A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects With Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Biogen



Protocol 233AS101
Version 8
Phase 1/2/3 Study of BIIB067 in Adults with ALS
CONFIDENTIAL
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Biogen MA Inc.
3
TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................3
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
1.
SPONSOR INFORMATION .....................................................................................11
2.
LIST OF ABBREVIATIONS.....................................................................................12
3.
SYNOPSIS .................................................................................................................15
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 233AS101.....................................................................................................22
4.1.
Study Schematic .........................................................................................................23
4.2.
Schedule of Activities.................................................................................................26
5.
INTRODUCTION......................................................................................................39
5.1.
Overview of Amyotrophic Lateral Sclerosis..............................................................39
5.2.
Current Therapies for Amyotrophic Lateral Sclerosis................................................39
5.3.
Profile of Previous Experience with BIIB067............................................................39
5.3.1.
Nonclinical Experience...............................................................................................39
5.3.1.1.
Toxicology..................................................................................................................40
5.3.1.2.
Pharmacokinetics........................................................................................................40
5.3.2.
Clinical Experience.....................................................................................................41
5.4.
Study Rationale...........................................................................................................41
5.5.
Rationale for Dosing Regimen ...................................................................................42
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................44
6.1.
Parts A (SAD) and B (MAD) .....................................................................................44
6.1.1.
Primary Objective.......................................................................................................44
6.1.1.1.
Primary Endpoints ......................................................................................................44
6.1.2.
Secondary Objective...................................................................................................44
6.1.2.1.
Secondary Endpoint....................................................................................................44
6.1.3.
Exploratory Objectives and Endpoints.......................................................................44
6.2.
Part C (Pivotal) ...........................................................................................................45
6.2.1.
Primary Objective.......................................................................................................45
6.2.1.1.
Primary Efficacy Endpoint .........................................................................................45
6.2.1.2.
Secondary Efficacy Endpoints....................................................................................45

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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45
6.2.2.
Secondary Objective...................................................................................................45
6.2.2.1.
Safety/Tolerability Endpoint ......................................................................................45
6.2.2.2.
Pharmacodynamic Endpoint.......................................................................................45
6.2.2.3.
Biomarker Endpoint....................................................................................................46
46
6.2.3.1.
Pharmacokinetic Endpoints ........................................................................................46
46
46
7.
STUDY DESIGN .......................................................................................................47
7.1.
Study Overview ..........................................................................................................47
7.1.1.
Part A: SAD Evaluation..............................................................................................47
7.1.2.
Part B: MAD Evaluation ............................................................................................48
7.1.2.1.
Parts A and B..............................................................................................................48
7.1.3.
Part C: Pivotal.............................................................................................................48
7.2.
Study Specifics ...........................................................................................................49
7.2.1.
Dose Escalation ..........................................................................................................49
7.2.1.1.
Part A: Single Ascending Dose ..................................................................................49
7.2.1.2.
Part B: Multiple Ascending Dose...............................................................................50
7.2.2.
Within Cohort Staggered Dosing................................................................................52
7.2.2.1.
Part A: Single Ascending Dose ..................................................................................52
7.2.2.2.
Part B: Multiple Ascending Dose...............................................................................52
7.2.2.3.
Part C ..........................................................................................................................53
7.2.3.
Dose-Limiting Toxicity ..............................................................................................53
7.3.
Overall Study Duration and Follow-Up .....................................................................53
7.3.1.
Screening ....................................................................................................................53
7.3.1.1.
Part A: Single Ascending Dose ..................................................................................53
7.3.1.2.
Part B: Multiple Ascending Dose...............................................................................53
7.3.1.3.
Part C ..........................................................................................................................54
7.3.2.
Dosing.........................................................................................................................54
7.3.2.1.
Part A: Single Ascending Dose ..................................................................................54
7.3.2.2.
Part B: Multiple Ascending Dose...............................................................................54

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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7.3.2.3.
Part C: Pivotal.............................................................................................................54
7.3.3.
Follow-Up Procedures................................................................................................54
7.3.3.1.
Part A: Single Ascending Dose ..................................................................................54
7.3.3.2.
Part B: Multiple Ascending Dose...............................................................................54
7.3.3.3.
Part C: Pivotal.............................................................................................................55
7.4.
Study Stopping Rules .................................................................................................55
7.4.1.
Dose Suspension (Parts A and B only).......................................................................55
7.4.2.
Dose Termination .......................................................................................................56
7.4.2.1.
Parts A and B..............................................................................................................56
7.4.2.2.
Part C ..........................................................................................................................56
7.5.
End of Study ...............................................................................................................56
8.
SELECTION OF PARTICIPANTS ...........................................................................57
8.1.
Parts A (SAD) and B (MAD) .....................................................................................57
8.1.1.
Inclusion Criteria ........................................................................................................57
8.1.2.
Exclusion Criteria.......................................................................................................58
8.2.
Part C (Pivotal) ...........................................................................................................59
8.2.1.
Inclusion Criteria ........................................................................................................59
8.2.2.
Exclusion Criteria.......................................................................................................60
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................63
9.1.
Screening and Enrollment...........................................................................................63
9.2.
Randomization and Registration of Participants ........................................................63
9.3.
Blinding Procedures....................................................................................................64
10.
DISCONTINUATION OF STUDY TREATMENT OR WITHDRAWAL 
OF PARTICIPANTS FROM THE STUDY...............................................................65
10.1.
Withdrawal from the Study (Part A) or Discontinuation of Study Treatment 
(Parts B and C)............................................................................................................65
11.
STUDY TREATMENT USE .....................................................................................66
11.1.
Regimen......................................................................................................................66
11.1.1.
BIIB067 ......................................................................................................................66
11.1.2.
Placebo........................................................................................................................66
11.2.
Modification of Dose and/or Treatment Schedule......................................................66
11.3.
Concomitant Therapy and Procedures........................................................................67
11.3.1.
Concomitant Therapy .................................................................................................67

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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11.3.1.1.
Allowed Concomitant Therapy...................................................................................67
11.3.1.2.
Disallowed Concomitant Therapy..............................................................................67
11.3.2.
Concomitant Procedures.............................................................................................68
12.
STUDY TREATMENT MANAGEMENT................................................................69
12.1.
BIIB067 ......................................................................................................................69
12.1.1.
BIIB067 Preparation...................................................................................................69
12.1.2.
BIIB067 Storage.........................................................................................................69
12.1.3.
BIIB067 Handling and Disposal.................................................................................70
12.1.4.
BIIB067 Accountability..............................................................................................70
12.2.
Placebo Product ..........................................................................................................70
13.
CLINICAL FUNCTION, PHARMACOKINETIC, AND 
PHARMACODYNAMIC ASSESSMENTS..............................................................71
13.1.
Assessments of the Effect of BIIB067 on Clinical Function......................................71
13.1.1.
ALS Functional Rating Scale-Revised.......................................................................71
13.1.2.
Slow Vital Capacity....................................................................................................71
13.1.3.
Participant Diary/eDiary (Part C only).......................................................................71
71
72
13.1.6.
Handheld Dynamometry.............................................................................................72
72
72
72
73
73
73
73
13.2.
Pharmacokinetic Assessments....................................................................................74
13.3.
Pharmacodynamic Assessments.................................................................................74
74
75
14.
SAFETY ASSESSMENTS ........................................................................................76
14.1.
Clinical Safety Assessments.......................................................................................76

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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14.2.
Laboratory Safety Assessments..................................................................................76
77
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................78
15.1.
Definitions ..................................................................................................................78
15.1.1.
Adverse Event.............................................................................................................78
15.1.2.
Serious Adverse Event................................................................................................78
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................79
15.2.
Safety Classifications..................................................................................................79
15.2.1.
Investigator Assessment of Events.............................................................................79
15.2.2.
Relationship of Events to Study Treatment................................................................80
15.2.3.
Severity of Events.......................................................................................................80
15.2.4.
Expectedness of Events ..............................................................................................81
15.3.
Monitoring and Recording Events..............................................................................81
15.3.1.
Adverse Events...........................................................................................................81
15.3.2.
Serious Adverse Events..............................................................................................81
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................81
15.3.3.1.
Deaths .........................................................................................................................82
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................82
15.4.
Procedures for Handling Special Situations ...............................................................82
15.4.1.
Pregnancy ...................................................................................................................82
15.4.2.
Overdose.....................................................................................................................83
15.4.3.
Medical Emergency....................................................................................................83
15.4.3.1.
Unblinding for Medical Emergency...........................................................................83
15.5.
Contraception Requirements ......................................................................................83
15.6.
Safety Responsibilities................................................................................................84
15.6.1.
The Investigator..........................................................................................................84
15.6.2.
Biogen.........................................................................................................................85
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........86
16.1.
Part A (SAD) and Part B (MAD) ...............................................................................86
16.1.1.
Clinical Function ........................................................................................................86
16.1.1.1.
Analysis Population....................................................................................................86

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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16.1.1.2.
Methods of Analysis...................................................................................................86
16.1.2.
Pharmacokinetics........................................................................................................86
16.1.2.1.
Analysis Population....................................................................................................86
16.1.2.2.
Methods of Analysis...................................................................................................86
16.1.3.
Pharmacodynamics.....................................................................................................86
16.1.3.1.
Analysis Population....................................................................................................86
16.1.3.2.
Methods of Analysis...................................................................................................87
16.1.4.
Biomarker and Pharmacogenomic Analyses..............................................................87
16.1.4.1.
Analysis Population....................................................................................................87
16.1.4.2.
Methods of Analysis...................................................................................................87
16.1.5.
Safety..........................................................................................................................87
16.1.5.1.
Analysis Population....................................................................................................87
16.1.5.2.
Methods of Analysis...................................................................................................87
88
88
88
88
16.1.8.
Sample Size Considerations .......................................................................................89
16.2.
Part C ..........................................................................................................................89
16.2.1.
Clinical Function ........................................................................................................89
16.2.1.1.
Analysis Population....................................................................................................89
16.2.1.2.
Methods of Analysis...................................................................................................89
16.2.2.
Pharmacokinetics........................................................................................................93
16.2.2.1.
Analysis Population....................................................................................................93
16.2.2.2.
Methods of Analysis...................................................................................................93
16.2.3.
Pharmacodynamics.....................................................................................................93
16.2.3.1.
Analysis Population....................................................................................................93
16.2.3.2.
Methods of Analysis...................................................................................................93
16.2.4.
Safety..........................................................................................................................94
16.2.4.1.
Analysis Population....................................................................................................94
16.2.4.2.
Methods of Analysis...................................................................................................94
95

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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95
95
95
95
17.
ETHICAL REQUIREMENTS ...................................................................................97
17.1.
Declaration of Helsinki...............................................................................................97
17.2.
Ethics Committee........................................................................................................97
17.3.
Participant Information and Consent..........................................................................97
17.4.
Participant Data Protection.........................................................................................98
17.5.
Compensation for Injury.............................................................................................98
17.6.
Conflict of Interest......................................................................................................98
17.7.
Registration of Study and Disclosure of Study Results..............................................98
18.
ADMINISTRATIVE PROCEDURES.......................................................................99
18.1.
Study Site Initiation....................................................................................................99
18.2.
Quality Assurance.......................................................................................................99
18.3.
Monitoring of the Study..............................................................................................99
18.4.
Study Funding.............................................................................................................99
18.5.
Publications.................................................................................................................99
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION......................100
19.1.
Public Health Emergencies.......................................................................................100
19.2.
External Contract Organizations...............................................................................101
19.2.1.
Contract Research Organization...............................................................................101
19.2.2.
Interactive Response Technology.............................................................................101
19.2.3.
Electronic Data Capture............................................................................................101
19.2.4.
Laboratory Assessments...........................................................................................101
19.3.
Study Committees.....................................................................................................102
19.3.1.
Safety Surveillance Team.........................................................................................102
19.3.2.
Independent Data Monitoring Committee................................................................102
19.3.3.
Endpoint Adjudication Committee...........................................................................102
19.4.
Changes to Final Study Protocol ..............................................................................102
19.5.
Ethics Committee Notification of Study Completion or Termination......................102
19.6.
Retention of Study Data............................................................................................102

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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19.7.
Study Report Signatory.............................................................................................103
20.
REFERENCES .........................................................................................................104
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.......................................106
APPENDIX A.
CONTINUOUS REASSESSMENT METHOD .............................................107
LIST OF TABLES
Table 1:
Schedule of Activities: Part A – Single Ascending Dose...........................................26
Table 2:
Schedule of Activities: Part B – Multiple Ascending Dose .......................................29
Table 3:
Schedule of Activities: Part C (Pivotal)......................................................................33
LIST OF FIGURES
Figure 1:
Study Design: Part A – Single Ascending Dose.........................................................23
Figure 2:
Study Design: Part B – Multiple Ascending Dose .....................................................24
Figure 3:
Study Design: Part C (Pivotal) ...................................................................................25
Figure 4:
Dose Escalation Schematic (Parts A and B)...............................................................51

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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1.
SPONSOR INFORMATION
Biogen MA Inc. is the Sponsor of the study. 
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.

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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2.
LIST OF ABBREVIATIONS
Ab
antibody
AE
adverse event
ALS
amyotrophic lateral sclerosis
ALSFRS-R
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised
ANCOVA
analysis of covariance
anti-HBc
total hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
APTT
activated partial thromboplastin time
ASO
antisense oligonucleotide
AUC
area under the concentration-time curve
CNS
central nervous system
CRF
case report form
CRM
continuous reassessment method
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
DHA
Directions for Handling and Administration
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DPS
diaphragm pacing system
EAC
event adjudication committee
ECG
electrocardiogram
EEG
electroencephalogram
EOS
end of study
FIH
first-in-human
FSH
follicle-stimulating hormone
FU
follow-up
FVC
forced vital capacity
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HED
human equivalent dose
HHD
handheld dynamometry

Protocol 233AS101
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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IgM anti-HBc
immunoglobulin antibody to hepatitis B core antigen
INR
international normalized ratio
IRT
interactive response technology
ITT
intent-to-treat
JRT
joint rank test
LP
lumbar puncture
LTE
long-term extension
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
mITT
modified intent-to-treat
MMSE
Mini-Mental State Examination
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
NfL
neurofilament light chain
NHP
nonhuman primate
NOAEL
no observed adverse effect level
PD
pharmacodynamic(s)
PHI
protected health information
PI
principal investigator
PK
pharmacokinetic(s)
pNfH
phosphorylated axonal neurofilament heavy chain
PT
prothrombin time
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SD
standard deviation
SOD1
superoxide dismutase 1
SUSAR
suspected unexpected serious adverse reaction
SVC
slow vital capacity
t½
elimination half-life
TEAE
treatment-emergent adverse event
V
visit

Protocol 233AS101
Version 8
Phase 1/2/3 Study of BIIB067 in Adults with ALS
CONFIDENTIAL
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Protocol 233AS101
Version 8
Phase 1/2/3 Study of BIIB067 in Adults with ALS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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3.
SYNOPSIS
Protocol Number:
233AS101
Protocol Title:
A Study to Evaluate the Efficacy, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of BIIB067 
Administered to Adult Subjects with Amyotrophic Lateral 
Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Version Number
8
Name of Study Treatment:
BIIB067
Study Indication:
Amyotrophic lateral sclerosis and confirmed superoxide 
dismutase 1 mutation
Study Rationale
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 (SOD1-ALS). Since SOD1-ALS was 
first described in 1993, over 180 SOD1 mutations have been 
reported to cause this form of ALS. Although the 
mechanism by which mutations cause SOD1-ALS is not 
known, data suggest that toxic gain of function, not loss of 
SOD1 activity, is the likely trigger that initiates the cascade 
of events resulting in motor neuron death. 
The only currently approved treatments for ALS are riluzole 
and edaravone. Riluzole provides a modest increase in 
survival (2 to 3 months) without noticeable improvement in 
strength or disability. Edaravone lessens functional decline 
as measured by ALSFRS-R. The effect of edaravone on 
survival is unknown. No specific SOD1-ALS treatments are 
available. Reducing SOD1 mRNA and, subsequently, toxic 
SOD1 protein may offer therapeutic benefit for SOD1-ALS 
participants. Delivery of an ASO targeting SOD1 mRNA is 
a viable method to reduce toxic SOD1 protein.

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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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BIIB067 is an investigational ASO inhibitor of SOD1 
mRNA, under development to reduce levels of SOD1 
protein in patients with SOD1-ALS.
Phase of Development:
1/2/3
Study Objectives and 
Endpoints:
Parts A (SAD) and B (MAD)
The primary objective of Parts A and B of this study is to 
evaluate the safety, tolerability, and PK of BIIB067 in adults 
with ALS and a confirmed SOD1 mutation.
The primary endpoints are as follows:

Incidence of AEs and SAEs

Incidence of abnormalities in clinical laboratory 
assessments, vital signs, physical and 
neurological examinations, and ECGs

PK measures, including plasma and CSF levels 
of BIIB067
The secondary objective is to evaluate the effects of 
BIIB067 on levels of total SOD1 protein in the CSF.

The secondary endpoint is the change from 
baseline in CSF levels of total SOD1 protein.
Exploratory objectives and endpoints are listed in 
Section 6.1.
Part C (Pivotal)
Primary Objective
The primary objective of Part C of this study is to evaluate 
the clinical efficacy of BIIB067 administered to adult 
participants with ALS and a confirmed SOD1 mutation.

Primary Efficacy Endpoint
The primary efficacy endpoint is the change from 
baseline to Week 28 in the ALSFRS-R total score.

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
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Change from baseline to Week 28 in SVC

Changes from baseline to Week 28 in HHD 
megascore to assess muscle strength, as 
measured by the HHD device

Time to death or permanent ventilation 
(≥ 22 hours of mechanical ventilation [invasive 
or noninvasive] per day for ≥ 21 consecutive 
days)

Time to death
Secondary Objective
The secondary objective is to evaluate the safety, 
tolerability, PD, and biomarker effects of BIIB067 
administered to adult participants with ALS and a confirmed 
SOD1 mutation.

Safety/Tolerability Endpoint
The safety/tolerability endpoint is the incidence of 
AEs and SAEs.

Pharmacodynamic Endpoint
The PD endpoint is the change from baseline in total 
SOD1 protein concentration in CSF.

Biomarker Endpoint
The biomarker endpoint is the change from baseline 
in NfL concentration in plasma.
Exploratory objectives and endpoints are listed in 
Section 6.2.
Study Design:
This is a randomized, double-blind, placebo-controlled, 
3-part dose escalation study to examine the efficacy, safety, 
tolerability, PK, and PD of BIIB067, administered by 
intrathecal bolus injection to up to approximately 183 adult 
participants with ALS and a confirmed SOD1 mutation. 
Part A (SAD)
Part A will be a randomized, double-blind, 
placebo-controlled, SAD study of up to 4 dose levels of 
BIIB067 administered to participants with SOD1-ALS. The 
dose levels will be evaluated sequentially. Final sample size 

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Phase 1/2/3 Study of BIIB067 in Adults with ALS
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for Part A will be determined by the incidence of DLT. If no 
DLTs are encountered, a minimum of 20 participants will be 
randomized. The maximum sample size for Part A is 
36 participants. 
Part B (MAD)
Part B will be a randomized, double-blind, 
placebo-controlled, MAD evaluation of up to 4 dose levels 
of BIIB067 administered up to 5 times to approximately 
48 participants with SOD1-ALS. 
Part C (Pivotal)
Part C will be a randomized, double-blind, 
placebo-controlled evaluation of 100 mg of BIIB067 
administered 8 times over approximately 24 weeks to 
approximately 99 participants with SOD1-ALS. Participants 
will be randomized to receive BIIB067 or placebo in a 2:1 
(active:placebo) ratio. The primary analysis population 
(N = ~60) will comprise participants who meet prognostic 
enrichment criteria for rapid disease progression, defined as 
those with a prerandomization ALSFRS-R slope decline of 
at least 0.9/month OR a protocol-defined SOD1 mutation 
and prerandomization ALSFRS-R slope decline of at least 
0.2/month.
Randomization will be stratified by 3 factors: 

whether a participant meets the prognostic 
enrichment criteria for rapid disease progression 

whether a participant uses edaravone at baseline

whether a participant uses riluzole at baseline

Use of both edaravone and riluzole will not 
be a separate stratum but will be classified as 
only edaravone use.
Study Location:
Approximately 42 sites are planned in approximately 
15 countries globally.
Number of Planned 
Participants:
Approximately 183 participants are planned to be dosed: 
36 participants in Part A, 48 participants in Part B, and 
99 participants in Part C.
Study Population:
This study will be conducted in participants who are at least 
18 years of age with SOD1-ALS.
Detailed criteria are described in Section 8.

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Treatment Groups:
Cohorts 1 through 4 (Part A) and Cohorts 5 through 8 
(Part B) will be randomized to receive BIIB067 or placebo 
in a 3:1 (active:placebo) ratio. Cohort 9 (Part C) will be 
randomized to receive BIIB067 or placebo in a 2:1 
(active:placebo) ratio.
Part A (SAD)
Up to 4 cohorts will be enrolled in Part A (SAD). Cohorts 
1 through 3 will enroll at least 4 participants each: 
1 participant will be administered placebo, and 
3 participants will be administered BIIB067 at 10, 20, or 
40 mg. Cohort 4 will enroll approximately 8 participants: 
2 participants will be administered placebo, and 
6 participants will be administered BIIB067 at 60 mg. Up to 
16 additional participants may be enrolled into any of the 
cohorts (up to 4 placebo and up to 12 BIIB067), based on 
the incidence of DLT. If no DLTs are observed in the 
2 lower dose cohorts, then participants within these 2 lower 
dose cohorts may re-enroll, after a washout period of at least 
5 times the t½ [~20 weeks including the 8-week FU period], 
within the 2 higher dose cohorts. These participants will 
repeat the screening assessments prior to re-enrolling and 
will be rerandomized into either the BIIB067 or placebo 
group.
Part B (MAD)
Up to 4 cohorts will be enrolled in Part B (MAD). Each 
cohort will enroll approximately 12 participants: 
3 participants per cohort will be administered placebo, and 
9 participants per cohort will be administered BIIB067 at 
20, 40, 60, or 100 mg. 
Part C (Pivotal) 
A single cohort of approximately 99 participants will be 
enrolled in Part C (Pivotal): approximately 33 participants 
will be administered placebo, and approximately 
66 participants will be administered BIIB067 at 100 mg. 

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Duration of Treatment and 
Follow-Up:
Part A (SAD)
Duration of the study for each participant participating only 
in Part A (SAD) will be up to approximately 15 weeks, 
which will include up to 7-week screening period and an 
8-week FU period. For participants who choose to re-enroll 
in a higher dose cohort, the total duration will be 
approximately 35 weeks, which will include a washout 
period of 3 × t½ (~12 weeks) after the 8-week postdose FU 
visit (total washout of 5 × t½, or ~20 weeks). 
Part B (MAD)
For participants participating in only Part B (MAD), the 
duration will be up to approximately 31 weeks, which will 
include up to 7-week screening period, a 12-week treatment 
period (consisting of 3 loading doses of BIIB067, 
administered approximately once every 2 weeks, followed 
by 2 maintenance doses of BIIB067, administered 
approximately once every 4 weeks), and a 12-week FU 
period.
Part A (SAD) and Part B (MAD)
For participants participating in both Part A (SAD) and 
Part B (MAD), duration will be approximately 51 weeks. 
This will include 15 weeks in Part A, approximately 
12 weeks between the end of Part A and dosing in Part B, 
12 weeks of dosing in Part B, and the 12-week FU period in 
Part B. For participants who enroll in 2 cohorts during 
Part A and participate in Part B, the total duration will be 
approximately 71 weeks. 
Part C (Pivotal)
For participants in Part C (Pivotal), the study duration will 
be approximately 32-36 weeks including a 4-week screening 
period, a 24-week treatment period (3 loading doses 2 weeks 
apart followed by 5 maintenance doses 4 weeks apart), and a 
4- to 8-week FU period as follows:

Part C participants who enroll (uninterrupted) in 
the LTE study (233AS102): Week 28 Visit will 
serve as EOS Visit

Part C participants with delays between their 
Week 28 Visit and enrollment in the LTE study: 
a Safety FU (Alternative EOS) Visit will be 
conducted (either in person or by telephone 
contact) to collect AEs, SAEs, and concomitant 
medications or procedures. This Safety FU 
(Alternative EOS) Visit can be performed at 

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Week 32 or prior to (within 2 days) enrollment in 
the LTE, whichever comes first.

Part C participants who do not enroll in the LTE 
study: Week 32 Visit will serve as EOS (either in 
person or by telephone contact) Visit.
In the event of a decision by the Study Sponsor to terminate 
the study earlier on the grounds that conducting a 
placebo-controlled study is no longer deemed ethical based 
on the assessment of risk-benefit of Study 233AS101, all 
participants will be invited for an EOS visit, during which 
all Week 28 assessments will be conducted. For participants 
not entering the LTE study or in the event the study is 
stopped early, there will be an additional safety FU visit 
8 weeks after the last dose of study treatment.

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4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 233AS101
Key assessments are included in Figure 1, Figure 2, and Figure 3 for Parts A, B, and C of the 
study, respectively. For a full list of assessments and their timing, please see Table 1, Table 2, 
and Table 3 for Parts A, B, and C, respectively.

