A Phase 1/2 Multiple-Ascending-Dose Study With a Long-Term Open-Label Extension to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Effect on Disease Progression of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral Sclerosis With or Without Poly-CAG Expansion in the ATXN2 Gene
Phase: PHASE1
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Biogen

COVER PAGE 
Official Title: 
A Phase 1/2 Multiple-Ascending-Dose Study With a Long-Term Open-
Label Extension to Assess the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Effect on Disease Progression of BIIB105 
Administered Intrathecally to Adults With Amyotrophic Lateral Sclerosis 
With or Without Poly-CAG Expansion in the ATXN2 Gene
NCT Number: NCT04494256
Document Date: 
07 September 2023

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
SPONSOR INFORMATION
This study is a partnership between Biogen and IONIS. Biogen is responsible for 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
For urgent medical issues in which the study 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 CRO and other third 
parties; however, Biogen retains overall accountability for these activities.

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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TABLE OF CONTENTS
SPONSOR INFORMATION ..........................................................................................................2
SPONSOR SIGNATURE PAGE ....................................................................................................3
TABLE OF CONTENTS.................................................................................................................4
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
1.
KEY STUDY ELEMENTS........................................................................................10
1.1.
Synopsis......................................................................................................................10
Study Design Schematic ................................................................................................................26
Schedule of Activities....................................................................................................................27
2.
LIST OF ABBREVIATIONS.....................................................................................50
3.
INTRODUCTION......................................................................................................52
3.1.
Study Rationale...........................................................................................................52
3.1.1.
Rationale for Study Population...................................................................................53
3.1.2.
Rationale for Starting Dose and Maximum Exposure................................................53
3.1.3.
Rationale for the Collection of Genetic Samples .......................................................55
3.2.
Background.................................................................................................................56
3.2.1.
Overview of ALS........................................................................................................56
3.2.2.
Current Therapies for ALS.........................................................................................56
3.2.3.
Profile of Previous Experience with BIIB105............................................................57
3.2.3.1.
Nonclinical Experience...............................................................................................57
3.2.3.2.
Clinical Experience.....................................................................................................60
3.3.
Benefit-Risk Assessment............................................................................................60
4.
STUDY OBJECTIVES AND ENDPOINTS..............................................................62
5.
STUDY DESIGN .......................................................................................................66
5.1.
Study Overview ..........................................................................................................66
5.1.1.
Part 1...........................................................................................................................66
5.1.2.
Part 2...........................................................................................................................67
5.2.
Study Duration for Participants ..................................................................................67
5.2.1.
Study Duration for Participants in Part 1....................................................................67
5.2.2.
Study Duration for Participants in Part 2....................................................................68
5.3.
Dosing.........................................................................................................................69

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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5.3.1.
Dose Escalation (Part 1) .............................................................................................69
5.3.2.
Dosing (Part 2)............................................................................................................70
5.4.
Study and Cohort Stopping Rules...............................................................................71
5.4.1.
Cohort Suspension......................................................................................................71
5.4.2.
Dose Termination .......................................................................................................72
5.4.3.
Study Termination ......................................................................................................73
5.5.
Unscheduled Visits.....................................................................................................73
5.6.
End of Study ...............................................................................................................74
5.6.1.
End of Part 1...............................................................................................................74
5.6.2.
End of Study ...............................................................................................................74
6.
STUDY POPULATION.............................................................................................75
6.1.
Inclusion Criteria ........................................................................................................75
6.1.1.
Part 1...........................................................................................................................75
6.1.2.
Part 2...........................................................................................................................76
6.2.
Exclusion Criteria.......................................................................................................77
6.2.1.
Part 1...........................................................................................................................77
6.2.2.
Part 2...........................................................................................................................79
6.3.
Screening, Retesting, and Screen Failures..................................................................81
6.3.1.
Screening ....................................................................................................................81
6.3.2.
Retesting .....................................................................................................................82
6.3.3.
Screen Failures............................................................................................................82
7.
STUDY TREATMENT..............................................................................................84
7.1.
Regimen......................................................................................................................84
7.2.
Study Treatment Management....................................................................................85
7.3.
Study Treatment..........................................................................................................85
7.3.1.
BIIB105 ......................................................................................................................85
7.3.1.1.
Preparation..................................................................................................................85
7.3.1.2.
Storage........................................................................................................................85
7.3.1.3.
Handling and Disposal................................................................................................86
7.3.1.4.
Accountability.............................................................................................................86
7.3.2.
Placebo........................................................................................................................86
7.4.
Blinding Procedures....................................................................................................86

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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7.5.
Precautions..................................................................................................................87
7.6.
Compliance.................................................................................................................87
7.7.
Concomitant Therapy and Procedures........................................................................87
7.7.1.
Concomitant Therapy .................................................................................................87
7.7.1.1.
Allowed Concomitant Therapy...................................................................................87
7.7.1.2.
Disallowed Concomitant Therapy..............................................................................88
7.7.2.
Concomitant Procedures.............................................................................................88
7.8.
Continuation of Treatment..........................................................................................89
8.
RULES FOR DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL FROM STUDY FOR INDIVIDUAL PARTICPANTS ................90
8.1.
Discontinuation of Study Treatment...........................................................................90
8.2.
Lost to Follow-Up.......................................................................................................90
8.3.
Withdrawal of Participants From the Study ...............................................................91
9.
SAFETY ASSESSMENTS ........................................................................................92
9.1.
Clinical Assessments ..................................................................................................92
9.2.
Laboratory Assessments.............................................................................................92
9.3.
Product-Specific Safety Assessments.........................................................................93
10.
PHARMACOKINETIC ASSESSMENTS.................................................................94
11.
PHARMACODYNAMIC AND EFFICACY ASSESSMENTS................................95
11.1.
Pharmacodynamic Assessments.................................................................................95
11.2.
Assessments of Clinical Function and Survival .........................................................95
11.2.1.
Slow Vital Capacity....................................................................................................95
11.2.2.
ALS Functional Rating Scale-Revised (standard)......................................................96
96
96
96
11.2.6.
Handheld Dynamometry.............................................................................................97
97
97
97
11.2.10.
Participant Ventilation Diary......................................................................................97
11.2.11.
Collection of Vital Status Before and After Study Withdrawal or Completion.........98

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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11.3.
Pharmacogenetic and Genetic Assessments...............................................................98
99
12.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES ...............................................................................................100
12.1.
Definitions ................................................................................................................100
12.1.1.
Adverse Event...........................................................................................................100
12.1.2.
Serious Adverse Event..............................................................................................100
12.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments..............101
12.2.
Safety Classifications................................................................................................101
12.2.1.
Investigator Assessment of Events...........................................................................101
12.2.2.
Relationship of Events to Study Treatment or Lumbar Puncture.............................102
12.2.3.
Severity of Events.....................................................................................................103
12.2.4.
Expectedness of Events ............................................................................................103
12.3.
Monitoring and Recording Events............................................................................103
12.3.1.
Adverse Events.........................................................................................................103
12.3.2.
Serious Adverse Events............................................................................................103
12.3.3.
Immediate Reporting of Serious Adverse Events.....................................................104
12.3.3.1.
Deaths .......................................................................................................................104
12.3.4.
Suspected Unexpected Serious Adverse Reactions..................................................104
12.4.
Procedures for Handling Special Situations .............................................................105
12.4.1.
Pregnancy .................................................................................................................105
12.4.2.
Overdose...................................................................................................................105
12.4.3.
Medical Emergency..................................................................................................105
12.4.3.1.
Unblinding for Medical Emergency.........................................................................106
12.5.
Contraception Requirements ....................................................................................106
12.6.
Safety Responsibilities..............................................................................................107
12.6.1.
The Investigator........................................................................................................107
12.6.2.
The Sponsor..............................................................................................................108
13.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE.........109
13.1.
General Considerations.............................................................................................109
13.2.
Analysis Populations ................................................................................................109
13.2.1.
Part 1.........................................................................................................................109

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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13.2.2.
Part 2.........................................................................................................................109
13.2.3.
Integrated Part 1 and Part 2 ......................................................................................110
13.3.
Methods of Analysis.................................................................................................110
13.3.1.
Safety........................................................................................................................110
13.3.1.1.
Adverse Events.........................................................................................................110
13.3.1.2.
Laboratory Results....................................................................................................111
13.3.1.3.
Vital Signs ................................................................................................................111
13.3.1.4.
C-SSRS.....................................................................................................................111
13.3.1.5.
Electrocardiogram.....................................................................................................111
13.3.2.
Pharmacokinetics......................................................................................................111
13.3.3.
Pharmacodynamics/Biomarkers ...............................................................................112
13.3.4.
Clinical Function and Quality of Life Measures ......................................................112
13.3.5.
Time to Death or Permanent Ventilation, Time to Death.........................................113
113
13.4.
Interim Analyses.......................................................................................................113
13.5.
Sample Size Considerations .....................................................................................114
14.
ETHICAL REQUIREMENTS .................................................................................115
14.1.
Declaration of Helsinki.............................................................................................115
14.2.
Ethics Committee......................................................................................................115
14.3.
Changes to Final Protocol.........................................................................................116
14.4.
Informed Consent .....................................................................................................116
14.5.
Participant Data Protection.......................................................................................117
14.6.
Compensation for Injury...........................................................................................117
14.7.
Conflict of Interest....................................................................................................117
14.8.
Study Report Signatory.............................................................................................117
14.9.
Registration of Study and Disclosure of Study Results............................................117
14.10.
Retention of Study Data............................................................................................118
15.
KEY ROLES AND STUDY GOVERNANCE COMMITTEES.............................119
15.1.
Vendors.....................................................................................................................119
15.1.1.
Contract Research Organization...............................................................................119
15.1.2.
Interactive Response Technology.............................................................................119
15.1.3.
Electronic Data Capture............................................................................................119

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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15.1.4.
Digital Clinical Outcomes Data Capture..................................................................119
15.1.5.
Central Laboratories for Laboratory Assessments ...................................................119
15.1.6.
Central Facility for Other Assessments....................................................................120
15.2.
Study Committees.....................................................................................................120
15.2.1.
Safety Surveillance Team.........................................................................................120
16.
ADMINISTRATIVE PROCEDURES.....................................................................121
16.1.
Study Site Initiation..................................................................................................121
16.2.
Quality Control and Quality Assurance....................................................................121
16.3.
Monitoring of the Study............................................................................................121
16.4.
Study Funding...........................................................................................................122
16.5.
Publications...............................................................................................................122
16.6.
Public Health Emergencies.......................................................................................122
17.
REFERENCES .........................................................................................................124
18.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.......................................127
LIST OF TABLES
Table 1:
Part 1 Schedule of Activities: Cohorts A, B, C1, C2..................................................27
Table 2: 
Part 1 Schedule of Activities: Cohort D1 and D2.......................................................32
Table 3:
Schedule of Activities Part 2 (all Cohorts).................................................................41
Table 4:
Predicted ATXN2 mRNA Reduction (Cortex and Spinal Cord), ATXN2 
protein reduction (CSF), and Safety Margins at Steady-state at Proposed 
Dose Levels ................................................................................................................55
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................26

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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1.
KEY STUDY ELEMENTS
1.1.
Synopsis
Protocol Title:
A Phase 1/2 Multiple-Ascending-Dose Study With a Long-Term 
Open-Label Extension to Assess the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Effect on Disease 
Progression of BIIB105 Administered Intrathecally to Adults 
With Amyotrophic Lateral Sclerosis With or Without PolyCAG 
Expansion in the ATXN2 Gene
Protocol Number:
275AS101
Version Number:
5
Name of Study 
Treatment:
Research Name:
BIIB105
Generic Name:
Not Applicable
Study Phase:
1/2
Study Indication:
Amyotrophic lateral sclerosis (ALS) and ALS associated with 
ataxin-2 (ATXN2) polyCAG expansion (polyQ-ALS)
Study Rationale:
ALS is a rare neurodegenerative disease resulting in pathologic 
loss of motor neurons and their axons within the cortex, 
brainstem, spinal cord, and peripheral nerves with functional 
decline and death, typically from respiratory failure. There are no 
effective drug therapies to cure or substantially moderate 
functional decline or improve survival.
A hallmark of ALS pathogenesis in the majority of patients is the 
presence of cytoplasmic inclusions containing aggregated TDP-
43 in motor neurons [Ling 2013; Neumann 2006]. TDP-43 is a 
ubiquitously expressed protein that plays a variety of roles in 
RNA processing. Mutations in the TDP-43 gene have been shown 
to cause familial ALS; however, most patients do not carry an 
associated TDP-43 genetic mutation, suggesting that abnormal 
cytoplasmic aggregation of the wild-type protein may play a role 
in disease pathogenesis [Scotter 2015a, 2015b].
A potential therapeutic approach to indirectly affect TDP-43 is 
modulation of the ATXN2 protein. While the exact mechanism 
remains unclear, ATXN2 modulation has been shown to impact 
TDP-43 toxicity in nonclinical models, where toxicity caused by 
overexpression of TDP-43 was enhanced with increased 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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expression of ATXN2 and was reduced when ATXN2 levels 
were depleted [Becker 2017; Elden 2010].
These nonclinical findings linking ATXN2 to ALS have been 
supported by human genetic studies and pathological 
observations in ALS patient tissue. Intermediate-length expansion 
of the polyCAG region in ATXN2 has been identified as a 
significant risk factor for developing ALS [Elden 2010; 
Neuenschwander 2014; Sproviero 2017]. This repeat region 
encodes a polyQ segment at the N-terminus of the ATXN2 
protein, and when expanded, is believed to stabilize the protein 
[Elden 2010]. Additionally, retrospective analysis of patients with 
ALS harboring a polyCAG expanded allele (polyQ patients) 
compared with matched patients with ALS harboring only normal 
polyCAG length alleles has shown that patients with ATXN2 
polyQ demonstrate faster clinical progression, as measured by the 
ALSFRS-R and respiratory vital capacity, suggesting that 
ATXN2 polyQ expansions also confer a risk of more aggressive 
disease [McMillan 2020]. Finally, ATXN2 protein lacking a 
polyQ expansion has been found to be aberrantly localized in 
~25% of motor neurons in multiple ALS patients [Elden 2010].
BIIB105 is a novel ASO being developed for the treatment of 
ALS. The ASO targets the ATXN2-mRNA for degradation, as a 
means to decrease ATXN2 protein levels and thereby mitigate 
TDP-43 toxicity as seen in nonclinical models.
Given the rapidly progressing, life-threatening, and rare nature of 
the disease as well as the high unmet medical need in ALS, the 
first-in-human Phase 1/2 study will be a two-part evaluation of 
BIIB105 in adult participants with ALS and polyQ-ALS. Part 1 
will be a placebo-controlled MAD assessment of the safety, 
tolerability, pharmacokinetics, pharmacodynamics, and effect on 
disease progression of BIIB105. Part 2 will be an extension study 
to assess the long-term safety, tolerability, pharmacokinetics, 
pharmacodynamics, and effect on disease progression of BIIB105 
in participants who complete Part 1 through Week 25 (Day 175 
Visit for Cohorts A, B, C1, and C2; Day 176 Visit for Cohorts D1 
and D2).
This study design will minimize the number of participants 
receiving subtherapeutic doses and/or dosing durations. For all 
cohorts in Part 1, the 72-hour safety data review following 
sentinel dosing of the first 2 participants of each dosing cohort 
and the 7-day safety review for each participant after 
administration of the first dose and prior to administration of the 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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second dose will allow evaluation of potential acute safety and 
tolerability findings in each participant prior to the administration 
of additional doses, similar to a single-ascending-dose study 
design. Part 2 will provide up to 104 weeks of dosing of BIIB105 
for study participants who complete 25 weeks in Part 1. The 
safety, PK, PD, and clinical function data collected from Part 2 
will allow for the understanding of the long-term effect of 
BIIB105 in participants with ALS and polyQ-ALS. 
Rationale for Starting 
Dose and Maximum 
Exposure:
A single-dose, NHP, toxicity study identified a maximum 
tolerated dose (
 mg) and reversible AEs at
mg, which can be 
monitored clinically. The maximum dose of 
mg used in this 
study, will provide an approximately 
-fold safety margin to the 
HED (
 mg) of the NOAEL of
mg in the 13-week NHP 
repeat-dose toxicology study and a
-fold safety margin of the 
HED (
) of the NOAEL of 
 mg in the 41-week NHP repeat-
dose study. 
The selection of the starting dose for this study is based on the 
NOAEL dose of 
 mg, established in the 13-week toxicology 
study in NHPs, and on the expected PD of BIIB105 in the brain 
cortex and spinal cord. The monkey provided the lowest HED, 
which was calculated to be 
 mg utilizing a CSF volumetric 
scaling factor of 10. This represents a conservative estimate of 
CSF volume ratio between humans and monkeys. The HED value 
was divided by the conventional safety factor of 10 to yield the 
MRSD, 
 mg. The proposed  mg starting dose is below the 
MRSD, has a 
-fold safety factor over the HED (
 mg) of the 
NOAEL from the 13-week toxicology study, and is expected to 
produce minimal to moderate pharmacologic effects in the brain 
and spinal cord, respectively.
The preclinical evidence suggests a dose-dependent relationship 
between ATXN2 levels and clinical outcomes in TDP-43 models 
of disease [Becker 2017; Elden 2010]. In TDP-43 transgenic 
mice, ASO-induced reduction of Atxn2 mRNA levels in CNS 
tissues by 77% on average resulted in a 35% increase in median 
lifespan compared with control ASO littermates [Becker 2017]. 
An mRNA reduction of approximately 
% is therefore 
considered the target BIIB105 PD effect in humans that could be 
indicative of potential clinical efficacy. The MRSD of 
mg is 
estimated to reduce ATXN2 mRNA levels approximately
% in 
the cortex and approximately 
% in the spinal cord, after
doses. In consideration of the higher reduction of ATXN2 mRNA 
in spinal cord, a starting dose of mg is anticipated to reduce 
ATXN2 mRNA levels by approximately % in the cortex and 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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Study Objectives and Endpoints:
Part 1
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability 
of BIIB105 in participants with ALS or 
polyQ-ALS.
Incidence of AEs and SAEs in Part 1
Secondary Objectives
Secondary Endpoints
To assess the PK profile of BIIB105 in 
serum and CSF of participants with 
ALS or polyQ-ALS.
Serum and CSF concentrations of BIIB105 in Part 1.
To evaluate the following serum PK parameters in 
Part 1:
•
AUCinf 
•
AUClast
•
Cmax 
•
Tmax 
•
t½
To evaluate the biomarker effect of 
BIIB105 in participants with ALS or 
polyQ-ALS.
Secondary biomarker measure:
•
Changes from baseline in plasma levels of 
NfL
Part 2
Primary Objective
Primary Endpoint
To evaluate the long-term safety and 
tolerability of BIIB105 in participants 
with ALS or polyQ-ALS.
Incidence of AEs and SAEs in Part 2

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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Integrated Part 1 and 2
Primary Objective
Primary Endpoint
To evaluate the long-term safety and 
tolerability of BIIB105 in participants 
with ALS or polyQ-ALS.
Incidence of AEs and SAEs during the BIIB105-
treated period in Part 1 and/or Part 2
Secondary Objectives
Secondary Endpoints
To assess the long-term PK profile of 
BIIB105 in serum and CSF of 
participants with ALS or polyQ-ALS.
Serum and CSF concentrations of BIIB105 in Part 1 
and Part 2.
•
CSF trough PK concentration
•
Serum PK concentration if available
To evaluate the long-term biomarker 
effect of BIIB105 in participants with 
ALS or polyQ-ALS, and to assess the 
impact of earlier initiation of BIIB105 
(i.e., at start of Part 1) compared with 
delayed initiation of BIIB105 (i.e., at 
start of Part 2) on biomarkers.
Secondary biomarker measure:
•
Changes from Part 1 baseline in plasma 
levels of NfL 
To evaluate the long-term effect of 
BIIB105 on measures of clinical 
function and to assess the impact of 
earlier initiation of BIIB105 (i.e., at 
start of Part 1) compared with delayed 
initiation of BIIB105 (i.e., at start of 
Part 2) on measures of clinical 
function.
Changes from Part 1 baseline in the following 
assessments:
•
SVC
•
ALSFRS-R score
•
Muscle strength, as measured by HHD
Survival analyses:
•
Time to death or permanent ventilation 
(≥ 22 hours of mechanical ventilation 
[invasive or noninvasive] per day for ≥ 21 
consecutive days)
•
Time to death

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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•
Time to death, incorporating post-study 
withdrawal or study completion vital status 
data
Study Design:
Part 1 is a Phase 1/2, randomized, double-blind, placebo-
controlled, MAD evaluation of the safety, tolerability, PK, PD, 
and effect on disease progression of BIIB105, administered IT to 
approximately 98 participants (76 participants with ALS and 
22 participants with polyQ-ALS) at approximately 15 sites 
globally. Cohorts A, B, C1, and C2 will receive up to 5 doses 
over approximately 3 months. Cohorts D1 and D2 will receive up 
to 8 doses over approximately 6 months.  
Part 2 is an extension study to assess the long-term safety, 
tolerability, pharmacokinetics, pharmacodynamics, and effect on 
disease progression of BIIB105 administered to adults with ALS 
and polyQ-ALS who complete Part 1 through Week 25.  
Study Location:
Approximately 15 sites globally are planned for this study.
Study Population:
This study will be conducted in participants who meet the 
following criteria.
Criteria for inclusion of participants Part 1: 
Aged at least 18 years at the time of informed consent or 
participant meets the minimum age of consent in accordance with 
national regulations (whichever is higher).
Participants in Cohorts A, B, C1 and D1, must meet the 
laboratory-supported probable, probable, or definite criteria for 
diagnosing ALS according to the World Federation of Neurology 
El Escorial criteria (revised according to the Airlie House 
Conference 1998 [Brooks 2000]). Participants in Cohort C2 and 
D2, must meet any of the prior conditions, but may also only 
meet clinically possible criteria for diagnosing ALS, or exhibit 
weakness attributable to ALS in the presence of ATXN2 
intermediate repeats.
In participants in Cohorts C2 and D2, confirmed intermediate 
CAG/CAA repeat expansion in the ATXN2 gene as defined by at 
least 1 allele carrying 30 to 33 CAG/CAA repeats.
SVC criteria:

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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In participants in Cohorts A, B, C1, and D1, SVC ≥ 60% of 
predicted value as adjusted for sex, age, and height (from the 
sitting position). 
In participants in Cohorts C2 and D2, SVC ≥ 50% of predicted 
value as adjusted for sex, age, and height (from the sitting 
position).
Criteria for exclusion of participants from Part 1:
In participants in Cohorts A, B, and C1, prescreening ALSFRS-R 
slope > -0.4 points/month, where prescreening ALSFRS-R slope 
is defined as: (ALSFRS-R score at Screening - 48) / (months 
from date of symptom onset to date of Screening).
Part 2 will be conducted in participants with ALS or polyQ-ALS 
who have completed Part 1 through Week 25 (Day 175 Visit for 
Cohorts A, B, C1, C2; Day 176 Visit for Cohorts D1 and D2). 
Detailed criteria are described in Section 6.
Number of Planned 
Participants:
A total of approximately 98 participants are planned to be 
randomized in the study. Participants who withdraw may be 
replaced in a cohort at the discretion of the Sponsor. With 
potential replacement, approximately 108 participants could be 
randomized in this study.

