohorts in Study 233AS102.  The SST will consist of the 
Biogen Medical Director, Safety and Benefit-Risk Management (SABR) Physician, 
Biostatistician, Clinical Pharmacologist, and, if required, any ad hoc members.  If after reviewing 
the safety data for the first subject Before dosing the first subject enrolling after completing 
Part B of Study 233AS101 in the each cohort of the extension study, the SST must agrees that 
the current emerging safety and tolerability data support opening the cohort, then the subject can 
continue into the extension study continued exposure for these subjects.   
In addition, at this time, subjects who have completed only Part A of Study 233AS101 may also 
be screened for inclusion eligible to participate in Study 233AS102.  In Study 233AS101, each 
cohort will be randomized in blocks of 4 (3 active, 1 placebo).  Therefore, the SST will also 
review any additional safety data for the second subject to complete Study 233AS101 during 
study Days 106 to 169, before allowing the remainder of the cohort to continue into Study 
233AS102.  This timeframe will allow for safety assessment in the event that the first subject 
received placebo.  If the first and second subjects reach Day 169 within 2 weeks of one another, 
the SST may have one meeting to review the data for both subjects.  Before the start of the 
higher dose extension cohorts, the SST will also review available safety data from the previous 
cohorts in Study 233AS102.  Part A-only participants may be screened for inclusion in the 
currently enrolling cohort of Study 233AS102 after at least 3 subjects in the corresponding 
dose level cohort in Part B of Study 233AS101 have received a cumulative dose of BIIB067 
greater than or equal to the sum of the dose which the subject being screened received in 
Part A of Study 233AS101 and the first dose that this subject will receive in 

Protocol 233AS102, Version 2
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
Study 233AS102.  (For example, a subject who received a 20-mg dose of BIIB067 in Part A 
of Study 233AS101 may be eligible to enroll into the 40-mg dose cohort of Study 233AS102 
after at least 3 subjects in the 40-mg dose cohort in Part B of Study 233AS101 have 
received a cumulative dose of at least 60 mg of BIIB067.)  Prior to enrollment of the first 
Part A subject in any 233AS102 cohort, the SABR Physician must review the 
Study 233AS101 Part B exposure up to that time to ensure this criterion has been met.  
Rationale:  Emerging safety and tolerability data from the ongoing Study 233AS101 have been 
favorable, making the lengthy follow-up for the first subjects enrolling in each cohort of the 
extension study unnecessary.  This change will decrease the wait time between the last dose in 
Study 233AS101 and the first dose in extension Study 233AS102 for affected subjects.
Edits to the text describing criteria for enrolling subjects who complete only Part A of 
Study 233AS101 were made for clarity, in response to feedback from study sites.  

Protocol 233AS102, Version 2
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Section 9.1, Screening and Enrollment
Change:  A condition under which subjects may be rescreened was added.
Now reads:  
Subjects (or their legally authorized representative [e.g., spouse], where applicable) must provide 
informed consent before any screening tests are performed (see Section 17.3).  When a subject 
signs the informed consent form (ICF), that subject is considered to be enrolled in the study.  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in this study.  If a subject is excluded from the study, the reasons for exclusion will be 
documented in the subject’s source documents and on the screening log.
Eligible subjects who are not able to complete the Day 1 Visit within 28 days of starting 
their screening assessments may be rescreened.
Rationale:  This change will allow eligible subjects who could not, for logistical reasons, 
complete the Day 1 Visit in time an opportunity to rescreen.

Protocol 233AS102, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
5
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

The Sponsor Signature information was updated.

Minor grammatical errors were corrected.