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4.2.
Schedule of Activities
Table 1:
Schedule of Activities: Part A – Single Ascending Dose
Dosing Inpatient Period
Follow-Up
Screening
Day 1
Tests and Assessments
V11
≤ 21 days 
before V2
V22
Day -28 to 
Day -1
Predose
Dosing/ 
Postdose
Day 2
24 (±1) 
hours 
Postdose
Days 8 & 
29 
(±3 days)
Day 57 (±3 days)/
Early 
Termination 
Visit
Informed Consent (main)
X
X3
Medical History
X
X
Clinical Laboratory Samples to Verify 
Eligibility4
X
FVC
X
Admission to Inpatient Facility
X
Physical Examination
X
X
X5
X5
X5
Weight
X
X
X
Height
X
Neurological Examination
X
X
X6
X
X
X
Vital Signs (temperature, blood pressure, pulse 
rate, respiratory rate)
X
X
X7
X
X
X
12-Lead ECG8
X
X
X7
X
X
X
C-SSRS Questionnaire
X
X9
Urine Pregnancy Test10
X
X
X
FSH Test11
X

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Dosing Inpatient Period
Follow-Up
Screening
Day 1
Tests and Assessments
V11
≤ 21 days 
before V2
V22
Day -28 to 
Day -1
Predose
Dosing/ 
Postdose
Day 2
24 (±1) 
hours 
Postdose
Days 8 & 
29 
(±3 days)
Day 57 (±3 days)/
Early 
Termination 
Visit
Randomization
X
Study Drug Administration
X
SVC
X
X
X
ALSFRS-R
X
X
X
X
HHD
X
X12
X
Clinical Laboratory Samples for Hematology, 
Chemistry, and Urinalysis
X
X
X
X
X
CSF Samples13
X
X14
X
Blood Samples for Plasma anti-BIIB067 Ab
X
X
X
Blood Samples for Biomarkers
X
X12
X
Blood Samples for Plasma PK
X
X16
X
X
X
Discharge from Inpatient Facility
X
AE and Concomitant Therapy and Procedures 
Recording
-------------------------------------------------X (ongoing) ----------------------
------------------
SAE Recording
-------------------------------------------------X (ongoing) -----------------------------

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1 Required only for participants without a prior documentation of SOD1 mutation. Results must be available before performing Screening Visit 2 assessments.
2 Screening assessments can be performed over ~2 days (need not be consecutive) to minimize participant burden.
3 Not required if collected during Screening Visit 1.
4 Including blood samples for HIV, HCV, and HBV tests, and platelet and coagulation tests. 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. Participants with nonclinically significant and stable out-of-range values 
for coagulation tests may be eligible to enroll in the study at the discretion of the Investigator, and after a consultation with the Sponsor.
5 Limited physical examination will be conducted at the Investigator's discretion.
6 To be assessed at 3 and 6 hours postdose.
7 To be assessed within an hour prior to drawing PK blood samples at 2 and 4 hours postdose.
8 Triplicate 12-lead (paper) ECGs will be obtained after the participant has rested in a supine position for at least 10 minutes. The first ECG will be interpreted, 
and the last 2 will be checked for consistency and quality.
9 Use the “Since Last Visit” version of C-SSRS.
10For women of childbearing potential only.
11To confirm postmenopausal status in postmenopausal female participants.
12Day 29 only.
13LP will be performed to collect CSF samples for PK, PD, safety, and biomarker analysis. The results of the most recent (i.e., obtained at Screening or other 
visit during the study) coagulation tests and platelet count must be reviewed before each LP can be performed. Should the results suggest, in the opinion of the 
Investigator, that an LP may be safely performed, then no further laboratory values need to be reviewed. However, should, in the opinion of the Investigator, 
repeat coagulation and platelet tests be clinically indicated, then these tests may be done locally to facilitate timely review. Results of any repeat tests must be 
available before the LP can be performed.
14To be collected at Day 29 only. Participants will remain under observation in the clinic for approximately 1 hour after the LP procedure and will receive a 
safety FU telephone contact ~24 hours after the procedure.
16To be collected at 1, 2, 4, and 6 hours postdose.

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Table 2:
Schedule of Activities: Part B – Multiple Ascending Dose
Screening
Dosing Inpatient Period
Follow-Up
Day 1
Tests and Assessments
V11
≤ 21 days 
before V2
V22
Day -28 
to Day -1
Predos
e
Dosing/
Postdose
Day 2
24 (±1) 
Postdose
Dosing
Days 15, 
29, 57 & 
85
(±3 days)
Days 83, 
22, 36, 
64, 92, 
and 106
(±3 days)
Days 50 & 
78 
(±3 days) 
via 
Telephone 
Contact
Day 169
(±3 days) 
/Early 
Termination 
Visit
Informed Consent (main)
X
X4
Medical History
X
X
Clinical Laboratory Samples 
to Verify Eligibility5
X
FVC
X
Admission to Inpatient 
Facility
X
Physical Examination
X
X
X6
X6
X6
X6
Weight
X
X
X
Height
X
Limited Neurological 
Examination (including the 
MMSE)7
X
X
X8
X
X9
X
X
Vital Signs (temperature, 
blood pressure, pulse rate, 
respiratory rate)
X
X
X10
X
X11
X
X
12-Lead ECG12
X
X
X10
X
X11
X
X
C-SSRS Questionnaire
X
X13

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Screening
Dosing Inpatient Period
Follow-Up
Day 1
Tests and Assessments
V11
≤ 21 days 
before V2
V22
Day -28 
to Day -1
Predos
e
Dosing/
Postdose
Day 2
24 (±1) 
Postdose
Dosing
Days 15, 
29, 57 & 
85
(±3 days)
Days 83, 
22, 36, 
64, 92, 
and 106
(±3 days)
Days 50 & 
78 
(±3 days) 
via 
Telephone 
Contact
Day 169
(±3 days) 
/Early 
Termination 
Visit
Urine Pregnancy Test14
X
X
X15
X
FSH Test16
X
Randomization
X
Study Drug Administration
X
X
SVC
X
X15
X
ALSFRS-R
X
X
X
X17
X
HHD
X
X17
X
Clinical Laboratory Samples 
for Hematology, 
Coagulation, Chemistry, and 
Urinalysis
X
X
X
X
X
CSF Samples18
X
X19
X20
X

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Screening
Dosing Inpatient Period
Follow-Up
Day 1
Tests and Assessments
V11
≤ 21 days 
before V2
V22
Day -28 
to Day -1
Predos
e
Dosing/
Postdose
Day 2
24 (±1) 
Postdose
Dosing
Days 15, 
29, 57 & 
85
(±3 days)
Days 83, 
22, 36, 
64, 92, 
and 106
(±3 days)
Days 50 & 
78 
(±3 days) 
via 
Telephone 
Contact
Day 169
(±3 days) 
/Early 
Termination 
Visit
Blood Samples for 
Biomarkers
X
X
X22
X
Blood Samples for Plasma 
PK
X
X23
X
X24
X
X
Discharge from Inpatient 
Facility
X
AE, and Concomitant 
Therapy and Procedures 
Recording
-------------------------------------------------X (ongoing) ------------------------------------------
SAE Recording
-------------------------------------------------------------------X (ongoing)------------------------------------------------------------
1 Required only for participants without a prior documentation of SOD1 mutation. Results must be available before performing Screening Visit 2 assessments.
2 Screening assessments can be performed over ~2 days (need not be consecutive) to minimize participant burden.
3 Participants may, at the discretion of the Investigator, have the option of home visits for non-dosing visits that do not require CSF collection or strength and 
electrophysiological measures, which are visits on Days 8, 36, and 64.
4 Not required if collected during Screening Visit 1.
5 Including blood samples for HIV, HCV, and HBV tests, and platelet and coagulation tests. 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. Participants with nonclinically significant and stable out-of-range values 
for coagulation tests may be eligible to enroll in the study at the discretion of the Investigator, and after a consultation with the Sponsor.

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6 Limited physical examination will be conducted at the Investigator's discretion.
7 The components of the limited neurological examination are cranial nerves, coordination/cerebellar function, reflexes, motor, and MMSE.
8 To be assessed at 3 and 6 hours postdose.
9 To be assessed predose, and 3 and 6 hours postdose.
10To be assessed just prior to drawing PK blood samples at 2 and 4 hours postdose.
11To be assessed just prior to drawing PK blood samples at predose, and 2 and 4 hours postdose.
12Triplicate 12-lead (paper) ECGs will be obtained after the participant has rested in a supine position for at least 10 minutes. The first ECG will be interpreted, 
and the last 2 will be checked for consistency and quality.
13Use “Since Last Visit” version of C-SSRS.
14For women of childbearing potential only.
15To be performed predose.
16To confirm postmenopausal status in postmenopausal female participants.
17Day 22 and Day 92 for 
 HHD; Day 92 for ALSFRS-R 
18LP will be performed to collect CSF samples for PK, PD, safety, and biomarker analysis. The results of the most recent (i.e., obtained at Screening or other 
visit during the study) coagulation tests and platelet count must be reviewed before each LP can be performed. Should the results suggest, in the opinion of the 
Investigator, that an LP may be safely performed, then no further laboratory values need to be reviewed. However, should, in the opinion of the Investigator, 
repeat coagulation and platelet tests be clinically indicated, then these tests may be done locally to facilitate timely review. Results of any repeat tests must be 
available before the LP can be performed.
19To be collected predose. Participants will remain under observation in the clinic for approximately 6 hours after the LP procedure and will receive a safety FU 
telephone contact ~24 hours after the procedure.
20To be collected on Day 106 only. Participants will remain under observation in the clinic for approximately 1 hour after the LP procedure and will receive a 
safety FU telephone contact ~24 hours after the procedure.
22Day 106 only.
23To be collected at 1, 2, 4, and 6 hours postdose.
24To be collected predose at each visit; collected at 1, 2, 4, and 6 hours postdose for Day 85 only.

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Table 3:
Schedule of Activities: Part C (Pivotal)
Loading Dose Treatment Period
Maintenance 
Treatment Period
EOS Visit2,3
Safety FU 
(Alternative EOS) 
Visit4
(In Person or 
Telephone Contact) 
Screening1
Baseline
(Dose 1)
Week 2
(Dose 2)
Week 4
(Dose 3)
Week 8, 12, 16, 20, 
and 24
Week 28 OR 
(4 Weeks 
After Last 
Dose)
Week 32 OR
(8 Weeks After Last 
Dose)
Day 1
(±3 days)
Day 15
(±3 days)
Day 29
(±3 days)
Days 57, 85, 113, 
141, and 169 
(±3 days)
Tests and Assessments5
Day
-28 to
Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Day 197 OR 4 
Weeks After 
Last Dose 
(±3 days)
Day 225 OR 8 Weeks 
After Last Dose 
(±3 days)
Informed Consent 
(main)6 
X
Medical History
X
Confirmation of 
Eligibility Criteria
X
X
Randomization
X
Telephone Contact7
X
X
X
X
Ventilation Use8,9
X
X
X
X
X
ALSFRS-R8
X
X
X
X
X
X
SVC8,10 
X
X
X
X
X
X
HHD8
X
X
X
X
X

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Loading Dose Treatment Period
Maintenance 
Treatment Period
EOS Visit2,3
Safety FU 
(Alternative EOS) 
Visit4
(In Person or 
Telephone Contact) 
Screening1
Baseline
(Dose 1)
Week 2
(Dose 2)
Week 4
(Dose 3)
Week 8, 12, 16, 20, 
and 24
Week 28 OR 
(4 Weeks 
After Last 
Dose)
Week 32 OR
(8 Weeks After Last 
Dose)
Day 1
(±3 days)
Day 15
(±3 days)
Day 29
(±3 days)
Days 57, 85, 113, 
141, and 169 
(±3 days)
Tests and Assessments5
Day
-28 to
Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Day 197 OR 4 
Weeks After 
Last Dose 
(±3 days)
Day 225 OR 8 Weeks 
After Last Dose 
(±3 days)
C-SSRS Questionnaire8
X
X13
X13
X13
Height
X
Weight14
X
X
X
X

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Loading Dose Treatment Period
Maintenance 
Treatment Period
EOS Visit2,3
Safety FU 
(Alternative EOS) 
Visit4
(In Person or 
Telephone Contact) 
Screening1
Baseline
(Dose 1)
Week 2
(Dose 2)
Week 4
(Dose 3)
Week 8, 12, 16, 20, 
and 24
Week 28 OR 
(4 Weeks 
After Last 
Dose)
Week 32 OR
(8 Weeks After Last 
Dose)
Day 1
(±3 days)
Day 15
(±3 days)
Day 29
(±3 days)
Days 57, 85, 113, 
141, and 169 
(±3 days)
Tests and Assessments5
Day
-28 to
Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Day 197 OR 4 
Weeks After 
Last Dose 
(±3 days)
Day 225 OR 8 Weeks 
After Last Dose 
(±3 days)
Vital Signs 
(temperature, blood 
pressure, pulse rate, 
respiratory rate)14,15
X
X
X
X
X
X
X
X
X
X
12-Lead ECG14,16
X
X
X17
X11
X17
X
Physical Examination14
X
X
X18
X18
X18
X18
Limited Neurological 
Examination14,19
X
X
X
X
X
X
X
X
X
X
MMSE
X
X
X
X11
X11
X
FSH Test20
X
Pregnancy Test14,21,22
X (serum)
X
X
X
X
X (serum)
Blood Sampling for 
HIV, HCV, and HBV 
Testing
X

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Loading Dose Treatment Period
Maintenance 
Treatment Period
EOS Visit2,3
Safety FU 
(Alternative EOS) 
Visit4
(In Person or 
Telephone Contact) 
Screening1
Baseline
(Dose 1)
Week 2
(Dose 2)
Week 4
(Dose 3)
Week 8, 12, 16, 20, 
and 24
Week 28 OR 
(4 Weeks 
After Last 
Dose)
Week 32 OR
(8 Weeks After Last 
Dose)
Day 1
(±3 days)
Day 15
(±3 days)
Day 29
(±3 days)
Days 57, 85, 113, 
141, and 169 
(±3 days)
Tests and Assessments5
Day
-28 to
Day -1
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Day 197 OR 4 
Weeks After 
Last Dose 
(±3 days)
Day 225 OR 8 Weeks 
After Last Dose 
(±3 days)
Clinical Laboratory 
Samples for 
Hematology, 
Coagulation, Chemistry, 
and Urinalysis8,23
X
X
X
X
X
X

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7 Telephone contact to be performed approximately 24 hours after LP.
8 Predose assessments can be performed in a single visit up to 2 days prior to dosing.
9 Participants 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/eDiary will be reviewed with study site staff at each visit.
10If a facemask is used at screening and/or baseline it should be used for all SVC assessments for the duration of the study. If a facemask is not used at screening 
and/or baseline it should not be used 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. 
11To be performed on Week 12 (Day 85) and Week 24 (Day 169) only.
13Use “Since Last Visit” version of C-SSRS.
14Assessment must occur on the day of dosing.
15Temperature, 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.
16Triplicate 12-lead ECGs will be obtained after the participant has rested in a supine position for at least 10 minutes. All ECGs will be centrally read; ECGs will 
be read by the Investigator at collection and then sent to a central ECG reader for further evaluation and to confirm eligibility at Screening. The first ECG will 
be interpreted, and the last 2 will be checked for consistency and quality.
17To be assessed just prior to drawing PK blood samples at 2, 4, and 6 hours postdose on Day 1 and Day 85 only.
18Limited physical examination will be conducted at the Investigator’s discretion.
19The components of the limited neurological examination include motor, reflexes, and coordination/cerebellar function.
20To confirm postmenopausal status (in postmenopausal female participants only).
21Results from urine or serum pregnancy tests must be reviewed predose in order to determine if dose should be administered or held.
22For women of childbearing potential only. Serum test to be performed at Screening and EOS Visit; urine or serum test to be performed at all other timepoints.
23The results of most recent (i.e., obtained at previous visit) centrally read coagulation tests and platelet count must be reviewed before LP can be performed. 
Coagulation tests may be repeated at local laboratory once if, in the opinion of the Investigator, values of the initial tests are out of range but deemed not 
clinically significant).
24CSF samples collected during the LP procedure will be analyzed to evaluate for blood contamination. CSF samples for safety will be tested at local 
laboratories.
28Participants 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.

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5.
INTRODUCTION 
BIIB067 is an investigational second-generation ASO inhibitor of SOD1 mRNA, under 
development to reduce levels of total SOD1 protein in patients with ALS and a confirmed SOD1 
mutation (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. Since SOD1-ALS was first 
described in 1993, over 180 SOD1 mutations have been reported to cause this form of ALS 
(referred to as SOD1-ALS) [ALSoD 2015; Rosen 1993]. Disease progression for individual 
mutations is variable, with survival of less than 15 months seen with the most severe mutations 
[Cudkowicz 1997]. Although the mechanism by which mutations cause SOD1-ALS is not 
known, compelling data suggest that toxic gain of function, not loss of SOD1 activity, is the 
likely trigger that initiates the cascade of events resulting in motor neuron death [Bruijn 1998; 
Rosen 1993]. 
5.2.
Current Therapies for Amyotrophic Lateral Sclerosis
The only currently approved treatments for ALS are riluzole and edaravone. 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 SOD1-ALS treatments are available. 
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, intrathecal bolus injection study in rats (0.1, 0.3, 1.0, and 3.0 mg); a 
repeated-dose, 13-week, intrathecal bolus injection study in cynomolgus monkeys (4, 12, and 
35 mg); and a repeated-dose, 9-month, intrathecal bolus injection study in cynomolgus monkeys 
(4, 12, and 35 mg). 
See the Investigator’s Brochure for detailed information on nonclinical studies.

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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 (intrathecal) was used were 1 mg (rat) and 35 mg (monkey). 
In rats, a single intrathecal 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 intrathecal 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, intrathecal 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, which was not observed in any animal at the end of the 
13-week dosing period. The relationship 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 are 
not adverse. 
From the 9-month cynomolgus monkey toxicology study, the NOAEL for repeated, 
intrathecally-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 
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 intrathecal 
(monkey and rat) or subcutaneous (mouse) administration. 
Following bolus intrathecal administration in monkeys, BIIB067 concentrations in CSF declined 
in a multiphasic manner with a rapid distribution phase, followed by a slower and longer 

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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 intrathecal 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, then 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 intrathecal 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 intrathecal 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 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 intrathecal administration.
5.3.2.
Clinical Experience
This is the FIH study 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 reduction in total CSF SOD1 protein concentration was observed in the BIIB067 
100 mg group (37% reduction) compared with the placebo group (no reduction). Interim 
exploratory analyses showed a slowing of decline in functional (ASLFRS-R), respiratory (SVC), 
and strength measures (HHD Megascore). These data support the continued development of 
BIIB067 for the treatment of SOD1-ALS.
5.4.
Study Rationale
BIIB067 is an investigational ASO inhibitor of SOD1 mRNA, under development to reduce 
levels of SOD1 protein in patients with SOD1-ALS.
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 

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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 [Saccon 2013]. Thus, correlation between disease severity and 
normal SOD1 activity has not been observed [Andersen 1997; Ratovitski 1999; Saccon 2013]. In 
contrast, reduction of SOD1 with intracerebroventricular-delivered SOD1 ASO extends 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. Intrathecal delivery of an ASO targeting SOD1 mRNA is a viable method to reduce 
toxic SOD1 protein.
Parts A (SAD) and B (MAD)
Pharmacology and toxicology data in rats, mice, and monkeys indicate that BIIB067 is well 
tolerated. Parts A and B of the study will evaluate the safety, tolerability, and PK profile of a 
range of single and multiple intrathecal BIIB067 doses from a projected minimal pharmacologic 
dose to either the MTD or the highest planned dose of 100 mg. MTD for this study is defined as 
the highest tested dose with a less than 33% DLT rate at Day 15. See Section 7.2.3 for the 
definition of DLT.
Part C (Pivotal)
Based on the interim data from Parts A and B summarized in Section 5.3.2, a randomized, 
double-blind, placebo-controlled, pivotal phase (Part C) has been designed to assess the efficacy 
and safety of BIIB067 100 mg versus placebo. Approximately 99 participants with SOD1-ALS 
will be randomized to receive BIIB067 or placebo and treated for 24 weeks.
5.5.
Rationale for Dosing Regimen
BIIB067 will be administered via intrathecal bolus at single ascending doses to cohorts in Part A, 
and at multiple ascending doses to cohorts in Part B.
The BIIB067 dosing regimens for Parts A and B of this study were selected based on nonclinical 
toxicology and PK observations in NHP studies using repeated-dosing intrathecal administration 
for 13 weeks and 9 months, and target tissue concentrations from SOD1 transgenic mouse 
models. 
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 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 this study (10 mg in Part A) is 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. 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 reduction 

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in total CSF SOD1 protein of 25% to 30%. This reduction is expected to be clinically 
meaningful, based on the expectation that the reduction of 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 intrathecal injections, and the rapid, fatal nature of ALS, 
the following dose intervals were selected for Part B of the study (MAD): 3 loading doses, once 
every 2 weeks, and 2 maintenance doses, administered once every 4 weeks. 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 to facilitate effective 
total SOD1 protein reduction in the CSF within Part B of the study (MAD). 
From the 9-month NHP toxicology study, the NOAEL for repeated, intrathecally-administered 
BIIB067 was 12 mg. This NOAEL was converted to an 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 12-fold 
safety margin for the BIIB067 starting dose (10 mg), 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 (AUC from time 0 to 24 hours) from the 20-mg MAD cohort 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 233AS101 are predicted to be pharmacologically 
active, while maintaining sufficient safety margins calculated from the 9-month intrathecal NHP 
toxicology study. 
For Part C (Pivotal), the dose of 100 mg of BIIB067 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 ALS participants. The 
selection of the 100 mg BIIB067 dose for Part C is supported by PK/PD and exploratory efficacy 
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.
Parts A (SAD) and B (MAD)
6.1.1.
Primary Objective 
The primary objective of Parts A and B of this study is to evaluate the safety, tolerability, and PK 
of BIIB067 in adult participants with ALS and a confirmed SOD1 mutation.
6.1.1.1.
Primary Endpoints
The primary endpoints are as follows:

Incidence of AEs and SAEs.

Incidence of abnormalities in clinical laboratory assessments, vital signs, physical and 
neurological examinations, and ECGs.

PK measures, including plasma and CSF levels of BIIB067.
6.1.2.
Secondary Objective
The secondary objective is to evaluate the effects of BIIB067 on levels of total SOD1 protein in 
the CSF. 
6.1.2.1.
Secondary Endpoint
The secondary endpoint is the change from baseline in CSF levels of total SOD1 protein.
6.1.3.
Exploratory Objectives and Endpoints
To evaluate the effect of BIIB067 on 
 HHD.

The endpoints that relate to this objective are the changes from baseline in 
 
 HHD scores.
To evaluate the effect of BIIB067 on measures of clinical function.

The endpoints that relate to this objective are changes from baseline in the following 
measures: 

ALSFRS-R scores

SVC

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7.
STUDY DESIGN
7.1.
Study Overview
This is a randomized, double-blind, placebo-controlled, 3-part study to examine the efficacy, 
safety, tolerability, PK, and PD of BIIB067, administered by intrathecal bolus injection to up to 
approximately 183 participants with ALS and a confirmed SOD1 mutation. Parts A and B are 
single and multiple dose escalating parts, respectively, in which participants will be randomized 
to receive BIIB067 or placebo in a 3:1 (active:placebo) ratio. In Part C, participants will be 
randomized to receive BIIB067 100 mg or placebo in a 2:1 (active:placebo) ratio. The study will 
be conducted at approximately 42 sites in approximately 15 countries globally. See Figure 1, 
Figure 2, and Figure 3 for Parts A, B, and C of the study, respectively. 
7.1.1.
Part A: SAD Evaluation
Part A will be a randomized, double-blind, placebo-controlled, SAD study of up to 4 dose levels 
of BIIB067 administered to participants with SOD1-ALS. The dose levels will be evaluated 
sequentially. Final sample size for Part A of the study will be determined by the incidence of 
DLT. If no DLTs are encountered, a minimum of 20 participants will be randomized. The 
maximum sample size for Part A is 36 participants. The first 3 dose levels will be assessed in 
cohorts of 4 participants each: 1 participant will be administered placebo, and 3 participants will 
be administered BIIB067 at 10, 20, or 40 mg. The last dose level will be assessed in a cohort of 
8 participants: 2 participants will be administered placebo, and 6 participants will be 
administered BIIB067 at 60 mg. Up to 16 additional participants may be enrolled into the 
selected dose levels (4 administered placebo and 12 administered BIIB067), based on the 
incidence of DLT. See Section 7.2.1 for a detailed description of dose escalation.
If no DLTs are observed in the 2 lower dose cohorts, then participants within these 2 lower dose 
cohorts may re-enroll, after a washout period of at least 5 times the t½ (~20-week; including the 
8-week FU period), within the 2 higher dose cohorts. These participants will repeat the screening 
assessments prior to re-enrolling, and will be rerandomized into either the BIIB067 or placebo 
group.
The duration of study participation for each participant enrolled in Part A will be up to 
approximately 15 weeks, which will include up to 7-week screening period and an 8-week FU 
period. For participants who choose to re-enroll in a higher dose cohort, the total duration will be 
approximately 35 weeks, which will include a washout period of 3 times the t½ (~12 weeks) after 
the 8-week FU visit (total washout of 5 times the t½, or ~20 weeks). Participants who re-enroll in 
a higher cohort will repeat Screening Visit 2 assessments, which can occur during the washout 
period.
The SAD portion of the study will be completed when any one of the following criteria is met. 

MTD or the highest planned dose has been given to up to 9 active participants.

A maximum of 36 participants have been enrolled.