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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Biogen MA Inc.
18
Treatment Groups:
In Part 1:
Participants with ALS:
Cohort A: BIIB105 5 mg (6 participants) or placebo 
(2 participants)
Cohort B: BIIB105 20 mg (6 participants) or placebo 
(2 participants)
Cohort C1: BIIB105 60 mg (9 participants) or placebo 
(3 participants)
Cohort D1: BIIB105 120 mg (approximately 36 participants) or 
placebo (approximately 12 participants)
Participants with polyQ-ALS:
Cohort C2: BIIB105 60 mg (3 participants) or placebo (1 
participant)
Cohort D2: BIIB105 120 mg (approximately 12 participants) or 
placebo (approximately 6 participants)
Participants in Cohorts A, B, C1, and C2 will receive 3 loading 
doses administered every 2 weeks (on Days 1, 15, and 29), 
followed by 2 maintenance doses administered once every 
4 weeks (on Days 57 and 85), for a total of 5 doses over 
approximately 13 weeks.
Participants in Cohorts D1 and D2 will receive 3 loading doses 
administered every 2 weeks (on Days 1, 15, and 29), followed by 
5 maintenance doses administered once every 4 weeks (on 
Days 57, 85, 113, 141, and 169), for a total of 8 doses over 
approximately 25 weeks.
In Part 2: 
Part 2 is an open-label evaluation of BIIB105 administered IT to 
participants with ALS and polyQ-ALS who have completed Part 
1 through Week 25 (Day 175 Visit for Cohorts A, B, C1, C2; Day 
176 Visit for Cohorts D1, D2). Participants will receive up to 
approximately 41 doses in Part 2. Two dose levels will be 
administered – participants from Part 1 Cohorts A, B, C1, and C2 
will receive 60 mg BIIB105; participants from Part 1 Cohorts D1 
and D2 will receive 120 mg BIIB105.  

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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19
In Part 2, the 60 mg dose may be increased, based on Sponsor 
review of emerging safety, PK, PD, and/or clinical data from the 
study, to doses up to 120 mg. Doses in Part 2 may also be 
decreased, based on Sponsor review of emerging safety, PK, PD, 
and/or clinical data from the study.
Sample Size 
Determination:
Part 1: 
The sample size of this first-in-human clinical study was selected 
with the goal of balancing between safety and tolerability 
considerations in dose escalation and obtaining sufficient initial 
information related to the safety and biological activities of 
BIIB105. Sample sizes of 6 participants receiving active 
treatment in lower dose Cohorts A and B will allow an 
% or 
greater probability to observe at least 1 occurrence of an AE with 
event rates of 
% or greater. The sample size of 9, 36, and 12 
participants exposed to active doses in Cohorts C1, D1, and D2, 
respectively, allow an 
% or greater probability to observe at 
least 1 occurrence of an AE with event rates of 
%, 
%, and 
%, or greater, respectively.
Cohort C2 will expose 3 participants with polyQ-ALS to active 
treatment as part of additional dose escalation step specifically for 
participants with intermediate-repeat CAG expansions in ATXN2 
gene as they may be more sensitive to the effects of BIIB105. The 
sample size of 3 was selected solely as precaution step before 
exposing participants with polyQ-ALS to 120 mg dose of 
BIIB105 in Cohort D2.
The sample size of Cohort D1 provides approximately 
% 
power to detect a 
% difference in the ratio to baseline in plasma 
NfL, in the BIIB105 versus placebo group, based on Cohort D1 
120 mg data (N on BIIB105 = 36) vs pooled placebo data across 
Cohorts A through D1 (N = 19), with 2-sided % significance 
level, assuming 
% SD in both groups. 
Part 2: 
The sample size of this extension is based on the sample size of 
Study 275AS101 Part 1. Up to approximately 98 participants will 
be dosed in Study 275AS101 Part 2. 
Statistical Methods:
Placebo data in Part 1 may be pooled across cohorts for analyses. 
The Pooled Placebo 1 population is defined as participants from 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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Biogen MA Inc.
23
Visit Schedule:
Part 1: 
Participants in Cohorts A, B, C1, and C2 will have up to 13 CVs 
and 9 TCs during the study, which include at least 1 Screening 
Visit, 5 Dosing Visits of which the first dose will require an 
inpatient stay of 2 days, 7 Follow-up Visits, and 9 TCs. Visit days 
are calculated with respect to Day 1 (the date of first dose). 
Participants in Cohorts D1 and D2 will have up to 19 CVs and 15 
TCs which will include at least 1 Screening Visit, 8 Dosing Visits 
of which the first will require an inpatient stay of 2 days, up to 10 
Follow-up Visits, and up to 15 TCs. Participants in Cohorts D1 
and D2 who enroll in Part 2 will not complete the Follow-up 
Visits and TCs in Part 1 that occur after enrollment in Part 2. 
Part 2: 
Participants will have up to approximately 44 CVs and 43 TCs 
during Part 2 of the study, which will include at least 1 Screening 
Visit, up to approximately 41 Dosing Visits, 2 Follow-Up Visits, 
and up to 43 TCs.
For participants from Cohorts D1 and D2, the Screening Visit for 
Part 2 may be combined with their Part 1 Day 169 and/or 
Day 176 Visits.
Study assessments conducted at each visit are listed in Table 1. 
Duration of Study 
Participation:
Part 1: 
Study duration for each participant in Cohorts A, B, C1, and C2 
will be approximately 29 weeks: 
4-week Screening Period
13-week Treatment Period
Approximately 12-week Follow-up Period
Study duration for each participant in D1and D2 will be between 
approximately 29 and 41 weeks: 
4-week Screening Period

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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24
25-week Treatment Period
Approximately 12-week Follow-up Period (only completed if the 
participant does not enter Part 2 after the Treatment Period)
Part 2:
Study duration for all participants will be up to approximately 
172 weeks:
4-week Screening Period (for participants from Cohorts D1 and 
D2, Screening Period begins with Day 169 Visit of Part 1)
Up to approximately 156-week Treatment Period: either 104 
weeks, or until the last participant enrolled has had the 
opportunity for their Part 2 Day 365 visit (Week 52), whichever 
occurs later.
Approximately 12-week Follow-up Period
Benefit-Risk Analysis:
The potential benefit of BIIB105 in ALS has not been 
established. The study has been designed with appropriate dose 
escalation, safety monitoring, and stopping rules to minimize 
risks to participants. The results of this study may offer key 
insights into the development of a disease-modifying therapy for 
ALS.
This is a first in human study, thus the risk in humans is 
unknown. Emerging clinical data can be found in the 
Investigator’s Brochure.
Nonclinical work with Atxn2 homozygous knockout mice 
suggests that ATXN2 reduction could be associated with risks of 
metabolic complications (adult-onset obesity and insulin 
resistance) and subtle neurological deficits such as motor 
hyperactivity and abnormal fear conditioning [Huynh 2009; Kiehl 
2006; Lastres-Becker 2008]. Human data from the Genome-Wide 
Association Studies database suggest that variation in ATXN2 
could be associated with changes in blood pressure and 
cardiometabolic phenotypes [Auburger 2014]. From the 
nonclinical safety studies in NHPs, the adverse effect level was 
considered to be 
 mg based on severe but reversible and 
monitorable clinical signs: 1 of 3 animals exhibited increased 
muscle tone, whole body spasms, and tremors that required 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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Biogen MA Inc.
25
administration of diazepam. The animal fully recovered by 
 hours. No adverse metabolic effects were seen in toxicology 
studies. Participants will be monitored in the clinical setting with 
neurological and physical examinations and careful monitoring of 
blood chemistries, among other safety assessments.  
Reproductive toxicity studies were conducted in mice and rabbits 
using SC administration of BIIB105 once every other day. In a 
definitive combined fertility and embryo-fetal development study 
in male and female mice, there was no effect of BIIB105 on 
fertility in either sex. BIIB105 did not produce any fetal external, 
visceral, or skeletal malformations or variations in mice or 
rabbits. However, there were BIIB105-related effects on embryo-
fetal development in both species. In mice, there were lower 
mean fetal body weights that were considered adverse at the 
highest dose tested (
mg/kg). In a dose-range finding study in 
rabbits, dose-limiting BIIB105-related findings included body 
weight losses, reduced food consumption, and abortions. There 
was very limited fetal exposure in mice only. 
Due to these adverse findings in the reproductive toxicity 
nonclinical studies, all men and women of childbearing potential 
must use highly effective contraception during the study and for 
at least 
after the study (for female participants) and at 
least 
after the study (for male participants).
Although LP is generally considered a safe procedure, certain 
complications can occur in a subset of patients. These may 
include, but are not limited to, back pain, headache, nausea, 
infection, bleeding, radicular pain and numbness, and bruising or 
injury at the injection site. These potential risks can be mitigated 
by using atraumatic needles, avoiding contraindicated 
medications, and testing coagulation and platelet counts prior to 
the procedure. Importantly, life-threatening cerebral herniation is 
a possible complication of a LP procedure.
ALS is a debilitating, rapidly progressing, and life-threatening 
disease with a high unmet need for effective therapies. Overall, 
the benefit-risk profile is positive for the development of BIIB105 
for the treatment of ALS and polyQ-ALS.

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
26
Study Design Schematic
Figure 1:
Study Design

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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27
Schedule of Activities
Table 1:
Part 1 Schedule of Activities: Cohorts A, B, C1, C2
Follow-Up 
Period
 
 
Screening1
Dose 1 (Inpatient)
CV
Dose 2
TC
CV
Dose 3
TC
CV
TC
Dose 4
TC
CV
TC
Dose 5
TC
CV
TC
CV
TC
Final/ ET 
Visit
TC
1
2
176 
(+1)
Days
 
 
 
Assessments
-28 to -1
Predose
Dosing/ 
Postdose
(24 ±1 h) 
postdose
8
(±2)
15
(±3)
16 
(+1)
22
(±3)
29
(±3)
30 
(+1)
36
(±3)
50
(±3)
57
(±3)
58 
(+1)
64
(±3)
78
(±3)
85
(±3)
86 
(+1)
92
(±3)
93 
(+1)
130
(±3)
131 
(+1)
175
(±3)
 
UV
ICF (Main)
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF (Informant/ 
Caregiver)2
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
ALS Diagnosis
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for 
DNA (assessment of 
polyQ status and 
ALS-causative 
genes)
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Samples for Viral 
Serology3
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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28
Follow-Up 
Period
 
 
Screening1
Dose 1 (Inpatient)
CV
Dose 2
TC
CV
Dose 3
TC
CV
TC
Dose 4
TC
CV
TC
Dose 5
TC
CV
TC
CV
TC
Final/ ET 
Visit
TC
1
2
176 
(+1)
Days
 
 
 
Assessments
-28 to -1
Predose
Dosing/ 
Postdose
(24 ±1 h) 
postdose
8
(±2)
15
(±3)
16 
(+1)
22
(±3)
29
(±3)
30 
(+1)
36
(±3)
50
(±3)
57
(±3)
58 
(+1)
64
(±3)
78
(±3)
85
(±3)
86 
(+1)
92
(±3)
93 
(+1)
130
(±3)
131 
(+1)
175
(±3)
 
UV
Serum Pregnancy 
Test4
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test5
 
X
 
 
 
X
 
 
X
 
 
 
X
 
 
 
X
 
 
 
 
 
X
 
 
FSH Test6
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination7 
X
X
 
X
X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
Neurological 
Examination (cranial 
nerves, cerebellar 
function, motor, and 
reflexes)8
X
X
X
X
X
X
 
X 
X
 
X
 
X
 
X 
 
X
 
X
 
X
 
X
 
X
MMSE
 
X
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
 
 
 
 
 
Weight
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
X
 
 
Height
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG9
X
X
X
X
 
X
 
X
X
 
X
 
X
 
X
 
X
 
X
 
 
 
X
 
X
Vital Signs 
(temperature, blood 
pressure, heart rate, 
respiratory rate)9
X
X
X
X
X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
SVC10
X
X
 
 
 
X
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
X
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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29
Follow-Up 
Period
 
 
Screening1
Dose 1 (Inpatient)
CV
Dose 2
TC
CV
Dose 3
TC
CV
TC
Dose 4
TC
CV
TC
Dose 5
TC
CV
TC
CV
TC
Final/ ET 
Visit
TC
1
2
176 
(+1)
Days
 
 
 
Assessments
-28 to -1
Predose
Dosing/ 
Postdose
(24 ±1 h) 
postdose
8
(±2)
15
(±3)
16 
(+1)
22
(±3)
29
(±3)
30 
(+1)
36
(±3)
50
(±3)
57
(±3)
58 
(+1)
64
(±3)
78
(±3)
85
(±3)
86 
(+1)
92
(±3)
93 
(+1)
130
(±3)
131 
(+1)
175
(±3)
 
UV
ALSFRS-R11
X
X
 
 
 
 
 
 
X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
 
 
Randomization/ 
Admission to 
Inpatient Facility
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
Administration12
 
 
X
 
 
X
 
 
X
 
 
 
X
 
 
 
X
 
 
 
 
 
 
 
 
C-SSRS 
Questionnaire13
 
X
 
 
X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
 
X
Clinical Laboratory 
Samples for 
Hematology, 
Coagulation, Blood 
Chemistry, and 
Urinalysis14
X
X
 
X
 
X
 
 
X
 
 
 
X
 
X
 
X
 
X
 
X
 
X
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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30
Follow-Up 
Period
 
 
Screening1
Dose 1 (Inpatient)
CV
Dose 2
TC
CV
Dose 3
TC
CV
TC
Dose 4
TC
CV
TC
Dose 5
TC
CV
TC
CV
TC
Final/ ET 
Visit
TC
1
2
176 
(+1)
Days
 
 
 
Assessments
-28 to -1
Predose
Dosing/ 
Postdose
(24 ±1 h) 
postdose
8
(±2)
15
(±3)
16 
(+1)
22
(±3)
29
(±3)
30 
(+1)
36
(±3)
50
(±3)
57
(±3)
58 
(+1)
64
(±3)
78
(±3)
85
(±3)
86 
(+1)
92
(±3)
93 
(+1)
130
(±3)
131 
(+1)
175
(±3)
 
UV
Serum Sampling for 
PK15
 
X
X
X
X
X
 
 
X
 
 
 
X
 
 
 
X
 
X
 
 
 
 
 
 
Blood Sampling for 
Biomarkers10
 
X
 
 
 
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
X
 
 
CSF Sampling16
 
X
 
 
 
X
 
 
X
 
 
 
X
 
 
 
X
 
X
 
X
 
X
 
 
Discharge From 
Inpatient Facility
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Therapy and 
Procedures 
Recording
 
-------------------------------------------------------------------------------Ongoing----------------------------------------------------------------
X
AE Recording
 
-------------------------------------------------------------------------------Ongoing----------------------------------------------------------------
X
SAE Reporting
----------------------------------------------------------------------------------------Ongoing------------------------------------------------------------
X
1 Screening assessments can be performed on multiple days (up to 7 days) for ease of participant burden.
2 An informant/caregiver should be available at Screening, and the participation of the same informant/caregiver for the duration of the study. The informant/ 
caregiver must provide written informed consent to participate in the study prior to providing any information on either themselves and/or participants.
3 Including blood samples for HIV, HCV, and hepatitis B virus.
4 For women of childbearing potential only; to be performed centrally.
5 Performed predose on dosing days for women of childbearing potential only; to be performed locally

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
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31
6 To be conducted only in female participants presenting with a history of being postmenopausal to confirm postmenopausal status.
7 Limited physical examination from Day 8 to Day 175 and UV per the Investigator’s discretion.
8 On dosing days, to be assessed predose and at 3 and 6 hours postdose. At UV, a limited neurological examination may be performed per the Investigator’s 
discretion.
9 On dosing days, ECG and vital signs are to be assessed just prior to drawing PK blood samples at predose, and 2 and 4 hours postdose. Vital signs may be 
measured in either the sitting or supine position, and ECGs are to be done in triplicate after resting in the supine position for ≥ 5 minutes. During UV, ECGs are 
to be done if medically indicated. All 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.
10 On dosing days, to be performed before dosing.
11 To be collected prior to other assessments and before dosing, on dosing days.
12 Administered by LP.
13 Use “Since Last Visit” version of C-SSRS from Day 8 onward. Done predose on dosing days. At UV, may be assessed per the Investigator’s discretion.
14 HbA1c and lipid panel to be assessed at Screening and on Days 1, 85, and 175 only.
15 To be collected predose and at 1, 2, 4, and 6 hours postdose on dosing days.
16 To be collected predose on dosing days. Collected by LP. Participants to be observed in the clinic for ~6 hours after the LP procedure on dosing days and for 
~1 hour on nondosing days.

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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32
Table 2: 
Part 1 Schedule of Activities: Cohort D1 and D2
FU Period2
 
Screening1
Dose 1 (Inpatient)
CV
Dose 
2
TC
CV
Dose 
3
TC
CV
TC
Doses 
4, 5, 
6, 7
TC
CV
TC
Dose 
8
TC
CV
TC
CV
TC
Final/ 
ET 
Visit
TC
1
2
Days
 
 
 
 
 
Assessments5
-28 to -1
Predose
Dosing/Postdose
(24 ±1 h) postdose
8 
(±2)
15 
(±3)
16 
(+1)4
22 
(±3)
29 
(±3)
30 
(+1)4
36 
(±3)
50 
(±3)
57, 
85, 
113, 
141 
(±3)
58, 
86, 
114, 
142 
(+1)4
64, 
92, 
120, 
148 
(±3)
78, 
106, 
134, 
162 
(±3)
169 
(±3)3
170 
(+1)4
176 
(±3)
177 
(+1)4
214 
(±3)
215 
(+1)4
259 
(±3)
260 
(+1)4
UV
ICF (Main)
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF (Informant/ 
Caregiver)6
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of ALS 
Diagnosis
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for 
DNA (assessment of 
polyQ status and 
ALS-causative genes)
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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33
FU Period2
 
Screening1
Dose 1 (Inpatient)
CV
Dose 
2
TC
CV
Dose 
3
TC
CV
TC
Doses 
4, 5, 
6, 7
TC
CV
TC
Dose 
8
TC
CV
TC
CV
TC
Final/ 
ET 
Visit
TC
1
2
Days
 
 
 
 
 
Assessments5
-28 to -1
Predose
Dosing/Postdose
(24 ±1 h) postdose
8 
(±2)
15 
(±3)
16 
(+1)4
22 
(±3)
29 
(±3)
30 
(+1)4
36 
(±3)
50 
(±3)
57, 
85, 
113, 
141 
(±3)
58, 
86, 
114, 
142 
(+1)4
64, 
92, 
120, 
148 
(±3)
78, 
106, 
134, 
162 
(±3)
169 
(±3)3
170 
(+1)4
176 
(±3)
177 
(+1)4
214 
(±3)
215 
(+1)4
259 
(±3)
260 
(+1)4
UV
Clinical Laboratory 
Samples for Viral 
Serology7
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
Test8
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test9
 
X
 
 
 
X
 
 
X
 
 
 
X
 
 
 
 X
X 
 X
 
X
 
 
FSH Test10
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination11 
X
X
 
X
X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
X
 
X
 
X
Neurological 
Examination (cranial 
nerves, cerebellar 
function, motor, and 
reflexes)12
X
X
X
X
X
X
 
X 
X
 
X
 
X
 
X 
 
X
 
X
X
 
X
 
X
MMSE
 
X
 
 
X 
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
 
 
 
 
Weight
X
X
 
 
 
 
 
 
 
 
 
 
 
X13
 
 
X
 
 
X
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
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34
FU Period2
 
Screening1
Dose 1 (Inpatient)
CV
Dose 
2
TC
CV
Dose 
3
TC
CV
TC
Doses 
4, 5, 
6, 7
TC
CV
TC
Dose 
8
TC
CV
TC
CV
TC
Final/ 
ET 
Visit
TC
1
2
Days
 
 
 
 
 
Assessments5
-28 to -1
Predose
Dosing/Postdose
(24 ±1 h) postdose
8 
(±2)
15 
(±3)
16 
(+1)4
22 
(±3)
29 
(±3)
30 
(+1)4
36 
(±3)
50 
(±3)
57, 
85, 
113, 
141 
(±3)
58, 
86, 
114, 
142 
(+1)4
64, 
92, 
120, 
148 
(±3)
78, 
106, 
134, 
162 
(±3)
169 
(±3)3
170 
(+1)4
176 
(±3)
177 
(+1)4
214 
(±3)
215 
(+1)4
259 
(±3)
260 
(+1)4
UV
Height
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG14, 15
X
X
X
X
 X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
 X
 
X
 
X
Vital Signs 
(temperature, blood 
pressure, heart rate, 
respiratory rate)14
X
X
X
X
X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
X
 
X
 
X
Set Up Study Mobile 
Device16
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
35
FU Period2
 
Screening1
Dose 1 (Inpatient)
CV
Dose 
2
TC
CV
Dose 
3
TC
CV
TC
Doses 
4, 5, 
6, 7
TC
CV
TC
Dose 
8
TC
CV
TC
CV
TC
Final/ 
ET 
Visit
TC
1
2
Days
 
 
 
 
 
Assessments5
-28 to -1
Predose
Dosing/Postdose
(24 ±1 h) postdose
8 
(±2)
15 
(±3)
16 
(+1)4
22 
(±3)
29 
(±3)
30 
(+1)4
36 
(±3)
50 
(±3)
57, 
85, 
113, 
141 
(±3)
58, 
86, 
114, 
142 
(+1)4
64, 
92, 
120, 
148 
(±3)
78, 
106, 
134, 
162 
(±3)
169 
(±3)3
170 
(+1)4
176 
(±3)
177 
(+1)4
214 
(±3)
215 
(+1)4
259 
(±3)
260 
(+1)4
UV
Participant ventilation 
diary19
 
 X
 
Review ventilation 
use20
 
X
 
 
X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
X
 
X
 
 
SVC21
X
X
 
 
 
X
 
 
X
 
 
 
X
 
 
 
X
 
 
X
 
 X
 
 
ALSFRS-R 
(standard)22
X
X
 
 
 
 
 
X
 
X
 
X
 
X
 
X
 
X
X
 
 X
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
36
FU Period2
 
Screening1
Dose 1 (Inpatient)
CV
Dose 
2
TC
CV
Dose 
3
TC
CV
TC
Doses 
4, 5, 
6, 7
TC
CV
TC
Dose 
8
TC
CV
TC
CV
TC
Final/ 
ET 
Visit
TC
1
2
Days
 
 
 
 
 
Assessments5
-28 to -1
Predose
Dosing/Postdose
(24 ±1 h) postdose
8 
(±2)
15 
(±3)
16 
(+1)4
22 
(±3)
29 
(±3)
30 
(+1)4
36 
(±3)
50 
(±3)
57, 
85, 
113, 
141 
(±3)
58, 
86, 
114, 
142 
(+1)4
64, 
92, 
120, 
148 
(±3)
78, 
106, 
134, 
162 
(±3)
169 
(±3)3
170 
(+1)4
176 
(±3)
177 
(+1)4
214 
(±3)
215 
(+1)4
259 
(±3)
260 
(+1)4
UV
HHD21
 
X
 
 
 
 
 
 
X
 
 
 
X
 
 
 
X
 
 
X
 
 X
 
 
Randomization/ 
Admission to 
Inpatient Facility
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
Administration23
 
 
X
 
 
X
 
 
X
 
 
 
X
 
 
 
X
 
 
 
 
 
 
 
C-SSRS 
Questionnaire24
 
X
 
 
X
X
 
X
X
 
X
 
X
 
X
 
X
 
X
X
 
X
 
X

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
37
FU Period2
 
Screening1
Dose 1 (Inpatient)
CV
Dose 
2
TC
CV
Dose 
3
TC
CV
TC
Doses 
4, 5, 
6, 7
TC
CV
TC
Dose 
8
TC
CV
TC
CV
TC
Final/ 
ET 
Visit
TC
1
2
Days
 