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7.1.2.
Part B: MAD Evaluation
Part B will be a randomized, double-blind, placebo-controlled, MAD evaluation of up to 4 dose 
levels of BIIB067 administered up to 5 times, over approximately 3 months, approximately 
48 participants with SOD1-ALS. Each dose level will be assessed in cohorts of 12 participants: 
3 participants will be administered placebo, and 9 participants will be administered BIIB067 at 
20, 40, 60, or 100 mg. 
The duration of study participation for each participant enrolled in Part B will be up to 
approximately 31 weeks, which will include up to 7-week screening period, a 12-week treatment 
period (consisting of 3 loading doses of BIIB067, administered approximately once every 
2 weeks, followed by 2 maintenance doses of BIIB067, administered approximately once every 
4 weeks), and a 12-week FU period.
7.1.2.1.
Parts A and B
Participants with SOD1-ALS who participate in Part A (SAD) of the study will be able to re-
enroll in Part B (MAD), after a washout period of at least 3 times the t½ (~12-week), at a dose 
level that is either the same or at the next level up from the dose received in Part A (for 
participants who choose to re-enroll, this will be the last dose level received in Part A). For 
participants participating in both the SAD and the MAD portion of the study, duration will be 
approximately 51 weeks (71 weeks for participants who enroll in 2 cohorts during Part A). This 
will include all Part A visits, a period of at least 3 times the t½ (~12 weeks) between the 8-week 
FU visit of Part A and the first dosing visit of Part B (~20-week total washout), and all Part B 
visits, excluding the Part B screening period, which can occur during the washout period, within 
28 days before Day 1. 
7.1.3.
Part C: Pivotal
Part C will be a randomized, double-blind, placebo-controlled evaluation of 100 mg of BIIB067 
administered 8 times over approximately 24 weeks to approximately 99 participants with 
SOD1-ALS.
Part C: Screening-Only Sites
Some sites may be designated as screening-only sites and will only perform screening visit 
assessments. Participants who complete screening at screening-only sites and are deemed eligible 
for participation in Part C will be transferred to a full participation site for the remainder of the 
study. Participants may also be screened at full treatment sites and transferred to other full 
treatment sites for randomization.
Part C: Full Participation Sites
Randomization will occur only at full participation sites. It is planned to randomize 
approximately 99 participants total, of whom approximately 60 participants will meet the 
protocol-defined prognostic enrichment criteria for rapid disease progression (see Section 8.2.1). 

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Randomization will be stratified by the following 3 factors:

whether a participant meets the prognostic enrichment criteria for rapid disease 
progression 

whether a participant uses edaravone at baseline

whether a participant uses riluzole at baseline

Use of both edaravone and riluzole will not be a separate stratum but will be 
classified as edaravone use. 
For participants in Part C (Pivotal), the study duration will be approximately 32-36 weeks 
including a 4-week screening period, a 24-week treatment period (3 loading doses 2 weeks apart 
followed by 5 maintenance doses 4 weeks apart), and a 4- to 8-week FU period as follows:

Part C participants who enroll (uninterrupted) in the LTE study (233AS102): 
Week 28 Visit will serve as EOS Visit

Part C participants with delays between their Week 28 Visit and enrollment in the 
LTE study: a Safety FU (Alternative EOS) Visit will be conducted (either in person 
or by telephone contact) to collect AEs, SAEs, and concomitant medications or 
procedures. This Safety FU (Alternative EOS) Visit can be performed at Week 32 or 
prior to (within 2 days) enrollment in the LTE, whichever comes first.

Part C participants who do not enroll in the LTE study: Week 32 Visit will serve as 
EOS Visit (either in person or by telephone contact)
In the event of a decision by the Sponsor to terminate the study earlier on the grounds that 
conducting a placebo-controlled study is no longer deemed ethical based on the assessment of 
risk-benefit of Study 233AS101, all participants will be invited for an EOS Visit, during which 
all Week 28 assessments will be conducted. For participants not entering the LTE study or in the 
event the study is stopped early, there will be an additional safety FU visit 8 weeks after the last 
dose of study treatment.
7.2.
Study Specifics
7.2.1.
Dose Escalation
7.2.1.1.
Part A: Single Ascending Dose
The dose levels will be evaluated sequentially. After the 14-day safety review for the last 
participant within a cohort is completed (Day 15), and prior to dosing of the next cohort (the next 
planned dose level), a Biogen Medical Director and a Global Safety and Regulatory Sciences: 
Global Safety Physician will review participants’ available blinded safety data with the PI. These 
data include AEs and SAEs, vital signs, physical and neurological examinations, ECGs, and 
clinical laboratory safety tests. Review of blinded safety data may be followed by review of 
unblinded safety data of the current cohort and all available safety data from preceding cohorts 
by the Biogen Medical Director, Global Safety Physicians, Biostatistician, Clinical 
Pharmacologist, and, if required, any ad hoc members. Before escalating to the next higher dose 
level, there must be agreement that the current emerging safety and tolerability data support dose 

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escalation. Progression to each subsequent dose level will be based on the number of DLTs, as 
defined in Section 7.2.3, observed in participants treated with BIIB067. For each dose level, if 
any DLT is observed, then the Biogen Medical Director, Global Safety Physician, Biostatistician, 
Clinical Pharmacologist, and, if required, any ad hoc members will review the safety profile, 
integrating results from the CRM [see Appendix A], to decide dose expansion, escalation, or de-
escalation. A maximum of 12 participants can be dosed at each dose level. In general, the 
occurrence of DLTs in at least 3 out of 9 participants treated with BIIB067 in a cohort 
(i.e., ≥ 33.3% DLT rate) will result in the cohort being considered dose limiting. In this situation, 
the prior dose may be considered the MTD. The prior cohort may be expanded, if necessary, to 
confirm there is an acceptable toxicity profile at the lower dose prior to its designation as the 
MTD. 
See Figure 4 for a dose escalation schematic.
7.2.1.2.
Part B: Multiple Ascending Dose
After a minimum of 10 participants within a cohort complete the Day 106 FU Visit (~3 weeks 
after last dose), and prior to dosing of the next, higher dose cohort, a Biogen Medical Director 
and a Global Safety Physician will review all available blinded safety data with the PI. Review 
of blinded safety data may be followed by review of unblinded safety data of the current cohort 
and all available safety data from preceding cohorts by the Biogen Medical Director, Global 
Safety Physician, Biostatistician, Clinical Pharmacologist, and, if required, any ad hoc members. 
In addition to review of the safety data, a Biogen Medical Director, Clinical Pharmacologist, and, 
if required, any ad hoc members will review PK data through the trough levels after the fourth 
dose (samples collected predose on Day 85) for a minimum of 6 dosed participants within a 
cohort, prior to dosing of the next, higher dose cohort. Before escalating to the next, higher dose 
level, there must be agreement that the current emerging safety, tolerability, and PK data support 
dose escalation. The progression to each subsequent dose level will be based on the number of 
DLTs observed in participants treated with BIIB067. Prior to continuing to the 60-mg and 
100-mg dose cohorts, available CSF of the previous cohorts will be assessed to determine the 
level of total SOD1 protein reduction. Based on this total SOD1 protein level data, the decision 
will be made to proceed with the planned dosing regimen, to alter the dosing regimen, to conduct 
an interim analysis after the 60-mg cohort or 100-mg cohort, or to stop the study. Section 7.2.2.2 
provides specifics related to dosing Cohort 8.
Dosing for the first cohort of Part B (Cohort 5) may begin simultaneously with the last cohort of 
Part A (Cohort 4). See Figure 4 for a dose escalation schematic.

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Figure 4:
Dose Escalation Schematic (Parts A and B)

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7.2.2.
Within Cohort Staggered Dosing
7.2.2.1.
Part A: Single Ascending Dose
For the first 3 dose levels in Part A (10, 20, and 40 mg), participants will be randomized in 
blocks of 4 to receive BIIB067 or placebo in a 3:1 (active treatment:placebo) ratio. The first 
2 participants in each cohort will be dosed sequentially, each followed by a 72-hour safety data 
review period, during which the Biogen Medical Director and Global Safety Physician will 
review blinded safety data with the PI. The remaining participants within the cohort will then be 
dosed at least 24 hours apart, to allow for review of safety data. Depending on the accumulated 
DLT data from the first 3 cohorts, the 8 participants in Cohort 4 (60 mg) can either be 
randomized in a single block of 8, or be divided into 2 sequential blocks of 4, with the second 
block of 4 participants starting dosing only after the 14-day safety review for the last participant 
within the first block is completed, and the accumulated DLT data have been fully reviewed. 
Dosing within each randomized block of either 8 or 4 participants will be staggered similarly as 
for Cohorts 1-3.
7.2.2.2.
Part B: Multiple Ascending Dose
Within Cohorts 5 to 7 in Part B, participants will be randomized in blocks of 4 to receive 
BIIB067 or placebo in a 3:1 (active treatment:placebo) ratio. The 3 blocks of each cohort will be 
dosed sequentially, each followed by a 72-hour safety data review period, during which the 
Biogen Medical Director and Global Safety Physician will review blinded safety data with the 
PI. 
Given that safety and tolerability of the 100-mg dose of BIIB067 were not explored in Part A 
(SAD), both a sentinel dosing strategy and a review of safety data for every participant after the 
first dose will be incorporated into Cohort 8. 
In Cohort 8, the first 2 participants (1 participant receiving placebo and 1 participant receiving 
BIIB067) will be dosed as a sentinel group, followed by a 72-hour safety data review period, 
during which the Biogen Medical Director and Global Safety Physician will review blinded 
safety data with the PI. For the remaining participants in the cohort, no more than 2 participants 
will be given the first dose of study treatment on the same day throughout the study.
Cohort 8 follows the same loading dose/maintenance dose as the other MAD cohorts. While a 
100-mg dose has not been administered in the SAD portion of the study, the safety data collected 
between Week 2 and Week 4 postdose (or even Week 1 and Week 4 postdose) did not yield any 
additional information when compared with safety data collected for the first 2 weeks postdose. 
This justifies the absence of a 4-week safety observation period between doses 1 and 2.
Additional to the 72-hour safety review period, for every participant in Cohort 8, a review of all 
available safety and tolerability data will be performed approximately 1 week after the first dose 
is administered. This review will be performed by the Biogen Medical Director and Global 
Safety Physician with the PI. The second dose cannot be given until this review is complete. 

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7.2.2.3.
Part C
As the initial safety and tolerability of 100 mg BIIB067 have previously been explored in 
Cohort 8, staggered dosing is not required for Part C of the study.
7.2.3.
Dose-Limiting Toxicity
For Parts A and B only, a DLT will be defined as an AE that, in the judgment of an Investigator 
and/or the Sponsor, is of sufficient significance to be dose limiting, is related to study treatment 
(i.e., the AE is substantially less likely to occur in participants not treated with study treatment), 
and is not a known 1) sign or symptom of ALS, or 2) effect of the LP procedure. 
For Part C, a single dose level of BIIB067 (100 mg) is to be used, and DLT evaluation will not 
be done. The dose level of 100 mg BIIB067 has been determined from interim analyses of data 
from Parts A and B of this study, in which BIIB067 at dose levels up to and including 100 mg 
was generally well tolerated. 
7.3.
Overall Study Duration and Follow-Up
The study period will consist of screening, dosing, and FU.
7.3.1.
Screening
7.3.1.1.
Part A: Single Ascending Dose
For participants who do not have documentation of an SOD1 mutation, the screening period will 
involve an additional visit (Screening Visit 1), where a blood sample will be collected for DNA 
analysis. The rationale for the extra screening visit is to ensure DNA analysis results prior to 
assessing the rest of the eligibility criteria. Participant eligibility for the study will be determined 
during Screening Visit 2, up to approximately 21 days after Screening Visit 1 and within 28 days 
prior to admission to the inpatient facility for dosing (Day 1). Participants in the 2 lowest dose 
cohorts, who choose to re-enroll into 1 of the 2 highest dose cohorts, will have to repeat 
screening assessments before receiving the second dose. This additional Screening Visit can 
occur during the washout period, within 28 days prior to their second admission to the inpatient 
facility for dosing. 
 
The Screening Visit 2 assessments may be performed over 2 days, which do not need to be 
consecutive, to minimize participant burden. All assessments must be completed before Day 1.
7.3.1.2.
Part B: Multiple Ascending Dose
For participants who do not have documentation of an SOD1 mutation, the screening period will 
involve an additional visit (Screening Visit 1), 
 
. Participant eligibility for the study will be determined during Screening Visit 2, up to 
approximately 21 days after Screening Visit 1, and within 28 days before admission to the 
inpatient facility for dosing (Day 1). 
The Screening Visit 2 assessments may be performed over 2 days to minimize participant 
burden. All assessments must be completed before Day 1.

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7.3.1.3.
Part C
Participant eligibility for Part C of the study will be determined during the Screening Visit, up to 
approximately 4 weeks prior to the first dose (Day 1). All assessments must be completed before 
Day 1. 
7.3.2.
Dosing
7.3.2.1.
Part A: Single Ascending Dose
Eligible participants will report to the study site for admission to the inpatient unit on Day 1 to 
complete baseline assessments and reaffirm eligibility. Participants will stay in the clinic until 
completion of all 24-hour postdose assessments.
7.3.2.2.
Part B: Multiple Ascending Dose
Eligible participants will report to the study site for admission to the inpatient unit on Day 1 to 
complete baseline assessments and reaffirm eligibility. Participants will stay in the clinic until 
completion of all 24-hour postdose assessments. Following the inpatient stay on Day 1, 
participants will return to the clinic on an outpatient basis to receive 4 more doses on Days 15, 
29, 57, and 85. CSF sampling on Days 15, 29, 57, and 85 will be performed predose. On dosing 
days, participants will remain under observation for approximately 6 hours after the LP 
procedure and will receive a safety FU telephone contact approximately 24 hours after the 
procedure. 
7.3.2.3.
Part C: Pivotal
Following the initial dosing on Day 1, participants will return to the clinic on an outpatient basis 
to receive up to 7 additional doses at Weeks 2 (Day 15), 4 (Day 29), 8 (Day 57), 12 (Day 85), 
16 (Day 113), 20 (Day 141), and 24 (Day 169). CSF sampling will be performed predose at all 
dosing visits. On dosing days/CSF sampling days, participants will remain under observation at 
the study site for at least 1 hour after the LP procedure 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 FU telephone 
contact approximately 24 hours after the procedure to provide information on AEs, SAEs, and 
concomitant medications or procedures.
7.3.3.
Follow-Up Procedures
7.3.3.1.
Part A: Single Ascending Dose
Following the inpatient stay, participants participating in Part A will return to the clinic for 
FU visits on Days 8, 29, and 57. On the day of CSF sampling during the FU period (Days 29 and 
57), participants will remain under observation for approximately 1 hour after the LP procedure 
and will receive a safety FU telephone contact approximately 24 hours after the procedure.
7.3.3.2.
Part B: Multiple Ascending Dose
Participants will return to the study site for FU visits after each dose on Day 8 (after first dose), 
Day 22 (after second dose), Day 36 (after third dose), Day 64 (after fourth dose), Days 92 

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and 106 (after fifth dose), and on the final study visit on Day 169. On the days of CSF sampling 
(Day 106 and Day 169), participants will remain under observation for approximately 1 hour 
after the procedure and will receive a safety FU telephone contact approximately 24 hours after 
the procedure. Participants will also receive FU telephone contacts on Day 50 (after third dose) 
and Day 78 (after fourth dose) to provide information on AEs, SAEs, and concomitant 
medications or procedures. Participants may, at the discretion of the Investigator, have the option 
of home visits for non-dosing visits that do not require CSF collection or strength and 
electrophysiological measures, which are visits on Days 8, 36, and 64.
7.3.3.3.
Part C: Pivotal 
Participants participating in Part C (Pivotal) will return to the site for an EOS Visit 4 weeks after 
their last dose (at Week 28), as described in the Schedule of Activities (Table 3) they will have 
the option to participate in the LTE study (233AS102), if eligible. This will be done without 
unblinding the treatment group.
For participants with delays between their Week 28 Visit and enrollment in the LTE study, a 
Safety FU (Alternative EOS) Visit will be conducted (either in person or by telephone contact) to 
collect AEs, SAEs, and concomitant medications or procedures. This Safety FU (Alternative 
EOS) Visit can be performed at Week 32 or prior to (within 2 days) enrollment in the LTE, 
whichever comes first.
Participants who do not roll over into the LTE study will have an additional safety FU visit 
8 weeks after their last dose (at Week 32) to collect information on AEs, SAEs, and concomitant 
medications or procedures (in person or by telephone contact). 
7.4.
Study Stopping Rules
7.4.1.
Dose Suspension (Parts A and B only)
If 1 participant experiences either an SAE or a clinically significant AE (as defined by the 
Investigator or the Sponsor), the Biogen Medical Director and Global Safety Physician will 
discuss the event with the Investigator and review the SAE form (if applicable). If the AE is 
assessed as unrelated to the study treatment by both the Investigator and the Sponsor (e.g., it is a 
known sign or symptom of ALS, or it is an effect of the LP procedure), dose suspension is not 
necessary. 
If the SAE or clinically significant AE (as determined by the Investigator or the Sponsor) is 
assessed as related to the study treatment by the Investigator or the Sponsor, all dosing will be 
suspended until the event has been fully evaluated by the Biogen Medical Director, Global 
Safety Physician, and, if required, any ad hoc members. Depending on the nature, severity, 
suspected on- or off-target toxicity, outcome, and frequency of the event, a decision (documented 
with supporting rationale) will be made to proceed with one of the following: 

Request additional safety data 

Continue dosing remaining participants within the cohort

Enroll additional participants to the current cohort 

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
Proceed with the planned dose escalation in the next cohort

Enroll additional participants to previous (lower-dose) cohort

Stop the study
The review will also include available preliminary PK data from the preceding cohort(s).
Dosing of the cohort cannot resume until Biogen completes the safety evaluation, and the 
Investigator has received written approval from Biogen to resume dosing. 
Dose suspension rules are not applicable for Part C of the study.
7.4.2.
Dose Termination 
7.4.2.1.
Parts A and B
After evaluation of safety, tolerability, and PK data by the Biogen Medical Director, Global 
Safety Physician, and, if required, any ad hoc members, further dosing at the current level and 
dose escalation will be terminated if any of the following is observed:

Two similar SAEs (unless clearly unrelated to BIIB067 upon medical review) are 
reported for 2 participants on active study treatment within the same cohort.

Three or more similar AEs (unless clearly unrelated to BIIB067 upon medical review) 
that are either not tolerable (as reported by the participants) or deemed a medically 
unacceptable risk by the Biogen Medical Director, Global Safety Physician, and, if 
required, any ad hoc members.

Sponsor requests that dosing be terminated. 
The study will be terminated if no dose is deemed to be safe. Biogen may terminate this study at 
any time, after informing the Investigator. The Investigator will be notified by Biogen if the 
study is placed on hold, completed, or closed.
7.4.2.2.
Part C
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 safe and proper treatment of participants. 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.
Biogen may terminate this study at any time, after informing the Investigator. The Investigator 
will be notified by Biogen if the study is placed on hold, completed, or closed.
7.5.
End of Study
The EOS is last participant, last visit for Part C (either in person or by telephone contact). In the 
event of a decision by the Sponsor to terminate the study earlier on the grounds that conducting a 
placebo-controlled study is no longer deemed ethical based on the assessment of risk-benefit of 
Study 233AS101, all participants will be invited for the EOS Visit, during which all Week 28 
assessments will be conducted. The EOS Visit should occur 4 weeks after the last dose of study 

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treatment. After completing the EOS Visit, participants will be considered study completers and 
they will have an option to participate in the LTE study, if eligible. For participants with delays 
between their Week 28 Visit and enrollment in the LTE study, a Safety FU (Alternative EOS) 
Visit will be conducted (either in person or by telephone contact) to collect AEs, SAEs, and 
concomitant medications or procedures. This Safety FU (Alternative EOS) Visit can be 
performed at Week 32 or prior to (within 2 days) enrollment in the LTE, whichever comes first. 
For participants not entering the LTE study or in the event the study is stopped early, there will 
be an additional safety FU visit 8 weeks after the last dose of study treatment.
8.
SELECTION OF PARTICIPANTS
8.1.
Parts A (SAD) and B (MAD)
8.1.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening, or at the timepoint specified in the individual eligibility criterion listed:
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use PHI in accordance with national and local 
participant privacy regulations. In the case that a participant is legally incapable of 
providing informed consent, the participant’s legally authorized representative will be 
able to provide the informed consent.
2. Aged  18 years at the time of informed consent. 
3. Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2. 
4. An FVC ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting 
position). Participants with stable FVC < 50% but ≥ 45%, whose FVC has not declined 
by more than 5% in the last 6 months may be considered for inclusion, at the discretion of 
the Investigator. 
5. If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and 
expected to remain at that dose until the final study visit.
6. 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.
7. Screening values of coagulation parameters including platelet count, INR, PT, and APTT 
should be within normal ranges. Coagulation tests may be repeated once if, in the opinion 
of the Investigator, values of the initial tests are only slightly out of range. Participants 
with nonclinically significant and stable out-of-range values may be eligible to enroll in 
the study at the discretion of the Investigator and after a consultation with the Sponsor. 
(For normal ranges, please refer to the study reference guide). 
8. 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 

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their last dose of study treatment. For further details of contraceptive requirements for 
this study, please refer to Section 15.5.
8.1.2.
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:
1. History of or positive test result for HIV.
2. History of, or positive test result at Screening, for HCV Ab. 
3. Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). 
Participants 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.
4. Treatment with another investigational drug (including investigational drugs for ALS 
through compassionate use programs), biological agent, or device within 1 month or 
5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with 
small interfering RNA, stem cell therapy, or gene therapy is allowed.
5. Current enrollment in any other interventional study.
6. Current or anticipated need, in the opinion of the Investigator, of a DPS during the study 
period.
7. 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.
8. Current or recent use (within 30 hours prior to screening), or anticipated need of 
edaravone (Radicava®).
9. Presence of any implanted vascular devices.
10. History of drug abuse or alcoholism within ≤ 6 months of study enrollment that would 
limit participation in the study, as determined by the Investigator.
11. Tracheostomy.
12. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the screening period.
13. Ongoing medical condition (e.g., wasting or cachexia, severe anemia) that according to 
the Investigator would interfere with the conduct or assessments of the study. 
14. Female participants who are pregnant or currently breastfeeding.
15. 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.
16. History of allergies to a broad range of anesthetics.

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17. 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 intraoperative or 
postoperative bleeding. These 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). 
18. Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet 
or anticoagulant medication (e.g., clopidogrel) for 7 days before or 48 hours after an LP. 
19. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
20. Clinically significant abnormalities in hematology or clinical chemistry parameters, as 
determined by the Investigator, which would render the participant unsuitable for 
enrollment. For a list of normal, acceptable, and exclusionary ranges, please refer to the 
study reference guide.
21. 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.
22. Inability to comply with study requirements.
23. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
participant unsuitable for enrollment.
8.2.
Part C (Pivotal)
8.2.1.
Inclusion Criteria
To be eligible to participate in Part C (Pivotal) of this study, candidates must meet the following 
eligibility criteria at Screening, or at the timepoint specified in the individual eligibility criterion 
listed:
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use PHI in accordance with national and local 
participant privacy regulations. In the case that a participant is legally incapable of 
providing informed consent, the participant’s legally authorized representative will be 
able to provide the informed consent.
2. Aged  18 years at the time of informed consent. 
3. Weakness attributable to ALS and a confirmed SOD1 mutation. 
a.
SOD1 mutation must be confirmed by the central reader based on the sample 
obtained during the Screening Visit; participants with an SOD1 mutation interpreted 
by the central reader to be pathogenic or likely pathogenic will be eligible.
b. Additionally: 

Prognostic enrichment criteria for rapid disease progression (participants may be 
eligible based on 1 of the following 2 criteria) [Hamidou 2017; Proudfoot 2016]:

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a.
One of the following SOD1 mutations and a prerandomization ALSFRS-R 
slope decline of ≥ 0.2 per month (calculated as [48-baseline score]/time 
since symptom onset):
p.Ala5Val, p.Ala5Thr, p.Leu39Val, p.Gly42Ser, p.His44Arg, p.Leu85Val, 
p.Gly94Ala, p.Leu107Val, and p.Val149Gly  
OR
b. SOD1 mutation other than those listed in item ‘a.’ with prerandomization 
ALSFRS-R slope decline of ≥ 0.9 per month (calculated as [48-baseline 
score]/time since symptom onset)

Criteria for all other eligible participants: SOD1 mutation other than those listed in 
item ‘a.’ (no ALSFRS-R slope decline requirement).
4. For participants who meet prognostic enrichment criteria for rapid disease progression, 
SVC ≥ 65% of predicted value as adjusted for sex, age, and height (from the sitting 
position). For all other eligible participants, SVC ≥ 50% of predicted value as adjusted 
for sex, age, and height (from the sitting position).
Note: For SVC testing, at least 3 acceptable tests with the 2 highest acceptable (largest 
and next largest) efforts within 150 mL of vital capacity should be achieved.
5. If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and 
expected to remain at that dose until the final study visit.
6. If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment 
cycles) prior to Day 1 and expected to remain at that dose until the final study visit, 
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 of this study. 
7.  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.
8. All women 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 Section 15.5.
8.2.2.
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:
1. History of or positive test result for HIV.
2. Current hepatitis C infection (defined as positive HCV Ab and detectable HCV RNA). 
Participants with positive HCV Ab and undetectable HCV RNA are eligible to participate 
in the study (United States Centers for Disease Control and Prevention).

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3. Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). 
Participants with immunity to hepatitis B from previous natural infection (defined as 
negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as 
negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in 
the study.
4. Treatment with another investigational drug (including investigational drugs for ALS 
through compassionate use programs), biological agent, or device within 1 month or 
5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with 
small interfering RNA, stem cell therapy, or gene therapy is allowed.
5. Current enrollment in any other interventional study.
6. Current or anticipated need, in the opinion of the Investigator, of a DPS during the study 
period.
7. 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.
8. History of drug abuse or alcoholism within ≤ 6 months of study enrollment that would 
limit participation in the study, as determined by the Investigator.
9. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the screening period.
10. Ongoing medical condition (e.g., wasting or cachexia, severe anemia) that according to 
the Investigator would interfere with the conduct or assessments of the study. 
11. Female participants who are pregnant or currently breastfeeding.
12. 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.
13. History of allergies to a broad range of anesthetics.
14. Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not 
managed optimally could place a participant at an increased risk for intraoperative or 
postoperative bleeding. These 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). 
15. Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet 
or anticoagulant medication that cannot be safely held before and/or after an LP 
procedure according to local or institutional guidelines and/or Investigator determination. 
16. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
17. Clinically significant abnormalities in hematology or clinical chemistry parameters, as 
determined by the Investigator, which would render the participant unsuitable for 

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enrollment. For a list of normal, acceptable, and exclusionary ranges, please refer to the 
study reference guide.
18. 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.
19. Inability to comply with study requirements.
20. 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.
For Part C (Pivotal), participants who fail screening can be rescreened up to one time at the 
discretion of the Investigator. 
All screening assessments would need to be repeated during rescreening except for the 
following: 

FSH level in female participants with postmenopausal state confirmed by level obtained 
in previous screening for Part C of this study

Confirmation of SOD1 mutation by the central reader if available from previous 
screening for Part C (Pivotal) of this study
9.2.
Randomization and Registration of Participants
Parts A and B
Participants will be registered and randomized 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 prior to assignment of a unique 
identification number (registration) and randomization. Any participant identification numbers 
that are assigned will not be reused, even if the participant does not receive treatment.
Participants who withdraw from the study prior to completing the final FU visit may be replaced 
at the discretion of the Sponsor. Up to 8 replacement participants may be enrolled in Part B of 
the study (2 per cohort). These additional participants will be assigned to receive the same study 
treatment as the withdrawn participants they will replace.
Part C
For Part C, participants will be registered at Screening when a centralized IRT system will assign 
a participant identification number to each participant. Once a participant has been allocated an 
identification number, he or she is considered registered for the study. The participant’s 
identification number will be used on all of that participant’s CRFs and on all laboratory and 
other requisition forms. Any participant identification numbers that are assigned will not be 
reused even if the participant does not receive treatment. 
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 in Part C will be 
randomized 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 8.2.1 and 8.2.2 

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and that all criteria to determine which stratum the participant should be randomized to have 
been correctly entered in the IRT system. These criteria include whether the participant meets the 
prognostic enrichment criteria for rapid disease progression, SVC, riluzole use, and edaravone 
use. No participant may begin treatment prior to randomization. 
Eligible participants will be randomized in a 2:1 ratio to receive BIIB067 100 mg or placebo, 
respectively. Randomization will be stratified by 3 factors: 1) whether a participant meets the 
prognostic enrichment criteria for rapid disease progression; 2) whether a participant uses 
edaravone at baseline; and 3) whether a participant uses riluzole at baseline. Use of edaravone 
and riluzole will not be a separate stratum but will be classified as edaravone use.
Refer to the study reference guide for details on registration and randomization.
9.3.
Blinding Procedures
This is a randomized, double-blind, placebo-controlled study.
Investigators, study staff (except for a designated pharmacist/technician), and study participants 
will be blinded to the randomized study treatment assignments. The designated unblinded Study 
Pharmacy Staff will dispense the study treatment according to the DHA and randomization 
schedule and will not have responsibilities for any other study assessments. 
To maintain the study blind, it is imperative that participant treatment assignments are not shared 
with the participants, their families, or any member of the study team, either at the study site or 
at Biogen, except the unblinded designated Study Pharmacy Staff and designated Biogen 
personnel.
For Parts A and B only, the Biogen Medical Director, Global Safety Physician, Biostatistician, 
Clinical Pharmacologist, and, if required, any ad hoc members, may be unblinded in order to 
review all safety and available PK data, to assess safety and tolerability, and to make informed 
decisions regarding dose escalation (Section 7.2.1).
At each study site, a qualified and trained study site staff member will consistently perform the 
ALSFRS-R for a participant and will remain blinded both to the participants’ treatment 
assignments and to the results of other assessments.
At the end of the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, Biogen will provide the randomization codes to 
Investigators, who then can inform their participants about the treatment received. 
For information pertaining to unblinding for medical emergencies, see Section 15.4.3.1.

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10.
DISCONTINUATION OF STUDY TREATMENT OR 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY
10.1.
Withdrawal from the Study (Part A) or Discontinuation of Study 
Treatment (Parts B and C)
A participant must be withdrawn from Part A of the study (SAD), or permanently discontinue 
study treatment in Part B (MAD) and Part C (Pivotal) of the study, 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 experiences a medical emergency that necessitates unblinding of the 
participant’s treatment assignment.

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 treatment in Part B may remain in the study and continue 
protocol-required tests and assessments.
Participants who discontinue study treatment in Part C will be encouraged to remain in the study 
and complete all appropriate protocol-specified tests and assessments. It is recommended that 
participants who terminate early (i.e., discontinue both study treatment and study assessments) 
perform the assessments of the EOS Visit (Week 28 Visit) within 4 weeks after the last dose of 
study treatment. Home assessments will be allowed at the discretion of the Investigator for 
participants who cannot come to the site in person for their Early Termination Visit. 

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11.
STUDY TREATMENT USE
11.1.
Regimen
Each participant will receive a 15-mL intrathecal bolus (over 1-3 minutes) of study treatment 
(BIIB067 or placebo). 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. Detailed instructions are provided in the DHA. 
11.1.1.
BIIB067
In Part A (SAD), a single dose of BIIB067 will be administered by intrathecal bolus over 
1-3 minutes at the following planned dose levels: 
Cohort 1: BIIB067 10 mg (FIH dose)
Cohort 2: BIIB067 20 mg
Cohort 3: BIIB067 40 mg
Cohort 4: BIIB067 60 mg
In Part B (MAD), 5 doses of BIIB067 will be administered by intrathecal bolus over 1-3 minutes 
as follows: a loading regimen of 3 doses on Days 1, 15, and 29, followed by maintenance dosing 
on Days 57 and 85 for each cohort. The following dose levels are planned:
Cohort 5: BIIB067 20 mg
Cohort 6: BIIB067 40 mg
Cohort 7: BIIB067 60 mg
Cohort 8: BIIB067 100 mg
In Part C (Pivotal), 8 doses of BIIB067 100 mg will be administered by intrathecal bolus over 
1-3 minutes as follows: a loading regimen of 3 doses on Days 1, 15, and 29, followed by 
5 maintenance doses every 28 days (or 4 weeks).
11.1.2.
Placebo
Matching placebo will be administered by intrathecal bolus over 1-3 minutes, following the same 
dosing regimen as BIIB067, for each cohort.
11.2.
Modification of Dose and/or Treatment Schedule
The dosage should not be modified, other than as stated in Section 7.2.1. However, for Parts A 
and B only, if necessary (e.g., dose is not tolerated), after review of all available data by the 
Biogen Medical Director, a Global Safety Physician, the PI, and, if required, any ad hoc 
members, an alternative dose or dosing regimen may replace the planned dose or dosing regimen 
for the subsequent cohort.
No dosage modification will be done in Part C.

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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 study 
visit (Day 57 for participants participating in Part A [SAD] only; Day 169 for participants 
participating in both Parts A [SAD] and B [MAD] or in Part B [MAD]; and Day 197 or Day 225 
for participants participating in Part C [Pivotal] only).
11.3.1.1.
Allowed Concomitant Therapy
Participants taking concomitant riluzole 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 riluzole should be discontinued for 
medical reasons, in which case it may not be restarted.
For Part C, 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) 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 of this study.
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.
Daily intake of all concomitant vitamins and supplements should be stabilized at least 14 days 
prior to Day 1. Doses of vitamins, minerals, and supplements greater than the recommended 
daily dose should be discouraged during the study.
Supplements that are subject to dose limits from at least 14 days prior to Day 1 and that should 
remain stable throughout the study are as follows: creatine 5 g per day and vitamin E 1000 IU 
per day. These daily limits include the total doses obtained through the combination use of daily 
multivitamins and supplements.
11.3.1.2.
Disallowed Concomitant Therapy
Any antiplatelet or anticoagulant medication that cannot be safely held before and/or after an LP 
procedure 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. 
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. 

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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 FU visit.

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12.
STUDY TREATMENT MANAGEMENT
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
For Parts A and B, Biogen will supply BIIB067 as a liquid in vials containing approximately 
5.5 mL per vial, to ensure 5.0 mL deliverable volume. The drug product is a sterile, parenteral 
solution formulation that contains BIIB067 drug product 20 mg/mL, sodium dihydrogen 
phosphate dihydrate 0.050 mg/mL, sodium phosphate dibasic anhydrous 0.097 mg/mL, sodium 
chloride 7.597 mg/mL, potassium chloride 0.224 mg/mL, calcium chloride dihydrate 
0.206 mg/mL, and magnesium chloride hexahydrate in water for injection 0.163 mg/mL. If 
necessary, pH is adjusted to a target pH of 7.2 with hydrogen chloride or sodium hydroxide 
during compounding.
For Part C, Biogen 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 0.03 mg/mL, sodium phosphate dibasic 
anhydrous 0.11 mg/mL, sodium chloride 8.77 mg/mL, potassium chloride 0.22 mg/mL, calcium 
chloride dihydrate 0.21 mg/mL, and magnesium chloride hexahydrate in water for injection 
0.16 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 Biogen 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 Biogen, 
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 Biogen, by providing, in writing, the destruction 
policy or details of the method of destruction. After such destruction, Biogen 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, all vials both used and unused, must be saved 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 Biogen. A written 
explanation must be provided for any discrepancies.
12.2.
Placebo Product
Biogen manufactures the matching placebo (artificial CSF), supplied as a liquid in vials 
containing approximately 20 mL per vial for use in Parts A and B and approximately 21 mL per 
vial for use in Part C. The drug supply label will include conditions for storage, lot number, and 
other pertinent information. 
Placebo is to be stored at 2C to 8C (36F to 46F), in a monitored, locked cabinet with limited 
access.

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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: 

cranial nerves, coordination/cerebellar function, reflexes, motor, and MMSE (a 
30-point questionnaire that is used to measure cognitive impairment) [in Part B]

MMSE, motor, reflexes, and coordination/cerebellar function (in Part C) 

Vital sign measurements: temperature, pulse rate, systolic and diastolic blood 
pressure, and respiratory rate will be performed after the participant has rested in a 
sitting position for at least 5 minutes

Weight measurements

12-Lead ECGs in triplicate (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.

Coagulation: INR, PT, and APTT

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

Urinalysis: dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal) 

Urine and/or serum pregnancy tests

CSF analysis: red blood cell count, white blood cell count, protein, and glucose  

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14.3.
Product-Specific Safety Assessments
Anti-BIIB067 Ab 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

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 

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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
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment.
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 Biogen 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 FU 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, each post-LP telephone contact, the EOS 
Visit (Part C Week 28), or the Safety FU (Alternative EOS) Visit (Week 32) for participants who 
do not roll over or have delays in rollover into the LTE Study 233AS102), the Investigator will 
assess the participant for AEs and will record any new AEs or updates to previously reported 
AEs on the CRF.
15.3.2.
Serious Adverse Events
Any SAE experienced by the participant between the time of the signing of the first (main) ICF 
and the last FU 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 Biogen within 24 hours as described 
in Section 15.3.3. FU information regarding an SAE also must be reported within 24 hours. 
Participants will be followed for all SAEs until the final study visit. Thereafter, the event should 
be reported to Biogen 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.
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 Biogen within 24 hours of the study site staff becoming aware of the SAE. It is 
the Investigator’s responsibility to ensure that the SAE reporting information and procedures are 
used and followed appropriately.

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Reporting Information for SAEs
A report must be submitted to Biogen 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 FU information on an SAE, fax or email 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. The Investigator should make every effort to obtain and send death 
certificates and autopsy reports to Biogen. 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 Biogen to be related to 
the study treatment administered.
Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory reporting. 
Biogen will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies according 
to local law. Biogen will submit SUSARs to Investigators in a blinded fashion.
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 Biogen 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 Biogen. 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.

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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 Biogen within 24 hours of the site 
becoming aware of the overdose. An overdose must be reported to Biogen 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 or 
emailed to Biogen; 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 when knowledge of the participant’s treatment assignment may 
influence the participant’s clinical care, the Investigator and, if applicable, designated personnel 
at Biogen may access the participant’s 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 treatment assignment to any individual not 
directly involved in managing the medical emergency, nor to personnel involved with the 
analysis and conduct of the study. The Investigator can contact Biogen or designee to discuss 
such situations.
15.5.
Contraception Requirements
All women of childbearing potential must ensure that effective contraception is used during the 
study and for 5 months 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) 

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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.
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 Biogen within 24 hours of 
the study site staff becoming aware of the event.

Pursue SAE FU information actively and persistently. FU information must be 
reported to Biogen within 24 hours of the study site staff becoming aware of new 
information.

Ensure all AE and SAE reports are supported by documentation in the participants’ 
medical records.

Pursue AE FU information, if possible, until the event has resolved or become stable.

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
Report SAEs to local ethics committees, as required by local law.
15.6.2.
Biogen 
Biogen’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.

Biogen 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.
Part A (SAD) and Part B (MAD)
The ITT population is defined as all randomized participants who receive at least 1 or a part of 
1 dose of study treatment.
16.1.1.
Clinical Function
16.1.1.1.
Analysis Population
The clinical function set is defined as the subset of the ITT population who have at least 
1 postdose measurement.
All participants receiving placebo will be combined to form placebo control groups for Part A 
(SAD) and for Part B (MAD). A separate statistical analysis will be performed for Part A (SAD) 
and for Part B (MAD).
16.1.1.2.
Methods of Analysis
The change and percent change from baseline in 
 HHD, ALSFRS-R, SVC, 
 will be summarized by visit and dose level using 
descriptive statistics and, where warranted, presented graphically. A 2-sample Student’s t-test 
will be used to compare these data between each dose of BIIB067 and placebo at a 2-sided alpha 
level of 0.10. 
16.1.2.
Pharmacokinetics
16.1.2.1.
Analysis Population
The PK population is defined as the subset of the ITT population of participants with at least 
1 postdose PK measurement.
16.1.2.2.
Methods of Analysis
Plasma and CSF PK parameters and BIIB067 concentrations in plasma and CSF for the PK 
population will be summarized using descriptive statistics and, where warranted, presented 
graphically.
16.1.3.
Pharmacodynamics
16.1.3.1.
Analysis Population
The PD population is defined as the ITT population of participants with at least 1 PD 
measurement after baseline.

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16.1.3.2.
Methods of Analysis
Changes and percent changes from baseline for total SOD1 protein levels will be summarized 
and presented by visit and by dose level. A 2-sample Student's t-test will be used to compare 
each dose of BIIB067 and placebo at a 2-sided alpha level of 0.10.
16.1.4.
Biomarker and Pharmacogenomic Analyses
16.1.4.1.
Analysis Population
The biomarker population is defined as the ITT population of participants with at least 
1 postbaseline biomarker measurement.
16.1.4.2.
Methods of Analysis
CSF and blood samples may be assayed for biomarkers that may include, but will not be limited 
to, 
 pNfH, and NfL.
Exploratory potential biomarker candidates related to BIIB067 biological activity will be 
summarized using descriptive statistics and will be presented by dose level.
Summary statistics (raw and logarithmic scale) for the above potential biomarkers will be 
calculated and presented by dose level and by visit, and their mean and median levels will be 
plotted over time, as appropriate.
See Section 4 for information on when samples will be collected.
Sampling for this analysis will be approved at the discretion of each site’s ethics committee. If a 
site’s ethics committee does not approve the sampling for the analysis, this section will not be 
applicable to that site.
16.1.5.
Safety
16.1.5.1.
Analysis Population
The safety population is defined as the ITT population of participants.
16.1.5.2.
Methods of Analysis
16.1.5.2.1. Adverse Events
AEs will be coded using MedDRA.
The incidence of all AEs and SAEs will be summarized by system organ class and preferred term 
for each dose level. AEs will also be summarized by severity and relationship to study treatment. 
Narratives of deaths, SAEs, and AEs that led to study withdrawal, at a minimum, will also be 
provided.
16.1.5.2.2. Clinical Laboratory Results
Clinical laboratory evaluations include hematology, coagulation, blood chemistry, and urinalysis. 
Laboratory data will be summarized using shift tables. The number and percentage of 
participants with shifts from baseline to high or low status for hematology, coagulation, and 

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blood chemistry, and shifts from baseline to high or positive status for urinalysis will be 
presented by dose level. In addition, summaries of the shift from baseline to the maximum 
postbaseline value and the shift from baseline to the minimum postbaseline value will presented 
by cohort. 
16.1.5.2.3. Vital Signs
Changes from baseline will be summarized for all vital signs by dose levels. A separate summary 
will be presented for incidence of clinically significant changes from baseline.
16.1.5.2.4. Columbia Suicide Severity Rating Scale
C-SSRS data will be summarized by dose level using descriptive statistics (number of 
participants, mean, SD, median, minimum, and maximum) for continuous variables, and using 
frequency and percentage for discrete variables.
16.1.5.2.5. Physical Examinations
The changes from baseline will be summarized by dose level.
16.1.5.2.6. Limited Neurological Examinations
The changes from baseline in the limited neurological examination (MMSE, cranial nerves, 
coordination/cerebellar function, motor and reflexes) will be summarized by dose level.
16.1.5.2.7. 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 be 
summarized by dose level. 
16.1.6.
Antigenicity/Immunogenicity Data
16.1.6.1.
Analysis Population
The analysis population for immunogenicity is defined as all participants who receive at least 
1 dose of study treatment and have at least 1 postdose immunogenicity sample collected.
16.1.6.2.
Methods of Analysis
Results will be summarized by dose level.
16.1.7.
Interim Analyses
In Part A (SAD) of the study, CRM will be used as supporting evidence for continuous 
assessment of MTD for dose escalation decisions. In Part B (MAD) of the study, in addition to 
the safety review (blinded), a designated team of staff will review the available unblinded but 
de-identified PD and/or biomarker data (e.g., levels of total SOD1 protein and pNfH) from all 
previous cohorts at the completion of the last Day 106 visit of each cohort to determine whether 
to proceed with the subsequent planned dose cohorts. An interim analysis of key safety, 
secondary, and exploratory endpoints may be conducted based on data up to the 60-mg and/or 

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100-mg dose cohort to allow for the planning of the pivotal efficacy and safety study. The 
participants, investigative staff, and sponsor’s staff responsible for site monitoring and data 
management will remain blinded to treatment assignment during the ongoing data review, as 
well as during interim analyses, to minimize the potential for bias in the data cleaning process. 
Details of the interim analysis will be provided in a separate statistical analysis plan.
16.1.8.
Sample Size Considerations
The maximum sample size of 36 participants for Part A of the study (SAD) is based on clinical 
rather than statistical considerations. Participants will be randomized to receive BIIB067 or 
placebo in a 3:1 ratio in each cohort. Each cohort will have a minimum of 4 participants (3 active 
and 1 placebo), and a maximum of 12 participants (9 active and 3 placebo). The final number for 
each cohort will be dependent on the DLT profile. If no DLT occurs in any dose level, then a 
total of 20 participants (15 active and 5 placebo) will be randomized. This design will allow for 
adequate evaluation of the safety of BIIB067, should DLT be encountered, as well as minimize 
participant exposure at subtherapeutic single doses.
For Part B (MAD), up to 48 participants will be enrolled in up to 4 cohorts, with up to 
9 participants randomized to receive BIIB067 and 3 participants randomized to receive placebo 
for each cohort. This design will provide approximately 80% power to detect a difference in total 
SOD1 protein reduction between 25% from the BIIB067 group and 12% from the placebo group 
at a 10% significance level. The sample size calculation assumes the same 10.5% SD in the 
2 treatment groups.
16.2.
Part C
The ITT population is defined as all participants who are randomized and receive at least 1 dose 
of study treatment.
16.2.1.
Clinical Function
16.2.1.1.
Analysis Population
The primary analyses of clinical function will be evaluated in the mITT population (see 
Section 8.2.1 for definition) comprising the subset of the population who meet prognostic 
enrichment criteria for rapid disease progression who are randomized and receive at least 1 dose 
of study treatment. The primary analysis population will comprise participants who meet 
prognostic enrichment criteria for rapid disease progression to enable detection of a statistically 
significant and clinically meaningful treatment effect on clinical function over the 6-month 
treatment duration. The treatment effect of clinical function endpoints in the non-mITT 
population will be analyzed, where relevant, with nominal p-values presented. The clinical 
function data in the overall ITT population will be summarized and analyzed where relevant.
16.2.1.2.
Methods of Analysis
16.2.1.2.1. Analysis of the Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline to Week 28 in the ALSFRS-R total 
score, which will be analyzed as follows, depending on 2 scenarios:

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1. If the number of deaths across both treatment arms is ≥ 3 (i.e., ≥ 5% deaths out of a total 
of 60 patients in the mITT population), the JRT methodology to account for mortality 
[Berry 2013] will be used for the primary inference. When implementing the JRT 
methodology, MI will be used to handle withdrawals. The estimates will be obtained 
from an ANCOVA for change from baseline in ALSFRS-R at Week 28 with missing data 
imputed using MI. The corresponding nominal p-value from the ANCOVA will be 
presented as a sensitivity analysis. 
2. If the number of deaths is < 3 (i.e., < 5% deaths out of a total of 60 patients in the mITT 
population), ANCOVA with MI will be used as the primary analysis method for both 
inference and estimates. The p-value from the JRT will be presented as a sensitivity 
analysis.
The primary estimand is described as follows:
The primary analysis for the primary endpoint is the composite estimand [ICH 2017]. The 
estimand of the primary analysis is defined as follows:

Population: all participants in the mITT population.

Variable: change from baseline to Day 197 in the ALSFRS-R total score.

Handling of intercurrent events: Relevant intercurrent events are handled using a 
composite strategy in which participants who have these intercurrent events are 
ranked against each other and against participants without any intercurrent event 
using the joint rank methodology based on MI datasets. The relevant intercurrent 
events are deaths and withdrawals. These participants will be handled using the 
composite strategy and ranked as described in this section. For withdrawals, this will 
be based on the imputed value for Day 197 from the MI datasets. 

Summary statistics: difference between treatment groups in least square means of 
Day 197 change from baseline with corresponding standard errors and 95% 
confidence intervals taken from the ANCOVA for change from baseline to Day 197, 
based on the MI datasets. The ANCOVA model will include treatment group as a 
fixed effect and covariates for ALSFRS-R total score, baseline disease duration since 
symptom onset, and use of riluzole or edaravone. 
For the JRT analysis, the ranked scores will be analyzed for each of the 
100 MI-complete datasets using an ANCOVA model with treatment included as a 
fixed effect and adjusted for the following covariates: baseline disease duration since 
symptom onset, baseline ALSFRS-R total score, and use of riluzole or edaravone. 
The p-value will be based on combining the estimates for the treatment differences 
using PROC MIANALYZE. The difference between treatment groups in median 
changes from baseline to each visit will be presented with 95% confidence intervals 
based on the MI datasets, as well as the p-value from the JRT for Day 197. The joint 
rank analysis will only be performed for the mITT population. 
The joint rank procedure allows for a statistical test of the treatment effect on the ALSFRS-R 
total score while accounting for truncation of data due to deaths. In this analysis, a participant’s 
joint rank score will be calculated by comparing each participant to every other participant in the 

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study, resulting in a score of +1 if the outcome was better than the participant being compared, -1 
if worse, and 0 if the same. The participant’s score will then be calculated by summing their 
comparison to all the other participants in the study. 
For the purpose of this calculation, participants will be grouped into the following 2 categories:

Group 1: Participants who complete the study and have data available at the Day 197 
assessment AND participants who withdraw from the study due to reasons other than 
death

Group 2: Participants who die
MI will be used to impute all missing data before determining the rank score, including 
intermittent data and data after withdrawal from the study except after death.
In each of the 100 imputed datasets, participants will be ranked as follows:

Participants in Group 2 will be given lower ranks than participants in Group 1, with 
the lowest ranks being given to the participants who die in the shortest time after first 
dose. Progressively higher ranks will be given to participants who die at longer times 
after first dose.

Participants in Group 1 will rank higher than participants in Group 2. Progressively 
higher ranks will be given to participants with a higher change from baseline at 
Day 197, i.e., a smaller decline at Day 197.
Further details will be described in the statistical analysis plan. 
The primary inference will be based on the mITT population. The treatment comparison will be 
based on a 2-sided α level of 0.05. 
If the second scenario occurs, i.e., in both the active and placebo treatment groups combined the 
number of participants who died is < 3 (e.g., < 5% deaths out of a total of 60 participants in the 
mITT population), the primary efficacy analysis will be the change from baseline in ALSFRS-R 
total score, analyzed using an ANCOVA based on data imputed using MI. The ANCOVA model 
will include treatment group as a fixed effect and covariates for each of the corresponding 
baseline value for ALSFRS-R total score, baseline disease duration since symptom onset and use 
of riluzole or edaravone. The primary inference will be based on the treatment comparison at 
Week 28. A 2-sided α level of 0.05 will be used. Treatment differences at other visits will also be 
presented with nominal p-values.
Sensitivity, supplementary and subgroup analyses of the primary efficacy endpoint will be 
specified in the statistical analysis plan.
For the non-mITT population, the analysis will be the change from baseline in ALSFRS-R total 
score, analyzed using an ANCOVA based on data imputed using MI. The ANCOVA model will 
include treatment group as a fixed effect and covariates for each of the corresponding baseline 
value for ALSFRS-R total score, baseline disease duration since symptom onset, and use of 
riluzole or edaravone. Least square means with standard errors will be presented for each 
treatment group. The difference between treatment groups in least square means for change from 
baseline at each visit, with corresponding standard errors and 95% confidence intervals, will be 
presented with nominal p-values.