 
 
 
 
Assessments5
-28 to -1
Predose
Dosing/Postdose
(24 ±1 h) postdose
8 
(±2)
15 
(±3)
16 
(+1)4
22 
(±3)
29 
(±3)
30 
(+1)4
36 
(±3)
50 
(±3)
57, 
85, 
113, 
141 
(±3)
58, 
86, 
114, 
142 
(+1)4
64, 
92, 
120, 
148 
(±3)
78, 
106, 
134, 
162 
(±3)
169 
(±3)3
170 
(+1)4
176 
(±3)
177 
(+1)4
214 
(±3)
215 
(+1)4
259 
(±3)
260 
(+1)4
UV
Clinical Laboratory 
Samples for 
Hematology, 
Coagulation, Blood 
Chemistry, and 
Urinalysis25
X
X
 
X
 
X
 
 
X
 
 X
 
X
 
X
 
X
 
X
X
 
X
 
 
Serum Sampling for 
PK26
 
X
X
X
X
X
 
 
X
 
 
 
X
 
 
 
X
 
X
 
 
 
 
 
Blood Sampling for 
Biomarkers21
 
X
 
 
 
 
 
 
X
 
 
 
X
 
 
 
X
 
 
X
 
X
 
 
CSF Sampling29
 
X
 
 
 
X
 
 
X
 
 
 
X
 
 
 
X
 
X30
X
 
X
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
38
FU Period2
 
Screening1
Dose 1 (Inpatient)
CV
Dose 
2
TC
CV
Dose 
3
TC
CV
TC
Doses 
4, 5, 
6, 7
TC
CV
TC
Dose 
8
TC
CV
TC
CV
TC
Final/ 
ET 
Visit
TC
1
2
Days
 
 
 
 
 
Assessments5
-28 to -1
Predose
Dosing/Postdose
(24 ±1 h) postdose
8 
(±2)
15 
(±3)
16 
(+1)4
22 
(±3)
29 
(±3)
30 
(+1)4
36 
(±3)
50 
(±3)
57, 
85, 
113, 
141 
(±3)
58, 
86, 
114, 
142 
(+1)4
64, 
92, 
120, 
148 
(±3)
78, 
106, 
134, 
162 
(±3)
169 
(±3)3
170 
(+1)4
176 
(±3)
177 
(+1)4
214 
(±3)
215 
(+1)4
259 
(±3)
260 
(+1)4
UV
Discharge From 
Inpatient Facility
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Therapy 
and Procedures 
Recording
 
X
AE Recording
 
X
SAE Reporting
           X
1 Screening assessments can be performed on multiple days (up to 7 days) for ease of participant burden.
2 Participants in Cohorts D1 and D2 who enter Part 2 after their Treatment Period (after the Day 176 Visit) will not be required to complete the follow-up visits 
in Part 1 that occur after their enrollment in Part 2. Participants from Cohorts D1 and D2 who do not enter Part 2 will have two follow-up clinic visits and two 
TCs approximately 6 and 12 weeks after their last dosing visit.
3 The Part 1 Day 169 Visit may serve as the start of screening period for Part 2. Results from Part 1 Day 169 and Day 176 Visit assessments may be used for the 
purpose of screening and do not need to be repeated, as long as they are conducted within one month of the Part 2 Day 1 Visit.
4 TCs that are scheduled for the day after an LP are only required if LP was performed on the previous day.
5 All clinic visits are expected to take place on site unless participants are unable to travel to the site due to a public health emergency (see Section 16.6)
6 An informant/caregiver should be available at Screening, and the participation of the same informant/ caregiver for the duration of the study. The informant/ 
caregiver must provide written informed consent to participate in the study prior to providing any information on either themselves and/or participants.
7 Including blood samples for HIV, HCV, and hepatitis B virus.
8 For women of childbearing potential only; to be performed centrally.

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
39
9 Performed predose on dosing days for women of childbearing potential only; to be performed locally.
10 To be conducted only in female participants presenting with a history of being postmenopausal to confirm postmenopausal status.
11 Limited physical examination from Day 8 to Day 259 and UV per the Investigator’s discretion.
12 On dosing days, to be assessed predose and at 3 and 6 hours postdose (±15 minutes). At UV, a limited neurological examination may be performed per the 
Investigator’s discretion.
13 Day 92 CV only.
14 On dosing days, ECG and vital signs are to be assessed just prior to drawing PK blood samples at predose, and 2 and 4 hours postdose (±15 minutes). Vital 
signs may be measured in either the sitting or supine position, and ECGs are to be done in triplicate after resting in the supine position (or semi-recumbent 
position, if supine is not possible) for ≥ 5 minutes.
15 During UV, ECGs are to be done if medically indicated. All 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.
16 Assessments completed on the mobile device include 
 the participant ventilation diary. The participant should complete 
the first set of mobile device assessments in clinic on Day 1. Assessments on the mobile device after Day 1 will be completed on a weekly basis and may be 
completed at home. Participants should be encouraged to bring the device with them to each study visit.  
19 On Day 1, the participant should complete the ventilation diary in clinic and enter ventilation data for the week prior (i.e., for Days -7 to -1) into the diary on 
the mobile device. After Day 1, the participant will complete the ventilation diary on the mobile device on a weekly basis.  
20 Study staff should review the participant's ventilation diary with the participant. If there are missing data or discrepancies, the site may document their 
conversation with the participant as source to supplement the ventilation diary data. For dosing visits, this procedure may be completed up to 24 hours prior to 
dosing except on Part 1 Day 1, when it should be completed on the dosing day.
21 When required on dosing days, assessment to be done predose. 
 SVC, 
 and HHD may be collected up to 24 hours 
prior to dosing. 
22Refers to the ALSFRS-R that is administered by a certified evaluator. The evaluator should be blinded to the participant’s treatment assignment and to the 
results of other assessments. To be performed before dosing; may be performed up to 24 hours prior to dosing except on Part 1 Day 1, when it should be 
administered on the dosing day.
23 Administered by LP.
24 Use “Since Last Visit” version of C SSRS from Day 8 onward. At UV may be assessed per the Investigator’s discretion.
25 On dosing days, to be collected before dosing. HbA1c and lipid panel to be assessed at Screening and on Days 1, 85, 176, and 259 only.
26 To be collected predose and at 1, 2, 4, and 6 hours (±15min) postdose on dosing days. 
or 
27 On Day 85 Visit only.

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
40
29 To be collected predose on dosing days. Collected by LP. 
 
 Participants to be observed in the clinic for ~6 hours after the LP procedure on dosing days and for ~1 hour on 
nondosing days.
30 This LP is only done if participant is not entering LTE.

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
41
Table 3:
Schedule of Activities Part 2 (all Cohorts)
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
ICF (Main)
X
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF (Informant/ 
Caregiver)
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
Eligibility Criteria
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History
X
X
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Samples for Viral 
Serology4
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test5
X
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
42
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
Urine Pregnancy Test6
 
X
 
X
 
X
 
X
 
X
 
 
X
 
 
FSH Test7
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination8
X
X
 
X
 
X
 
X
 
X
 
X
 
X
Neurological 
Examination (cranial 
nerves, cerebellar 
function, motor, and 
reflexes)9
X
X
 
X
 
X
 
X
 
X
 
X
 
X
Weight
X
X
 
 
 
 
 
X10 
 
 
 
 
X
 
 
Height
X
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
43
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
12-Lead ECG11
X
X
 
X
 
X
 
X
 
X 
 
X
 
X
Vital Signs 
(temperature, blood 
pressure, heart rate, 
respiratory rate)12
X
X
 
X
 
X
 
X
 
X
 
X
 
X
Set up study mobile 
device for Part 213
 
X
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
44
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
Participant Ventilation 
Diary16
 
Ongoing weekly collection
 
 
Review ventilation 
use17
 
 
X 
 
X
 
X
 
X
 
X
 
X
 
 
ALSFRS-R 
(standard)18
 
X
X
 
X
 
X
 
X
 
X
 
X
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
45
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
SVC19
X
X
 
X
 
X
 
X
 
X
 
X
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
46
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
HHD19
 
 
X
 
 
 
 
 
X10 
 
 
 
 
X 
 
 
Study Treatment 
Administration
 
X22
 
X
 
X
 
X
 
 
 
 
 
 
C-SSRS 
Questionnaire19, 23
 
X 
 
X
 
X
 
X
 
X
 
X
 
X
Clinical Laboratory 
Samples for 
Hematology, 
Coagulation, Blood 
Chemistry, and 
Urinalysis24
X
X 
 
X
 
X
 
X
 
X
 
X
 
 
Serum Sampling for 
PK19
 
X 
 
 
 
 
 
X21
 
 
 
 
 
 

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
47
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
Blood Sampling for 
Biomarkers19
 
X 
 
 
 
X
 
X
 
X
 
X
 
 
CSF Sampling25
 
X 
 
X
 
X
 
X
 
X
 
X
 
 
Concomitant Therapy 
and Procedures 
Recording
 
 
Ongoing
X
AE Recording
 
 
Ongoing
X

Protocol 275AS101, Version 5
A Phase 1/2 MAD Study and Long-Term OLE in Adults With ALS With or Without ATXN2 PolyCAG Expansion
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
48
Loading Dose Period
Maintenance Dose Period
Follow Up Period
 
 
Screening1
Dose 1
TC
Dose 
2
TC
Dose 
3
TC
Maintenance 
Dose Visit
TC
CV
TC
Final/ 
ET 
Visit
TC
Days
 
 
 
 
 
Assessments2
-28 to -1
1
(±3)
2 (+1)3
15 
(±3)
16 
(+1)3
29 
(±3)
30 
(+1)3
57, 85, 113, 
141, 169, 197, 
225, 253, 281, 
309, 337, 365, 
393, 421, 449, 
477, 505, 533, 
561, 589, 617, 
645, 673, 701, 
729, 757, 785, 
813, 841, 869, 
897, 925, 953, 
981, 1009, 
1037, 1065, 
1093 (±3)
1 day after 
each 
maintenance 
dose visit 
(+1)3
45d 
after 
last 
dose 
(+/-3)
1 day 
after 
Follow-
up CV 
(+1)3
90d 
after 
last 
dose 
(+/-3)
1 day after 
Final/ETV 
(+1)3
UV
SAE Reporting
 
                                       Ongoing
X
1 For participants from Cohorts D1 and D2, the Part 1 Day 169 Visit may serve as the start of screening period for Part 2. Results from Part 1 Day 169 and 
Day 176 Visit assessments may be used for the purpose of screening and do not need to be repeated, as long as they are conducted within one month of the Part 
2 Day 1 Visit.
2 All clinic visits are expected to take place on site unless participants are unable to travel to the site due to a public health emergency (see Section 16.6).
3 TCs that are scheduled for the day after an LP are only required if LP was performed on the previous day.
4 Including blood samples for HIV, HCV, and hepatitis B virus.
5 Only for participants from Cohorts A, B, C1, and C2. For women of childbearing potential only; to be performed centrally.
6 Performed predose on dosing days for women of childbearing potential only; to be performed locally
7 To be conducted only in female participants presenting with a history of being postmenopausal and whose postmenopausal status was not already confirmed in 
Part 1, to confirm postmenopausal status for Part 2.
8 Limited physical examination from Day 15 onward, and in UV, per the Investigator’s discretion.
9 On dosing days, to be assessed predose and postdose. At UV, a limited neurological examination may be performed at the Investigator's discretion.
10 To be completed on Day 85, 169, 253, 337, 421, 505, 589, 673, 757, 841, 925, 1009, 1093 Visits only (i.e., every 12 weeks).

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11 ECGs to be assessed predose on dosing days. ECGs are to be done in triplicate after resting in the supine position (or semi-recumbent position, if supine is not 
possible) for ≥5 minutes. During UV ECGs are to be done if medically indicated. All 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.
12 Vital signs to be assessed both predose and postdose on dosing days. May be measured in either the sitting or supine position.
13 Participants from Cohorts D1 and D2 must bring their study mobile device to their Part 2 Day 1 visit. Participants from Cohorts A, B, C1, and C2 will receive 
their study mobile device on Part 2 Day 1. Assessments completed on the mobile device include 
 and the participant 
ventilation diary. The participant should complete the first set of mobile device assessments for Part 2 in clinic on Part 2 Day 1. Assessments on the mobile 
device after Day 1 will be completed on a weekly basis and may be completed at home. Participants should be encouraged to bring the device with them to 
each study visit.  
16 On Part 2 Day 1, the participant should complete the ventilation diary in clinic and enter ventilation data for the week prior (i.e., for Part 2 Days -7 to -1) into 
the diary on the mobile device. After Day 1, the participant will complete the ventilation diary on the mobile device on a weekly basis.  
17 Study staff should review the participant's ventilation diary with the participant. If there are missing data or discrepancies, the site may document their 
conversation with the participant as source to supplement the ventilation diary data. For dosing visits, this procedure may be completed up to 24 hours prior to 
dosing except on Part 2 Day 1, when it should be completed on the dosing day.
18 Refers to the ALSFRS-R that is administered by a certified evaluator. For participants in Cohorts D1 and D2, during the blinded loading period, the evaluator 
should be blinded to the participant’s treatment assignment and to the results of other assessments. To be performed before dosing; may be performed up to 
24 hours prior to dosing, except on Part 2 Day 1, when it should be administered on the dosing day.
19 When required on dosing days, assessment to be done predose. 
 SVC, 
 and HHD may be collected up to 24 hours 
prior to dosing. 
21 Only completed on Day 169, 337, 505, 673, 841, 1009 Visits (i.e., every 24 weeks).
22 Administered by LP. Participants must not receive their first dose in Part 2 less than 4 weeks after their last dose in Part 1.
23 Participants from Cohorts D1 and D2 will use "Since Last Visit" version of C-SSRS on Day 1 onward. Participants from Cohorts A, B, C1, and C2 will use the 
“Since Last Visit” version of the C-SSRS from Day 15 onward. At UV may be assessed per the Investigator’s discretion.
24 On dosing days, to be collected before dosing. Lipid panel and HbA1c to be completed on Screening, Day 1, 85, 169, 253, 337, 421, 505, 589, 673, 757, 841, 
925, 1009, 1093 Visits only (i.e., every 12 weeks).
25 To be collected predose by LP on dosing days. Participants receiving 60mg dose to be observed in the clinic for ~1 hour after the LP procedure. Participants 
receiving 120mg dose to be observed in the clinic for at least 2 hours after the LP procedure.

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2.
LIST OF ABBREVIATIONS
aCSF
artificial cerebrospinal fluid
ADA
anti-drug antibody
AE
adverse event
ALS
amyotrophic lateral sclerosis
ALSFRS-R
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised
ANCOVA
analysis of covariance
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
APTT
activated partial thromboplastin time
ASO
antisense oligonucleotide
ATXN2 1
ataxin-2 gene or RNA
ATXN2  1
ataxin-2 protein
AUC0-24
area under the concentration-time curve from time 0 to 24 hours
AUCinf 
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to time of the 
last measurable concentration
CAA
cytosine-adenine-adenine
CAG
cytosine-adenine-guanine 
CMAP
compound muscle action potential
Cmax
maximum observed concentration
CNS
central nervous system
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CV
clinic visit
DHA
Directions for Handling and Administration
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ET
early termination
FAS
full analysis set
FSH
follicle-stimulating hormone
FUS
fused in sarcoma 
GCP
Good Clinical Practice
GD
gestation day
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus

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HED
human equivalent dose
HHD
handheld dynamometry
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
ICV
intracerebroventricular
INR
international normalized ratio
IRT
interactive response technology
IT
intrathecal(ly)
LP
lumbar puncture
MAD
multiple-ascending dose
MMSE
Mini-Mental State Examination
mRNA
messenger ribonucleic acid
MRSD
maximum recommended starting dose
NfL
neurofilament light chain
NHP
nonhuman primate
NOAEL
no observed adverse effect level
OLE
open label extension
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
polyQ
polyglutamine 
PT
prothrombin time
RNA
ribonucleic acid
SAE
serious adverse event
SC
subcutaneous
SLC22A23  1
solute carrier family 22 member 23
SLC25A12  1
solute carrier family 25 member 12
SOD1
superoxide dismutase 1
SST
safety surveillance team
SUSAR
suspected unexpected serious adverse reaction
SVC
slow vital capacity
t½
elimination half-life
TC
telephone contact
TDP-43
transactive response deoxyribonucleic acid-binding protein 43
Tmax
time to reach maximum observed concentration
UV
Unscheduled Visit
 1Based on formatting guidelines (https://www.biosciencewriters.com/Guidelines-for-Formatting-Gene-and-Protein-
Names.aspx), references to genes and mRNAs are italicized, and references to proteins are in standard font.

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3.
INTRODUCTION 
BIIB105 is a novel ASO in development for the treatment of ALS and polyQ-ALS. 
3.1.
Study Rationale
Ataxin-2, encoded by the ATXN2 gene, is a cytoplasmic RNA-binding protein that has been 
implicated in the pathology of ALS through several mechanisms, including, but not limited to, 
cytoplasmic mislocalization of, and aggregation with, other proteins implicated with ALS such 
as TDP-43. A potential therapeutic approach to indirectly affect TDP-43 is modulation of the 
ATXN2 protein. While the exact mechanism remains unclear, ATXN2 modulation has been 
shown to affect TDP-43 toxicity in nonclinical models, where toxicity caused by overexpression 
of TDP-43 was enhanced with increased expression of ATXN2 and was reduced when ATXN2 
levels were depleted [Becker 2017; Elden 2010]. 
These nonclinical findings linking ATXN2 to ALS have been supported by human genetic studies 
and pathological observations in ALS patient tissue. Intermediate-length expansion of the 
polyCAG region in ATXN2 has been identified as a significant risk factor for developing ALS 
[Elden 2010; Neuenschwander 2014; Sproviero 2017]. This repeat region encodes a polyQ 
segment at the N-terminus of the ATXN2 protein, and when expanded, is believed to stabilize 
the protein [Elden 2010]. Additionally, retrospective analysis of patients with ALS harboring a 
polyCAG expanded allele (polyQ patients) as compared with matched patients with ALS 
harboring normal polyCAG length alleles has shown that patients with ATXN2 polyQ 
demonstrate faster clinical progression, as measured by the ALSFRS-R and respiratory vital 
capacity, suggesting that ATXN2 polyQ expansions also confer a risk of more aggressive disease 
[McMillan 2020]. Finally, ATXN2 protein lacking a polyQ expansion has been found to be 
aberrantly localized in ~25% of motor neurons in multiple ALS patients [Elden 2010].
BIIB105 is a novel ASO being developed for the treatment of ALS. The ASO targets the 
ATXN2-mRNA for degradation, as a means to decrease ATXN2 protein and thereby mitigate 
TDP-43 toxicity as seen in nonclinical models.
When delivered systemically, ASOs do not cross the blood-brain barrier at sufficient levels to 
modulate gene expression in the brain or spinal cord [Agrawal 1991; Broaddus 2000; Cossum 
1993]. Thus, to achieve antisense pharmacology in brain or spinal cord, ASOs such as BIIB105 
are delivered directly into the CSF space by IT administration.
Given the rapidly progressing, life-threatening, and rare nature of the disease as well as the high 
unmet medical need in ALS, the first-in-human Phase 1/2 study will be a two-part evaluation of 
BIIB105 in adult participants with ALS and polyQ-ALS. Part 1 will be a placebo-controlled 
MAD assessment of the safety, tolerability, pharmacokinetics, pharmacodynamics, and effect on 
disease progression of BIIB105. Part 2 will be an extension study to assess the long-term safety, 
tolerability, pharmacokinetics, pharmacodynamics, and effect on disease progression of BIIB105 
in participants who complete Part 1 through Week 25 (Day 175 Visit for Cohorts A, B, C1, and 
C2; Day 176 Visit for Cohorts D1 and D2).

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This study design will minimize the number of participants receiving subtherapeutic doses and/or 
dosing durations. For all cohorts in Part 1, the 72-hour safety data review following sentinel 
dosing of the first 2 participants of each dosing cohort and the 7-day safety review for each 
participant after administration of the first dose and prior to administration of the second dose 
will allow evaluation of potential acute safety and tolerability findings in each participant prior to 
the administration of additional doses, similar to a single-ascending-dose study design. Part 2 
will provide up to 104 weeks of dosing of BIIB105 for study participants who complete 
25 weeks in Part 1. The safety, PK, PD, and clinical function data collected from Part 2 will 
allow for the understanding of the long-term effect of BIIB105 in participants with ALS and 
polyQ-ALS. 
3.1.1.
Rationale for Study Population
This study will be conducted in participants diagnosed with ALS and polyQ-ALS for the 
following reasons:
•
Nonclinical data support the development of BIIB105 in this population.
•
Due to the rare, rapidly progressive, and life-threatening nature of ALS that lacks an 
available cure, there is an urgent need for an effective therapy. The administration of 
BIIB105 to participants with ALS in the first-in-human study will allow assessment 
of the safety, tolerability, PK, and potential efficacy of BIIB105 in a relevant 
population as quickly as possible, while minimizing the number of participants who 
are exposed to subtherapeutic doses and minimizing the risk to each study participant. 
•
This study includes a subset of participants with polyQ-ALS as they reflect a 
subpopulation that carries a genetic risk for developing ALS [Elden 2010; 
Neuenschwander 2014; Sproviero 2017] and demonstrate faster clinical progression 
as measured by the ALSFRS-R and respiratory vital capacity [McMillan 2020].
3.1.2.
Rationale for Starting Dose and Maximum Exposure
A single-dose NHP toxicity study identified a maximum tolerated dose (
 mg) and reversible 
AEs at 
 mg, which can be monitored clinically. Specifically, 1 of 3 animals dosed at 
 mg 
exhibited increased muscle tone, whole body spasms, and tremors that required administration of 
diazepam. The animal fully recovered by 
 hours. Additional nonclinical NHP data was 
obtained from a 13-week study with doses of BIIB105 administered at 
 mg and a 
41-week study with 
 doses of BIIB105 administered at 
 mg.
BIIB105 was tested in 2 pharmacologically relevant species: NHP and mouse. Because BIIB105 
produced no adverse effects at any of the dose levels used in the repeat-dose GLP studies, the 
highest dose of each study was identified as the NOAEL. Specifically, the NOAEL for the 
13-week monkey IT study is 
 mg, the NOAEL for the 41-week monkey IT study is 
 mg, the 
NOAEL for both the 14-week and 26-week mouse SC studies is 
 mg/kg, and the NOAEL for 
the 57-day mouse ICV study is 
 mg. The NHP was deemed the most sensitive species because 
dose-limiting effects were identified in a GLP single-dose NHP study at 
 mg, whereas no 