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16.2.1.2.2. Analysis of the Secondary Efficacy Endpoints
Formal testing of secondary efficacy endpoints will be in the mITT population alone. For the 
non-mITT and ITT populations, there will be no formal testing of efficacy endpoints. Testing of 
PD endpoints is discussed in Section 16.2.3. The analyses of secondary endpoints for the mITT 
population will be based on a sequential testing procedure in the order of the rank of secondary 
endpoints as listed below if the primary endpoint is statistically significant at a 2-sided α level 
of 0.05:

Change from baseline (i.e., ratio) to Week 28 (Day 197) in CSF total SOD1 protein

Change from baseline (i.e., ratio) to Week 28 (Day 197) in NfL in plasma

Change from baseline to Week 28 (Day 197) in SVC

Change from baseline to Week 28 (Day 197) in HHD megascore to assess muscle 
strength, as measured by the HHD device

Time to death or permanent ventilation, which is defined as the time to the earliest 
occurrence of one of the following events:

Death 

Permanent ventilation (≥ 22 hours of mechanical ventilation [invasive or 
noninvasive] per day for ≥ 21 consecutive days)

Time to death
The treatment effect will be assessed at each step at a 2-sided α level of 0.05. The primary 
inference at each step will be based on the mITT population.
This procedure will control the Type I error for the secondary endpoints. If statistical 
significance is not achieved for a secondary endpoint, all secondary endpoints of a lower rank 
will not be considered statistically significant. 
There will be no adjustment for multiple testing for the sensitivity or supplementary analyses for 
the primary and secondary endpoints, the exploratory endpoints or subgroup analyses.
The first and second endpoints in the ranking are PD endpoints, for which the analysis is 
described in Section 16.2.3.
The third secondary endpoint will be change from baseline to Day 197 in percent predicted SVC. 
If the number of deaths across both treatment arms is ≥ 3 (i.e., ≥ 5% deaths out of a total of 
60 patients in the mITT population), the primary inference will be based on the JRT 
methodology with MI to impute missing data; ANCOVA with MI for change from baseline will 
be used to obtain the estimates, and nominal p-values will be presented. If the number of deaths 
is < 3 (i.e., < 5% deaths out of a total of 60 patients in the mITT population), ANCOVA with MI 
will be used as the primary analysis of this endpoint. The ANCOVA model will include 
treatment group as a fixed effect and covariates for baseline percent predicted SVC, baseline 
disease duration since symptom onset, and use of riluzole or edaravone. Treatment differences at 
other visits will also be derived from the model for exploratory purpose.

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16.2.4.
Safety
16.2.4.1.
Analysis Population
The safety population will be defined as all participants who received at least 1 dose of study 
treatment (i.e., the overall ITT population).
16.2.4.2.
Methods of Analysis
All AEs, laboratory data, ECG, neurological and physical examinations, and vital signs will be 
evaluated for safety.
16.2.4.2.1. Adverse Events
Only TEAEs will be presented in the summary tables. Treatment-emergent is defined as having 
an onset date that is on or after start of study treatment, or that is worsened after the start of study 
treatment.
Incidence of TEAEs will be summarized by treatment groups, overall, by severity, by 
relationship to LP, and by relationship to study treatment. SAEs, discontinuations and 
withdrawals due to AEs, AEs leading to hospitalization, and deaths will also be summarized or 
listed, depending on number of events. The summary tables will include incidence estimates for 
overall system organ class as well as for preferred terms within each system organ class. AEs 
will be coded using MedDRA. A subset of AE outputs will also be presented by disease 
progression subgroup (“participants who meet prognostic enrichment criteria for rapid disease 
progression”, “other eligible participants”).
16.2.4.2.2. Clinical Laboratory Results
Laboratory data will be summarized using shift tables. Shifts from baseline to high/low status for 
hematology and blood chemistry parameters, and shifts from baseline to high/positive status for 
urinalysis will be presented. In addition, the shift from baseline to the maximum postbaseline 
value and the shift from baseline to the minimum postbaseline status will be presented for each 
laboratory test by treatment group. Summary statistics for actual values and change from 
baseline will also be presented for quantitative laboratory data. 
16.2.4.2.3. Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities. 
16.2.4.2.4. Electrocardiogram
The number and percentage of participants with shifts to categorical values (abnormal not AE, or 
abnormal AE) will be summarized by treatment group. 
16.2.4.2.5. Columbia Suicide Severity Rating Scale
The C-SSRS data will be summarized by treatment group.

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16.2.5.
Participant-Reported Outcomes on Quality of Life
16.2.5.1.
Analysis Population
The analysis of the participant-reported outcome endpoints will be performed primarily for the 
mITT population but also for the non-mITT population. 
16.2.5.2.
Methods of Analysis
The quality of life measures will be analyzed using an ANCOVA with MI with fixed effect for 
treatment and covariates for corresponding baseline value, baseline disease duration since 
symptom onset and use of riluzole or edaravone. The treatment difference at Day 197 will be 
derived from the model. Treatment differences at other visits will also be derived from the model 
for exploratory purpose. Nominal p-values will be presented.
16.2.6.
Interim Analyses
There will be no interim analysis performed.
16.2.7.
Sample Size Considerations
For Part C, approximately 99 participants will be randomized, with approximately 66 participants 
administered BIIB067 100 mg and approximately 33 participants administered placebo in a 2:1 
ratio.
This sample size for Part C is selected primarily based on the JRT combining the Week 28 
change from baseline in ALSFRS-R and mortality in the mITT population (N = 60). The 
observed results from an interim analysis of Study 233AS101 in participants who met the 
prognostic criteria for rapid disease progression as well as the observed ALSFRS-R slope decline 
in participants who received placebo in a similar ALS population with SOD1 mutation [Benatar 
2018] are the basis of assumed treatment effect and the variability. Participants from both 
datasets were matched with the prognostic criteria for rapid disease progression specified in this 
protocol for Part C (i.e., one of the protocol-defined SOD1 mutations and a prerandomization 
ALSFRS-R slope decline of ≥ 0.2 per month or a prerandomization ALSFRS-R slope decline of 
≥ 0.9 with SOD1 mutation NOT on the protocol-defined list). This resulted in a total of 12 
placebo control participants who met the prognostic criteria for rapid disease progression (8 from 
the historical placebo data [Benatar 2018] and 4 from Study 233AS101) and 4 matched 
participants treated with BIIB067 100 mg from interim data of a very small cohort in Study 
233AS101. The observed mean slope of decline was -3.83 for the matched placebo participants 
and -0.74 for the matched BIIB067 100 mg participants, with a pooled SD of 3.166. In the 12 
matched participants on placebo, there was 1 death and 2 participants with permanent assisted 
ventilation less than 6 months but none in the BIIB067 100 mg matched participants. Based on 
this and overall survival data in patients who met the prognostic criteria for rapid disease 
progression from the literature on patientss with an A4V SOD1 mutation, the survival at Week 
28 was assumed to be 82% in the placebo control and 90% in the BIIB067 100 mg group. 
Under the above assumptions, with N = 60 participants in the mITT population and a two-sided 
significance level of 0.05, the JRT gives 84% power. Because events of death have been factored 
into the analysis, no sample size overage is planned for missing values. 

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For the non-mITT population, the primary focus will be on the PD endpoint, CSF total SOD1 
protein concentration, as this population is anticipated to have a slower decline in clinical 
function compared to the mITT population. A sample size of 26 participants in the treated group 
and 13 participants in the placebo group for the non-mITT population would provide 97% power 
to detect a 25% reduction in CSF total SOD1 protein from baseline in the treated group, with an 
assumed SD of 0.216 (natural log scale), compared to the placebo group. 

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17.
ETHICAL REQUIREMENTS
Biogen 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. Biogen will submit documents on behalf of the 
investigational sites. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
Biogen. After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
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 Biogen.
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. 
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.

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Participants will be informed, where applicable, that their race and ethnicity will be collected 
during the study (unless the collection is not permitted by applicable law or not approved by the 
governing ethics committee) and the data will be used during analysis of study results. 
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 be collected (unless the collection is not 
permitted by applicable law or not approved by the governing ethics committee). These data will 
be used in the analysis of the safety and/or PK profile of the study treatment. It is unknown 
whether the effects of the study treatment are influenced by race or ethnicity. 
The participant will not be identified by name in the CRF or in any study reports, and these 
reports will be used for research purposes only. Biogen, 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
Biogen 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 
Biogen or partnering companies) with the participant before the participant makes a decision to 
participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen 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 Biogen 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 Biogen 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 due to 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 due to participant’s 
preference. 
A third-party vendor has been engaged to perform the following assessments at the study 
participant’s home:
1. Limited neurological examination, including the MMSE
2. Physical examination
3. Vital signs
4. Height and body weight collection
5. SVC
7. Pregnancy test (if applicable)
8. HHD
10. Collection/shipment of ventilation diary records
The following assessments can be performed via the phone (telemedicine) by the site staff:
1. ALSFRS-R
4. Assessing changes in signs and symptoms as well as review of concomitant medications 
and AEs
The following assessments can be performed at the study participant’s home OR via the phone 
(telemedicine) by the site staff:
1.  Health outcome measures
a.

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19.3.
Study Committees
19.3.1.
Safety Surveillance Team
A safety surveillance team, consisting, at a minimum, of the Biogen Medical Director and a 
Global Safety Physician will monitor dose escalation, as described in Section 7.2.1.
19.3.2.
Independent Data Monitoring Committee
An IDMC will be formed to review ongoing safety and tolerability data, as described in 
Section 7.4.2.2. 
19.3.3.
Endpoint Adjudication Committee
In Part C, time to death or permanent ventilation will be determined in a blinded fashion by a 
central, independent EAC. Procedures for reviewing and adjudicating events are described in the 
Charter that governs the operation of the EAC. 
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, Biogen 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 laws or regulations. Prior to proceeding 
with destruction of records, the Investigator must notify Biogen in writing and receive written 
authorization from Biogen to destroy study records. In addition, the Investigator must notify 
Biogen 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
Biogen 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 Biogen.

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20.
REFERENCES
Amyotrophic Lateral Sclerosis Online Genetics Database (ALSoD). 2015.
Andersen PM, Nilsson P, Keränen ML, et al. Phenotypic heterogeneity in motor neuron disease 
patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain. 1997;120 ( Pt 
10):1723-37.
Benatar M, Wuu J, Andersen PM, et al. Randomized, double-blind, placebo-controlled trial of 
arimoclomol in rapidly progressive. Neurology. 2018;90(7):e565-e574. Epub 2018/01/24.
Berry JD, Miller R, Moore DH, et al. The Combined Assessment of Function and Survival 
(CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal 
Degener. 2013;14(3):162-8. Epub 2013/01/17.
Bruijn LI, Cleveland DW. Mechanisms of selective motor neuron death in ALS: insights from 
transgenic mouse models of motor neuron disease. Neuropathol Appl Neurobiol. 
1996;22(5):373-87.
Bruijn LI, Houseweart MK, Kato S, et al. Aggregation and motor neuron toxicity of an ALS-
linked SOD1 mutant independent from wild-type SOD1. Science. 1998;281(5384):1851-4.
Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating 
scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). 
J Neurol Sci. 1999;169(1-2):13-21.
Cudkowicz ME, McKenna-Yasek D, Sapp PE, et al. Epidemiology of mutations in superoxide 
dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997;41(2):210-21.
Fischer LR, Li Y, Asress SA, et al. Absence of SOD1 leads to oxidative stress in peripheral 
nerve and causes a progressive distal motor axonopathy. Exp Neurol. 2012;233(1):163-71.
Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human 
Cu,Zn superoxide dismutase mutation. Science. 1994;264(5166):1772-5.
Hamidou B, Marin B, Lautrette G, et al. Exploring the diagnosis delay and ALS functional 
impairment at diagnosis as relevant criteria for clinical trial enrolment. Amyotroph Lateral Scler 
Frontotemporal Degener. 2017;18(7-8):519-527. Epub 2017/08/01.
International Council For Harmonisation Of Technical Requirements For Pharmaceuticals For 
Human Use. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials.
Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur 
Respir J. 2005;26(1):153-61.
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor 
neuron disease (MND). Cochrane Database Syst Rev. 2012;3:CD001447.

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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Study to Evaluate the Efficacy, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects with 
Amyotrophic Lateral Sclerosis and Confirmed 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)

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APPENDIX A. CONTINUOUS REASSESSMENT METHOD
A CRM is a working model that operates by continuously refining the assumptions about the 
dose toxicity relationship after each participant or group of participants are dosed and observed 
[O'Quigley 1990]. By utilizing the information from nonclinical and clinical studies, and 
continuously updating the information during the study, the CRM is able to minimize the number 
of participants exposed to lower doses, which are not expected to be effective, and obtain a more 
accurate estimate of the MTD. The MTD for this therapy is defined as the highest tested dose 
with a less than 33% DLT rate at Day 15. 
With this CRM, the DLT rate will be continuously assessed as data from groups of 4 participants 
(3 randomized to active treatment and 1 to placebo) becomes available. The first group will 
receive the lowest dose level (10 mg). For dose escalation or de-escalation decisions, no more 
than 1 dose level will be allowed at a time. The CRM algorithm requires specifying prior 
distributions on the model parameter. A vague prior distribution is normally utilized based on 
nonclinical animal toxicology data and relevant clinical data. Whenever DLT data from each 
group of participants are available, the parametric model will be updated with all the 
accumulated DLT data. The posterior probability of DLT of each dose will be calculated and 
used to find the highest dose that has at most 50% posterior probability of being intolerable (i.e., 
DLT rate > 33%).
Specifically, the probability of observing a DLT, p(x) at each dose level (d) will be estimated 
through a 2-parameter logistic model:
P(Y = 1|dose = x=log(d/10)) = p(x) = exp(β0+ β1x)/[1+ exp(β0+ β1x) ],
where Y is the binary indicator of a DLT for a given dose d, and x is the standardized dose for d, 
in reference to the 10-mg dose. At the beginning of the study, we set slightly informative prior 
distributions for the 2 logistic regression parameters, the intercept (β0) and the slope (β1) as 
follows: β0~ N(-3.89, 1.02) and β1 ~ N(1.82, 0.32)I(0, ∞). The truncated normal distribution for β1 
ensures that the probability of DLT is a monotonic increasing function of dose. After DLT data 
from 15 participants receiving active treatment are available, the prior distribution for β0 will be 
replaced by N(-3.89, 2.02). Similarly, after DLT data from the 60 mg cohort are available, the 
prior distribution for β1 will be replaced by N(1.82, 0.62)I(0,∞). Such change will ensure that the 
dose toxicity curve is more driven by the safety data collected toward the end of the study.
These initial prior distributions are selected so that the induced prior distributions on DLT rate 
will yield a median DLT rate of approximately 2% (95% credible interval 0.003, 0.127) at the 
10-mg dose, and approximately 35% (95% credible interval 0.054, 0.832) at the 60-mg dose. The 
expected DLT rates were determined based on the safety data on BIIB067 from the toxicology 
study in monkeys, where no clinical findings were observed, and from prior clinical trials, where 
up to 12 mg of other ASO treatments were shown to be well tolerated in repeated-dose studies in 
patients with ALS or spinal muscular atrophy. Toward the end of the study, the prior 
distributions β0~ N(-3.89,2.02) and β1 ~ N(1.82, 0.62)I(0,∞) will induce prior distributions with 
the same median DLT rate but much wider 95% credible intervals (0, 0.513 for 10-mg and 0.006, 
0.979 for 60-mg dose, respectively).

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The details of the CRM algorithm are as follows:
Step 1: The first group of participants will be assigned to the lowest dose level, i.e., 10 mg. Set 
d1*=log(d1/10)=0.
Step 2: For any group k, we calculate the posterior probability of DLT rate ≥ 33% for all d1*,… 
dr*, where di* =log(di/10),
πk(di*) = P(p(di*) ≥ 0.33 | yk), i=1,…, r,
where yk denotes the DLT data collected from the first (k-1) groups. 
The kth group will be assigned to the highest planned dose level whose posterior probability of 
DLT rate larger than 33% is less than 50%, with a restriction to a change of no more than one 
dose level at a time. 
Step 2 will be repeated until one of the following conditions is encountered:
1. a total of 27 active and 9 placebo participants have been enrolled, or
2. the highest planned dose has tested 6 active and 2 placebo participants and the posterior 
probability of DLT rate of the highest dose larger than 33% is less than 20%, or
3. MTD dose has tested 9 active and 3 placebo participants.
At the completion of the trial, the highest tested dose with less than 50% posterior probability of 
being intolerable will be labeled as the MTD, or highest tested safe dose, which will be based on 
all the trial data, including the last group of participants.

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Biogen MA Inc.
225 Binney Street
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United States
Biogen Idec Research Limited
Innovation House
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SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS101
A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral 
Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Version 8
Date: 15 June 2021
EUDRA CT Number: 2015‐004098‐33
Version 8 of the protocol has been prepared for this amendment, which supersedes Version 7.

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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 233AS101 is to update to reflect the final 
statistical analysis plans.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 16.2.1.2.1, Analysis of the Primary Efficacy Endpoint
Change: The statistical methodology was updated consistent with the study's Statistical Analysis 
Plan.
Now reads:
The primary efficacy endpoint is the change from baseline to Week 28 in the ALSFRS-R total 
score, which will be analyzed using the joint rank methodology to account for mortality [Berry 
2013].  This joint ranking procedure allows for a statistical test of the treatment effect on the 
ALSFRS-R total score while accounting for loss of data due to deaths. In this analysis, a 
subject’s Combined Assessment of Function and Survival (CAFS) score will be calculated by 
comparing each subject to every other subject in the study, resulting in a score of +1 if the 
outcome was better than the subject being compared, -1 if worse, and 0 if the same.  The 
subject’s score will then be calculated by summing their comparison to all the other subjects in 
the study.
For example, if 2 subjects complete the study up to Week 28, their comparison score will be 
based on the change from baseline in ALSFRS-R total score at Week 28.  A subject who dies 
will rank lower than any subject who completes the study up to Week 28.  Two subjects who 
both die will be ranked based on the time of death, with a longer time to death corresponding to a 
higher rank.  Hence, in general, these comparisons will result in subjects who die being assigned 
the worst scores and ranked according to time of death.  Subjects who survive and complete the 
study will be ranked more favorably than subjects who die.
The ranked scores will be analyzed using an analysis of covariance model with treatment 
included as a fixed effect and adjusted for the following covariates : baseline disease duration 
since symptom onset, baseline ALSFRS-R total score, and use of riluzole or edaravone.  The 
primary inference will be based on the mITT population. The treatment comparison will be 
based on a 2-sided α level of 0.05.
If there are insufficient number of deaths, the change from baseline in ALSFRS-R total score 
will be analyzed using a mixed model for repeated measures (MMRM) with fixed effect for 
treatment, time (as a categorical variable), treatment by time interaction and adjustment for 
baseline ALSFRS-R score, baseline ALSFRS-R score by time interaction, baseline disease 
duration since symptom onset, and use of riluzole or edaravone.  An unstructured covariance 
(UN) matrix will be used to model the within subject variance-covariance errors.  The primary 

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3
inference will be based on the treatment comparison at Week 28. A 2 sided α level of 0.05 will 
be used.
Sensitivity analyses of the primary efficacy endpoint will be specified in the statistical analysis 
plan. 
The primary efficacy endpoint is the change from baseline to Week 28 in the ALSFRS-R 
total score, which will be analyzed as follows, depending on 2 scenarios:
1. If the number of deaths across both treatment arms is ≥ 3 (i.e., ≥ 5% deaths out of a 
total of 60 patients in the mITT population), the JRT methodology to account for 
mortality [Berry 2013] will be used for the primary inference. When implementing 
the JRT methodology, MI will be used to handle withdrawals. The estimates will be 
obtained from an ANCOVA for change from baseline in ALSFRS-R at Week 28 
with missing data imputed using MI. The corresponding nominal p-value from the 
ANCOVA will be presented as a sensitivity analysis. 
2. If the number of deaths is < 3 (i.e., < 5% deaths out of a total of 60 patients in the 
mITT population), ANCOVA with MI will be used as the primary analysis method 
for both inference and estimates. The p-value from the JRT will be presented as a 
sensitivity analysis.
The primary estimand is described as follows:
The primary analysis for the primary endpoint is the composite estimand [ICH E9 (R1) 
Addendum 2017]. The estimand of the primary analysis is defined as follows:

Population: all participants in the mITT population.

Variable: change from baseline to Day 197 in the ALSFRS-R total score.

Handling of intercurrent events: Relevant intercurrent events are handled using 
a composite strategy in which participants who have these intercurrent events 
are ranked against each other and against participants without any intercurrent 
event using the joint rank methodology based on MI datasets. The relevant 
intercurrent events are deaths and withdrawals. These participants will be 
handled using the composite strategy and ranked as described in this section. 
For withdrawals, this will be based on the imputed value for Day 197 from the 
MI datasets. 

Summary statistics: difference between treatment groups in least square means 
of Day 197 change from baseline with corresponding standard errors and 95% 
confidence intervals taken from the ANCOVA for change from baseline to Day 
197, based on the MI datasets. The ANCOVA model will include treatment 
group as a fixed effect and covariates for ALSFRS-R total score, baseline disease 
duration since symptom onset, and use of riluzole or edaravone. 

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For the JRT analysis, the ranked scores will be analyzed for each of the 
100 MI-complete datasets using an ANCOVA model with treatment included as 
a fixed effect and adjusted for the following covariates: baseline disease duration 
since symptom onset, baseline ALSFRS-R total score, and use of riluzole or 
edaravone. The p-value will be based on combining the estimates for the 
treatment differences using PROC MIANALYZE. The difference between 
treatment groups in median changes from baseline to each visit will be presented 
with 95% confidence intervals based on the MI datasets, as well as the p-value 
from the JRT for Day 197. The joint rank analysis will only be performed for the 
mITT population. 
The joint rank procedure allows for a statistical test of the treatment effect on the 
ALSFRS-R total score while accounting for truncation of data due to deaths. In this 
analysis, a participant’s joint rank score will be calculated by comparing each participant 
to every other participant in the study, resulting in a score of +1 if the outcome was better 
than the participant being compared, -1 if worse, and 0 if the same. The participant’s score 
will then be calculated by summing their comparison to all the other participants in the 
study. 
For the purpose of this calculation, participants will be grouped into the following 2 
categories:

Group 1: Participants who complete the study and have data available at the 
Day 197 assessment AND participants who withdraw from the study due to 
reasons other than death

Group 2: Participants who die
MI will be used to impute all missing data before determining the rank score, including 
intermittent data and data after withdrawal from the study except after death.
In each of the 100 imputed datasets, participants will be ranked as follows:

Participants in Group 2 will be given lower ranks than participants in Group 1, 
with the lowest ranks being given to the participants who die in the shortest time 
after first dose. Progressively higher ranks will be given to participants who die 
at longer times after first dose.

Participants in Group 1 will rank higher than participants in Group 2. 
Progressively higher ranks will be given to participants with a higher change 
from baseline at Day 197 i.e., smaller decline at Day 197.
Further details will be described in the statistical analysis plan. 
The primary inference will be based on the mITT population. The treatment comparison 
will be based on a 2-sided α level of 0.05. 

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If the second scenario occurs, i.e., in both active and placebo treatment groups combined 
the number of participants who died is < 3 (e.g., < 5% deaths out of a total of 
60 participants in the mITT population), the primary efficacy analysis will be the change 
from baseline in ALSFRS-R total score, analyzed using an ANCOVA based on data 
imputed using MI. The ANCOVA model will include treatment group as a fixed effect and 
covariates for each of the corresponding baseline value for ALSFRS-R total score, baseline 
disease duration since symptom onset and use of riluzole or edaravone. The primary 
inference will be based on the treatment comparison at Week 28. A 2-sided α level of 0.05 
will be used. Treatment differences at other visits will also be presented with nominal 
p-values.
Sensitivity, supplementary and subgroup analyses of the primary efficacy endpoint will be 
specified in the statistical analysis plan.
For the non-mITT population, the analysis will be the change from baseline in ALSFRS-R 
total score, analyzed using an ANCOVA based on data imputed using MI. The ANCOVA 
model will include treatment group as a fixed effect and covariates for each of the 
corresponding baseline value for ALSFRS-R total score, baseline disease duration since 
symptom onset, and use of riluzole or edaravone. Least square means with standard errors 
will be presented for each treatment group. The difference between treatment groups in 
least square means for change from baseline at each visit, with corresponding standard 
errors and 95% confidence intervals, will be presented with nominal p-values.
Rationale:
The primary efficacy endpoint and analysis have been clarified to distinguish between the 
methodology used for statistical testing and the analysis for obtaining the estimates of the 
treatment difference.  The joint rank methodology is a statistical test of the treatment effect on 
the ALSFRS-R total score while accounting for truncation of data due to deaths. A rank score is 
calculated to obtain the p-value. As the range of this rank score depends on the sample size, it is 
not possible to provide a clinically meaningful interpretation using this score. Therefore, an 
ANCOVA on the change from baseline is used to obtain the estimates of the treatment 
difference.
The traditional joint rank method for the CAFS has also been replaced by the joint rank 
methodology with multiple imputation for handling missing data due to withdrawals. This 
provides a more robust method for the joint rank test.
For the alternative analysis when there are an insufficient number of deaths, ANCOVA with 
multiple imputation will be used to account for missing data as a more robust method, instead of 
MMRM.
There is clarification on what is deemed as an insufficient number of deaths to determine 
whether the joint rank test will be used for the primary efficacy analysis. This threshold is based 
on the duration of the study and the requirement of SVC ≥ 65% at screening for participants in 
the mITT population.