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dose-limiting toxicities have been identified in the rodent studies. At the time of selection of the 
starting dose for this study, the 13-week NHP study also provided the lowest HED, which was 
calculated to be 
 mg utilizing a CSF volumetric scaling factor of 10. This represented the 
most conservative estimate based on CSF volume ratio between humans and NHPs and as 
compared with the HED in the mouse ICV (
 mg) and mouse SC (
 mg or 
 mg/kg 
based on a 60 kg human) toxicity studies. 
Therefore, the selection of the starting dose for Part 1 of this study is based on the NOAEL dose 
of 
 mg, established in the 13-week toxicology study in cynomolgus monkeys, and on the 
expected PD of BIIB105 in the brain cortex and spinal cord. The HED value was divided by the 
conventional safety factor of 10 to yield the MRSD of 
mg. The proposed mg starting dose is 
below the MRSD, has a 
-fold safety factor over the HED (
 mg) of the NOAEL from the 
13-week toxicology study, and is expected to produce minimal to moderate pharmacologic 
effects in the brain and spinal cord. 
There were 2 chronic toxicology GLP studies conducted to support the dosing duration for Part 2 
of this study. In the 41-week NHP study BIIB105 was administered IT (
 mg) on 
Days 
, then 
until Day 
. In the 26-week mouse study BIIB105 was 
administered SC (
mg/kg/dose) every 
 from Day  through Day 
. 
NOAEL for both of the studies was considered to be the highest dose tested. The 41-week NHP 
chronic toxicology study provided the lowest HED, which was calculated to be 
 mg utilizing 
a CSF volumetric scaling factor of 10. These chronic toxicology studies support the proposed 
dose levels and dosing duration in the study.
A physiologically based PK model was used to establish the expected relationship between IT 
doses of BIIB105 and its concentrations in various brain regions. The potency of BIIB105 
determined in transgenic mouse studies was used to project expected mRNA lowering in 
humans. The potency of BIIB105 is anticipated to be higher in the spinal cord than brain, with 
reported concentrations at 
% of maximum observed biologic effect of 
 μg/g and 
 μg/g in the brain cortex and spinal cord, respectively. Results from a TDP-43 transgenic 
mouse model of ALS suggest a dose-dependent increase in survival with decreasing levels of 
ATXN2. It was shown that in TDP-43 transgenic mice, ASO induced reduction of ATXN2 mRNA 
levels in CNS tissues by 
% on average and resulted in a 
% increase in median lifespan 
compared with control ASO littermates [Becker 2017]. An mRNA reduction of approximately 
% is therefore considered the target BIIB105 PD effect in humans that could be indicative of 
potential clinical efficacy.
The predicted ATXN2 mRNA reductions in the target CNS regions and safety margins at steady 
state at the proposed dose levels planned in this study are shown in Table 4. The MRSD of 
 mg is estimated to reduce ATXN2 mRNA levels approximately 
% in the cortex and 
approximately 
% in the spinal cord after reaching steady state. In consideration of the higher 
reduction of ATXN2 mRNA in the spinal cord, a starting dose of  mg is proposed, which is 
anticipated to reduce ATXN2 mRNA levels by approximately % in the cortex and 
% in the 
spinal cord. A maximum dose of 
 mg is proposed at this time and is estimated to reduce 
ATXN2 mRNA levels in the cortex by approximately 
% and in the spinal cord by 
approximately 
% at steady state and will provide an approximately 
-fold safety margin to 

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participant population. Access to utilize these samples for future analyses may help further ALS 
research.
3.2.
Background
3.2.1.
Overview of ALS 
ALS is a rare neurodegenerative disease resulting in pathologic loss of motor neurons and their 
axons within the cortex, brainstem, spinal cord, and peripheral nerves. Patients suffer from 
progressive loss of muscle mass, strength, and function in bulbar, respiratory, and voluntary 
muscles. ALS is formally defined by clinical history and examination that demonstrate loss of 
both upper and lower motor neuron function over time. Functional decline and death, typically 
from respiratory failure, are inevitable and occur approximately 2 to 5 years from disease onset 
unless tracheostomy and mechanical ventilation are elected to support life.
A hallmark of ALS pathogenesis in the majority of patients is the presence of cytoplasmic 
inclusions containing aggregated TDP-43 in motor neurons [Ling 2013; Neumann 2006]. 
TDP-43 is a ubiquitously expressed protein that plays a variety of roles in RNA processing. 
Mutations in the TDP-43 gene have been shown to cause familial ALS; however, most patients 
do not carry an associated TDP-43 genetic mutation, suggesting that abnormal cytoplasmic 
aggregation of the wild-type protein may play a role in disease pathogenesis [Scotter 2015a, 
2015b].
3.2.2.
Current Therapies for ALS 
Available treatments for ALS include riluzole, edaravone, and sodium phenylbutyrate and 
taurursodiol, with approvals varying by region. Each has demonstrated modest effects on disease 
progression.
Riluzole provides a modest increase in survival (2 to 3 months) without noticeable improvement 
in strength or disability [Miller 2012]. The mode of action of riluzole is unknown, but its 
pharmacological activities include inhibition of glutamate release, inactivation of 
voltage-dependent sodium channels, and interference with intracellular events that follow 
neurotransmitter binding at excitatory amino acid receptors.
In a 6-month randomized study, Japanese patients with early-stage ALS receiving edaravone 
demonstrated a decreased decline in ALSFRS-R scores as compared with patients who received 
placebo [Writing Group and Edaravone (MCI-186) ALS 19 Study Group 2017]. The mechanism 
of action of edaravone in ALS is unknown. 
In a 6-month randomized study in the United States, patients with ALS who received a 
combination of sodium phenylbutyrate and taurursodiol demonstrated less decline in ALSFRS-R 
scores over 24 weeks compared with patients who received placebo [Paganoni 2020]. The 
mechanism of action of sodium phenylbutyrate in ALS is unknown, but its pharmacological 
activities include histone deacetylase inhibition and upregulation of heat shock proteins. The 

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Following SC administration in mice, BIIB105 is rapidly and extensively distributed from serum 
to liver and kidney. BIIB105 concentrations in serum peaked 
 after dosing, 
indicating rapid absorption into the systemic circulation.
Dose-dependent tissue distribution of BIIB105 was seen in all repeat-dose toxicology studies 
with no clear or consistent evidence of a sex difference in distribution to tissues. After IT 
administration in monkeys, BIIB105 distributed broadly to CNS tissues. Relatively high 
concentrations were observed in the liver and kidneys, indicating that a significant proportion of 
the administered dose was distributed from CSF to the systemic circulation. A similar systemic 
distribution profile was observed following ICV administration in mice.
Nonclinical evaluation of BIIB105 metabolites has not yet been conducted; however, based on 
previous experience with similar classes of ASOs 
 
, BIIB105 metabolites are expected to be consistent with nuclease-mediated 
metabolism. In vitro or in vivo drug-drug interaction studies have not been conducted; however, 
based on previous experience, BIIB105 is not expected to be a substrate for 
cytochrome P450-mediated oxidative metabolism and therefore should not compete with other 
drugs for this metabolic pathway [Geary 2003; Yu 2007]. 
Nonclinical evaluation of the urinary excretion of BIIB105 has not been performed. The 
metabolism of similar classes of ASOs in tissues has been reported to be slow, followed by 
urinary excretion of mainly metabolites, with a minor component of the administered compound 
excreted as parent [Geary 2003; Post 2019]. A similar disposition is expected for BIIB105.
Nonclinical toxicity of BIIB105 was assessed after single- and repeat-dosing studies were 
conducted in mice and NHPs, the latter being deemed as the most relevant species. 
In the 5 GLP repeat-dose studies in mice and NHPs, BIIB105 produced no adverse effects at any 
of the dose levels used in each study. The NOAEL for the 13-week NHP IT study is 
 mg, the 
NOAEL for the 41-week NHP IT is 
 mg, the NOAEL for both the 14-week and 26-week 
mouse SC study is 
mg/kg, and the NOAEL for the 57-day mouse ICV study is 
 mg. A 
single-dose NHP toxicity study identified a maximum tolerated dose (
 mg) and reversible AEs 
at 
 mg that can be monitored and controlled clinically. These doses correspond to HED values 
of 
mg and 
 mg, respectively, based on CSF volume scaling in the most sensitive species. 
Central administration of BIIB105 in mice (  ICV doses over 57 days) or NHP (  IT doses over 
13 weeks and 
 IT doses over 41 weeks) produced no CNS adverse effects. In NHPs, BIIB105-
related CNS effects included transient decreases of spinal reflexes and postural reactions in 
individual animals after each dosing session. Due to the transient nature and lack of persistent 
impact to ambulatory function, these reduced or absent spinal reflexes were considered 
nonadverse, with no histopathologic correlates to these findings. One animal in the 41-week 
NHP study at the 
mg dose level had more persistent head-holding, tremors, and abnormal 
general attitude which did not affect the animal’s functionality. This animal additionally had 
systemic and CNS inflammatory changes with an AUC-time curve exposure comparable to the 
mg dose level and a high accumulation without evidence of neuronal necrosis or degeneration 
on histopathology. The clinical and histopathologic findings in this animal were nonadverse.

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Repeated central administration of BIIB105 produced nonadverse microscopic changes in both 
mice and NHPs. Micro- and/or macro-vesicular neuronal vacuolation were noted in CNS tissues 
as well as in multiple systemic tissues in NHP. Nonadverse vacuolar findings were of low 
severity and had no associated neuronal degeneration or necrosis/apoptosis or correlating clinical 
signs. Macrovesicular neuronal vacuolation has been observed for IT-administered ASOs, which 
was attributable to the tissue fixation in the presence of drug (Ionis Study 396443-AS11 and 
Biogen Study No. PD17-12).
Repeated systemic administration of BIIB105 in mice resulted nonadverse microscopic effects 
related to BIIB105 including macrophage vacuolation in multiple tissues, tubular basophilic 
granules in the kidney, decreased erythroid cellularity of the bone marrow, tubular vacuolation in 
the kidney, increase in incidence of hematopoiesis in the spleen, and increase in incidence of 
decreased lymphoid cellularity in the thymus. These changes were considered nonadverse based 
on their minimal to mild severity, lack of clinical pathology correlate, and/or absence of function 
impairment. Kidneys are a known target organ for nonspecific, ASO-associated histopathologic 
changes due to the preferential uptake of ASOs by proximal tubular epithelium and processing 
within endosomes and lysosomes [Henry 2008; Monteith 1999].
The macrophage vacuolation noted in multiple tissues in both the NHP (IT) study and mouse 
(SC) study was considered to be class-related effects of ASO compounds. Cytoplasmic 
vacuolation of macrophages has been reported to reflect lysosomal accumulation of 
oligonucleotides [Braendli-Baiocco 2017] or cellular activation and cytokine production without 
oligonucleotide accumulation [Frazier 2015] and is not considered to be adverse because 
impairment of function has not been reported [Lenz 2018].
In NHPs, the transient mild increases in complement Bb fragment, sC5b-9, and C3a observed 
following dosing were consistent with the well-documented proinflammatory effects of ASO 
treatment in NHPs [Engelhardt 2015; Henry 2014]. Nonadverse elevated C-reactive protein 
concentration in individual animals with mild increases in fibrinogen reflected acute phase 
reactions that were mostly mild and generally not associated with clinical signs, neurological 
deficits, or histopathologic findings. 
BIIB105 is not a genotoxicant as negative results were observed in the bacterial reverse 
mutation, in vitro chromosomal aberration, and in vivo rat micronucleus assays at limit 
concentrations/doses.
In a fertility study, there were no BIIB105-related effects on sperm concentration or morphology 
in male mice. In female mice, there were no BIIB105-related effects on female reproductive 
parameters, estrous cycle length, or precoital intervals. The NOAEL for reproductive toxicity 
was 
 mg/kg/dose. The corresponding serum exposure was a mean Cmax of 
 µg/mL and a 
mean AUC0-24 of
µg*h/mL after repeat dosing in males. The exposures in pregnant females 
were a mean Cmax of
µg/mL and a mean AUC0-24 of 
 µg*h/mL on GD 14.
In mice, BIIB105 did not result in any effects on embryo-fetal survival. A statistically 
significantly lower mean fetal weight was observed at 
 mg/kg/day and was considered adverse. 
BIIB105 did not produce any fetal external, visceral, or skeletal malformations or variations in 

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mice. The NOAEL for developmental toxicity in mice was considered to be 
 mg/kg/dose, 
which corresponded to a mean Cmax of 
 µg/mL and a mean AUC0-24 of 
µg*h/mL in 
females. Fetal exposure, based on BIIB105 concentrations in liver, was approximately 
 
times lower than the maternal Cmax.
A dose level of 
 mg/kg/dose was considered to be the NOAEL for maternal toxicity and 
embryo-fetal development when BIIB105 was administered via SC injection to New Zealand 
White rabbits. This dose level was associated with a mean serum Cmax of 
 µg/mL and a mean 
AUClast of 
 µg*h/mL on GD 
. There was no detectable BIIB105 in fetal livers in rabbit.
3.2.3.2.
Clinical Experience 
This is the first-in-human study of BIIB105. Emerging clinical data can be found in the 
Investigator’s Brochure. 
3.3.
Benefit-Risk Assessment
The potential benefit of BIIB105 in ALS has not been established. This study has been designed 
with appropriate dose escalation, safety monitoring, and stopping rules to minimize risks to 
participants. The results of this study may offer key insights into the development of a disease-
modifying therapy for ALS.
This is a first in human study, thus the risk in humans is unknown. Emerging clinical data can be 
found in the Investigator’s Brochure.
Nonclinical work with Atxn2 homozygous knockout mice suggests that ATXN2 reduction could 
be associated with risks of metabolic complications (adult-onset obesity and insulin resistance) 
and subtle neurological deficits [Huynh 2009; Kiehl 2006; Lastres-Becker 2008]. Human data 
from the Genome-Wide Association Studies database suggest that variation in ATXN2 could be 
associated with changes in blood pressure and cardiometabolic phenotypes [Auburger 2014]. 
From the nonclinical safety studies in NHPs, the adverse effect level was considered to be 
 mg 
based on severe but reversible and monitorable clinical signs: 1 of 3 animals exhibited increased 
muscle tone, whole body spasms, and tremors that required administration of diazepam. The 
animal fully recovered by 
 hours. No adverse metabolic effects were seen in toxicology 
studies. Participants will be monitored in the clinical setting with neurological and physical 
examinations and careful monitoring of blood chemistries, among other safety assessments.
Although LP is generally considered a safe procedure, certain complications can occur in a 
subset of patients. These may include, but are not limited to, back pain, headache, nausea, 
infection, bleeding, radicular pain and numbness, and bruising or injury at the injection site. 
These potential risks can be mitigated by using atraumatic needles, avoiding contraindicated 
medications, and testing coagulation and platelet counts prior to the procedure. Importantly, 
life-threatening cerebral herniation is a possible complication of a lumbar puncture procedure.
Reproductive toxicity studies were conducted in mice and rabbits using SC administration of 
BIIB105 once every other day. In a definitive combined fertility and embryo-fetal development 

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study in male and female mice, there was no effect of BIIB105 on fertility in either sex. BIIB105 
did not produce any fetal external, visceral, or skeletal malformations or variations in mice or 
rabbits. However, there were BIIB105-related effects on embryo-fetal development in both 
species. In mice, there were lower mean fetal body weights that were considered adverse at the 
highest dose tested (
 mg/kg). In a dose-range finding study in rabbits, dose-limiting BIIB105-
related findings included body weight losses, reduced food consumption, and abortions. There 
was very limited fetal exposure in mice only, with concentrations of BIIB105 detected in fetal 
mouse liver approximately 
-fold lower than the maternal Cmax. Due to these adverse 
findings in the reproductive toxicity nonclinical studies, all men and women of childbearing 
potential must use highly effective contraception during the study and for at least 
 after 
the study (for female participants) and at least 
 after the study (for male participants).
ALS is a debilitating, rapidly progressing, and life-threatening disease with a high unmet need 
for effective therapies. Overall, the benefit-risk profile is positive for the continued clinical 
development of BIIB105 for the treatment of ALS and polyQ-ALS.

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4.
STUDY OBJECTIVES AND ENDPOINTS
Part 1
Primary Objective
Primary Endpoint
To evaluate the safety and 
tolerability of BIIB105 in 
participants with ALS or 
polyQ-ALS.
Incidence of AEs and SAEs in Part 1.
Secondary Objective
Secondary Endpoints
To assess the PK profile of 
BIIB105 in serum and CSF of 
participants with ALS or 
polyQ-ALS.
Serum and CSF concentrations of BIIB105 in Part 1.
To evaluate the following serum PK parameters in Part 1:
•
AUCinf 
•
AUClast
•
Cmax
•
Tmax
•
t½
To evaluate the biomarker effect of 
BIIB105 in participants with ALS 
or polyQ-ALS.
Secondary biomarker measure:
•
Changes from baseline in plasma levels of 
NfL in Part 1
Exploratory Objectives
Exploratory Endpoints
To evaluate the PD effect of 
BIIB105 in participants with ALS 
or polyQ-ALS.
Exploratory PD measure:
•
Change from baseline in CSF levels of 
ATXN2 protein in Part 1.

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Part 2 
Primary Objective
Part 2 Primary Endpoint
To evaluate the long-term safety and 
tolerability of BIIB105 in 
participants with ALS or 
polyQ-ALS.
Incidence of AEs and SAEs in Part 2.

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Integrated Part 1 and Part 2
Primary Objective
Primary Endpoint
To evaluate the long-term safety and 
tolerability of BIIB105 in 
participants with ALS or polyQ-
ALS.
Incidence of AEs and SAEs during the BIIB105-treated 
period in Part 1 and/or Part 2.
Secondary Objective
Secondary Endpoints
To assess the long-term PK profile of 
BIIB105 in serum and CSF of 
participants with ALS or 
polyQ-ALS.
Serum and CSF concentrations of BIIB105 in Part 1 
and Part 2.
•
CSF trough PK concentration
•
Serum PK concentration if available
To evaluate the long-term biomarker 
effect of BIIB105 in participants with 
ALS or polyQ-ALS, and, where 
relevant, to assess the impact of 
earlier initiation of BIIB105 (i.e., at 
start of Part 1) compared with 
delayed initiation of BIIB105 (i.e., at 
start of Part 2) on biomarkers.
Secondary biomarker measure:
•
Changes from Part 1 baseline (Cohorts D1, 
D2) or Part 2 baseline (Cohorts A, B, C1, 
C2) in plasma levels of NfL 
To evaluate the long-term effect of 
BIIB105 on measures of clinical 
function and, where relevant, to 
assess the impact of earlier initiation 
of BIIB105 (i.e., at start of Part 1) 
compared with delayed initiation of 
BIIB105 (i.e., at start of Part 2) on 
measures of clinical function.
Changes from Part 1 baseline (Cohorts D1, D2) or Part 
2 baseline (Cohorts A, B, C1, C2) in the following 
assessments:
•
SVC
•
ALSFRS-R score
•
Muscle strength, as measured by HHD
Survival analyses:
•
Time to death or permanent ventilation 
(≥ 22 hours of mechanical ventilation 
[invasive or noninvasive] per day for ≥ 21 
consecutive days)

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•
Time to death
•
Time to death, incorporating post-study 
withdrawal or study completion vital status 
data
Exploratory Objectives
Exploratory Endpoints
To evaluate the long-term PD effect 
of BIIB105 in participants with ALS 
or polyQ-ALS, and, where relevant, 
to assess the impact of earlier 
initiation of BIIB105 (i.e., at start of 
Part 1) compared with delayed 
initiation of BIIB105 (i.e., at start of 
Part 2) on the PD measure.
Exploratory PD measure:
•
Change from Part 1 baseline (Cohorts D1, 
D2) or Part 2 baseline (Cohorts A, B, C1, 
C2) in CSF levels of ATXN2 protein.
This study collects samples that under separate optional consent may be used for future scientific 
and genetic research. Objectives related to this future research have not been determined.

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5.
STUDY DESIGN
5.1.
Study Overview
5.1.1.
Part 1 
Part 1 is a Phase 1/2, randomized, double-blind, placebo-controlled, MAD evaluation of the 
safety, tolerability, and PK of BIIB105, administered IT to approximately 98 participants 
(76 participants with ALS and 22 participants with polyQ-ALS) at approximately 15 sites 
globally. Cohorts A, B, C1, and C2 will receive up to 5 doses over approximately 3 months. 
Cohorts D1 and D2 will receive up to 8 doses over approximately 6 months.  
Approximately 98 participants are planned to be randomized in Part 1. Participants who 
withdraw may be replaced in a cohort at the discretion of the Sponsor. With potential 
replacement, approximately 108 participants could be randomized.
Adult participants with ALS will be randomized at a ratio of 3:1 (active drug:placebo) in 
Cohorts A, B, C1, and D1. Adult participants with polyQ-ALS will be randomized at a ratio of 
3:1 in Cohort C2 and at a ratio of 2:1 in Cohort D2. Cohorts C1 and C2 can dose concurrently. 
Cohorts D1 and D2 can dose concurrently.
If dosing stops at one of the lower dosing cohorts, the cohort with the highest tolerated dose may 
be expanded to include an additional 20 participants with ALS (3:1, active drug:placebo) and an 
additional 18 participants with polyQ-ALS (2:1, active drug:placebo).
The first 2 participants in all cohorts, except cohort C2, will be randomized at a ratio of 1:1 
(active drug:placebo) and dosed as a sentinel group. No other participants within the cohort will 
be dosed until the Investigators have reviewed 72 hours of safety data after dosing the first 
2 participants and communicated with the Sponsor Medical Director and Global Medical Safety 
Physician. Based on this safety evaluation, the Sponsor will determine if the rest of the cohort 
can be dosed. For the remainder of participants in all cohorts, except for cohort C2, no more than 
2 participants will receive their first dose of study treatment on the same day throughout the 
study. For cohort C2, the participants will be randomized 3:1 (active drug:placebo). Treatment 
will be staggered by 72 hours for the first 2 participants. The first 2 participants will be dosed as 
a sentinel group, and no other participant will be dosed until the Investigators have reviewed 
safety data after dosing the first 2 participants and communicated with the Sponsor Medical 
Director and Global Medical Safety Physician. This phone call will occur 72 hours after the 
dosing of the second participant. Based on this safety evaluation, the Sponsor will determine if 
the rest of the cohort can be dosed. If approved, the third and fourth participants may receive 
their first dose of study treatment on the same day.
For each participant, a review of all available safety and tolerability data will be performed 
approximately 7 days after the first dose is administered and before administration of the second 
dose on Day 15. This single-dose review will be performed by the site’s Principal Investigator or 

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designee and communicated to the Sponsor Medical Director and Global Medical Safety 
Physician, or their appropriate designees. The Sponsor Medical Director and Safety Physician 
will determine if each participant can proceed with subsequent doses. The second dose cannot be 
administered until this review is complete.
Randomization will be performed using IRT. See Figure 1 for a schematic of the study design.
5.1.2.
Part 2 
Part 2 is an open-label evaluation of BIIB105 administered IT to participants with ALS and 
polyQ ALS who have completed Part 1 through Week 25 (Day 175 Visit for Cohorts A, B, C1, 
C2; Day 176 Visit for Cohorts D1, D2).
Participants will receive up to approximately 41 doses in Part 2. Two dose levels will be 
administered – participants from Part 1 Cohorts A, B, C1, and C2 will receive 60 mg BIIB105; 
participants from Part 1 Cohorts D1 and D2 will receive 120 mg BIIB105.  
In Part 2, the 60 mg dose may be increased, at the Sponsor’s discretion, to doses up to 120 mg. 
Before increasing the dose level, the SST must review safety and PK data for Cohorts D1 and D2 
(Part 1) and there must be agreement that the current emerging safety, tolerability, and PK data 
support the dose increase. Doses in Part 2 may also be decreased at the Sponsor’s discretion at 
any time during the study. 
5.2.
Study Duration for Participants
5.2.1.
Study Duration for Participants in Part 1
The total Part 1 study duration for each participant in Cohorts A, B, C1, and C2 will be 
approximately 29 weeks:
•
Screening Period of up to 4 weeks
•
Treatment Period of 13 weeks
•
Follow-up Period of approximately 12 weeks
Participants in Cohorts A, B, C1, and C2 will have up to 13 CVs and 9 TC during the study, 
which include at least 1 Screening Visit, 5 Dosing Visits of which the first dose will require an 
inpatient stay of 2 days, 7 Follow-up Visits, and 9 TC. All visits should be performed within the 
number of days from the nominal visit day, specified in Section 1. Visit days are calculated with 
respect to Day 1 (the date of first dose).
The total Part 1 study duration for each participant in D1 and D2 will be between approximately 
29 and 41 weeks: 
•
Screening Period of up to 4 weeks

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•
Treatment Period of 25 weeks 
•
Follow-up Period of approximately 12 weeks (only completed if the participant does 
not enter Part 2 after the Treatment Period)  
Participants in Cohorts D1 and D2 will have up to 19 CVs and 15 TCs which will include at least 
1 Screening Visit, 8 Dosing Visits of which the first will require an inpatient stay of 2 days, up to 
10 Follow-up Visits, and up to 15 TCs.  
Participants in Cohorts D1 and D2 who enter Part 2 after their Treatment Period (after the Day 
176 Visit) will not be required to complete the follow-up visits in Part 1 that occur after their 
enrollment in Part 2. Participants from Cohorts D1 and D2 who do not enter Part 2 will have two 
follow-up clinic visits and two TCs approximately 6 and 12 weeks after their last dosing visit.
Of note, if the Study Sponsor decides to terminate Part 1 without terminating Part 2, participants 
who are active in Part 1 at the time of the Sponsor’s decision will have the opportunity to end 
Part 1 and screen and enroll into Part 2 prior to completing Week 25. 
5.2.2.
Study Duration for Participants in Part 2
Study duration for each participant in Part 2 will be up to approximately 172 weeks:
•
Screening Period of up to 4 weeks (for participants from Cohorts D1 and D2, 
Screening Period begins with Day 169 Visit of Part 1)
•
Treatment Period of up to approximately 156 weeks: either 104 weeks, OR until the 
last participant enrolled has had the opportunity for their Part 2 Day 365 visit (Week 
52), whichever occurs later 
•
Follow-up Period of approximately 12 weeks
Participants will have up to approximately 44 CVs and 43 TCs during Part 2 of the study, which 
will include at least 1 Screening Visit, up to approximately 41 Dosing Visits, 2 Follow-Up Visits, 
and up to 43 TCs.
The end of study date for a participant may be the last study visit, last follow-up TC, or last 
protocol-specified assessment, or if the participant has ongoing AEs that are being followed up, 
the date may be the date of AE resolution.
After a participant’s end of study date, follow-up on vital status and date of death (if deceased) 
will be performed for participants who provide optional consent for data collection after study 
completion.