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Section 16.2.1.2.2, Analysis of the Secondary Efficacy Endpoints
Change: The ordering of secondary endpoints in the sequential testing procedure for the mITT 
population and the statistical methodology for secondary endpoints was amended for consistency 
with the study's Statistical Analysis Plan.
Now reads:
The analyses of secondary efficacy endpoints will be based on a sequential closed testing 
procedure in the order of the rank of secondary endpoints as listed in Section 6.2. The treatment 
effect will be assessed at each step at a 2-sided α level of 0.05. The primary inference at each step 
will be based on the mITT population.
The first secondary efficacy endpoint will be change from baseline to Week 28 in percent 
predicted SVC, which will be analyzed using a MMRM with fixed effect for treatment, time (as 
a categorical variable), treatment by time interaction and adjustment for baseline SVC, baseline 
SVC by time interaction, baseline disease duration since symptom onset, use of riluzole or 
edaravone. Overall treatment difference across visits and treatment difference at Week 28 will be 
derived from the model. Treatment differences at other visits will also be derived from the model 
for exploratory purpose.  
The second and third secondary efficacy endpoints, VAFS and overall survival, respectively, will 
be analyzed as time to event. Kaplan-Meier estimates of the cumulative probability of event 
occurrence over time will be determined.  Treatment comparison will be based on a stratified log 
rank test.  A Cox regression model will be used to obtain the hazard ration and 95% confidence 
intervals for each of these endpoints.
The muscle strength as measured by HHD will be summarized by individual muscles and 
megascore. The megascore will be analyzed using a MMRM with fixed effect for treatment, time 
(as a categorical variable), treatment by time interaction and adjustment for baseline HHD 
megascore, baseline HHD megascore by time interaction, baseline disease duration since 
symptom onset, and use of riluzole or edaravone.  Overall treatment difference across visits and 
treatment difference at Week 28 will be derived from the model. Treatment differences at other 
visits will also be derived from the model for exploratory purpose.
Formal testing of secondary efficacy endpoints will be in the mITT population alone. For 
the non-mITT and ITT populations, there will be no formal testing of efficacy endpoints. 
Testing of PD endpoints is discussed in Section 16.2.3. The analyses of secondary endpoints 
for the mITT population will be based on a sequential testing procedure in the order of the 
rank of secondary endpoints as listed below if the primary endpoint is statistically 
significant at a 2-sided α level of 0.05:

Change from baseline (i.e., ratio) to Week 28 (Day 197) in CSF total SOD1 
protein

Change from baseline (i.e., ratio) to Week 28 (Day 197) in NfL in plasma

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
Change from baseline to Week 28 (Day 197) in SVC

Change from baseline to Week 28 (Day 197) in HHD megascore to assess muscle 
strength, as measured by the HHD device

Time to death or permanent ventilation, which is defined as the time to the 
earliest occurrence of one of the following events:

Death 

Permanent ventilation (≥ 22 hours of mechanical ventilation [invasive or 
noninvasive] per day for ≥ 21 consecutive days)

Time to death
The treatment effect will be assessed at each step at a 2-sided α level of 0.05. The primary 
inference at each step will be based on the mITT population.
This procedure will control the Type I error for the secondary endpoints. If statistical 
significance is not achieved for a secondary endpoint, all secondary endpoints of a lower 
rank will not be considered statistically significant. 
There will be no adjustment for multiple testing for the sensitivity or supplementary 
analyses for the primary and secondary endpoints, the exploratory endpoints or subgroup 
analyses.
The first and second endpoints in the ranking are PD endpoints for which the analysis is 
described in Section 16.2.3.
The third secondary endpoint will be change from baseline to Day 197 in percent predicted 
SVC. If the number of deaths across both treatment arms is ≥ 3 (i.e., ≥ 5% deaths out of a 
total of 60 patients in the mITT population) the primary inference will be based on the JRT 
methodology with MI to impute missing data; ANCOVA with MI for change from baseline 
will be used to obtain the estimates, and nominal p-values will be presented.  If the number 
of deaths is < 3 (i.e., < 5% deaths out of a total of 60 patients in the mITT population), 
ANCOVA with MI will be used as the primary analysis of this endpoint. The ANCOVA 
model will include treatment group as a fixed effect and covariates for baseline percent 
predicted SVC, baseline disease duration since symptom onset, and use of riluzole or 
edaravone.  Treatment differences at other visits will also be derived from the model for 
exploratory purpose.
The secondary efficacy endpoints, time to death or permanent ventilation and time to 
death, will each be analyzed as time to event endpoints. Kaplan-Meier estimates of the 
cumulative probability of event occurrence over time will be determined. Treatment 
comparison will be based on a stratified log rank test. A Cox regression model will be used 
to obtain the hazard ratio and 95% confidence intervals for each of these endpoints. The 

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analysis for each endpoint will also be repeated for the non-mITT population with nominal 
p-values presented.
Rationale:
The hierarchy for the sequential closed testing procedure has been modified to account for the 
likelihood of statistical success for each endpoint in the 28-week duration of this study. CSF 
SOD1 and plasma NfL are also now included in the closed testing procedure and placed above 
SVC. Due to the COVID-19 pandemic, the level of missing data for SVC is likely to be higher 
due to individual site restrictions for handling the pandemic. The time-to-event endpoints are 
ranked lowest as the duration of the study and the inclusion criteria for SVC ≥ 65% at Screening 
in the mITT population reduces the chance to observe a large number of events in these 
endpoints over 28 weeks. It is expected that a greater treatment effect may be observed on SVC 
and muscle strength measured by HHD than on the time-to-event endpoints.
Change from baseline in SVC will be analyzed similarly to change from baseline in ALSFRS-R 
to account for mortality, depending on the number of deaths. The analysis specified provides a 
more robust method for estimating the treatment effect on this endpoint.
ANCOVA with multiple imputation is also specified as the analysis of HHD megascore instead 
of MMRM to provide a more robust method for handling missing data.
Section 6.2.1.2 Secondary Efficacy Endpoints
Change: The time to event endpoints were renamed so that VAFS was relabeled as time to death 
or permanent ventilation; and overall survival was renamed to time to death.
Now reads: 
The secondary efficacy endpoints are as follows:

Ventilation assistance free survival (VAFS), which is defined as the time to the 
earliest occurrence of 1 of the following events:
Death. 

Permanent ventilation (≥ 22 hours of mechanical ventilation [invasive or 
noninvasive] per day for ≥ 21 consecutive days).

•
Overall survival.

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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presented with nominal p-values. CSF, NFL, p NFH 
 will be 
analyzed similarly. 
Rationale: ANCOVA with multiple imputation is also specified as the analysis of PD/biomarker 
endpoints instead of MMRM to provide a more robust method for handling missing data.
This change also affects Section 6.2.3.1, Analysis Population.
Section 16.2.4.2.1, Adverse Events
Change: Included additional key AE summaries and listings to be consistent with the study's 
Statistical Analysis Plan. 
Now reads: 
Incidence of TEAEs will be summarized by treatment groups, overall, by severity, by 
relationship to LP, and by relationship to study treatment. SAEs, discontinuations and 
withdrawals due to AEs, AEs leading to hospitalization, and deaths will also be 
summarized or listed, depending on number of events. The summary tables will include 
incidence estimates for overall system organ class as well as for preferred terms within each 
system organ class. AEs will be coded using the MedDRA. A subset of AE outputs will also be 
presented by disease progression subgroup ("participants who met prognostic enrichment 
criteria for rapid disease progression", "other eligible participants").
Rationale: The protocol was updated to clarify some of the additional AE summaries presented. 
The subgroup analysis was added in line with the analysis populations used for clinical function 
and pharmacodynamic endpoints. 
Section 16.2.5.2, Methods of Analysis
Change: Amended statistical methodology to be consistent with study's Statistical Analysis Plan
Now reads: 
The quality of life measures will be analyzed using a MMRM with baseline disease duration 
since symptom onset, baseline value, and use of riluzole or edaravone as covariates an 
ANCOVA with MI with fixed effect for treatment and covariates for corresponding 
baseline value, baseline disease duration since symptom onset and use of riluzole or 
edaravone.  Overall treatment differences across visits and The treatment difference at Week 28 
Day 197 will be derived from the model.  Treatment differences at other visits will also be 
derived from the model for exploratory purpose. Nominal p-values will be presented.
Rationale: ANCOVA with multiple imputation is specified as the analysis of quality of life 
endpoints instead of MMRM to provide a more robust method for handling missing data.
Section 16.2.6, Interim Analyses

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Change: Specified that no interim analysis will be performed.
Now reads: 
An interim efficacy analysis may be performed.  The specifics around the optional interim 
analysis will be detailed in the statistical analysis plan.  In order to maintain the treatment blind, 
an independent unblinded team not to be involved in the conduct of the study after unblinding 
will perform the interim analysis.   The unblinded team will present the unblinded interim 
analysis to the IDMC.  There will be no interim analysis performed.
Rationale: No interim analysis will be conducted due to potential impact to study power with 
minimal opportunity to accelerate study timelines.
This change also affects Section 9.3, Blinding Procedures.

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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 1.1, Synopsis
The synopsis was revised to reflect changes made throughout the protocol.
Section 4.2, Schedule of Activities
Change: Footnote 9 in Table 3 was clarified to specify that the diary/eDiary will be completed 
only for days when the participant uses mechanical ventilation.
Now reads:
9 Participants 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/eDiary will be reviewed with study site staff at each visit.
Rationale: Clarification
Section 8.2.1, Inclusion Criteria
Change: The nomenclature for the disease progression subgroups (previously "fast progressors" 
and "non-fast progressors") was modified to more accurately represent the population enrolled. 
Now reads:
3. Weakness attributable to ALS and a confirmed SOD1 mutation. 
a.
SOD1 mutation must be confirmed by the central reader based on the sample 
obtained during the Screening Visit; subjectsparticipants with an SOD1 mutation 
interpreted by the central reader to be pathogenic or likely pathogenic will be eligible.
b. Additionally: 

Fast progressor criteria Prognostic enrichment criteria for rapid disease 
progression (subjectsparticipants may be eligible based on 1 of the following 2 
criteria) [Hamidou 2017; Proudfoot 2016]:
a.
One of the following SOD1 mutations and a prerandomization ALSFRS-R 
slope decline of ≥ 0.2 per month (calculated as [48-baseline score]/time 
since symptom onset):
p.Ala5Val, p.Ala5Thr, p.Leu39Val, p.Gly42Ser, p.His44Arg, p.Leu85Val, 
p.Gly94Ala, p.Leu107Val, and p.Val149Gly  

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OR
b. SOD1 mutation other than those listed in item ‘a.’ with prerandomization 
ALSFRS-R slope decline of ≥ 0.9 per month (calculated as [48-baseline 
score]/time since symptom onset)

Non fast progressor criterion Criteria for all other eligible participants: SOD1 
mutation other than those listed in item ‘a.’ (no ALSFRS-R slope decline 
requirement).
4. For fast progressors participants who meet prognostic enrichment criteria for rapid 
disease progression, SVC ≥ 65% of predicted value as adjusted for sex, age, and height 
(from the sitting position).  For non fast progressors all other eligible participants, SVC 
≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position).
Rationale:
The primary analysis population 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 was 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. 
This change also affects Sections 7.1.3, Part C: Pivotal; 9.2, Randomization and Registration of 
Participants; 16.2.1.1, Analysis Population, and 16.2.7, Sample Size Considerations.
Section 6.2.2, Secondary Objective
Change: Added biomarker effects to the secondary objective.
Now reads: The secondary objective is to evaluate the safety, tolerability, and PD, and 
biomarker effects of BIIB067 administered to adult participants with ALS and a confirmed 
SOD1 mutation.
Rationale: Updated to clarify that biomarker effects are also a secondary objective.
Section 6.2.2.1, Safety/Tolerability Endpoint
Change: Added “secondary” to the endpoint.
Now reads: The secondary safety/tolerability endpoint is the incidence of AEs and SAEs.
Rationale: Clarification.

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Section 6.2.2.2, Pharmacodynamic Endpoint
Change: Specified that the change from baseline in total SOD1 protein concentration in CSF is a 
secondary PD endpoint.
Now reads: The secondary PD endpoint is the change from baseline in total SOD1 protein 
concentration in CSF
Rationale: Updated to reflect that total SOD1 protein concentration in CSF will be tested as a 
secondary endpoint.
Section 6.2.2.3, Biomarker Endpoint
Change: The key secondary biomarker and matrix were changed.
Now reads: The secondary biomarker endpoint is the change from baseline in p NFH NfL 
concentration in CSF plasma.
Rationale: Updated to reflect that plasma NfL will be tested as a key secondary (biomarker) 
endpoint. 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 
Healthineers NfL assay which has good analytical performance and utilizes a fully automated 
instrument.
Section 6.2.3.2, Additional Biomarkers
Change: Clarified additional biomarkers to be measured in serum, plasma, and/or CSF.
Now reads:

Blood (serum) and CSF concentrations of NFLNfL

Blood concentration (plasma, serum) and/or CSF concentrations of pNF-HpNfH
Rationale: Clarification.
Section 7.1.3, Part C: Pivotal
Change: Updated to clarify that a Safety Follow-up (Alternative EOS) Visit should occur when 
enrollment in the LTE study is delayed.
Now reads:
For subjects participating in Part C (Pivotal) and continuing (uninterrupted) in the LTE study 
(233AS102), the study duration will be approximately 32 weeks. This will include up to a 
4-week screening period, a 24-week treatment period (consisting of 3 loading doses of BIIB067 
administered approximately once every 2 weeks, followed by 5 maintenance doses of BIIB067 

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administered approximately once every 4 weeks), and an EOS Visit at Week 28 (4 weeks after 
the last dose). After completing the EOS visit, subjects will be considered study completers and 
they will have the option to participate in the LTE study (233AS102). This will be done without 
unblinding to subject’s treatment group.
For subjects who do not roll over into the LTE study, the duration will be approximately 36 
weeks, as the subjects will have an additional safety follow up visit at Week 32 (8 weeks after 
the last dose) [either in person or by telephone contact]. End of study date is the last visit or 
contact with the subject.
For participants in Part C (Pivotal), the study duration will be approximately 32-36 weeks 
including a 4-week screening period, a 24-week treatment period (3 loading doses 2 weeks 
apart followed by 5 maintenance doses 4 weeks apart), and a 4- to 8- week FU period as 
follows:

Part C participants who enroll (uninterrupted) in the LTE study (233AS102): 
Week 28 Visit will serve as EOS Visit

Part C participants with delays between their Week 28 Visit and enrollment in 
the LTE study: a Safety FU (Alternative EOS) Visit will be conducted (either in 
person or by telephone contact) to collect AEs, SAEs, and concomitant 
medications or procedures. This Safety FU (Alternative EOS) Visit can be 
performed at Week 32 or prior to (within 2 days) enrollment in the LTE, 
whichever comes first.

Part C participants who do not enroll in the LTE study: Week 32 Visit will serve 
as EOS Visit (either in person or by telephone contact)
Rationale: Updated to clarify that a Safety FU (Alternative EOS) Visit should occur at Week 32 
or prior to (within 2 days) enrollment in the LTE study, whichever is first, when there is a delay 
between the Week 28 visit and enrollment in the LTE study. This follow-up visit will ensure 
continuity of monitoring (adverse events, serious adverse events, concomitant medications, 
concomitant procedures) through entry in the LTE or for at least 8 weeks after the last dose of 
study treatment. 
This change also affects Section 4.1, Study Schematic; Section 4.2, Schedule of Activities; 
Section 7.3.3.3, Part C: Pivotal; Section 7.5, End of Study; and 15.3.1 Adverse Events.
Section 12, Study Treatment Management
Change:  Replaced “supersedes” with “aligns with”
Now reads: 
The DHA supersedesaligns with all other references, (e.g., protocol)including the protocol.

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Rationale: Wording was modified to align with updates to the protocol template. 
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’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.
Rationale: Remote evaluation of data and source documents is being implemented to allow the 
sponsor and CRO to continue to provide oversight to 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 19.1, Public Health Emergencies
Change: Added contingency plan in the event of 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 due to 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 

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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.

A new signatory’s name and title were added.  The previous signatory’s name and 
title were removed.

Section 2, List of Abbreviations, was updated.

Replaced “subject” with “participant” throughout the protocol (with exception of the 
title).

Deleted “tertiary/” preceding exploratory objectives.

The abbreviation for neurofilament light was changed from “NFL” to NfL” and the 
abbreviation for phosphorylated axonal neurofilament heavy chain was changed from 
“pNF-H” to “pNfH.”

Differentiated between SOD1 gene/mutation and total SOD1 protein.

Abbreviations were deleted from the footnotes in tables and figures and added to the 
List of Abbreviations to align with the updated protocol template

The expanded forms of abbreviations were deleted at first use to align with the 
updated style guide

Replaced “population outside the mITT” with “non-mITT population.”

Typographical errors and formatting were corrected.
            

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LIST OF ABBREVIATIONS
AE
adverse event
ALS
amyotrophic lateral sclerosis
ALSFRS-R
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised
ANCOVA
analysis of covariance
CAFS
Combined Assessment of Function and Survival
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
DHA
Directions for Handling and Administration
EOS
end of study
FU
follow-up
GCP
Good Clinical Practice
HHD
handheld dynamometry
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
ITT
intent-to-treat
JRT
joint rank test
LTE
long-term extension
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
mITT
modified intent-to-treat
MMRM
mixed model for repeated measures
MMSE
Mini-Mental State Examination
NfL
neurofilament light chain
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
pNfH
phosphorylated axonal neurofilament heavy chain
SAE
serious adverse event
SOD1
superoxide dismutase 1
SVC
slow vital capacity

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TEAE
treatment-emergent adverse event
UN
unstructured covariance
VAFS
ventilation assistance-free survival

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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 233AS101
A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics 
of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral Sclerosis and Confirmed 
Superoxide Dismutase 1 Mutation
Version 7
Date: 30 September 2019
EUDRA CT Number: 2015-004098-33
Version 7 of the protocol has been prepared for this amendment, which supersedes Version 6, 
dated 19 September 2019.

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
No major changes are being made in this amendment.

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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.

Section 4.2, Schedule of Activities (Table 3 – Schedule of Activities: Part C 
[Pivotal]), 
 

Section 6.2.3.2, Additional Biomarkers, sub-bullet blood and CSF concentrations of 
pNF-H was updated to blood concentration of pNF-H, as change in CSF 
concentration of p-NFH is already covered as a biomarker endpoint under Section 
6.2.2.3 (Biomarker Endpoint).

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 233AS101
A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral 
Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Version 6
Date: 19 September 2019
EUDRA CT Number: 2015-004098-33
Version 6 of the protocol has been prepared for this amendment, which supersedes Version 5 
dated 20 December 2018.

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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 233AS101 is to describe the changes to the 
primary endpoint and statistical methodology, sample size considerations, and inclusion of an 
optional interim efficacy analysis for Part C (Pivotal) of the study. 
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 6.2.1., Primary Objective
Now reads:
6.2.1.1.
Primary Efficacy Endpoint
The primary efficacy endpoint of Part C is the postrandomization slope of the ALSFRS R score 
measured change from baseline to Week 28 in the ALSFRS-R total score.
Section 16.2.1.2.1., Analysis of the Primary Efficacy Endpoint
Now reads: 
The primary efficacy endpoint is the postrandomization slope of ALSFRS R scores measured 
from baseline to Week 28.  The postrandomization ALSFRS R score over all time points change 
from baseline to Week 28 in the ALSFRS-R total score, which will be analyzed using the 
joint rank methodology to account for mortality [Berry 2013].  This joint ranking 
procedure allows for a statistical test of the treatment effect on the ALSFRS-R score over 
all time points total score while accounting for loss of data due to deaths. In this analysis, a 
subject’s Combined Assessment of Function and Survival (CAFS) score will be calculated 
by comparing each subject to every other subject in the study, resulting in a score of +1 if 
the outcome was better than the subject being compared, -1 if worse, and 0 if the same.  
The subject’s score will then be calculated by summing their comparison to all the other 
subjects in the study. 
For example, if 2 subjects complete the study up to Week 28, their comparison score will be 
based on the change from baseline in ALSFRS-R total score at Week 28.  A subject who 
dies will rank lower than any subject who completes the study up to Week 28.  Two 
subjects who both die will be ranked based on the time of death, with a longer time to death 
corresponding to a higher rank.  Hence, in general, these comparisons will result in 
subjects who die being assigned the worst scores and ranked according to time of death.  
Subjects who survive and complete the study will be ranked more favorably than subjects 
who die.

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The ranked scores will be analyzed using an analysis of covariance model with treatment 
included as a fixed effect and adjusted for the following covariates: baseline disease 
duration since symptom onset, baseline ALSFRS-R total score, and use of riluzole (yes or 
no), and use of edaravone (yes or no with yes including the use of both edaravone and 
riluzole).  The primary inference will be based on the mITT population. The treatment 
comparison will be based on a 2-sided α level of 0.05. 
If there are insufficient number of deaths, the change from baseline in ALSFRS-R total 
score will be analyzed using a mixed model for repeated measures (MMRM) with fixed effect 
for treatment, time (as a continuous categorical variable), treatment by time interaction, and 
adjustment for baseline ALSFRS-R score, baseline ALSFRS-R score by time interaction,
baseline disease duration since symptom onset, use of riluzole (yes or no), and use of riluzole or 
edaravone (yes or no with yes including the use of both edaravone and riluzole).  An 
unstructured covariance (UN) matrix will be used to model the within-subject variance-
covariance errors If the unstructured covariance structure matrix results in a lack of convergence, 
the first order autoregressive covariance structure will be used.  The Kenward Roger 
approximation will be used to estimate the denominator degrees of freedom.  The primary 
inference will be based on the estimated treatment by time interaction in the mITT population.  
The estimated difference in slope of decline between BIIB067 and placebo, and the associated 
95% confidence interval, will be derived from the model.  The treatment effect will be assessed 
at a 1 sided α level of 0.05 (or 2 sided α level of 0.10).  In addition, as a supportive analysis, the 
slope of each individual subject will be derived using simple least square estimate, and treatment 
comparison using the Mann Whitney test, based on ranked data, will be made.  As a further 
sensitivity analysis, the slope of decline in 92 days observed in subjects from Part B who 
received placebo or BIIB067 100 mg will be pooled with Part C slopes over 92 days, and the 
Mann Whitney test will be performed on the pooled data.  The treatment effect in the overall ITT 
population will also be assessed similarly.  The ALSFRS R score will be set to 0 upon 
occurrence of death.  The primary inference will be based on the treatment comparison at 
Week 28. A 2-sided α level of 0.05 will be used. 
Sensitivity analyses of the primary efficacy endpoint will be specified in the statistical
analysis plan.
Rationale for Section 6.2.1 and Section 16.2.1.2.1: The primary efficacy endpoint was revised
from ALSFRS-R slope to total score (change from baseline to Week 28) and will be analyzed via 
a joint-rank analysis that combines the ALSFRS-R score and survival time. This approach 
minimizes the dependency on linearity assumptions (of the ALSFRS-R slope decline) and 
enables a robust mechanism for accounting for missing data due to death.

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Section 16.2.7., Sample Size Considerations
Now reads:
For Part C, up to 60 subjects approximately 99 subjects will be enrolled in a single cohort 
randomized, with 40 approximately 66 subjects administered BIIB067 100 mg and 20 
approximately 33 subjects administered placebo in a 2:1 ratio.
This sample size for Part C is selected primarily based on the primary endpoint, joint rank test 
combining the slope of decline Week 28 change from baseline in ALSFRS-R and mortality, 
in the mITT population (fast progressor group, N = 60). The observed results from an interim 
analysis of BIIB067 100 mg from Study 233AS101 in the fast progressor subject group as well 
as the observed ALSFRS-R decline in subjects who received placebo in a similar fast progressor 
ALS population with SOD1 mutation [Benatar 2018] are the basis of assumed treatment effect 
and the variability.  The observed mean ± SD of the slope of decline in the historical placebo 
data [Benatar 2018] was 3.2 ± 2.5 per month (markedly more rapid than that in the overall ALS 
population).  The interim data of a very small cohort in Study 233AS101 suggested a treatment 
difference between BIIB067 100 mg and placebo of 5.8 per month in favor of BIIB067 100 mg 
with an estimated pooled SD of 1.4 and an estimated mean decline in the active group of 0.8 per 
month.  Given the small sample size for the treatment comparison in Study 233AS101, a 
conservative assumption of a treatment difference of 2.4 per month (the difference between 
historical placebo mean and observed mean of BIIB067 100 mg in Study 233AS101) and a SD 
of 2.5 (from historical data) was made.  With a 2:1 randomization ratio, a sample size of 
36 subjects in the fast progressor population (mITT population) would provide the study with 
85% power at 1 sided α of 0.05 to detect such treatment differences.  Because events of death or 
permanent ventilation assistance have been factored in the analysis, no sample size overage is 
planned for missing values. Subjects from both datasets were matched with the criteria for a 
fast progressor specified in this protocol for Part C (i.e., one of the protocol-defined SOD1 
mutations and a pre-randomization ALSFRS-R decline slope ≥0.2 per month or a pre-
randomization ALSFRS-R decline slope ≥0.9 with SOD1 mutation NOT on the 
protocol-defined list). This resulted in a total of 12 placebo control fast progressors (8 from
the historical placebo data [Benatar 2018] and 4 from Study 233AS101) and 4 fast progressors 
treated with BIIB067 100 mg from interim data of a very small cohort in Study 233AS101. 
The observed mean slope of decline was -3.83 for the matched placebo subjects and -0.74 
for the matched BIIB067 100 mg subjects, with a pooled SD of 3.166.  In the 12 matched 
fast progressors on placebo, there was 1 death and 2 subjects with PAV less than 6 months 
but none in the BIIB067 100 mg potential fast progressors. Based on this and overall 
survival data in fast progressors from the literature on subjects with an A4V SOD1 
mutation, the survival at Week 28 was assumed to be 82% in the placebo control and 90% 
in the BIIB067 100 mg group. 
Under the above assumptions, with N = 60 fast progressors and a two-sided significance 
level of 0.05, the joint rank test gives 84% power. Because events of death have been 
factored in the analysis, no sample size overage is planned for missing values. 