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5.3.
Dosing
5.3.1.
Dose Escalation (Part 1)
For each dose escalation, safety (AEs/SAEs, vital signs, ECGs, and laboratory parameters) and 
available PK data will be reviewed. The proposed dose escalation is illustrated in Figure 1 and 
the proposed dosing groups are as follows:
Participants with ALS:
Cohort A: BIIB105 5 mg (6 participants) or placebo (2 participants)
Cohort B: BIIB105 20 mg (6 participants) or placebo (2 participants)
Cohort C1: BIIB105 60 mg (9 participants) or placebo (3 participants)
Cohort D1: BIIB105 120 mg (approximately 36 participants) or placebo (approximately 12 
participants)
Participants with polyQ-ALS:
Cohort C2: BIIB105 60 mg (3 participants) or placebo (1 participant)
Cohort D2: BIIB105 120 mg (approximately 12 participants) or placebo (approximately 6 
participants)
See Section 3.1.2 for details regarding the rationale for the starting dose and dose escalation.
After a cohort (Cohorts A, B, C1, and C2) is fully randomized and at least 36 days have elapsed 
since the randomization and dosing of the eighth participant, a Sponsor SST will hold a dose 
escalation meeting to review all available blinded safety data from all randomized participants. 
There must be a minimum of 6 evaluable participants for the dose escalation meeting to occur. In 
Cohort C2, all 4 participants must be evaluable for the dose escalation meeting to occur. 
Evaluable participants are defined as those who have completed 3 dosing visits and the Day 36 
CV. This CV occurs 1 week after the Day 29 dose, the dose that is projected to result in the 
targeted steady-state exposures for the cohort. Dosing of Cohort D1 is dependent on the SST 
approving the safety of Cohort C1, and dosing of Cohort D2 is dependent on an SST approving 
the safety of Cohort C2.
For Cohort D1, the safety review will occur after the cohort is fully randomized, and at least 
92 days have elapsed since the randomization and dosing of the 36th participant. The SST will 
review all available blinded safety data from all randomized participants in the cohort, which 
must include a minimum of 33 evaluable participants (those who completed all of the first 5 
dosing visits as well as the Day 92 clinic visit). This review will be for a final safety review for 
Cohort D1. Should Part 1 be terminated early (per Section 5.2.1 and Section 13.4) prior to 
reaching randomization of the entire D1 cohort or minimal evaluable criteria as defined, a final 

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safety SST will be held for Cohort D1 with all available safety data at the time of Part 1 
termination.
For Cohort D2, the safety review will occur after the cohort is fully randomized, and at least 
92 days after the randomization of the 15th participant. The SST will review all available blinded 
safety data from all randomized participants in the cohort, which must include a minimum of 12 
evaluable participants (those who completed all of the first 5 dosing visits as well as the Day 92 
clinic visit). This review will be for a final safety review for Cohort D2. Should Part 1 be 
terminated early (per Section 5.2.1 and Section 13.4) prior to reaching randomization of the 
entire D2 cohort or minimal evaluable criteria as defined, a final safety SST will be held for 
Cohort D2 with all available safety data at the time of Part 1 termination.
Cohorts D1 and D2 can be reviewed concurrently or in separate SSTs, depending on when the 
cohorts have reached the minimum evaluable patients.
Principal Investigators from sites where participants were dosed will be included in the blinded 
safety data review. Review of blinded safety data may be followed by review of unblinded safety 
data of the current and preceding cohorts by the SST. Details of the unblinded review as well as 
the personnel to be unblinded to support dose escalation will be clearly defined in the Dose 
Escalation Plan and Unblinding Plan for this study.
In addition to the review of all safety data, there will be a review of available PK data collected 
through the third dose prior to dosing of the next dose cohort for Cohorts A, B, C1, and C2. For 
Cohort D1, there will be a review of all available PK data for a minimum of 33 evaluable 
participants. For Cohort D2, there will be a review of all available PK data for a minimum of 12 
evaluable participants. Should Part 1 be terminated early (per Section 5.2.1 and Section 13.4) 
prior to reaching randomization of the entire D1 and/or D2 cohorts or minimal evaluable criteria 
as defined, a final safety SST will be held for Cohort D1 and/or D2 with all available PK data at 
the time of Part 1 termination.
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 appropriate quality 
control checks on the reviewed data and the conclusions of the SST will be documented in 
writing before allowing study progression.
Safety monitoring will continue after dose escalation, in accordance with the visit schedule, 
which encompasses approximately 12 additional weeks of follow-up.
5.3.2.
Dosing (Part 2)
Dosing in Part 2 will begin at the Sponsor’s discretion. Prior to start of dosing, the SST must 
review safety and PK data from Cohorts C1 and C2 (Part 1) and there must be agreement that the 
current emerging safety, tolerability, and PK data support the start of dosing in Part 2.
Participants who were assigned to Cohorts A, B, C1, and C2 and who have completed Week 25 
(Day 175) Visit in Part 1 will receive BIIB105 at 60 mg in Part 2. Participants who were 

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assigned to Cohorts D1 and D2 and who have completed Week 25 (Day 176) Visit in Part 1 will 
receive BIIB105 at 120 mg in Part 2. The 60 mg dose may be increased, at the Sponsor’s 
discretion, to doses up to 120 mg. Before increasing the dose level, the SST must review safety 
and PK data for Cohorts D1 and D2 (Part 1) as described in the Dose Escalation Plan and there 
must be agreement that the current emerging safety, tolerability, and PK data support the dose 
increase. Doses in Part 2 may also be decreased at the Sponsor’s discretion at any time during the 
study.
Participants who were assigned to Cohorts A, B, C1, and C2 will have a ≥16-week washout 
period between the time of their last dose of study treatment in Part 1 and their first dose in 
Part 2. Therefore, they will have a 4-week unblinded Loading Dose Period, during which they 
will receive 3 doses of BIIB105 administered every 2 weeks (on Days 1, 15, and 29).  
Participants who were assigned to Cohorts D1 and D2 will not have had a washout period 
between their last dose of study treatment in Part 1 and their first dose in Part 2. Therefore, they 
will have a 4-week blinded Loading Dose Period, to protect the blind in Part 1. During this 
blinded Loading Dose Period, participants who received BIIB105 during Part 1 will receive two 
doses of BIIB105, on Days 1 and 29, and placebo on Day 15. Participants who received placebo 
in Part 1 will receive three doses of BIIB105 administered every 2 weeks (on Days 1, 15, and 
29). Participants from Cohorts D1 and D2 must not receive their first dose in Part 2 sooner than 
4 weeks after their last dose in Part 1.
For all participants, the Loading Dose Period will be followed by an unblinded Maintenance 
Dose Period, where participants will receive maintenance doses of BIIB105 administered once 
every 4 weeks (up to approximately Week 156: either to Week 104, OR until the last participant 
enrolled has had the opportunity for their Part 2 Day 365 visit [Week 52], whichever occurs 
later). After the Maintenance Dose Period, participants will have an approximately 12-week 
follow-up period. 
The SST will review safety and PK data from the extension cohorts at regular intervals.
5.4.
Study and Cohort Stopping Rules
5.4.1.
Cohort Suspension
If 1 participant experiences either an SAE or a medically unacceptable AE (as defined by the 
Investigator or the Sponsor), the Sponsor Medical Director and Global Medical Safety Physician 
will review relevant safety information and obtain more information from the Investigator, if 
necessary. If the AE is assessed as unrelated to study treatment by both the Investigator and the 
Sponsor (e.g., is a known sign or symptom of ALS or is a known effect of the LP procedure), 
dose suspension is not necessary.
If the SAE or medically unacceptable AE (as determined by the Investigator or the Sponsor) is 
assessed as related to study treatment by the Investigator or the Sponsor, then dosing at and 
above the dose level at which the event occurred will be suspended until the event has been fully 
evaluated by the SST. Depending on the nature, severity, suspected on- or off-target toxicity, 

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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 the remaining participants within the cohort.
•
Randomize additional participants to the current cohort. 
•
Enroll additional participants to previous (lower dose) cohort.
•
Proceed with the planned dose escalation in the next cohort.
•
Dose a cohort with an intermediate lower dose.
•
Stop the study.
The review will also include all available preliminary PK data from the current and preceding 
cohort(s).
If the study is suspended, dosing of the cohort cannot resume until both of the following have 
occurred:
•
The Sponsor SST has completed the safety evaluation and the Investigator has 
received written approval from the Sponsor to resume dosing, and
•
Where applicable, a rationale for the continuation of the study, including an amended 
protocol if required, is submitted to the relevant regulatory agency(ies) as a 
substantial amendment and subsequently approved before dosing can resume.
Following the SST review of safety and PK data for Cohort D1 (Part 1), if there is agreement 
that the current emerging safety, tolerability, and PK data support continued dosing at 120 mg, 
the abovementioned dose suspension rules will no longer apply. The Sponsor may still determine 
that a dose suspension is required at any time due to emerging safety data.
5.4.2.
Dose Termination
After evaluation of safety, tolerability, and PK data by the SST, Investigator, 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:
•
Three similar SAEs (unless related to disease progression or unrelated to BIIIB105 
upon medical review) are reported for participants receiving active study treatment 
within the same cohort.
•
Four or more similar AEs are reported for participants receiving active study 
treatment (unless related to disease progression or unrelated to BIIIB105 upon 

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medical review) that are either not tolerable (as reported by the participant) or 
deemed a medically unacceptable risk by the SST.
•
Sponsor requests that dosing be terminated.
Following the SST review of safety and PK data for Cohort D1 (Part 1), if there is agreement 
that the current emerging safety, tolerability, and PK data support continued dosing at 120 mg, 
the abovementioned dose termination rules will no longer apply. The Sponsor may still 
determine that a dose termination is required at any time due to emerging safety data.
5.4.3.
Study Termination 
The Sponsor may terminate this study at any time after informing the Investigator, ethics 
committee, and applicable regulatory agencies. The Sponsor will notify Investigators when the 
study is to be placed on hold, completed, or terminated.
The study will be terminated if no dose is deemed to be safe. 
Other conditions that may warrant termination of the study include, but are not limited to, the 
following: 
•
The discovery of an unexpected or serious risk to participants enrolled in the study.
•
Dose termination for all ongoing cohorts and no agreement between the SST and 
Investigator to replace the planned dose of the current or subsequent cohorts with a 
lower dose.
•
A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.
If, in light of emerging data, the Sponsor decides to continue testing, evaluation, or development 
of the product only for a specific subpopulation of ALS (for example, PolyQ-ALS), the study 
may be terminated for participants who do not meet criteria for the subpopulation. 
5.5.
Unscheduled Visits
Data collected during UVs should be recorded on the participant’s CRFs only if the data support 
protocol objectives and/or are required for safety monitoring.

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5.6.
End of Study
5.6.1.
End of Part 1
The end of Part 1 (placebo-controlled study) is last participant, last visit in Part 1. Final analyses 
of Part 1 will be performed after the last participant, last visit has been completed for Part 1, and 
the database for Part 1 has been locked. 
5.6.2.
End of Study
The end of study is last participant, last visit for final collection of data in Study 275AS101. 
Following end of study, follow-up on vital status and date of death (if deceased) will be 
performed for participants who provide optional consent for data collection after study 
completion.

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6.
STUDY POPULATION
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. 
For Investigator questions regarding participant eligibility or clinical significance of 
abnormalities, discussion with the study Medical Monitor is strongly encouraged.
6.1.
Inclusion Criteria
6.1.1.
Part 1
1. Ability of the participant to understand the purpose and risks of the study and indicate 
informed consent, and the ability of the participant or the participant’s legally authorized 
representative, to provide signed and dated informed consent and authorization to use 
protected health information in accordance with national and local privacy regulations.
2. Aged 18 years or older at the time of informed consent or participant meets the minimum 
age of consent in accordance with national regulations (whichever is higher).
3. All women of childbearing potential and all men must ensure that highly effective 
contraception is used during the study and for at least 
 for female participants 
and 
 for male participants 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 
 after their last dose of study treatment, while male participants should not 
donate sperm for the duration of the study and for at least 
 after their last dose of 
study treatment.
4. Participants in Cohorts A, B, C1, and D1, must meet the laboratory-supported probable, 
probable, or definite criteria for diagnosing ALS according to the World Federation of 
Neurology El Escorial criteria (revised according to the Airlie House Conference 1998 
[Brooks 2000]). Participants in Cohorts C2 and D2 must meet any of the prior conditions 
but may also only meet clinically possible criteria for diagnosing ALS, or exhibit 
weakness attributable to ALS in the presence of ATXN2 intermediate repeats.
5. In participants in Cohorts C2 and D2, confirmed intermediate CAG/CAA repeat 
expansion in the ATXN2 gene as defined by at least 1 allele carrying 30 to 33 CAG/CAA 
repeats.
6. No known presence or family history of mutations in the SOD1 or FUS genes.
7. SVC criteria:
a.
In participants in Cohorts A, B, C1, and D1, SVC ≥ 60% of predicted value as adjusted 
for sex, age, and height (from the sitting position). 
b. In participants in Cohort C2 and D2, SVC ≥ 50% of predicted value as adjusted for sex, 
age, and height (from the sitting position). 

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8. 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, unless the Investigator 
determines that it should be discontinued for medical reasons, in which case it may not be 
restarted during the study.
9. Participants taking concomitant edaravone at study entry must be on a stable dose for 
≥ 60 days prior to the first dose of study treatment (Day 1). Participants taking 
concomitant edaravone must be willing to 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.
10. Screening values of coagulation parameters including platelet count, INR, PT, and APTT 
should be within normal ranges. Coagulation tests done at a local laboratory may be used 
for screening purposes, in order to reduce participant burden. Coagulation tests may be 
repeated once at the local laboratory if, in the opinion of the Investigator, values of the 
initial tests are out of range but not clinically significant. Participants with nonclinically 
significant and stable out-of-range values may be eligible to enroll in the study at the 
discretion of the Investigator and after a consultation with the Sponsor.
11. Has an informant/caregiver who, in the Investigator’s judgment, has frequent and 
sufficient contact with the participant as to be able to provide accurate information about 
the participant’s cognitive and functional abilities at Screening. An informant/caregiver 
should be available at Screening. The participation of the same informant/caregiver for 
the duration of the study is encouraged.
6.1.2.
Part 2
1. Ability of the participant to understand the purpose and risks of the study and indicate 
informed consent, and the ability of the participant or the participant’s legally authorized 
representative to provide signed and dated informed consent and authorization to use 
protected health information in accordance with national and local privacy regulations.
2. Participants must have completed Study 275AS101 Part 1 through Week 25 (Day 175 
Visit for Cohorts A, B, C1, C2; Day 176 Visit for Cohorts D1, D2). This inclusion 
criterion does not apply to a participant if Part 1 was terminated by the Sponsor before 
the participant reached Week 25. 
3. Participants from Cohorts A, B, C1, and C2 must have a washout of ≥16 weeks between 
the last dose of study treatment received in Study 275AS101 Part 1 and the first dose of 
BIIB105 received in Study 275AS101 Part 2. Participants from Cohorts D1 and D2 do 
not require a washout period. 
4. All women of childbearing potential and all men must ensure that highly effective 
contraception is used during the study and for at least 
 for female participants 
and 
 for male participants after their last dose of study treatment. In addition, 

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female participants should not donate eggs for the duration of the study and for at least 
 after their last dose of study treatment, while male participants should not 
donate sperm for the duration of the study and for at least 
 after their last dose of 
study treatment.
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, unless the Investigator 
determines that it should be discontinued for medical reasons, in which case it may not be 
restarted during the study.
6. Participants taking concomitant edaravone at study entry must be on a stable dose for 
≥ 60 days prior to the first dose of study treatment (Day 1). Participants taking 
concomitant edaravone must be willing to 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.
7. Screening values of coagulation parameters including platelet count, INR, PT, and APTT 
should be within normal ranges. Coagulation tests done at a local laboratory may be used 
for screening purposes, in order to reduce participant burden. Coagulation tests may be 
repeated once at the local laboratory if, in the opinion of the Investigator, values of the 
initial tests are out of range but not clinically significant. Participants with nonclinically 
significant and stable out-of-range values may be eligible to enroll in the study at the 
discretion of the Investigator and after a consultation with the Sponsor.
6.2.
Exclusion Criteria
6.2.1.
Part 1
Medical History and Current Health Status
1. History or positive test result at Screening for HIV. The requirement for testing at 
Screening may be omitted if it is not permitted by local regulations. 
2. Current hepatitis C infection (defined as positive HCV antibody and detectable HCV 
RNA). Participants with positive HCV antibody and undetectable HCV RNA are eligible 
to participate in the study.
3. Current hepatitis B infection (defined as positive for HbsAg and/or total 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. History of alcohol or substance abuse ≤ 6 months of Screening that would limit 
participation in the study, as determined by the Investigator.

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5. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing 
system during the study period.
6. Presence of tracheostomy.
7. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the Screening Period. 
8. History of a deep venous thrombosis or pulmonary embolism ≤ 2 years of Screening, or 
since the date of ALS diagnosis, whichever is longer. 
9. In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as 
determined by the Investigator.
10. In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes 
mellitus defined as HbA1c ≥ 8% during Screening.
11. Ongoing medical condition (e.g., wasting or cachexia, severe anemia) that would, in the 
opinion of the Investigator, interfere with the conduct or assessments of the study.
12. Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, 
including psychosis, suicidal ideation, suicide attempt, or untreated major depression 
≤ 90 days of Screening that in the opinion of the Investigator would interfere with the 
study procedures.
13. History of allergies to anesthetics that will be used for the LP procedure per institutional 
practice.
14. 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).
15. Presence or anticipated need of an implanted shunt for the drainage of CSF or an 
implanted CNS catheter at any time during the study.
16. Presence or anticipated need of an implanted intravenous port/catheter at any time during 
Part 1 of the study.
17. Clinically significant abnormalities in hematology or blood chemistry parameters, as 
determined by the Investigator that would render the participant unsuitable for 
enrollment.

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18. Clinically significant, as determined by the Investigator, 12-lead ECG abnormalities, 
including corrected QT interval using Fridericia’s correction method of > 450 msec for 
males and > 460 msec for females.
19. In participants in Cohorts A, B, and C1, prescreening ALSFRS-R slope 
> -0.4 points/month, where prescreening ALSFRS-R slope is defined as: (ALSFRS-R 
score at Screening - 48) / (months from date of symptom onset to date of Screening). This 
criterion is not applicable for Cohorts C2, D1, and D2. 
Medications
20. Treatment with another investigational drug (including investigational drugs for ALS 
through compassionate use programs) or biological agent within 1 month or 5 half-lives 
of study agent, whichever is longer, before Screening.
21. Treatment with an approved disease-modifying therapy for ALS other than riluzole or 
edaravone within 1 month or 5 half-lives of therapy, whichever is longer, before 
completion of Screening.
22. Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted 
for LP according to local standard of care and/or institutional guidelines, in the opinion of 
the Investigator or Prescriber.
Other
23. Female participants who are pregnant or currently breastfeeding and those intending to 
become pregnant during the study.
24. Current enrollment or a plan to enroll in any interventional clinical study. Participation in 
a noninterventional study focused on ALS natural history may be allowed at the 
discretion of the Investigator and after consultation with the Sponsor. 
25. Inability to comply with study requirements.
26. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
participant unsuitable for enrollment.
6.2.2.
Part 2
Medical History and Current Health Status
1. History or positive test result at Screening for HIV. The requirement for testing at 
Screening may be omitted if it is not permitted by local regulations. If participants from 
Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive for 
HIV during screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 
at the discretion of the Investigator.

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2. Current hepatitis C infection (defined as positive HCV antibody and detectable HCV 
RNA). Participants with positive HCV antibody and undetectable HCV RNA are eligible 
to participate in the study. If participants from Cohorts D1 and D2 who would seamlessly 
roll from Part 1 into Part 2 test positive for hepatitis C during screening for Part 2 but are 
clinically asymptomatic, they may enroll in Part 2 at the discretion of the Investigator.
3. Current hepatitis B infection (defined as positive for HbsAg and/or total 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. If participants from Cohorts D1 and D2 who would seamlessly roll from Part 1 
into Part 2 test positive for hepatitis B during screening for Part 2 but are clinically 
asymptomatic, they may enroll in Part 2 at the discretion of the Investigator.
4. History of alcohol or substance abuse ≤ 6 months of Screening that would limit 
participation in the study, as determined by the Investigator.
5. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing 
system during the study period.
6. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the Screening Period that, according 
to the Investigator, would interfere with the conduct or assessments of the study. 
7. In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as 
determined by the Investigator.
8. In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes 
mellitus defined as HbA1c ≥ 8% during Screening.
9. Ongoing medical condition (e.g., wasting or cachexia, severe anemia) that would, in the 
opinion of the Investigator, interfere with the conduct or assessments of the study.
10. Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, 
including psychosis, suicidal ideation, suicide attempt, or untreated major depression 
≤ 90 days of Screening that in the opinion of the Investigator would interfere with the 
study procedures.
11. History of allergies to anesthetics that will be used for the LP procedure per institutional 
practice.
12. 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).

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13. Presence or anticipated need of an implanted shunt for the drainage of CSF or an 
implanted CNS catheter at any time during the study.
14. Clinically significant abnormalities in hematology or blood chemistry parameters, as 
determined by the Investigator that would render the participant unsuitable for 
enrollment.
15. Clinically significant, as determined by the Investigator, 12-lead ECG abnormalities, 
including corrected QT interval using Fridericia’s correction method of > 450 msec for 
males and > 460 msec for females.
Medications
16. Treatment with another investigational drug (including investigational drugs for ALS 
through compassionate use programs; excluding BIIB105) or biological agent within 
1 month or 5 half-lives of study agent, whichever is longer, before Screening.
17. Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted 
for LP according to local standard of care and/or institutional guidelines, in the opinion of 
the Investigator or Prescriber.
Other
18. Female participants who are pregnant or currently breastfeeding and those intending to 
become pregnant during the study.
19. Current enrollment or a plan to enroll in any interventional clinical study. Participation in 
a noninterventional study focused on ALS natural history may be allowed at the 
discretion of the Investigator and after consultation with the Sponsor. 
20. Inability to comply with study requirements.
21. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the 
participant unsuitable for enrollment.
6.3.
Screening, Retesting, and Screen Failures
6.3.1.
Screening
Once informed consent is obtained, screening assessments can occur. At this time, a unique 
identification number is assigned that will be used on study-related documents pertaining to the 
participant. Any identification numbers that are assigned will not be reused even if the 
participant does not receive treatment or continue in the study. Study sites are required to 
document all screened participants initially considered for inclusion in the study. 
A participant or their legally authorized representative must provide written informed consent 
before any screening tests are performed. A participant’s informants/caregivers must also 

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provide written informed consent to participate in the study prior to providing any information 
on either themselves and/or participants. It is preferable that the same informant/caregiver 
participates and completes the informant/caregiver assessments for the duration of the study.
The Screening Period may be extended up to a total duration of 42 days for eligible individuals 
who cannot complete the Day 1 Visit within 28 days of signing the ICF.
Part 2 Screening: 
For consented participants from Cohorts D1 and D2, the Screening Period for Part 2 begins at the 
Part 1 Day 169 Visit. Results from Day 169 visit and Day 176 visits may be used for the purpose 
of screening and do not need to be repeated as long as they are conducted within 1-month of 
Baseline/loading dose visit (Part 2 Day 1).
For Cohorts A, B, C1 and C2, the Screening Period may be extended up to a total duration of 
42 days for eligible individuals who cannot complete the Day 1 Visit within 28 days of signing 
the ICF (Screening assessments may be performed over multiple days to reduce participant 
burden. 
6.3.2.
Retesting
Participants who have a nonclinically significant out-of-range laboratory result can be retested 
1 time only at the discretion of the Investigator after discussion with the Sponsor. The Screening 
Period may be extended up to a total duration of 42 days for eligible individuals who require 
retesting of laboratory results, including genetic testing results. Individuals who signed the ICF 
and subsequently do not meet concomitant medication criteria can have their Screening Period 
extended up to 42 days to ensure that the requirements for concomitant medication stabilization 
have been met.
The results of the most recent (i.e., obtained at a previous visit) centrally read 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 repeated 
locally to facilitate timely review. Results of any repeat tests must be available before the LP can 
be performed.
6.3.3.
Screen Failures
Screen failures are defined as participants who sign the ICF but are not subsequently 
randomized. If a participant is considered a screen failure, the reasons for exclusion must be 
documented in the participant’s source documents and on the screening log. Participants who fail 
screening may be permitted to be rescreened once at the Investigator’s discretion after discussion 
with the Sponsor. All screening assessments would need to be repeated during rescreening 
except for the following: 

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•
FSH level in female participants with postmenopausal state confirmed by level 
obtained in previous screening for this study.
•
For participants in Cohorts C2 or D2, confirmation of intermediate (30 to 33) 
CAG/CAA repeats in at least 1 allele in the ATXN2 gene by the central laboratory, if 
available from previous screening for this study. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 

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7.
STUDY TREATMENT 
7.1.
Regimen
In Part 1:
Each participant will receive an IT injection of study treatment (BIIB105 or placebo) over 
approximately 1 to 3 minutes every 14 days (i.e., Days 1, 15, and 29 in Part 1) during the loading 
period and every 28 days thereafter up to Day 85 (for Cohorts A, B, C1, and C2) or Day 169 (for 
Cohorts D1 and D2). Doses of BIIB105 will range from 5 mg up to 120 mg, all formulated in a 
final volume of 
 mL. Prior to injection, approximately 
 mL of CSF will be collected for 
analyses. Depending on institutional guidelines, anesthesia or sedation may be used for the LP 
procedure. Refer to and follow the DHA.
The dosage cannot be modified.
In Part 2:
Participants from Cohorts A, B, C1, and C2 will have a ≥16-week washout period. Participants 
will receive an IT injection of 60 mg BIIB105 
 every 14 days 
(i.e., Part 2 Days 1, 15, and 29) during the unblinded loading period, and every 28 days thereafter 
up to either Day 729 (Week 104), or until the last participant enrolled has had the opportunity for 
their Part 2 Day 365 visit (Week 52), whichever occurs later. The 60 mg dose may be increased, 
at the Sponsor’s discretion, to doses up to 120 mg. Before increasing the dose level, the SST 
must review safety and PK data for Cohort D1 (Part 1) and there must be agreement that the 
current emerging safety, tolerability, and PK data support the dose increase.
Participants from Cohorts D1 and D2 will not have a washout period and will have a blinded 
Loading Dose period. Participants who received placebo in Part 1 will receive 3 loading doses of 
BIIB105 120 mg approximately once every 2 weeks (Days 1, 15, and 29), while participants who 
received BIIB105 in Part 1 will receive 2 doses of BIIB105 120 mg, on Days 1 and 29, and 
placebo on Day 15. After the blinded Loading Dose Period, participants from Cohorts D1 and 
D2 will receive BIIB105 120 mg at each unblinded Maintenance Dose Visit thereafter (either up 
to Week 104, or until the last participant enrolled has had the opportunity for their Part 2 Day 
365 visit [Week 52], whichever occurs later). For participants from Cohort D1 and D2, the first 
dose for each participant in Part 2 will not occur less than 4 weeks after their last dose in Part 1. 
Doses in Part 2 for participants from all cohorts may be decreased at any time in the study at the 
Sponsor’s discretion.
Doses of BIIB105 in Study 275AS101 Part 2 will all be formulated in a final volume of 
 mL. 
Prior to injection, approximately 
 mL of CSF will be collected for analyses. Depending on 
institutional guidelines, anesthesia or sedation may be used for the LP procedure. Refer to and 
follow the DHA.
The dosage cannot be modified.

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7.2.
Study Treatment Management
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.
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.
7.3.
Study Treatment
7.3.1.
BIIB105
BIIB105 is supplied as a sterile, buffered, and isotonic solution in single-use clear vials 
containing study treatment either at a concentration of 
 mg/mL and a targeted volume of 
 
mL per vial to ensure maximum withdrawal of 
 mL for dose preparation, or at a concentration 
of mg/mL with a targeted volume of 
 mL per vial to ensure maximum withdrawal of 
 
mL for dose preparation (once this presentation is available for use at clinical study sites). This is 
accompanied by aCSF to be used as diluent where needed. Both BIIB105 and aCSF vials are 
sealed with a butyl rubber stopper and aluminum over seal with flip-off cap.
The contents of the BIIB105 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.
7.3.1.1.
Preparation
The individual preparing BIIB105 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 BIIB105, do not use the study treatment. The vial(s) in question should be saved at 
the study site and the problem immediately reported to the Sponsor.
Contact information for reporting a problem is provided in the study reference guide.
7.3.1.2.
Storage
Study treatment must be stored in a secure location. 
BIIB105 is to be stored at 2°C to 8°C (36°F to 46°F), in a monitored, locked refrigerator with 
limited access and protected from light. For the most up-to-date storage requirements, follow the 
instructions provided in the DHA.

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7.3.1.3.
Handling and Disposal
The Investigator must return all used and unused vials of BIIB105 as instructed by the Sponsor 
unless approved for onsite destruction.
If any BIIB105 supplies are to be destroyed at the study site, the institution or appropriate site 
staff must obtain prior approval from the Sponsor, by providing, in writing, the destruction 
policy or details of the method of destruction. After such destruction, the Sponsor must be 
notified, in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, 
quantities), the date of destruction, and proof of destruction.
7.3.1.4.
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. By the end of the study, reconciliation must be made between the amount of 
BIIB105 supplied, dispensed, and subsequently destroyed, lost, or returned to the Sponsor. A 
written explanation must be provided for any discrepancies.
7.3.2.
Placebo
Sponsor provided matching placebo is supplied as a sterile, buffered, and isotonic solution in 
vials. 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 refrigerator with 
limited access and protected from light.
7.4.
Blinding Procedures
The Investigator, study staff (except for designated pharmacy staff), and participants will be 
blinded to the randomized treatment assignments. 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 blinded study team, both at the site and at the Sponsor and CRO, except the 
unblinded designated Study Pharmacy Staff and designated Sponsor personnel.
The SST, 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 5.3 and/or for interim analyses 
of the data.

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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, the Sponsor will provide the randomization 
codes to Investigators, who then can inform their participants about the treatment received.
In the event of a medical emergency that requires unblinding of a participant’s treatment 
assignment, refer to Section 12.4.3.1.
7.5.
Precautions
Depending on institutional guidelines, anesthesia or sedation may be used for the LP procedure. 
On dosing days in Part 1, (except Dose 1), participants will remain at the study site for at least 
6 hours postdose for safety monitoring. In Part 2, participants who receive the 60 mg dose will 
remain at the study site for at least one hour postdose, and participants who receive the 120 mg 
dose will remain at the study site for at least 2 hours postdose for safety monitoring. Participants 
can be discharged at the discretion of the Investigator and in compliance with the institutional 
requirements, once the participant has adequately recovered from the dosing procedure. 
Participants will receive a safety follow-up TC approximately 24 hours after the procedure. 
During the Follow-up Period, participants will remain under observation in the clinic for 
approximately 1 hour after the LP procedure and will receive a safety follow-up TC 
approximately 24 hours after the procedure. Refer to and follow the DHA.
Any antiplatelet or anticoagulant medication that cannot be safely interrupted for an LP 
procedure, if necessary, according to local or institutional guidelines and/or Investigator 
determination is prohibited for the duration of the study.
7.6.
Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.
All doses of study treatment will be administered by the site staff.
7.7.
Concomitant Therapy and Procedures
7.7.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between Day 1 and the Final/ET 
Visit.
Participants should be instructed to contact their Investigators before taking any new 
medications, including nonprescription drugs and herbal preparations. Use of concomitant 
medication for symptom management during the study is at the discretion of the Investigator.
7.7.1.1.
Allowed Concomitant Therapy
Participants taking concomitant riluzole at study entry must be receiving a stable dose for 
≥ 30 days prior to the first dose of study treatment (Day 1) and should remain on this stable dose 
of riluzole until the Final/ET Visit, unless riluzole use must be discontinued in the judgment of 

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the Investigator, in which case it should not be restarted during the study. If participants are not 
receiving riluzole at Part 1 Day 1, they should not initiate it in Part 1.
Participants taking concomitant edaravone at study entry must be receiving a stable dose for 
≥ 60 days (2 treatment cycles) prior to the first dose of study treatment (Day 1) and should 
remain on this stable dose of edaravone until the Final/ET Visit, unless edaravone use must be 
discontinued in the judgment of the Investigator, in which case it should not be restarted during 
the study. If participants are not receiving edaravone at Part 1 Day 1, they should not initiate it in 
Part 1. Edaravone may not be administered on dosing days of this study.
Daily intake of all concomitant medication, 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/day and vitamin E 1000 IU/day. 
These daily limits include the total doses obtained through the combination use of daily 
multivitamins and supplements.
7.7.1.2.
Disallowed Concomitant Therapy
Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for LP 
according to local standard of care and/or institutional guidelines, in the opinion of the 
Investigator or Prescriber, should not be taken.
Use of a diaphragm pacing system, investigational drugs other than the investigational product 
(including drugs for ALS through compassionate use programs), or ASOs is prohibited for the 
duration of the study. 
Use of indwelling injection ports/catheters are prohibited during Part 1 of the study. 
Use of approved disease-modifying treatments for ALS other than riluzole or edaravone (i.e., 
sodium phenylbutyrate and taurursodiol in applicable geographies) is prohibited during Part 1 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.
7.7.2.
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 
Day 1 and the Final/ET Visit.

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7.8.
Continuation of Treatment 
There is currently no provision to provide study treatment after the study.

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8.
RULES FOR DISCONTINUATION OF STUDY TREATMENT 
AND WITHDRAWAL FROM STUDY FOR INDIVIDUAL 
PARTICPANTS
8.1.
Discontinuation of Study Treatment
A participant must permanently discontinue study treatment for any one of the following 
reasons:
•
The participant becomes pregnant. Report the pregnancy according to the instructions 
in Section 12.4.1.
•
The participant withdraws consent to continue study treatment. 
•
The participant experiences an AE 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 for medical reasons.
•
At the discretion of the Sponsor.
The primary reason for discontinuation of study treatment must be recorded in the participant’s 
CRF. 
If a participant received a dose of study treatment, then he or she will be encouraged to complete 
all the scheduled safety evaluations during the ET Visit.
Participants who discontinue treatment are encouraged to remain in the study and continue 
protocol-required tests and assessments, where possible.
8.2.
Lost to Follow-Up
Participants will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
The site must attempt to contact the participant, reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 

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schedule, and ascertain whether the participant wishes to and/or should continue in 
the study.
•
In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant. These contact 
attempts should be documented in the participant’s medical record.
•
Should the participant continue to be unreachable, that participant will be considered 
to have withdrawn from the study with a primary reason of lost to follow-up. 
8.3.
Withdrawal of Participants From the Study
Participants must be withdrawn from the study for any one of the following reasons:
•
The participant withdraws consent for participation in the study. 
•
The participant enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered.
•
The participant is unwilling or unable to comply with the protocol.
The primary reason for the participant’s withdrawal from the study must be recorded in the 
participant’s CRF.
Participants who withdraw from the study prior to completing study follow-up (last visit) in 
Part 1 may be replaced at the same dose cohort, at the discretion of the Sponsor.
After withdrawal from the study, follow-up on vital status and date of death (if deceased) will be 
performed for participants who provide optional consent for data collection after study 
withdrawal.  

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9.
SAFETY ASSESSMENTS
See Section 1 for the timing of all safety assessments.
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, participants will be asked to return to the 
clinic to have the evaluations repeated.
9.1.
Clinical Assessments
The following clinical assessments will be performed to evaluate the safety profile of BIIB105:
•
AE and SAE recording.
•
Physical examinations.
•
Neurological examinations (to be assessed by a trained specialist): Cranial nerves, 
motor, reflexes, cerebellar function, and mental status (MMSE in Part 1). A detailed 
list will be provided in the Study Reference Manual. 
•
Vital sign measurements: Temperature, heart rate, systolic and diastolic blood 
pressure, and respiratory rate will be measured after the participant has rested for at 
least 5 minutes.
•
Weight and height measurements.
•
12-Lead ECGs: ECGs are to be done in triplicate in the supine position (or semi-
recumbent position, if supine is not possible).
•
C-SSRS: 

In Part 1, the “Since Last Visit” version of C-SSRS will be used from Day 8 
onward.

In Part 2, participants from Cohorts D1 and D2 will use "Since Last Visit" version 
of C-SSRS on Day 1 onward. Participants from Cohorts A, B, C1, and C2 will use 
the “Since Last Visit” version of the C-SSRS from Day 15 onward. 
•
Concomitant therapy and procedure recording.
9.2.
Laboratory Assessments
Samples will be analyzed using Good Laboratory Practice-validated assays.
The following laboratory assessments will be performed to evaluate the safety profile of 
BIIB105:

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•
Hematology: Complete blood count with differential
•
Coagulation: INR, PT, and APTT
•
Blood chemistry: Total protein, albumin, HbA1c, lipid panel, 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
9.3.
Product-Specific Safety Assessments
Anti-BIIB105 antibody assessments will be conducted when indicated.

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10.
PHARMACOKINETIC ASSESSMENTS
BIIB105 concentrations in the serum and CSF will be determined using validated assays. 
Samples for analysis of BIIB105 concentrations in serum and CSF will be collected from each 
participant at timepoints specified in Table 1 and Table 2. 
See Section 1 for the timing of all assessments.
The following PK parameters will be assessed, when feasible, to assess the PK of BIIB105:
•
AUCinf 
•
AUClast
•
Cmax 
•
Tmax 
•
t½
Additional PK parameters may be calculated at the discretion of the Pharmacokineticist.

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11.2.11.
Collection of Vital Status Before and After Study Withdrawal or Completion 
Participants’ vital status will be collected throughout the study. For participants who provide 
optional consent for data collection after study withdrawal or completion, follow-up on vital 
status and date of death (if deceased) will be performed.
11.3.
Pharmacogenetic and Genetic Assessments
Genetic polymorphism impacting genes encoding drug targets or the downstream pathways, as 
well as proteins that impact drug absorption, distribution, metabolism, and elimination, may 
affect the safety and efficacy of the study treatment.
A DNA sample will be collected for genomic analysis. This is a one-time blood collection 
required at Screening for all participants, as outlined in Table 1 and Table 2 . For all cohorts, this 
collection is governed by the main ICF for the study.
Approximately 10% of patients diagnosed with ALS are known to be caused by genetic 
mutations; to date, at least 20 genes have been identified as causative of, or highly associated 
with ALS, including the ATXN2 intermediate polyCAG repeat mutation. The DNA sample will 
be used to determine the presence or absence of an ATXN2 intermediate polyCAG repeat 
mutation. The DNA sample may also be analyzed for genetic variation in the ATXN2 gene to 
determine the spectrum of likely pathogenic mutations in the gene and to assess if ATXN2 
polymorphisms affect response to treatment. In addition, these samples may be analyzed for 
genetic variation in other genes of known and probable relevance for the pathogenesis of ALS 
and neurodegeneration, including but not limited to TAR DNA binding protein, FUS, 
chromosome 9 open reading frame 72, optineurin, valosin-containing protein, ubiquilin 2, 
profilin 1, and SOD1.
In the event of an unusual response or observation of unexplained AEs, DNA samples may be 
used to determine if there are any pharmacogenetic associations with drug response. 
In the future, as the understanding of ALS and BIIB105 increases, additional genetic analyses 
may be warranted to refine the knowledge of the molecular basis of the disease and the drug 
response and to advance the development of novel therapeutics. This sample will only be used in 
genetic analyses to understand ALS, neurodegeneration, and the response to BIIB105.
The DNA samples will be coded with the participant’s identification number and may be stored 
for 15 years or a duration dictated by local, national, or regional laws or regulations. No 
genotyping or genetic data will be provided to the participant. Participants may withdraw consent 
and request to have their sample destroyed at any time and no further genetic data will be 
generated; any data already generated will not be destroyed.
In addition, where allowed by local, regional, and national regulatory authorities and ethics 
committees, participants will be offered the option for 
 
that may be used to understand the biology of 
ALS and other diseases and traits of interest to the Sponsor and/or to develop diagnostic and 

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12.
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 and/or his/her legally authorized representative and/or 
main informant/caregiver must be given the names and telephone numbers of site staff for 
reporting AEs and medical emergencies. Throughout the protocol, the Sponsor is named, but 
reporting may be done through a CRO.
12.1.
Definitions
12.1.1.
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 assessment (e.g., laboratory value, vital sign, and ECG) 
result meets the definition of an AE will be made by the Investigator. Abnormal results are not 
considered AEs unless one or more of the following criteria are met:
•
The result meets the criteria for an SAE.
•
The result requires the participant to receive specific corrective therapy.
•
The result is considered by the Investigator to be clinically significant.
12.1.2.
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.

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•
Results in a congenital anomaly/birth defect.
•
Is a medically important event.
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
participant or may require intervention to prevent one of the other outcomes listed in the 
definition above. (Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or convulsions occurring at home that do not require 
an inpatient hospitalization.)
12.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment 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 12.1.2 is met.
12.2.
Safety Classifications
12.2.1.
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 12.1.2.
•
The relationship of the event to study treatment or LP as defined in Section 12.2.2.
•
The severity of the event as defined in Section 12.2.3.

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12.2.2.
Relationship of Events to Study Treatment or Lumbar Puncture
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment or LP.
Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational product 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 investigational 
product and the AE, 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 product 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 
investigational product and the AE, a known response pattern of the suspected product, 
improvement following discontinuation or dose reduction, a biologically plausible 
relationship between the product 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 AE, 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 AE, 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.

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12.2.3.
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:
Severity of Event
Grade
Definition
1
Mild AE (asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated)
2
Moderate AE (minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living)
3
Severe or medically significant AE (not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living)
4
Life-threatening AE (urgent intervention indicated)
5
Death related to AE
12.2.4.
Expectedness of Events
Expectedness of all AEs will be determined by the Sponsor according to the Investigator’s 
Brochure for BIIB105. 
12.3.
Monitoring and Recording Events
12.3.1.
Adverse Events
Any AE experienced by the participant between the time of first dose of study treatment and the 
Final/ET 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, the Investigator will assess the participant for 
AEs and will record any new AEs or updates to previously reported AEs on the CRF.
AEs that are ongoing when the participant completes or discontinues the study will be followed 
up by the Investigator until the event has resolved, stabilized, or returned to baseline status. AE 
outcome will be recorded on the CRF, as applicable.
12.3.2.
Serious Adverse Events
Any SAE experienced by the participant between the time of the signing of the ICF and the 
Final/ET Visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment and must be reported to the Sponsor within 24 hours as described 
in Section 12.3.3. Follow-up information regarding an SAE also must be reported within 
24 hours.

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Participants will be followed up for all SAEs until the final study visit. Thereafter, the event 
should be reported to the Sponsor only if the Investigator considers the SAE to be related to 
study treatment. 
Any SAE that is ongoing when the participant completes or discontinues the study will be 
followed up by the Investigator until the event has resolved, stabilized, or returned to baseline 
status.
12.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify the Sponsor within 24 hours of the 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.
Reporting Information for SAEs
A report must be submitted to the Sponsor regardless of the following:
•
Whether or not the participant has undergone study-related procedures
•
Whether or not the participant has received study treatment
•
The severity of the event
•
The relationship of the event to study treatment
To report initial or follow-up information on an SAE, fax or email a completed SAE form; 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.
12.3.3.1.
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 the Sponsor. The term death should be reported as an SAE 
only if the cause of death is not known and cannot be determined.
12.3.4.
Suspected Unexpected Serious Adverse Reactions
SUSARs are SAEs that are unexpected and judged by the Investigator or the Sponsor to be 
related to the study treatment administered.
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting. The Sponsor will submit SUSARs (in blinded or unblinded fashion) to regulatory 

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agencies according to local law. The Sponsor will submit SUSARs to Investigators in a blinded 
fashion.
12.4.
Procedures for Handling Special Situations
12.4.1.
Pregnancy
Female participants should not become pregnant during the study and for at least 
 after their last dose of study treatment, while male participants should not 
impregnate their partners during the study and for at least 
 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 from first dose of 
study drug to 
 after their last dose of study treatment by faxing or emailing the 
appropriate form to the Sponsor within 24 hours of the site staff becoming aware of the 
pregnancy. Refer to the Study Reference Guide’s Official Study Contact List for complete 
contact information. The Investigator or site staff must report the outcome of the pregnancy to 
the Sponsor. A pregnancy is not considered an AE and should not be recorded on the AE CRF.
Congenital abnormalities and birth defects in the offspring of male or female participants should 
be reported as an SAE if conception occurred during the study Treatment Period or within 
 from their last dose of study treatment for females and 
 from their last dose of 
study treatment for males.
12.4.2.
Overdose
An overdose is any dose of study treatment administered to a participant or taken by a participant 
that exceeds the dose assigned to the participant according to the protocol. Overdoses are not 
considered AEs and should not be recorded as an AE on the CRF; however, all overdoses must 
be recorded on an Overdose form and faxed or emailed to the Sponsor within 24 hours of the site 
becoming aware of the overdose. An overdose must be reported to the Sponsor even if the 
overdose does not result in an AE. If an overdose results in an AE, the AE must be recorded. If 
an overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed 
or emailed to the Sponsor. All study treatment-related dosing information must be recorded on 
the dosing CRF.
12.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, 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.