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For the subject population outside of the mITT population, the primary focus will be on the PD 
endpoint, CSF SOD1 concentration, due to their likely slow clinical function decline as this 
population is anticipated to have a slower decline in clinical function compared to the 
mITT population. A sample size of 16 26 subjects in this group the treated group and 
13 subjects in the placebo group for the population outside of the mITT would provide 80%
97% power to detect a 19% 25% reduction in CSF SOD1 from baseline within group in the 
treated group, with an assumed SD of 0.28 0.216 (in natural log scale), as observed in this 
population in Study 233AS101 compared to the placebo group.
Rationale: The sample size for Part C of the study was increased to approximately 99 subjects 
(increased from up to 60 subjects) based on the following changes: 

Revised primary efficacy endpoint of change in ALSFRS-R total score from baseline to 
Week 28 analyzed via the joint-rank methodology

Two-sided alpha of 0.05 for the primary analysis

Revised survival assumptions based on further review of natural history data and data 
from an interim analysis of Part B of this study (82% survival in the placebo control 
group and 90% survival in the BIIB067-treated group)
Under these assumptions, approximately 60 subjects (increased from 36) are needed in the mITT 
population (fast progressors) to achieve approximately 84% power. The target sample size for 
the non-fast progressor population was increased to approximately 39 subjects (increased from 
24) to enable adequate power to detect a statistically significant reduction in CSF SOD1 
concentrations.
Also, the assumptions for the sample size needed for the population outside the mITT were 
updated based on current results from the Part B of this study (233AS101).
This change also affects Section 5.4, Study Rationale and Section 7.1, Study Overview.
Section 16.2.6, Interim Analyses
Now reads:
In Part C of the study, a blinded sample size re estimation may be conducted when 
approximately 18 subjects in the fast progressor population complete Day 169 assessments of 
ALSFRS R or have an outcome of death or permanent ventilation assistance.  At this interim 
timepoint, the SD for the primary endpoint will be estimated based on the blinded data.  The 
sample size of the fast progressor group may be increased to up to 60 (potentially increasing the 
total sample size to approximately 80 subjects) if the SD is estimated to be ≥3.  As this is based 
on blinded data, the type I error rate is maintained.

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An interim analysis may be performed. The specifics around the optional interim analysis 
will be detailed in the statistical analysis plan. In order to maintain the treatment blind, an 
independent unblinded team not to be involved in the conduct of the study after unblinding 
will perform the interim analysis. The unblinded team will present the unblinded interim 
analysis to the IDMC. 
A futility analysis may be performed at the interim.  The futility criteria will be prespecified in 
the analysis plan, and if conducted, all necessary procedures to safeguard the integrity of the 
blind will be set in place.  No early stopping for efficacy will be made at this interim analysis.
Section 7.1.3, Part C: Pivotal
Now reads: 
…
…
In the event of a decision by the Study Sponsor to terminate the study earlier on the 
grounds that conducting a placebo-controlled study is no longer deemed ethical based on 
the assessment of risk-benefit of Study 233AS101, all subjects will be invited for an EOS 
visit, during which all Week 28 assessments will be conducted.  For subjects not entering 
the LTE study or in the event the study is stopped early, there will be an additional safety 
follow-up visit 8 weeks after the last dose of study treatment.
Rationale for Section 16.2.6 and Section 7.1.3: An optional interim efficacy analysis has been 
included to enable the earliest opportunity to detect a clinically meaningful effect and potential to 
minimize placebo exposure should the study be terminated early due to a positive interim 
analysis.  Correspondingly, the text around futility analysis was removed.
This change also affects Section 4.2 (Table 3), Schedule of Activities: Part C (Pivotal); and 
Section 9.3, Blinding Procedures.

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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 6.2.1.2, Secondary Efficacy Endpoints; Section 6.2.3, Tertiary/Exploratory Objectives; 
and Section 6.2.3.3, Quality of Life Endpoints
Change: The Combined Assessment of Function and Survival (CAFS) and change from baseline 
in ALSFRS-R total score were removed as secondary endpoints. The assessments related to 
quality of life assessments were moved from the secondary efficacy endpoints section to the 
exploratory endpoints section.
Now reads: 
6.2.1.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Combined assessment of function and survival (CAFS) up to Week 28.

Change from baseline to Week 28 in ALSFRS R score.

Change from baseline to Week 28 in SVC.

Ventilation assistance-free survival (VAFS), which is defined as the time to the 
earliest occurrence of 1 of the following events:

Death. 

First use of non invasive ventilation (NIV) for ≥22 hours per day for 
≥10 consecutive days. Permanent ventilation (≥22 hours of mechanical 
ventilation (invasive or noninvasive) per day for ≥21 consecutive days).
First use of permanent assisted ventilation (PAV) for ≥22 hours per day for 
≥7 consecutive days.

Overall survival.

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interaction, baseline disease duration since symptom onset, baseline ALSFRS R score, and use 
of riluzole or edaravone as covariates.
The second and third secondary efficacy endpoints, ALSFRS R and SVC, respectively, will be 
analyzed using a MMRM with baseline disease duration since symptom onset, baseline value 
(ALSFRS R and SVC, respectively), and use of riluzole or edaravone as covariates.  The 
ALSFRS R score and SVC will be set to 0 upon occurrence of death or permanent ventilation 
assistance. Overall treatment difference across visits and treatment difference at Week 28 will be 
derived from the model. Treatment differences at other visits will also be derived from the model 
for exploratory purpose.  
The fourth second and fifth third secondary efficacy endpoints, VAFS and overall survival, 
respectively, will be analyzed as time to event. Kaplan-Meier estimates of the cumulative 
probability of event occurrence over time will be determined. Treatment comparison will be 
based on a Cox proportional hazards model with baseline disease duration since symptom onset, 
baseline ALSFRS R score, and use of riluzole or edaravone as covariates stratified log rank 
test.  A Cox regression model will be used to obtain the hazard ration and 95% confidence 
intervals for each of these endpoints.
The muscle strength as measured by HHD will be summarized by individual muscles and 
megascore. The megascore will be analyzed using a MMRM with fixed effect for treatment, 
time (as a categorical variable), treatment by time interaction and adjustment for baseline 
HHD megascore, baseline HHD megascore by time interaction, baseline disease duration 
since symptom onset, baseline value, and use of riluzole or edaravone. as covariates. The HHD 
megascore will be set to 0 upon occurrence of death or permanent ventilation assistance. Overall 
treatment difference across visits and treatment difference at Week 28 will be derived from the 
model. Treatment differences at other visits will also be derived from the model for exploratory 
purpose.
Rationale:  The analysis for the 2 secondary endpoints of CAFS up to Week 28 and change from 
baseline to Week 28 in ALSFRS-R total score was removed because these endpoints are now 
incorporated into the primary endpoint.
Section 8.2.1, Inclusion Criteria
Change: Criteria for screening values of coagulation parameters to be within normal range was 
removed.
Now reads: 
…
8.
Screening values of coagulation parameters including platelet count, INR, PT, and APTT 
should be within normal ranges.  Coagulation tests may be repeated once if, in the opinion of the 

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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.  (For normal ranges, please refer to the study reference guide).  
…
Rationale: Considering the stage of development of BIIB067 in this study and in the overall 
program, this criterion of coagulation parameters values to be in normal range is not required and 
was removed. The original criterion was more appropriate for early phase clinical studies.
Section 8.2.2, Exclusion Criteria
Change: Details for hepatitis C infection screening for Part C were updated based on the current 
protocol template guidelines. 
Now reads: 
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:
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. 
2
Current hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody 
and detectable HCV ribonucleic acid [RNA]). Subjects with positive HCV antibody 
and undetectable HCV RNA are eligible to participate in the study (United States 
Centers for Disease Control and Prevention).
3
Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc).  Subjects 
with immunity to hepatitis B from previous natural infection (defined as negative 
HBsAg, positive IgM anti-HBc, and positive anti-HBcHBs) or vaccination (defined as 
negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate 
in the study.
…
15 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 held
before and/or 48 hours after an LP procedure according to local or institutional 
guidelines and/or Investigator determination.
Rationale: Additional guidance text was provided to clarify the exclusion criterion of current 
hepatitis C infection. The hepatitis B criterion was reworded for accuracy and clarity as the text 

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in the current protocol (version 5) was not clear or completely accurate. These changes in 
hepatitis B and hepatitis C criteria are in alignment with the current protocol template guidance. 
Because study drug administration will occur via lumbar puncture, care must be exercised in the 
use of antiplatelet or anticoagulant medication. However, the criterion has been updated to allow 
for the local standard of care to be used, accounting for the many different indications, 
medications, and individual patient situations that may be relevant. 
The change in exclusion criterion 15 also affects Section 11.3.1.2, Disallowed Concomitant 
Therapy.
Section 9.1, Screening and Enrollment
Change: Rescreening criteria for subjects who fail to complete Day 1 Visit within 28 days of 
their screening assessments during Part C were 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 For Part C (Pivotal) subjects who are not able fail screening can be rescreened up to 
complete one time at the Day 1 Visit within 28 days discretion of their the Investigator.
All screening assessments (Screening Visit 2would need to be repeated during rescreening 
except for Parts A and B) may be rescreened.the following:

Follicle-stimulating hormone (FSH) level in female subjects with post-menopausal 
state confirmed by level obtained in previous screening for Part C of this study

Confirmation of SOD1 mutation by the central reader if available from previous 
screening for Part C (Pivotal) of this study
Rationale: It was clarified that rescreening during Part C of the study is allowed at the discretion 
of the Investigator, and the assessments that need not be performed during rescreening are listed.

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Section 4.2, Schedule of Activities
Change: Table 3, Schedule of Activities: Part C (Pivotal) was updated to revise the frequency of Mini-Mental State Examination
(MMSE) testing and to reflect changes in the assessment timepoints for 12-lead electrocardiogram (ECG) and blood sample for 
plasma pharmacokinetic (PK) evaluation.
Now reads: 
Screening1
Loading Dose Treatment Period
Maintenance 
Treatment Period
Follow Up 
Visit2 EOS 
Visit2,3 
(All Subjects)
End of Study or 
Telephone Call Safety 
FU Visit for Subjects 
not Continuing in the 
LTE Study4
(In Person or 
Telephone Contact)
Baseline5
(Dose 1)
Week 2
(Dose 2)
Week 4
(Dose 3)
Week 8, 12, 16, 20, 
and 24
Week 28 OR 
(4 Weeks After 
Last Dose)
Week 32 OR
(8 Weeks After Last 
Dose)
Tests and Assessments4 5
Day
-28 to
Day -1
Day 1
(±3 days)
Day 15
(±3 days)
Day 29
(±3 days)
Days 57, 85, 113, 141, 
and 169 (±3 days)
Day 197 OR 4 
Weeks After 
Last Dose 
(±3 days)
Day 225 OR 8 Weeks 
After Last Dose 
(±3 days)
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
Pre 
dose
LP
Post 
dose
12-Lead ECG 12,14 14,16
X
X
X17
X11
X17
X
Limited Neurological 
Examination (including 
MMSE)12,1414, 19
X
X
X
X
X
X
X
X
X
X
MMSE
X
X
X
X11
X11
X
5 All visits are expected to take place on site unless subjects are unable to travel to the site; then, a home visit may be possible at the discretion of the 
Investigator.
...
...
11To be performed on Week 12 (Day 85) and Week 24 (Day 169) only.

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…
14Assessment must occur on the day of dosing.
...
16Triplicate 12-lead ECGs will be obtained after the subject has rested in a supine position for at least 10 minutes.  All ECGs will be centrally read; ECGs will be 
read by the Investigator at collection, and then sent to a central ECG reader for further evaluation and to confirm eligibility at Screening.  The first ECG will be 
interpreted, and the last 2 will be checked for consistency and quality.
Rationale: In Part B of the study no significant safety findings were noted on the MMSE, so the frequency of the MMSE assessment 
was reduced to every 3 months during the treatment period in Part C of the study
Considering the median plasma Tmax of 3 hours (range 1 to 24 hours) for the 100 mg cohort of Part B and to support a potential waiver 
for Thorough QT (TQT) analysis, it was clarified that at the Baseline Visit, the ECGs should be assessed just prior to drawing PK 
blood samples at 2, 4, and 6 hours postdose. It was also clarified that blood samples for PK will be collected predose at all timepoints 
and postdose only at Day 1 and Day 85.

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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
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Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS101
A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral 
Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Version 5
Date: 20 December 2018
EUDRA CT: 2015-004098-33
Version 5 of the protocol has been prepared for this amendment, which supersedes Version 4.

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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 233AS101 is to include a third part (Part C
[Pivotal]) of approximately 60 subjects (2:1 randomization ratio of BIIB067:placebo) to assess 
the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of BIIB067 at 
100 mg. Part C will be conducted over a 4-week screening period, 24-week treatment period and 
4-week follow-up period. This inclusion of Part C also warrants a change in the phase of 
development of the study, the title of the protocol to accurately reflect study design and the 
objectives and endpoints. 
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 5.4, Study Rationale
Now reads:
Parts A (SAD) and B (MAD)
Pharmacology and toxicology data in rats, mice, and monkeys indicate that BIIB067 is well 
tolerated.  This Phase 1Parts A and B of the study will evaluate the safety, tolerability, and PK 
profile of a range of single and multiple intrathecal BIIB067 doses from a projected minimal 
pharmacologic dose to either the maximum tolerated dose (MTD) or the highest planned dose of 
100 mg.  MTD for this study is defined as the highest tested dose with a less than 33% 
dose-limiting toxicity (DLT) rate at Day 15.  See Section 7.2.3 for the definition of DLT.
Part C (Pivotal)
Interim analyses of data from subjects in Part B (MAD) Cohorts 5 to 8 treated for 85 days 
were conducted.  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 
ALS subjects.  Preliminary and exploratory analyses of clinical function data (ALSFRS-R, 
vital capacity, and muscle strength) further suggested possible emergence of early clinical 
efficacy signals.  Based on these emerging data from Parts A and B, a randomized, double-
blind, placebo-controlled, pivotal phase (Part C) is designed to assess the efficacy and 
safety of BIIB067 100 mg versus placebo.  Approximately 60 subjects with SOD1-ALS will 
be enrolled and randomized to receive BIIB067 or placebo and treated for 24 weeks.
Rationale: The interim analyses of Study 233AS101 were based on treated subjects in multiple
ascending dose Cohorts 5 to 8 treated for 85 days (pending review of 100 mg data for safety and 
efficacy). 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 amyotrophic 
lateral sclerosis (ALS) subjects. Preliminary and exploratory analyses of clinical function data 
(Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised [ALSFRS-R], vital capacity, 
muscle strength) further suggest possible emergence of clinical effect. In order to further assess 
the treatment, 60 subjects with superoxide dismutase 1 (SOD1)-ALS will be enrolled and 
randomized to BIIB067 or placebo and treated for 24 weeks duration.
This change also affects the phase of development; the title of the protocol; Section 3, Synopsis; 
Section 4, Study Schematic and Schedule of Activities for Study 233AS101; Section 4.1, Study 

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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.
Title Page
Change: The phase of development and protocol title were updated to accurately reflect the 
addition of Part C (Pivotal).
Now reads:
PHASE OF DEVELOPMENT:
1/2/3
PROTOCOL TITLE: A Phase 1, Placebo Controlled, Single and Multiple Ascending Dose
Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics, and 
Pharmacodynamics of BIIB067 Administered to Adult Subjects with Amyotrophic Lateral 
Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Rationale:  The primary objective of Part C (Pivotal) is efficacy; therefore, the overall phase of 
development of the study and the title of the study were changed to reflect this new objective and 
related endpoints.
Section 3, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 5.3.2, Clinical Experience
Change: Added that additional information on the safety, pharmacokinetics, and 
pharmacodynamics for BIIB067 can be found in the Investigator’s Brochure.
Now reads:
This is the first-in-human (FIH) study of BIIB067; therefore, no clinical experience is available 
to date. preliminary safety, PK, and pharmacodynamic (PD) information for BIIB067 can 
be found in the Investigator’s Brochure.  
…
Rationale:
Based on data analysis from Parts A and B of the study, the Investigator’s Brochure has been 
updated to reflect the current safety, pharmacokinetic, and pharmacodynamic information for 
BIIB067. 

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Section 6, Study Objectives and Endpoints
Change: Clarified that the primary objective of Parts A and B was to evaluate the safety, 
tolerability, and pharmacokinetics of BIIB067 in adult subjects with ALS and confirmed SOD1 
mutation.
Now reads:
6.1.
Parts A (SAD) and B (MAD)
6.1. 6.1.1.
Primary Objective and Endpoints
The primary objective of the Parts A and B of this study is to evaluate the safety, tolerability, 
and PK of BIIB067 in adults subjects with ALS and confirmed SOD1 mutation.
6.1.1.1. Primary Endpoints
…
6.1.21. Secondary Endpoints
…
Rationale: Subjects must have both ALS and confirmed SOD1 mutation in order to be enrolled 
into any part of the study.
Section 7.1, Study Overview
Change: Addition of Japan as potential location for sites.
Now reads:
…
The study will be conducted at approximately 1718 sites in the United States, Canada, Japan,
and Western Europe.  
…
Rationale: Adding Japan as an additional country for potential sites in order to enable eventual 
filing for Japan.
Section 8.2.1, Inclusion Criteria
Note: all the inclusion exclusion criteria of Part A and Part B of the study are applicable to 
Part C other than the changes mentioned below.
Change: Inclusion criterion 3 was updated to clarify inclusion of subjects with both non-fast and 
fast progression of disease.
Now reads:
3. Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit 2 Visit.
Additionally:

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
Fast progressor criteria:
a. One of the following SOD1 mutations and a prerandomization 
ALSFRS-R decline slope ≥0.2 per month (calculated as [48-baseline 
score]/time since symptom onset):
p.Ala5Val, p.Ala5Thr, p.Leu39Val, p.Gly42Ser, p.His44Arg, 
p.Leu85Val, p.Gly94Ala, p.Leu107Val, and p.Val149Gly  
OR
b. SOD1 mutation other than those listed in item ‘a.’ with 
prerandomization ALSFRS-R decline slope ≥0.9 per month 
(calculated as [48-baseline score]/time since symptom onset)

Non-fast progressor criterion: SOD1 mutation other than those listed in item ‘a.’ 
(no ALSFRS-R decline slope requirement).
Rationale: The rate of ALS progression can vary widely across both non-genetic and SOD1 
ALS.  In order to account for non-fast and fast progressor subjects, specific SOD1 mutations and 
pre-slope criteria have been included.
Change: Inclusion criterion 4, a slow vital capacity (SVC) of ≥65% of predicted value for fast 
progressors adjusted for sex, age, and height (from sitting position), was added as an inclusion 
criterion.  SVC≥50% for non-fast progressors was also added. 
Now reads:
4. For fast progressors, SVC ≥65% of predicted value as adjusted for sex, age, and 
height (from the sitting position).  Subjects with stable FVC <50% but ≥45%, whose 
FVC has not declined by more than 5% in the last 6 months may be considered for 
inclusion, at the discretion of the Investigator For non-fast progressors, SVC ≥50% of 
predicted value as adjusted for sex, age, and height (from the sitting position).
Rationale: In Parts A and B of this study, criterion for inclusion was forced vital capacity 
(FVC) ≥50% and study duration was 3 months. In Part C of the study, the duration of treatment 
is 6 months and thus in order to improve the probability of survival through 6 months the use of 
SVC ≥65% instead of FVC ≥50% was added to Part C. SVC is commonly used in ALS studies 
and is easier for patients and sites to perform consistently. 
Change: Inclusion criterion 6 permitting the use of edaravone was added as inclusion criterion 
as long as the subject initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1 and that 
edaravone may not be administered on dosing days.  The use of edaravone or any implanted 
vascular devices was removed as exclusionary criteria.  
Now reads: 
6. If taking edaravone, subject must have initiated edaravone ≥60 days (2 treatment 
cycles) prior to Day 1 and expected to remain at that dose until the final study visit, 

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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 of this study.
Rationale: Edaravone is now an approved medication for treatment of ALS in some regions of 
the world in which this study is being conducted. In order to not deprive subjects from an 
approved treatment, use of edaravone is allowed.
This change also affects Section 8.2.2, Exclusion Criteria.
Section 8.2.2, Exclusion Criteria
Change: Exclusion criterion 9 was removed to allow the use of vascular devices. 
Now reads:
9. Presence of any implanted vascular devices.
Rationale: Edaravone is administered via implanted vascular devices, and therefore, the 
inclusion of edaravone as an acceptable concomitant medication warrants the use of implanted 
vascular devices for Part C (Pivotal).
Change: Exclusion criterion 11 was removed to allow subjects with a tracheostomy to enroll. 
Now reads:
11. Tracheostomy.
Rationale: Most subjects with ALS will rely on a tracheostomy at some point, and the use of a
tracheostomy will not interfere with the study drug administration and data analysis of BIIB067. 
Section 13.1, Exploratory Assessments of the Effect of BIBB067 on Clinical Function
Change: Text was included to allow subjects to have a home visit if they are unable to travel to 
the site.
Now reads:
…
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 with Investigator approval.
Rationale: In order to relieve the burden on subjects and continue to collect data, subjects who 
are unable to travel to the site may be able to have a home visit. 
Section 13.1.1, ALS Functional Rating Scale-Revised
Change: Text was clarified to state that a dedicated, blinded staff member will perform the 
ALSFRS-R for a subject. 

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
12 continuous months of natural (spontaneous) amenorrhea without an 
alternative medical cause and a serum follicle-stimulating hormone 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, highly effective contraception is defined as use of more than 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 and 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.
Pregnancy reporting is described in Section 15.4.1.
Rationale:  Contraception requirements were updated to reflect current accepted contraception 
practices in the parts of the world that the study is being conducted.

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Section 17.4, Subject Data Protection
Change: Added text to state that the race and ethnicity of the subjects will be collected unless 
prohibited by local law.
Now reads:
…
During the study, subjects’ race and ethnicity will be collected (unless the collection is not 
permitted by applicable law or not approved by the governing ethics committee).  These 
data will be used in the analysis of the safety and/or PK profile of the study treatment.  It is 
unknown whether the effects of the study treatment are influenced by race or ethnicity. 
…
Rationale: The race and ethnicity of the subjects are important to capture in order to assess any 
trends in pharmacokinetic data that may be related to race and/or ethnicity.

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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.

Clarifications were made throughout the protocol in reference to whether information 
pertained to Parts A and/or B.

The Sponsor signatory was updated.

Section 2, List of Abbreviations, was updated.

Section 5, Introduction, a description of the mechanism of action information for 
BIIB067 was added from the Investigator’s Brochure.

Section 8.1.2, Exclusion Criteria; Section 8.2.2, Exclusion Criteria, and 
Section 11.3.1.2, Disallowed Concomitant Therapy, aspirin was removed as an 
excluded concomitant medication. 

Section 8.1.2, Exclusion Criteria and Section 8.2.2, Exclusion Criteria, hepatitis B 
serololigical test abbreviations updated.

Section 9.3, Blinding Procedures, text was added describing end of study unblinding 
procedures.

Section 14.2, Laboratory Safety Assessments, laboratory assessments were updated 
for clarity.

Section 15.1.2, Serious Adverse Event, text was updated to classify a medically 
important event as a serious adverse event (SAE).

Section 15.3.1, Adverse Events, text was added to clarify that at each study visit, the 
Investigator will assess the subject’s adverse events (AEs) and record any new AEs or 
updates to previously reported AEs.

Section 15.3.3, Immediate Reporting of Serious Adverse Events, “Reporting 
Information for SAEs” text was updated to remove text stating that any SAE between 
consent and last follow-up visit must be reported within 24 hours, and that thereafter, 
events should only be reported if related to study treatment. 

Section 15.4.1, Pregnancy, text was added to clarify that a pregnancy is not 
considered an AE and should not be recorded as such and that pregnancy can also be 
reported via email.

Sections 15.4.2, Overdose, and Section 15.6.1, The Investigator, text was added 
indicating that overdose and SAEs may be reported by email. 

Section 16.1.4.2, Methods of Analysis, p75 was added as a potential biomarker for 
analysis. 

Section 19.1.4, Laboratory Assessments, text added to clarify that serum pregnancy 
tests will be analyzed at a central laboratory. 

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
The vendor information was updated to Sponsor information throughout (changed 
from 
 to “Biogen”).

New references were added to the reference list.

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
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Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 233AS101
A Phase 1, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of BIIB067 Administered to Adult Subjects with 
Amyotrophic Lateral Sclerosis
Version 4
Date:  29 November 2017
EUDRA CT: 2015-004098-33
Version 4 of the protocol has been prepared for this amendment, which supersedes Version 3.

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PRIMARY REASONS FOR AMENDMENT
The primary reasons for this amendment to Protocol 233AS101 are to 1) add an 8th treatment 
cohort to assess the safety and tolerability of up to 5 doses of BIB067 100 mg, and 2) include the 
option of an interim analysis during Part B (multiple-ascending-dose portion) of the study.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7.1.2, Part B: Multiple-Ascending-Dose Evaluation
Now reads:
Part B will be a randomized, double-blind, placebo-controlled, MAD evaluation of up to 34 dose 
levels of BIIB067 administered up to 5 times, over approximately 3 months, to up to 36 48
subjects with SOD1-ALS.  Each dose level will be assessed in cohorts of 12 subjects:  3 subjects 
will be administered placebo, and 9 subjects will be administered BIIB067 at 20, 40, or 60, or
100 mg.  
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 (motor cortex) and 
spinal cord. Emerging preliminary pharmacokinetic (PK) data from the ongoing trial indicated 
that the exposure to BIIB067 was less than that predicted preclinically. The purpose of adding a 
higher dose cohort (100 mg) to the trial is 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.
This change also affects Sections 5.4, Study Rationale; 7.1, Study Overview; 7.2.1.2, Part B:  
Multiple Ascending Dose; Figure 3, Dose Escalation Schematic; 9.2, Randomization and 
Registration of Subjects; 11.1.1, BIIB067; and 16.8, Sample Size Considerations.
Section 16.7, Interim Analysis
Now reads: In Part A (SAD) of the study, CRM will be used as supporting evidence for 
continuous assessment of MTD for dose escalation decisions.  No formal interim analysis will be 
performed in Part B (MAD) of the study. In Part B (MAD) of the study, in addition to the 
safety review (blinded), a designated team of staff will review the available unblinded but 
de-identified PD and/or biomarker data (eg., levels of SOD-1 and p-NFH) from all previous 
cohorts at the completion of the last Day 106 visit of each cohort to determine whether to 
proceed with the subsequent planned dose cohorts.  An interim analysis of key safety, 
secondary and exploratory endpoints may be conducted based on data up to the 60-mg 
and/or 100-mg dose cohort to allow for the planning of the pivotal efficacy and safety study. 
The subjects, investigative staff, and sponsor’s staff responsible for site monitoring and 
data management will remain blinded to treatment assignment during the ongoing data 
review, as well as during interim analyses, to minimize the potential for bias in the data 
cleaning process. Details of the interim analysis will be provided in a separate statistical 
analysis plan.