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12.4.3.1.
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 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, or to personnel involved with the analysis and conduct of the study. The 
Investigator can contact the Sponsor or designee to discuss such situations. 
12.5.
Contraception Requirements
All women of childbearing potential and all men must ensure that highly effective contraception 
is used during the study and for at least 
 for female participants and 
 for male 
participants 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 
 after their last dose of study 
treatment, while male participants should not donate sperm for the duration of the study and for 
at least 
 after their last dose of study treatment.
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant, UNLESS they meet one of the following 
conditions:
1.
Postmenopausal
1.1.
52 continuous weeks of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum FSH level > 40 mIU/mL
1.2.
6 weeks after surgical bilateral oophorectomy with or without hysterectomy
2.
Posthysterectomy
For the purposes of the study, highly effective contraception is defined as use of 1 of the 
following: 
For females:
•
Established use of oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal methods of contraception associated with the 
inhibition of ovulation.
•
Established use of oral, injected, or implanted progestogen-only hormonal methods of 
contraception associated with the inhibition of ovulation. 
•
Placement of an intrauterine device or intrauterine hormone-releasing system.
•
Bilateral tubal occlusion.

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•
Female surgical sterilization (e.g., bilateral tubal ligation). 
•
Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate). 
For males:
•
Vasectomy with negative semen analysis at follow-up. If documentation is not 
available, the participant must use contraception. 
•
Sex only with a woman who uses the methods described for females if she is of 
childbearing potential.
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 study. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are 
not considered acceptable methods of contraception. 
Pregnancy reporting is described in Section 12.4.1. 
12.6.
Safety Responsibilities
12.6.1.
The Investigator
The Investigator’s responsibilities include the following:
•
Monitor and record all AEs, including SAEs, on the CRF 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 in female participants and follow up on the 
outcome of all pregnancies.
•
Complete an SAE form for each SAE and fax or email it to the Sponsor within 
24 hours of the site staff becoming aware of the event.
•
Pursue SAE follow-up information actively and persistently. Follow-up information 
must be reported to the Sponsor within 24 hours of the site staff becoming aware of 
new information.
•
Ensure all AE and SAE reports are supported by documentation in the participants’ 
medical records.

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•
Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. Record AE follow-up information, including resolution, on the CRF, as 
applicable.
•
Report SAEs to local ethics committees, as required by local law.
12.6.2.
The Sponsor 
The Sponsor’s responsibilities include the following:
•
Before a site can enroll any participants, the Clinical Monitor is responsible for 
reviewing with site staff the definitions of AE and SAE, as well as the instructions for 
monitoring, recording, and reporting AEs and SAEs.
•
The Sponsor is to notify all appropriate regulatory authorities, central ethics 
committees, and Investigators of SAEs, as required by local law, within required time 
frames.

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13.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 4.
13.1.
General Considerations
In general, for continuous data, summary statistics will be presented (e.g., mean, standard 
deviation, median, first and third quartile, and range). For categorical data, frequency counts and 
percentages will be presented. Demographic and baseline data will be summarized. 
Analyses will be performed on data from Part 1 alone, data from Part 2 alone, and on integrated 
data from Part 1 and Part 2. 
Placebo data in Part 1 may be pooled across cohorts for analyses. The Pooled Placebo 1 
population is defined as participants from Cohorts A, B, C1, and D1 who received placebo in 
Part 1. The Pooled Placebo 2 population is defined as participants from Cohorts C2 and D2 who 
received placebo in Part 1. 
13.2.
Analysis Populations
13.2.1.
Part 1 
The Part 1 FAS population is defined as all randomized participants who received at least 1 dose 
of study treatment in Part 1. In analyses performed on the FAS, participants will be analyzed, 
based on the intent-to-treat (ITT) principle, according to their randomized treatment assignment 
regardless of treatment received.
The Part 1 safety analysis population is defined as all randomized participants who received at 
least 1 dose of study treatment in Part 1.
The Part 1 PK analysis population is defined as all randomized participants who received at least 
1 dose of study treatment and have at least 1 postdose serum and/or CSF BIIB105 measurement 
in Part 1. 
The Part 1 PD population is defined as subjects who received at least 1 dose of study treatment 
and have at least 1 available postdose evaluation of the respective PD endpoint in the study in 
Part 1.
The Part 1 clinical function population is defined as the subset of the FAS population who have 
at least 1 postdose measurement in Part 1.
13.2.2.
Part 2
The Part 2 FAS population is defined as all enrolled participants who received at least 1 dose of 
study treatment in Part 2. 

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If, based on an interim analysis of Part 1, the Study Sponsor decides to terminate Part 1 of the 
study without terminating Part 2, participants who are active in Part 1 at the time of the 
Sponsor’s decision will have the opportunity to end Part 1 and screen and enroll into Part 2. In 
this scenario, participants screening for Part 2 will not have to meet Section 6.1.2 Part 2 
Inclusion Criterion #2 (having completed Part 1 through Week 25) to be eligible for Part 2.
Additional interim analyses may be performed during the conduct of Part 2, using data from 
Part 2 alone and/or integrated data from Part 1 and Part 2. Specifics will be detailed in the 
statistical analysis plan.
The participants, site staff, and Sponsor study team 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 will be provided in the Unblinding Plan and specific interim analysis plan.
13.5.
Sample Size Considerations
Part 1: 
The sample size of this first-in-human clinical study was selected with the goal of balancing 
between safety and tolerability considerations in dose escalation and obtaining sufficient initial 
information related to the safety and biological activities of BIIB105. Sample sizes of 
6 participants receiving active treatment in lower dose Cohorts A and B will allow an 
% or 
greater probability to observe at least 1 occurrence of an AE with event rates of 
% or greater. 
The sample size of 9, 36, and 12 participants exposed to active doses in Cohorts C1, D1, and D2, 
respectively, allow an 
% or greater probability to observe at least 1 occurrence of an AE with 
event rates of 
%, or greater, respectively.
Cohort C2 will expose 3 participants with polyQ-ALS to active treatment as part of additional 
dose escalation step specifically for participants with intermediate-repeat CAG expansions in 
ATXN2 gene as they may be more sensitive to the effects of BIIB105. The sample size of 3 was 
selected solely as precaution step before exposing participants with polyQ-ALS to 120 mg dose 
of BIIB105 in Cohort D2.
The sample size of Cohort D1 provides approximately 
% power to detect a 
% difference in 
the ratio to baseline in plasma NfL, in the BIIB105 versus placebo group, based on Cohort D1 
120 mg data (N on BIIB105 = 36) vs pooled placebo data across Cohorts A through D1 (N = 19), 
with 2-sided % significance level, assuming 
% SD in both groups. 
Part 2: 
The sample size of Part 2 is based on the sample size of Part 1. Up to approximately 98 
participants will be dosed in Part 2.

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14.
ETHICAL REQUIREMENTS
The Sponsor, any contracted third party, 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 Investigators are responsible for demonstrating timely oversight of all clinical study data 
from their site, including data external to the electronic data capture system, such as laboratory, 
imaging, and electronic clinical outcomes assessment data. Investigators must approve all their 
data on completed CRFs by signing electronically, at the participant, visit, or casebook level, at 
any time prior to an interim lock or database lock, as well as before any subsequent re-lock. The 
electronic data capture system does not prohibit Investigator approval or signing in any way.
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. The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
14.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
14.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study. The Sponsor will submit documents on behalf of the 
study sites in countries other than the United States.
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
the Sponsor. After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Sponsor 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 participant 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.

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At the completion or termination of the study, the study site must submit a close-out letter to the 
ethics committee and the Sponsor.
14.3.
Changes to Final Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law. Protocol modifications that affect participant safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study. If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a participant. In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 14.4).
14.4.
Informed Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, informed consent with the approved ICF must be obtained. 
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 and/or 
the participant’s legally authorized representative. The participant and/or the participant’s legally 
authorized representative must be given sufficient time to consider whether to participate in the 
study.
A copy of the signed and dated ICF must be given to the participant and/or the participant’s 
legally authorized representative. The original 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 and copies of the signed and dated ICFs.
Confirmation of informed consent must also be documented in the participant’s medical record.
When additional information that may affect participants’ willingness to continue in the study 
becomes available, the Investigators will be notified in a timely manner, according to all local 
and applicable law. An updated ICF may be required.
The participant’s informants/caregivers must also provide written informed consent to participate 
in the study. The original forms will be managed and archived in the same manner as the 
participants’ ICFs, as described in Section 14.4.

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14.5.
Participant Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by applicable national and local privacy regulations 
(e.g., Protected Health Information 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. 
Study reports will be used for research purposes only. The participant will not be identified by 
name in CRFs, study-related forms, study reports, or any related publications. The Sponsor, its 
partners and designees, ethics committees, and various government health agencies may inspect 
the records of this study. Every effort will be made to keep the participant’s personal medical 
data confidential.
14.6.
Compensation for Injury
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws.
14.7.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor or
) with the participant before the participant makes a decision to participate in 
the study.
14.8.
Study Report Signatory
The Sponsor will designate one or more of the participating Investigators as a signatory for the 
study report. This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or participant enrollment; or by other factors 
determined to be relevant by the Sponsor.
14.9.
Registration of Study and Disclosure of Study Results
The Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.
The Sponsor also will notify, when required, the regulatory authorities and ethics committees 
about the completion or termination of this study and send a copy of the study synopsis in 
accordance with necessary timelines.

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14.10.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records. 
In addition, the Investigator must notify the Sponsor of any changes in the archival arrangements 
including but not limited to archival at an offsite facility or transfer of ownership if the 
Investigator leaves the site.

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15.
KEY ROLES AND STUDY GOVERNANCE COMMITTEES
15.1.
Vendors
The Sponsor will ensure oversight of any study-related duties and functions carried out on its 
behalf and will specify in writing all duties and functions that are transferred. 
15.1.1.
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study including but not limited to 
study initiation, management of SAE reports, monitoring, and data management.
15.1.2.
Interactive Response Technology
IRT will be used in this study. Before participants are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system.
15.1.3.
Electronic Data Capture
Participant information will be captured and managed by study sites on electronic CRFs by a 
web-based electronic data capture tool configured by Sponsor and hosted by Metadata.
15.1.4.
Digital Clinical Outcomes Data Capture
Participant information, including 
 and ventilation diary 
logs, will be captured electronically to assess clinical outcomes. 
15.1.5.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by the Sponsor to analyze all hematology, coagulation 
testing, blood chemistry, and urine samples collected for this study, except for urine pregnancy 
tests and CSF, which will be analyzed by a local laboratory; repeat coagulation test will be 
analyzed by either the local laboratory or the central laboratory. A central laboratory will be 
utilized to test/confirm polyQ status for participation in Cohorts C2 and D2. 
PK samples will be analyzed at a laboratory selected by the Sponsor. Duplicate PK samples will 
be collected in case the original sample is lost, damaged, or not evaluable.
The central laboratory will also receive, track, and ship all blood samples for specialized 
genotyping, PK and PD biomarker analysis, 
 
, and CSF samples for PK and PD biomarker analysis, including aliquots from these 
samples, retained as backup in case original samples are lost or not evaluable. Residual blood 
samples for future DNA testing will be processed to purify DNA and stored by the central 
laboratory.

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15.1.6.
Central Facility for Other Assessments
A central facility has been selected by the Sponsor to read and interpret all 12-lead ECGs for this 
study.
15.2.
Study Committees
15.2.1.
Safety Surveillance Team
The Sponsor’s SST will serve as the study committee. The composition of the SST will follow 
Sponsor standard operating procedures. The SST, as described in Section 5.3, is responsible for 
reviewing the safety and PK data prior to dose escalation and at regular intervals in Part 2 and 
determining whether SAEs and clinically significant AEs result in cohort or study suspension.

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16.
ADMINISTRATIVE PROCEDURES
16.1.
Study Site Initiation
The Investigator must not screen any participants prior to completion of a study site initiation 
visit. This initiation visit with the Investigator and other site staff, as appropriate, will include a 
detailed review of the protocol, study procedures, and study responsibilities.
16.2.
Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform onsite audits or inspections. The Investigator will 
be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.
16.3.
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 study site at regular intervals during the study and after the 
study has completed, as appropriate. A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of review. It also will provide the monitoring strategy, 
with emphasis on participant safety, data integrity, and critical data and processes.
During these visits, CRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved. Documentation of 
results will be provided to the Sponsor or designee in a timely fashion to allow follow-up and 
verification of compliance with the monitoring plan. Remote evaluation of data (centralized 
monitoring) 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 the protection of participant rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the study site and its facilities.

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16.4.
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.
16.5.
Publications
Details are included in the clinical study agreement for this study.
16.6.
Public Health Emergencies
In the event of a public health emergency that results in site closure, travel restrictions, and/or the 
study being deprioritized at the site such that clinic visit(s) cannot occur, a protocol deviation 
would be incurred for any deviation from the protocol-specified visits and assessments, with 
additional notation that this protocol deviation is due to the public health emergency. If a 
protocol-specified clinical visit cannot occur because of a public health emergency, the following 
mitigating options should be pursued (if allowed per local regulations), in order of preference (in 
which the highest preference option that is feasible should be done): 1) transfer to another active 
study site that is open, 2) home visit, 3) telemedicine visit (e.g., by telephone or web conference), 
and 4) local laboratory visit. These mitigating options only apply in the setting of a public health 
emergency in which a protocol-specified clinic visit cannot occur and should not be pursued 
solely because of a participant’s preference. If the participant does not participate in one of these 
options, a Safety Telephone call must be conducted within 14 days of the last dosing visit.
A third-party vendor has been engaged to perform assessments at the study participant’s home, 
which may include but are not limited to:
•
Limited neurological examination
•
Physical examination
•
Vital signs
•
Height and body weight collection
•
•
•
•
C-SSRS
•
SVC
•
Biological sample collection

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•
Pregnancy test (if applicable)
•
HHD
•
Collection/shipment of ventilation diary records
The following assessments will be performed via telephone (telemedicine) by the site staff:
•
ALSFRS-R
•
Review of concomitant medications and AEs

Protocol 275AS101, Version 5
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Post N, Yu R, Greenlee S, et al. Metabolism and Disposition of Volanesorsen, a 2'-. Drug Metab 
Dispos. 2019;47(10):1164-1173. Epub 2019/07/26.
Scotter EL, Chen HJ, Shaw CE. Erratum to: TDP-43 Proteinopathy and ALS: Insights into 
Disease Mechanisms and Therapeutic Targets. Neurotherapeutics. 2015a;12(2):515-8.
Scotter EL, Chen HJ, Shaw CE. TDP-43 Proteinopathy and ALS: Insights into Disease 
Mechanisms and Therapeutic Targets. Neurotherapeutics. 2015b;12(2):352-63.
Shefner JM, Liu D, Leitner ML, et al. Quantitative strength testing in ALS clinical trials. 
Neurology. 2016;87(6):617-24. Epub 2016/07/06.
Sproviero W, Shatunov A, Stahl D, et al. ATXN2 trinucleotide repeat length correlates with risk 
of ALS. Neurobiol Aging. 2017;51:178.e1-178.e9. Epub 2016/11/24.
Writing Group, Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in 
well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-
controlled trial. Lancet Neurol. 2017;16(7):505-512. Epub 2017/05/15.
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man 
of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein 
B-100. Drug Metab Dispos. 2007;35(3):460-8.

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18.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Phase 1/2 Multiple-Ascending-Dose Study With a Long-
Term Open-Label Extension to Assess the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Effect on Disease Progression of BIIB105 Administered Intrathecally to 
Adults With Amyotrophic Lateral Sclerosis With or Without PolyCAG Expansion in the ATXN-2 
Gene,” 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 (DD MMM YYYY)
_______________________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)

CONFIDENTIAL 
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Biogen MA Inc. 
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 275AS101 
A Phase 1/2 Multiple Ascending Dose Study With a Long-Term Open-Label Extension to 
Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Effect on Disease 
Progression of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral 
Sclerosis With or Without PolyCAG Expansion in the ATXN2 Gene 
Version 5.0 
Date: 07 September 2023 
EUDRA CT Number: 2020‐000207‐36 
Version 5.0 of the protocol has been prepared for this amendment, which supersedes Version 4.0. 
 

Amendment Summary for Protocol 275AS101, Version 5.0 
 
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 275AS101 is to add a new clinical drug 
product presentation. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 7.3, Study Treatment 
Now reads: 
BIIB105 is supplied as a sterile, buffered, and isotonic solution in single-use clear vials 
containing 
 mg/mL of study treatment witheither at a concentration of 
mg/mL and a 
targeted volume of 
 mL per vial to ensure a deliverable volume maximum withdrawal of 
 mL for withdrawal from the vial and dose preparation, or at a concentration of mg/mL 
with a targeted volume of 
 mL per vial to ensure maximum withdrawal of 
mL for 
dose preparation (once this presentation is available for use at clinical study sites). This is 
accompanied by 
 to be used as diluent where needed. Both BIIB105 and 
 vials 
are sealed with a butyl rubber stopper and aluminum over seal with flip-off cap. 
Rationale: The protocol is being updated to reflect changes in the BIIB105 manufacturing 
process. The manufacturing changes affect the study drug product presentation (concentration 
and volume) but do not have any impact on the final formulation of BIIB105 administered to 
study participants.  
 
 
 

Amendment Summary for Protocol 275AS101, Version 5.0 
 
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3 
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 5.2.2, Study Duration for Participants in Part 2 
Change: Extended the maintenance dosing portion of the treatment period of Part 2 by up to 
approximately 52 weeks. The treatment period will be followed by the safety follow-up period as 
already defined in the protocol. 
Now reads: 
Study duration for each participant in Part 2 will be up to approximately 120172 weeks: 
• Screening Period of up to 4 weeks (for participants from Cohorts D1 and D2, 
Screening Period begins with Day 169 Visit of Part 1) 
• Treatment Period of up to approximately 156 weeks: either 104 weeks, OR until 
the last participant enrolled has had the opportunity for their Part 2 Day 365 
visit (Week 52), whichever occurs later  
• Follow-up Period of approximately 12 weeks 
Participants will have up to 31approximately 44 CVs and 3043 TCs during Part 2 of the study, 
which will include at least 1 Screening Visit, up to 28approximately 41 Dosing Visits, 2 
Follow-Up Visits, and up to 3043 TCs.  
Rationale: The extension in study duration is intended to enable generation of longer-term 
safety and efficacy data and continued access to study drug for study participants until after the 
Part 1 final analysis has been completed.  
This change also affects Figure 1, Study Design; Section 5.1.2, Study Overview Part 2; Section 
5.3.2, Dosing Part 2; and Section 7.1, Regimen.  
Section 5.4.2, Dose Termination 
Change: Amended dose termination rules, including lifting them if SST review of Cohort D1 
data supports continued dosing at the highest dose level. 
Now reads:  

Amendment Summary for Protocol 275AS101, Version 5.0 
 
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4 
After evaluation of safety, tolerability, and PK data by the SST, Investigator, 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: 
• TwoThree similar SAEs (unless related to disease progression or unrelated to 
BIIIB105 upon medical review) are reported for participants receiving active study 
treatment within the same cohort. 
• ThreeFour or more similar AEs are reported for participants receiving active study 
treatment (unless related to disease progression or unrelated to BIIIB105 upon 
medical review) that are either not tolerable (as reported by the participant) or 
deemed a medically unacceptable risk by the SST. 
• Sponsor requests that dosing be terminated. 
Following the SST review of safety and PK data for Cohort D1 (Part 1), if there is 
agreement that the current emerging safety, tolerability, and PK data support 
continued dosing at 120 mg, the abovementioned dose termination rules will no 
longer apply. The Sponsor may still determine that a dose termination is required at 
any time due to emerging safety data. 
Rationale: These changes update the scope and implementation of dose termination rules to 
reflect changes in study design from previous protocol amendments (Protocol Versions 3.0 and 
4.0), as follows:  
Increase in number of similar SAEs or AEs reported in participants receiving active study 
treatment to trigger dose termination: 
This change reflects the increase in sample size with Protocol Version 4.0 (addition of 28 
participants in Cohort D1, which increases the total number of participants in the 120 mg cohorts 
from 38 to 66).  
End of dose termination rules after final SST review of Cohort D1 (Part 1): 
This change aligns the dose termination rules with the cohort suspension rules, which were 
amended in Protocol Version 3.0. 
With Protocol Version 3.0, the original study design (3-month first-in-human, placebo-controlled 
MAD study) expanded to become a 3- to 6-month placebo-controlled MAD study (Part 1) 
followed by a 2-year open-label long-term extension (Part 2). Therefore, Section 5.4.1 was 
amended to specify that the cohort suspension rules no longer apply if the SST agrees with 
continued 120 mg dosing after the final SST evaluation of Cohort D1 (Part 1), which assesses the 
benefit/risk profile of BIIB105 at the top dose in the study.   
At the time of Protocol Version 3.0, the dose termination rules were not amended alongside the 
cohort suspension rules. However, the rationale for lifting the cohort suspension rules after the 

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8 
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 2, List of Abbreviations, was updated. 
• Typographical errors and formatting were corrected. 
• Table 2, Part 1 Schedule of Activities: Cohort D1 and D2: Footnote 4 was updated to 
include all TCs on days after nondosing LPs. 
• Table 3, Schedule of Activities Part 2 (all Cohorts): New footnote 3 was added to 
clarify that TCs are only required after days on which an LP was performed. Also, the 
list of Maintenance Dose days was expanded to cover the new study duration, and a 
3-day window was added for Dose 1 to reduce the risk of protocol deviation.Section 
4, Study Objectives and Endpoints: An additional survival analysis was added to the 
 Endpoints.Section 5.1.2, Study Overview Part 2: SST review of Part 1, 
Cohort D2 data was added as a requirement for increasing Part 2 60 mg doses to 120 
mg. 
• Section 5.3.1, Dose Escalation Part 1: Added clarification that in the event of early 
study termination, a final SST will be held for Cohort D1 with all available safety 
data. 
• Section 6.2.1, Exclusion Criteria Part 1: Updated exclusion criterion 21 to clarify that 
the benchmark is completion (not initiation) of Screening. 
• Section 7.2, Study Treatment Management: Removed statement that the DHA 
supersedes all other references. 
• Section 7.7.1.1, Allowed Concomitant Therapy: Clarified that riluzole and edaravone 
should not be initiated in Part 1. 
• Section 7.7.1.2, Disallowed Concomitant Therapy: Called out sodium phenylbutyrate 
and taurursodiol specifically. 
• Section 13.3.1.1, Adverse Events: Added a rationale for summarizing exposure-
adjusted incidence rates 
 

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9 
LIST OF ABBREVIATIONS 
aCSF 
artificial cerebrospinal fluid 
ADA 
anti-drug antibody 
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
CAG 
cytosine-adenine-guanine 
CV 
clinic visit 
DHA 
Directions for Handling and Administration 
LP 
lumbar puncture 
MAD 
multiple ascending dose 
PK 
pharmacokinetic(s) 
polyQ 
polyglutamine 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SST 
safety surveillance team 
TC 
telephone contact 
 

Amendment Summary for Protocol 275AS101, Version 4.0
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1
Biogen MA Inc.
225 Binney Street
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United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 275AS101
A Phase 1/2 Multiple-Ascending-Dose Study With a Long-Term Open-Label Extension to 
Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Effect on Disease 
Progression of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral 
Sclerosis With or Without Poly-CAG Expansion in the Ataxin-2 Gene 
Version 4.0
Date: 09 September 2022
EUDRA CT Number: 2020‐000207‐36
Version 4.0 of the protocol has been prepared for this amendment, which supersedes Version 3.0.