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Rationale: The implementation of an interim analysis during Part B of the study would allow for 
the timely determination of a possible effect on key biomarkers, thereby facilitating an earlier 
transition to pivotal studies without compromising overall study design.
This change also affects Section 7.2.1.2, Multiple Ascending Dose.

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
The major 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 5.2, Current Therapies for Amyotrophic Lateral Sclerosis
Change: Included information on edaravone.
Now reads:
The only currently approved treatments for ALS are is Rilutek® (riluzole (Rilutek®), which is 
marketed globally, and edaravone (Radicava™), which is approved in the United States, 
Japan, and South Korea.  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 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 SOD1 ALS 
treatments are available.
Rationale: Edaravone was recently approved as a treatment for ALS; this change updates the 
information on current therapies 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, 
intrathecally-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 dose rationale 
in this 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: Updated the rationale for dosing regimen to include the 100-mg dose of BIIB067.
Now reads:
BIIB067 will be administered via intrathecal bolus at single ascending doses (SAD) to cohorts in 
Part A, and at multiple ascending doses (MAD) to cohorts in Part B.
The BIIB067 dosing regimens for this study were selected based on nonclinical toxicology and 
PK observations in nonhuman primate (NHP) studies using repeated-dosing intrathecal 
administration for 13 weeks and 9 months, and target tissue concentrations from SOD1 
transgenic mouse models. 
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 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 this study (10 mg) is predicted to achieve greater than 0.9 µg/g 
tissue concentration in the spinal cord. and cortex, while tThe initial highest proposed dose (60 
mg, multiple dose) iswas 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.  These tissue concentrations are predicted to span the pharmacologically active 
range. 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.
Based on nonclinical PK and pharmacology data, and taking into consideration subject safety, 
the inconvenience of repeated intrathecal injections, and the rapid, fatal nature of ALS, the 
following dose intervals were selected for Part B of the study (MAD):  3 loading doses, once
every 2 weeks, and 2 maintenance doses, administered once every 4 weeks.  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 to facilitate effective 
SOD1 protein reduction in the CSF within Part B of the study (MAD).  
From the 139-weekmonth NHP toxicology study, the NOAEL for repeated, intrathecally-
administered BIIB067 was 35 12 mg.  No clinical or histologic observations were deemed 

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adverse in this study.  This NOAEL was converted to a human equivalent dose (HED) based on 
the nonclinical species 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 139-weekmonth, intrathecal NHP toxicology study 
was calculated to be 350 120 mg.  This provides a 3512-fold safety margin for the BIIB067 
starting dose (10 mg), and a 5.82-fold safety margin for the highest planned dose (60 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 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 233AS101 are predicted to be pharmacologically 
active, while maintaining sufficient safety margins calculated from the 139-weekmonth
intrathecal NHP toxicology study.
Rationale: This change was made based on BIIB067 exposure predictions related to addition of 
the 100-mg dose and updated information on the 9-month NHP toxicology study. The human 
equivalent dose and the safety margin relative to the new highest planned dose of 100 mg
(Cohort 8) were also included.
Section 7.2.2.2, Multiple Ascending Dose
Change: Added details of within cohort staggering for Cohort 8.
Now reads: 
Within eachcohorts 5-7 in Part B, subjects will be randomized in blocks of 4 to receive BIIB067 
or placebo in a 3:1 (active treatment:placebo) ratio.  The 3 blocks of each cohort will be dosed 
sequentially, each followed by a 72-hour safety data review period, during which the Biogen 
Medical Director and SABR Physician will review blinded safety data with the PI.
Given that safety and tolerability of the 100-mg dose of BIIB067 were not explored in Part 
A (SAD), both a sentinel dosing strategy and a review of safety data for every subject after 
the first dose will be incorporated into Cohort 8. 
In Cohort 8, the first 2 subjects (1 subject receiving placebo and 1 subject receiving 
BIIB067) will be dosed as a sentinel group, followed by a 72-hour safety data review period, 
during which the Biogen Medical Director and SABR Physician will review blinded safety 
data with the PI.  For the remaining subjects in the cohort, no more than 2 subjects will be 
given the first dose of study treatment on the same day throughout the study. 
Cohort 8 follows the same loading dose/maintenance dose as the other MAD cohorts. While 
a 100-mg dose has not been administered in the SAD portion of the study, the safety data 
collected between week 2 and week 4 postdose (or even week 1 and week 4 postdose) did 
not yield any additional information when compared with safety data collected for the first 
2 weeks postdose. This justifies the absence of a 4-week safety observation period between 
doses 1 and 2.

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Additional to the 72-hour safety review period, for every subject in Cohort 8, a review of all 
available safety and tolerability data will be performed approximately 1 week after the first 
dose is administered.  This review will be performed by the Biogen Medical Director and 
SABR Physician with the PI.  The second dose cannot be given until this review is 
complete.
Rationale: These changes were made to ensure safety evaluation of a single dose of BIIB067 
100 mg before proceeding with multiple dosing, as this dose level was not evaluated in the single 
ascending dose portion of this study.
Section 7.3.3.2, Part B:  Multiple Ascending Dose
Change:  To include the option of home visits.
Now reads:  
Subjects will return to the study site for follow-up visits after each dose on Day 8 (after first 
dose), Day 22 (after second dose), Day 36 (after third dose), Day 64 (after fourth dose), Days 92 
and 106 (after fifth dose), and on the final study visit on Day 169.  On the days of CSF sampling 
(Day 106 and Day 169), subjects will remain under observation for approximately 1 hour after 
the procedure and will receive a safety follow-up telephone call approximately 24 hours after the 
procedure.  Subjects will also receive follow-up telephone calls on Day 50 (after third dose) and 
Day 78 (after fourth dose) to provide information on AEs, SAEs, and concomitant medications 
or procedures.  Subjects may, at the discretion of the Investigator, have the option of home 
visits for non-dosing visits that do not require CSF collection or strength and 
electrophysiological measures, which are visits on Days 8, 36, and 64.
Rationale:  The Sponsor has a contract with Global Care to provide home visits; however, this 
option has not been used as the language was missing from the protocol.
This change also affects Section 4.1, Study Schematic: Figure 2; and Section 4.2, Schedule of 
Activities: Table 2, footnote 3. 
Section 7.4.1, Dose Suspension
Change: Updated language related to managing a serious adverse event (SAE) or a clinically 
significant adverse event (AE).
Now reads:
If 1 subject experiences either an SAE or a clinically significant AE (as defined by the 
Investigator or the Sponsor), the Biogen Medical Director and SABR Physician will discuss 
the event with the Investigator and review the SAE form (if applicable). If the AE is 
assessed as unrelated to the study treatment by both the Investigator and the Sponsor (e.g.,
it is a known sign or symptom of ALS, or it is an effect of the LP procedure), dose 
suspension is not necessary. 
If the SAE or clinically significant AE (as determined by the Investigator or the Sponsor) is 
assessed as related to the study treatment by the Investigator or the Sponsor, all dosing will 
be suspended until the event has been fully evaluated, including for potential relatedness to study 
drug, by the Biogen Medical Director, SABR Physician, Biostatistician, Clinical Pharmacologist,
and, if required, any ad hoc members.  Depending on the nature, severity, suspected on- or off-

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target toxicity, outcome, and frequency of the event, a decision (documented with supporting 
rationale) will be made to proceed with one of the following:  
•
Request additional safety data 
•
Continue dosing remaining subjects within the cohort
•
Enroll additional subjects to the current cohort 
•
Proceed with the planned dose escalation in the next cohort
•
Enroll additional subjects to previous (lower-dose) cohort
•
Stop the study
Rationale: This update was included to prevent any unnecessary dose suspensions for events 
clearly not related to the study treatment.
Section 7.4.2, Dose Termination
Change:  Updated dose termination criteria in case of recurrent SAEs or AEs. Also updated the 
individuals evaluating safety, tolerability, and PK data.
Now reads:  
After evaluation of safety, tolerability, and PK data by the Biogen Medical Director, SABR 
Physician, Biostatistician, Clinical Pharmacologist, and, if required, any ad hoc members, further 
dosing at the current level and dose escalation will be terminated if any of the following is 
observed:
•
Two similar SAEs (unless clearly unrelated to BIIB067 upon medical review) are 
reported for 2 subjects on active study treatment within the same cohortCurrent dose is not 
deemed to be safe.
•
Three or more similar AEs (unless clearly unrelated to BIIB067 upon medical 
review) that are either not tolerable (as reported by the subjects) or deemed a medically 
unacceptable risk by the Biogen Medical Director, SABR Physician, and, if required, any 
ad hoc members.
•
Sponsor requests that dosing be terminated. 
Rationale:  This change was made to explain the situations that could trigger dose termination if 
the dose administered is not deemed safe for the subjects.
Section 8.2, Exclusion Criteria
Change: Updated hepatitis C- and B-related exclusion criteria.
Now reads:
2.
History of, or positive test result at Screening, for hepatitis C virus 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-

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HBs) are eligible to participate in the studyor hepatitis B virus (defined as positive for both 
hepatitis B surface antigen and hepatitis B core antibody).
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.
Change: Included the use of edaravone as a criterion for exclusion from the study.
Now reads:
8.
Current or recent use (within 30 hours prior to screening), or anticipated need of 
edaravone (Radicava).
Rationale: Edaravone was recently approved as a treatment for ALS in the United States, and 
although its possible effect on various exploratory ALS biomarkers such as neurofilament or 
SOD1 clinically has not been reported, nonclinical models showed that it reduced SOD1 levels 
in rodent spinal cord. The use of edaravone was included as a criterion for exclusion from the 
study to avoid the interference from any of its potential clinical effects.
Change:  Included the presence of implanted vascular devices as a criterion for exclusion from 
the study.
Now reads:
9.
Presence of any implanted vascular devices.
Rationale: This change was made to avoid associated risks, including infection.
Section 9.1, Screening and Enrollment
Change: To permit rescreening of subjects who met eligibility but were not dosed within the 28-
day screening window.
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 their 
screening assessments (Screening Visit 2) may be rescreened.
Rationale: This change may help reduce the impact of an expired screening window on 
recruitment time and allow the team to include subjects who would otherwise be eligible for the 
study but for the screening window expiration.
14.1, Clinical Safety Assessments
Change: Included a list of the type of neurological examinations to be conducted at the sites.
Now reads: 

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•
Limited Nneurological examinations (to be assessed by a trained specialist) of cranial 
nerves, coordination/cerebellar function, reflexes, motor, and MMSE (Mini-Mental State 
Examination – a 30-point questionnaire that is used to measure cognitive impairment; in
Part B only).  In Part B of the study, the neurological examination will include the Mini Mental 
State Examination (MMSE) a 30 point questionnaire that is used to measure cognitive 
impairment
Rationale: This change will eliminate confusion and enable consistency in the type of 
neurological examinations performed across all sites conducting the study.
This change also affects Sections 4.2, Schedule of Activities: Table 2; and 16.5.2.6, Limited 
Neurological Examinations.
14.2, Laboratory Safety Assessments
Change: To separate coagulation from other hematology assessments and to exclude total cell 
count from CSF analysis.
Now reads:
•
Hematology:  complete blood count with differential, platelet count, and absolute 
neutrophil count.  INR, PT, and APTT will also be measured
•
Coagulation: INR, PT, and APTT
•
Blood chemistry:  electrolytes, 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
•
Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal) 
•
Urine pregnancy tests
•
CSF analysis:  total cell count, red blood cell count, white blood cell count, protein, and 
glucose
Rationale: These changes were made for clarity, as coagulation is not part of the standard 
hematology assessments and the total cell count is not required for standard CSF analysis.
This change also affects Sections 4.2, Schedule of Activities, Table 2; and 16.5.2.2, Clinical 
Laboratory Results.
17.3, Subject Information and Consent
Change: Included update that subjects will be informed about the collection of sensitive data 
(race and ethnicity).
Now reads:  
Subjects will be informed, where applicable, that their race and ethnicity will be collected 
during the study (unless the collection is not permitted by applicable law or not approved 

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by the governing ethics committee) and the data will be used during analysis of study 
results.
Rationale:  This update was made to keep subjects informed about the collection of sensitive 
data 

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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 address in the United States was updated.

The List of Abbreviations was updated.

Section 4.1, Study Schematic, Figures 1 and 2 were replaced to correct minor errors.

Section 9.3, Blinding Procedures, was updated for consistency in the description of 
safety review blinding.

Use of abbreviation only (vs. spelled-out term) was fixed in Section 13.2, 
Pharmacokinetic Assessments.

A new reference was added to the list.

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 233AS101 
A Phase 1, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of BIIB067 Administered to Adult Subjects with 
Amyotrophic Lateral Sclerosis 
Version 3 
Date:  17 November 2016 
EUDRA CT 2015‐004098‐33 
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2. 
 

Protocol 233AS101, Version 3 
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PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 233AS101 is to correctly reflect in Figure 2 
of the protocol that sampling for anti-BIIB067 antibody (Ab) will occur during nondosing 
clinical visits (except for predose on Day 1).  
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 4.1, Study Schematic (Figure 2: Study Design: Part B − Multiple Ascending Dose) 
Now reads: 
 

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Rationale:   
The schematic for Part B incorrectly lists collection of anti-BIIB067 Ab samples under dosing 
visits for doses 2 through 5. The sampling for anti-BIIB067 Ab should occur at all clinical 
follow-up visits, but not on the day of dosing per the Schedule of Events table.  Currently, 
Figure 2 indicates that sampling for anti-BIIB067 Ab occurs at the Follow-up Safety Visits and 
Dosing Visits.  
 
 

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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 4.2, Schedule of Activities (Table 2: Schedule of Activities: Part B − Multiple Ascending 
Dose) 
Change:  Table 2 Schedule of Activities:  Part B – Multiple Ascending Dose was updated to add 
the collection of height at Visit 2. 
Now reads: 

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Table 2: 
Schedule of Activities:  Part B – Multiple Ascending Dose 
Tests and Assessments 
Screening 
Dosing Inpatient Period 
Dosing 
Days 15, 
29, 57 & 
85 
(±3 days) 
Follow-Up 
V11 
≤21 days 
before V2 
V22 
Day -28 
to Day -1 
Day 1 
Day 2 
24 (±1) 
Postdose 
Days 8, 22, 
36, 64, 92, 
and 106 
(±3 days) 
Days 50 & 
78  
(±3 days) 
via 
Telephone 
 
Day 169 
(±3 days) /Early 
Termination 
Visit 
Predose 
Dosing/ 
Postdose 
Physical Examination 
 
X 
X 
 
X5 
X5 
X5 
 
X5 
Weight 
 
X 
X 
 
 
 
 
 
X 
Height 
 
X 
 
 
 
 
 
 
 

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Rationale:   
Height was being collected in Part A – Single Ascending Dose phase of the study and was not 
being collected in Part B – Multiple Ascending Dose phase.  Collection of height was added to 
Part B to align both components of the study. 
 
 
 

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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. 
• Minor editorial changes were made as appropriate (e.g., addition of abbreviations to 
figure and table footnotes).  
• The sponsor signature page was updated. 
• Section 4.1 Study Schematic, Figure 1 Study Design: Part A – Single Ascending 
Dose was updated to reflect the sampling of peripheral blood mononuclear cell at the 
dosing visit and the sampling of biomarkers only at Day 29 to align with Table 1. 
 

CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
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 233AS101 
A Phase 1, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of BIIB067 Administered to Adult Subjects with 
Amyotrophic Lateral Sclerosis 
Global Amendment Version 2 
Date:  10 October 2016 
EUDRA CT Number: 2015‐004098‐33  
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1. 
 

Protocol 233AS101, Version 2 
 
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reasons for this amendment to Protocol 233AS101 are 1) to add the review of 
pharmacokinetic (PK) data and clarify the review of safety data prior to each dose escalation in 
Part B (multiple-ascending-dose [MAD]) of the study and 2) to add the Mini-Mental State 
Examination (MMSE) as part of the neurological examination. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 7.2.1.2, Multiple Ascending Dose 
Now reads: 
After the last subject a minimum of 10 subjects within a cohort completes the Day 106 
Follow-Up Visit (~3 weeks after last dose), and prior to dosing of the next, higher dose cohort, a 
Biogen Medical Director and a SABR Physician will review the all available blinded safety data 
with the PI.  Review of blinded safety data may be followed by review of unblinded safety data 
of the current cohort and all available safety data from preceding cohorts by the Biogen Medical 
Director, SABR Physician, Biostatistician, Clinical Pharmacologist, and, if required, any ad hoc 
members.  In addition to review of the safety data, a Biogen Medical Director, Clinical 
Pharmacologist, and, if required, any ad hoc members will review PK data through the 
trough levels after the fourth dose (samples collected predose on Day 85) for a minimum of 
6 subjects within a cohort, prior to dosing of the next, higher dose cohort.  Before escalating 
to the next, higher dose level, there must be agreement that the current emerging safety, and 
tolerability, and PK data support dose escalation. 
Rationale:  To confirm that PK data will be obtained and analyzed before transitioning to the 
subsequent cohort for safety reasons and to ensure the assessment of PK at a steady state.   
This change also affects Figure 3: Dose Escalation Schematic. 
Section 14.1, Clinical Safety Assessments 
Now reads: 
The following clinical assessments will be performed to evaluate the safety profile of BIIB067: 
 Medical history 
 Physical examinations 
 Neurological examinations (to be assessed by a trained specialist).  In Part B of the 
study, the neurological examination will include the Mini-Mental State 
Examination (MMSE) – a 30-point questionnaire that is used to measure 
cognitive impairment 
Rationale:  The MMSE was added to assess possible changes in the subject’s cognitive 
performance. 
This change also affects Section 4.2, Schedule of Activities (Table 2: Part B – Multiple 
Ascending Dose). 
 

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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 6.3, Exploratory Objectives and Endpoints 
Change:  Questionnaires were added to the list of exploratory endpoints. 
Now reads: 
To evaluate the effect of BIIB067 on measures of clinical function. 
 The endpoints that relate to this objective are changes from baseline in the following 
measures:  
 ALS Functional Rating Scale - Revised (ALSFRS-R)  
 sSlow vital capacity (SVC). 
 
 
 
 
 
 
 
 
 
 
Rationale:  The questionnaires will enable assessment of any changes in subjects’ quality of life, 
which is an important component of clinical function. 
This change also affects Section 4.1, Study Schematic (Figure 2: Study Design: Part B – 
Multiple Ascending Dose); Section 4.2, Schedule of Activities (Table 2: Part B – Multiple 
Ascending Dose); Section 13.1, Exploratory Assessments of the Effect of BIIB067 on Clinical 
Function; and Section 16.1.2, Methods of Analysis. 
Section 7.1.1, Part A: Single-Ascending-Dose Evaluation: 
Change:  Eligibility criterion for Part A (single-ascending dose [SAD]) of the study was 
changed to allow only those patients with amyotrophic lateral sclerosis (ALS) caused by 
superoxide dismutase 1 (SOD1) mutation to enter the study. 
Now reads: 
Part A will be a randomized, double-blind, placebo-controlled, SAD study of up to 4 dose levels 
of BIIB067 administered to subjects with sporadic ALS or SOD1-ALS.  The dose levels will be 
evaluated sequentially.  Final sample size for Part A of the study will be determined by the 
incidence of DLT.  If no DLTs are encountered, a minimum of 20 subjects will be enrolled.  The 

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maximum sample size for Part A is 36 subjects.  Every attempt will be made to enroll subjects 
with SOD1 ALS into each dose cohort.  The first 3 dose levels will be assessed in cohorts of 
4 subjects each:  1 subject will be administered placebo, and 3 subjects will be administered 
BIIB067 at 10, 20, or 40 mg.   
Rationale:  This change was made to exclude subjects with sporadic ALS as these subjects were 
not expected to benefit from the treatment with the study drug.   
This change also affects Section 8.1, Inclusion Criteria 3. 
Section 7.3.1.1, Part A: Single-Ascending Dose 
Change:  The duration of Part A screening period was increased 
 
 
Now reads: 
For subjects who do not have documentation of a SOD1 mutation, the screening period will 
involve an additional visit (Screening Visit 1), where a blood sample will be collected for 
deoxyribonucleic acid (DNA) analysis.  The rationale for the extra screening visit is to 
ensure DNA analysis results prior to assessing the rest of the eligibility criteria.  Subject 
eligibility for the study will be determined during Screening Visit 2, up to approximately 
21 days after Screening Visit 1 and within 28 days prior to admission to the inpatient facility 
for dosing (Day 1).  Subjects in the 2 lowest dose cohorts, who choose to re-enroll into 1 of the 2 
highest dose cohorts, will have to repeat screening assessments before receiving the second dose.  
The This second additional Screening Visit can occur during the washout period, within 28 days 
prior to their second admission to the inpatient facility for dosing.  
 
. 
The Screening Visit 2 assessments may be performed over 2 days, which do not need to be 
consecutive, to minimize subject burden.  All assessments must be completed before Day 1. 
Rationale:  The duration of the study for Part A was increased 
 
. 
 
 
 
 
Section 9.2, Randomization and Registration of Subjects 
Change:  The number of replacement subjects that could be enrolled per cohort in Part B of the 
study was specified. 
Now reads: 
Up to 6 replacement subjects may be enrolled in Part B of the study (2 per cohort).  These 
additional subjects will be assigned to receive the same study treatment as the withdrawn 
subjects they will replace. 
Rationale:  This update was made to suggest that if subject(s) withdrew in Part B 
(multiple-ascending dose), and if the Sponsor decided to replace the subjects, then 2 subjects per 

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cohort (i.e., up to 14 subjects in each cohort) could be enrolled and would each receive the same 
treatment as the subject being replaced. 
 
Change:  
 
 
 
Now reads: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 

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Rationale:  
 
 
  
Section 15.5, Contraception Requirements 
Change:  Barrier method was removed from the list of highly effective contraception. 
Now reads: 
For the purposes of the study, highly effective contraception is defined as use of the following: 
For females: 
 Established use of oral, injected, or implanted hormonal methods of contraception. 
 Placement of an intrauterine device or intrauterine system. 
 Barrier methods of contraception with use of a spermicide: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/cream suppository. The 
use of barrier contraceptives should always be supplemented with the use of a 
spermicide. 
 Male 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: 
 Effective male contraception includes aA vasectomy with negative semen analysis at 
follow up, or the use of condoms with spermicide. 
Rationale:  It was decided that barrier method will not be considered as highly effective 
contraception to be compliant with requirements of European Regulatory Agencies.  

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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. 
 A sponsor signature page was added to the protocol. 
 Section 2, List of Abbreviations, was updated to reflect changes in the protocol.  This 
change also affects Section 17, Ethical Requirements, for the definition of 
International Council for Harmonisation.Section 4.2, Schedule of Activities (Table 2: 
Part B – Multiple Ascending Dose), footnotes were updated to indicate that the 
ALSFRS-R assessment 
 
 HHD will be performed on Day 22 and Day 92.  A 
footnote was added to indicate that blood sampling for biomarkers will be collected 
on Day 106.  The table was also updated to move the FSH assessment from Screening 
V1 to Screening V2. 
 Section 5.3.2, Clinical Experience, the name of the company was updated from ISIS 
Pharmaceuticals to Ionis Pharmaceuticals to reflect the company’s recent name 
change. 
 Section 8.1, Inclusion Criterion 7, was updated to indicate that screening coagulation 
values should be within normal ranges.  It was clarified that subjects with 
nonclinically significant and stable out-of-range values may be eligible to enroll in 
the study at the discretion of the Investigator and after a consultation with the 
Sponsor.  This change also affects Section 4.2, Schedule of Activities, Table 1 and 
Table 2, Footnote 4. 
 Section 8.2, Exclusion Criterion 3, was updated to clarify that subjects receiving 
treatment with another investigational drug, including investigational drugs for ALS 
through compassionate use programs, will not be eligible to participate in the study. 
 Section 11.3.1.2, Disallowed Concomitant Therapy, was updated to remove 
memantine and coenzyme Q that were included in the protocol as examples of 
off-label medications for ALS treatment to avoid any confusion resulting from citing 
an incomplete list of medications. 
 Section 13, Efficacy, Pharmacokinetic, and Pharmacodynamic Assessments, was 
updated to change all instances of the use of the term “efficacy” in the protocol to 
“clinical function” and to emphasize that the clinical function measurements will only 
be exploratory in nature.  This change also affects Section 16.1.1, Analysis 
Population, wherein the “efficacy set” is termed “clinical function set.” 
 Section 14.2, Laboratory Safety Assessments, was updated to clarify that 
cerebrospinal fluid (CSF) analysis will also include red blood cell count and white 
blood cell count.  Updates were made to clarify that platelet and coagulation tests will 
be collected at every visit (including screening) and analyzed centrally as safety 
laboratory tests for the study. 

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 Section 15.3.2, Serious Adverse Events, was updated to clarify that the ICF 
mentioned in this section refers to the first (main) ICF. 
 Section 19.1.4, Laboratory Assessments, was updated to clarify that urine pregnancy 
tests will be collected and analyzed in the clinic; however, CSF samples will be 
collected in the clinic and analyzed at the local laboratory.  In addition, it was 
clarified that repeat coagulation or hematology tests, if required, will be collected in 
the clinic and sent to the local laboratory for analysis.  The section header was 
updated to reflect this change. 
 Section 19.2, Publications, was moved to Section 18.5 to adhere to template 
guidance. 
 Section 20, References, was updated to reflect changes in the protocol.  Reference to 
the article by Brooks et al was removed because the reference to sporadic ALS has 
been removed from Inclusion Criteria 3.