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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 275AS101 is to increase the sample size in 
Cohort D1 from n = 20 to n = 48. 
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 13.5, Sample Size Considerations
Now reads: 
Part 1: 
The sample size of this first-in-human clinical study was selected with the goal of balancing 
between safety and tolerability considerations in dose escalation and obtaining sufficient initial 
information related to the safety and biological activities of BIIB105. Sample sizes of 
6 participants receiving active treatment in lower dose Cohorts A and B will allow an 
% or 
greater probability to observe at least 1 occurrence of an AE with event rates of 
% or greater. 
The sample size of 9, 1536, and 12 participants exposed to active doses in Cohorts C1, D1, and 
D2, respectively, allow an
% or greater probability to observe at least 1 occurrence of an AE 
with event rates of 
%, or greater, respectively.
…
The sample size also allows for an estimate of Cohort D1 provides approximately 
% power 
to detect a 
% difference in the reduction of 120 mg of ratio to baseline in plasma NfL, in 
the BIIB105 versus placebo in CSF ATXN2 proteingroup, based on Cohort D1 120 mg data (N 
= 15) andon BIIB105 = 36) vs pooled placebo data across Cohorts A, B, C1, and through D1 (N 
= 12) = 19), with a precision such that the width of the 2-sided % significance level, assuming 
% SD in both groups 95% CI is within 
-fold of the geometric mean of active to 
placebo ratio in -month fold change from baseline. For example, if the observed geometric 
mean active to placebo ratio is 
 (i.e., 
% reduction), the 95% CI would be (
). 
Part 2: 
The sample size of Part 2 is based on the sample size of Part 1. Approximately 70Up to 
approximately 98 participants will be dosed in Part 2.
Rationale: The sample size increase will increase the study’s power to investigate the safety, 
tolerability, PK, and effect on disease progression of 120 mg BIIB105 in ALS. 
This change also affects Figure 1, Study Design; Section 5.1.1, (Study Overview) Part 1; and 
Section 5.3.1, Dose Escalation (Part 1). 

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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.
Protocol Title
Change: Detail about the study structure, objectives, and phase was added.
Now reads: 
A Phase 1/2 Multiple-Ascending-Dose Study With a Long-Term Open-Label Extension to 
Assess the Safety, Tolerability, and Pharmacokinetics, Pharmacodynamics, and Effect on 
Disease Progression of BIIB105 Administered Intrathecally to Adults With Amyotrophic 
Lateral Sclerosis With or Without Poly-CAG Expansion in the Ataxin-2 Gene
Rationale: The long-term OLE (Part 2) was not reflected in the title and evaluating the 
biomarker effect of BIIB105 is elevated to a secondary objective. Therefore, the overall phase of 
development of the study and title of the study were changed to reflect the study design, elevated 
objective, and related endpoints.  
This change also affects Section 3.1, Study Rationale; Section 5.1, Study Overview; Section 18, 
Signed Agreement of the Study Protocol; and page headers. 
Section 1.1, Synopsis
The synopsis was revised to reflect changes made throughout the protocol.
Section 3.2.2, Current Therapies for ALS
Change: Information on a newly approved ALS therapy was added.
Now reads: 
There are no effective drug therapies to cure or substantially moderate functional decline or 
improve survival. Two treatments are currently approved for ALS. 
Available treatments for ALS include riluzole, edaravone, and sodium phenylbutyrate and 
ursodoxicoltaurine, with approvals varying by region. Each has demonstrated modest 
effects on disease progression.
… 

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In a 6-month randomized study in the United States, patients with ALS who received a 
combination of sodium phenylbutyrate and ursodoxicoltaurine demonstrated less decline in 
ALSFRS-R scores over 24 weeks compared with patients who received placebo [Paganoni 
2020]. The mechanism of action of sodium phenylbutyrate in ALS is unknown, but its 
pharmacological activities include histone deacetylase inhibition and upregulation of heat 
shock proteins. The mechanism of action of ursodoxicoltaurine in ALS is also unknown, 
but its pharmacological activities include reduction of mitochondrial permeability.
Rationale: Updated to reflect current ALS therapy approvals in regions where the study is 
running.
Section 3.2.3.1, Nonclinical Experience
Change: Newly available data from fertility and fetal toxicity studies were summarized.
Now reads: 
BIIB105 is not a genotoxicant as negative results were observed in the bacterial reverse 
mutation, in vitro chromosomal aberration, and in vivo rat micronucleus assays at limit 
concentrations/doses.
In a fertility study, there were no BIIB105-related effects on sperm concentration or 
morphology in male mice. In female mice, there were no BIIB105-related effects on female 
reproductive parameters, estrous cycle length, or precoital intervals. The NOAEL for 
reproductive toxicity was 
 mg/kg/dose. The corresponding serum exposure was a mean 
Cmax of 
 µg/mL and a mean AUC0-24 of 
 µg*h/mL after repeat dosing in males. The 
exposures in pregnant females were a mean Cmax of 
 µg/mL and a mean AUC0-24 of 
 µg*h/mL on GD 
.
In mice, BIIB105 did not result in any effects on embryo-fetal survival. A statistically 
significantly lower mean fetal weight was observed at 
mg/kg/day and was considered 
adverse. BIIB105 did not produce any fetal external, visceral, or skeletal malformations or 
variations in mice. The NOAEL for developmental toxicity in mice was considered to be 
mg/kg/dose, which corresponded to a mean Cmax of 
 µg/mL and a mean AUC0-24 of 
µg*h/mL in females. Fetal exposure, based on BIIB105 concentrations in liver, was 
approximately 
 times lower than the maternal Cmax.
A dose level of 
 mg/kg/dose was considered to be the NOAEL for maternal toxicity and 
embryo-fetal development when BIIB105 was administered via SC injection to New 
Zealand White rabbits. This dose level was associated with a mean serum Cmax of 
 µg/mL and a mean AUClast of 
 µg*h/mL on GD 
. There was no detectable 
BIIB105 in fetal livers in rabbit.

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Rationale: New reproductive toxicity nonclinical studies identified reproductive and 
developmental toxicity. These summaries were added to better inform potential safety risks. 
This change also affects Section 3.3, Benefit-Risk Assessment.
Section 3.3, Benefit-Risk Assessment
Change: References to new nonclinical reproductive and developmental toxicity data and 
emerging clinical data from the ongoing study were added to the Benefit-Risk Assessment, and a 
Sponsor position on the benefit-risk profile was added.
Now reads:
Participants are not expected to receive therapeutic benefit from participation in the study. The 
potential benefit of BIIB105 in ALS has not been established. This The study has been 
designed with appropriate dose escalation, safety monitoring, and stopping rules to minimize 
risks to participants. The results of this study may offer key insights into the development of a 
disease-modifying therapy for ALS.
This is a first in human study, thus the risk in humans is unknown. Emerging clinical data can 
be found in the Investigator’s Brochure.
…
ALS is a debilitating, rapidly progressing, and life-threatening disease with a high unmet 
need for effective therapies. Overall, the benefit-risk profile is positive for the continued 
clinical development of BIIB105 for the treatment of ALS and polyQ-ALS.
Detailed information about the known and expected benefits and risks of BIIB105 is provided in 
the Investigator’s Brochure and ICF. A high-level summary of those benefits and risks known 
during study design is provided here.
Rationale: These changes provide the Sponsor's position on the benefit-risk of developing 
BIIB105 for ALS and polyQ-ALS in the context of updated nonclinical data and emerging 
clinical safety data.
Section 4, Study Objectives and Endpoints
Change: CSF PK and plasma NfL were elevated from 
 to secondary endpoints. PD 
and biomarker endpoints were split out. Objectives and endpoints were separated out by study 
part (Part 1, Part 2) and prospectively defined for the integrated analyses (Integrated Part 1 and 
Part 2).

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Now reads:
Part 1
Primary Objective
Primary Endpoint
To evaluate the safety and 
tolerability of BIIB105 in 
participants with ALS or 
polyQ-ALS.
Incidence of AEs and SAEs in Part 1.
Secondary Objective
Secondary Endpoints
To assess the PK profile of 
BIIB105 in serum and CSF of 
participants with ALS or 
polyQ-ALS.
Serum and CSF concentrations of BIIB105 in Part 1.
To evaluate the following serum PK parameters in Part 
1:
•
AUCinf 
•
AUClast
•
Cmax
•
Tmax
•
t½
To evaluate the biomarker effect 
of BIIB105 in participants with 
ALS or polyQ-ALS.
Secondary biomarker measure:
•
Changes from baseline in plasma levels of NfL 
in Part 1
Exploratory Objectives
Exploratory Endpoints
To evaluate the PK profilePD 
effect of BIIB105 in the CSF of 
participants with ALS or polyQ-
ALS.
Exploratory PD measure:
•
Change from baseline in CSF 
concentrationslevels of BIIB105ATXN2 
protein in Part 1.

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Part 2 
Primary Objective
Part 2 Primary Endpoint
To evaluate the long-term safety 
and tolerability of BIIB105 in 
participants with ALS or 
polyQ-ALS.
Incidence of AEs and SAEs in Part 2.

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Integrated Part 1 and Part 2
Primary Objective
Primary Endpoint
To evaluate the long-term safety 
and tolerability of BIIB105 in 
participants with ALS or polyQ-
ALS.
Incidence of AEs and SAEs during the BIIB105-
treated period in Part 1 and/or Part 2.
Secondary Objective
Secondary Endpoints
To assess the long-term PK profile 
of BIIB105 in serum and CSF of 
participants with ALS or 
polyQ-ALS.
Serum and CSF concentrations of BIIB105 in Part 1 
and Part 2.
•
CSF trough PK concentration
•
Serum PK concentration if available
To evaluate the long-term 
biomarker effect of BIIB105 in 
participants with ALS or polyQ-
ALS, and to assess the impact of 
earlier initiation of BIIB105 (i.e., at 
start of Part 1) compared with 
delayed initiation of BIIB105 (i.e., 
at start of Part 2) on biomarkers.
Secondary biomarker measure:
•
Changes from Part 1 baseline in plasma 
levels of NfL 
To evaluate the long-term effect of 
BIIB105 on measures of clinical 
function and to assess the impact of 
earlier initiation of BIIB105 (i.e., at 
start of Part 1) compared with 
delayed initiation of BIIB105 (i.e., 
at start of Part 2) on measures of 
clinical function.
Changes from Part 1 baseline in the following 
assessments:
•
SVC
•
ALSFRS-R score
•
Muscle strength, as measured by HHD
Survival analyses:
•
Time to death or permanent ventilation 
(≥ 22 hours of mechanical ventilation 
[invasive or noninvasive] per day for ≥ 21 
consecutive days)

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•
Time to death
•
Time to death, incorporating post-study 
withdrawal or study completion vital 
status data
Exploratory Objectives
Exploratory Endpoints
To evaluate the long-term PD 
effect of BIIB105 in participants 
with ALS or polyQ-ALS, and to 
assess the impact of earlier 
initiation of BIIB105 (i.e., at start 
of Part 1) compared with delayed 
initiation of BIIB105 (i.e., at start 
of Part 2) on the PD measure.
Exploratory PD measure:
•
Change from Part 1 baseline in CSF 
levels of ATXN2 protein.
Rationale: Elevating CSF PK and plasma NfL to secondary endpoints better reflects the goals of 
the study. Reorganizing the endpoints and objectives by study part helps to clarify the analysis 
strategy. Prospectively designing an integrated analysis plan will enable evaluation of early-start 
versus delayed-start BIIB105.
This change also affects Section 3.1, Study Rationale.

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Section 5.3.1, Dose Escalation (Part 1)
Change: Safety surveillance team review criteria for Cohorts D1 and D2 were updated. 
Now reads:
For Cohort D1, the safety review will occur after the cohort is fully randomized, and at 
least 92 days have elapsed since the randomization and dosing of the 36th participant.  For 
Cohorts D1 and D2, the safety review for each cohort will occur after the cohort is fully 
randomized, and at least 92 days after the randomization of the 12th participant. The SST will 
review all available blinded safety data from all randomized participants in the cohort, which 
must include a minimum of 1233 evaluable participants (those who completed all of the first 5 
dosing visits as well as the Day 92 clinic visit) in each cohort. This review will be for a final 
safety review for Cohorts D1 and D2.
For Cohort D2, the safety review will occur after the cohort is fully randomized, and at 
least 92 days after the randomization of the 15th participant. The SST will review all 
available blinded safety data from all randomized participants in the cohort, which must 
include a minimum of 12 evaluable participants (those who completed all of the first 5 
dosing visits as well as the Day 92 clinic visit). This review will be for a final safety review 
for Cohort D2. Should Part 1 be terminated early (per Section 5.2.1 and Section 13.4) prior 
to reaching randomization of the entire D2 cohort or minimal evaluable criteria as defined, 
a final safety SST will be held for Cohort D2 with all available safety data at the time of 
Part 1 termination.
Cohorts D1 and D2 can be reviewed concurrently or in separate SSTs, depending on when the 
cohorts have reached the minimum evaluable patients.
Principal Investigators from sites where participants were dosed will be included in the blinded 
safety data review. Review of blinded safety data may be followed by review of unblinded safety 
data of the current and preceding cohorts by the SST. Details of the unblinded review as well as 
the personnel to be unblinded to support dose escalation will be clearly defined in the Dose 
Escalation Plan and Unblinding Plan for this study.
In addition to the review of all safety data, there will be a review of available PK data collected 
through the third dose prior to dosing of the next dose cohort for Cohorts A, B, C1, and C2.  For 
Cohorts D1 and D2, there will be a review of all available PK data for a minimum of 1233 
evaluable participants. For Cohort D2, there will be a review of all available PK data for a 
minimum of 12 evaluable participants. Should Part 1 be terminated early (per Section 5.2.1 
and Section 13.4) prior to reaching randomization of the entire D2 cohort or minimal 
evaluable criteria as defined, a final safety SST will be held for Cohort D2 with all available 
PK data at the time of Part 1 termination.
Rationale: Criteria to initiate the SST safety review for Cohort D1 was updated to reflect the 
increased sample size for this cohort. The criteria to initiate the SST safety review for Cohort D2 

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was corrected to reflect that at least 15 participants, not 12, should be randomized before the SST 
is held. 
Section 6.1.2, (Inclusion Criteria) Part 2
Change: ICF requirements were updated. 
Now reads:
1. Ability of the participant to review the initial informed consent completed in Part 1, 
understand the purpose and risks of the study and indicate continued informed consent, 
and the ability of the participant or the participant’s legally authorized 
representative to provide signed and dated informed consent.  and authorization to 
use protected health information in accordance with national and local privacy 
regulations.
Rationale: A separate ICF will need to be signed for Part 2.
Section 6.2.1, (Exclusion Criteria) Part 1
Change: The minimum prescreening ALFRS-R slope requirement was removed for Cohort D1. 
Now reads:
19. In participants in Cohorts A, B, and C1, pPrescreening ALSFRS-R slope > -0.4 
points/month, where prescreening ALSFRS-R slope is defined as follows: (ALSFRS-R 
score at Screening – 48) / (months from date of symptom onset to date of Screening) in 
participants from Cohorts A, B, C1, and D1. This criterion is not applicable for 
Cohorts C2, D1, and D2.
Rationale: The original intent of this exclusion criterion was to enrich the study population for 
faster-progressing participants, but ALSFRS-R prescreening slope has not been found to 
accurately predict disease progression due to nonlinear progression on the scale. Therefore, this 
exclusion criterion has been removed to allow participants who would otherwise be eligible to 
participate in the study.
Section 6.2.1, (Exclusion Criteria) Part 1
Change: A new exclusion criterion was added to restrict allowable ALS treatment for study 
participants. 

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Now reads:
21. Treatment with an approved disease-modifying therapy for ALS other than riluzole 
or edaravone within 1 month or 5 half-lives of therapy, whichever is longer, before 
Screening.
Rationale: This change ensures that the concomitant disease-modifying medications for ALS 
that are allowed in Study 275AS101 Part 1 are consistent for all cohorts, to enable pooling of 
placebo data from participants across cohorts for analysis.
This change also affects Section 7.7.1.2, Disallowed Concomitant Therapy.
Section 6.2.2, (Exclusion Criteria) Part 2
Change: Language was added to permit participants who contracted HIV, HBV, or HCV during 
Part 1 to continue into Part 2 if appropriate. 
Now reads:
1. History or positive test result at Screening for HIV. The requirement for testing at 
Screening may be omitted if it is not permitted by local regulations. If participants from 
Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive 
for HIV during screening for Part 2 but are clinically asymptomatic, they may 
enroll in Part 2 at the discretion of the Investigator.
2. Current hepatitis C infection (defined as positive HCV antibody and detectable HCV 
RNA). Participants with positive HCV antibody and undetectable HCV RNA are eligible 
to participate in the study. If participants from Cohorts D1 and D2 who would 
seamlessly roll from Part 1 into Part 2 test positive for hepatitis C during screening 
for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the 
discretion of the Investigator.
3. Current hepatitis B infection (defined as positive for HbsAg and/or total 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. If participants from Cohorts D1 and D2 who would seamlessly roll from 
Part 1 into Part 2 test positive for hepatitis B during screening for Part 2 but are 
clinically asymptomatic, they may enroll in Part 2 at the discretion of the 
Investigator.
Rationale: As participants in Cohorts D1 and D2 are anticipated to roll over seamlessly into the 
OLE, participants from these cohorts who happen to contract HIV, hepatitis B, or hepatitis C 
during Part 1 of the study and have been followed through Part 1 of the study and remain 

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asymptomatic could have the option of continuing into the OLE at the discretion of the 
Investigator. 
Section 6.3.3, Screen Failures
Changes: Language was updated to allow re-use of screening assessments that will not change 
over time.
Now reads:
Screen failures are defined as participants who sign the ICF but are not subsequently 
randomized. If a participant is considered a screen failure, the reasons for exclusion must be 
documented in the participant’s source documents and on the screening log. Participants who fail 
screening may be permitted to be rescreened once at the Investigator’s discretion after discussion 
with the Sponsor. 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 this study
•
For participants in Cohorts C2 or D2, confirmation of intermediate (30 to 33) 
CAG/CAA repeats in at least 1 allele in the ATXN2 gene by the central laboratory, if 
available from previous screening for this study.
Rationale: This change reduces participant burden and length of wait time between rescreening 
and Day 1 by allowing use of prior screening laboratory results that will not change over time 
(postmenopausal status, genetic testing) for rescreening purposes.
Section 11.2.11, Collection of Vital Status After Study Withdrawal and Completion
Changes: Language was added to permit optional collection of vital status.
Now reads:
11.2.11
Collection of Vital Status Before and After Study Withdrawal and 
Completion
Participants’ vital status will be collected throughout the study. For participants who 
provide optional consent for data collection after study withdrawal or completion, follow-
up on vital status and date of death (if deceased) will be performed.
Rationale: This change corrects an error in protocol version 3, where this data collection was 
added to the protocol but not to the list of assessments.

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Incidence of clinically relevant abnormalities and changes from baseline in ECGs will be 
summarized using frequency tables and descriptive statistics. 
…
Serum and CSF BIIB105 concentrations will be summarized using descriptive statistics and, 
where warranted, plotted graphically over time both on linear and logarithmic scales. For Part 1, 
summaries of BIIB105 PK parameters will also be summarized using descriptive statistics.
For analyses of Part 1, PK data will be summarized by dose level in Part 1 (BIIB105-
treated Cohorts A, B, C1 + C2, and D1 + D2). For integrated data from Part 1 and Part 2, 
PK data for BIIB105-treated periods in Part 1 and Part 2 will be summarized by the 60 mg 
dose level in Part 1, 60 mg dose level in Part 2, 120 mg dose level in Part 1, and 120 mg dose 
level in Part 2. 
…
Similar analyses will also be performed for other biomarkers in the plasma, serum, and/or CSF, 
which may include but are not limited to NfL 
. For analyses of Part 1, data will be 
analyzed in a similar way as specified for clinical function endpoints. For analyses of 
integrated data from Part 1 and Part 2, data will be analyzed in a similar way as specified 
for clinical function endpoints.  
13.3.4     Clinical Function and Quality of Life Measures
The actual scores and changes from baseline in each measure will be summarized using 
descriptive statistics. Missing data will be imputed using multiple imputation. Multiple 
imputation will be performed on actual values, domains, total scores, or summary scores 
depending on the endpoint. In addition, each clinical function measure maywill be analyzed 
using a mixed-effects repeated-measuresan ANCOVA model. The model may include dose 
group, visit, treatment-by-visit interaction, andcovariates such as corresponding baseline score. 
Additional covariates may be included in the model for age, sex, baseline NfL, duration from 
onset of symptoms to the first dose of study treatment, and site of onsetriluzole or edaravone 
use. The model will be used to estimate least-square (LS) means for each treatment group 
with standard errors (SEs), and LS mean differences between treatment groups with 
corresponding 95% confidence intervals (CIs). The p-values comparing treatment 
differences will also be presented.
Cohorts C2 and D2 are a genetically defined subpopulation with potentially faster disease 
progression, and their data will be analyzed separately for clinical function and quality of life 
measures. For analyses of Part 1, clinical function data will be presented by cohort and 
treatment assignment in Part 1 (BIIB105-treated Cohorts A, B, C1, C2, D1, and D2; Pooled 
Placebo 1 and Pooled Placebo 2). For integrated analyses of Part 1 and Part 2, clinical 
function data will be presented by cohort (Cohort A + B + C1, Cohort C2, Cohort D1, and 
Cohort D2). Within these cohorts, the treatment groups will be defined as: Early-start 

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BIIB105 (i.e., those who initiated BIIB105 in Part 1) and Placebo/Delayed-start (i.e., those 
who received placebo in Part 1) with baseline defined as Part 1 baseline. 
13.3.5     Time to Death or Permanent Ventilation, Time to Death
Time to death or permanent ventilation (i.e., ≥ 22 hours of mechanical ventilation [invasive or 
noninvasive] per day for ≥ 21 consecutive days) and time to death will be summarized using 
Kaplan-Meier curves based on the starting time using the following:
1. Entry intoRandomization in Study 275AS101 Part 1
2. Time of symptom onset
For time to death or permanent ventilation, and time to death, the median and percentiles 
and associated 95% confidence limits will be presented. P-values from log rank test and 
Cox regression model will be presented with the hazard ratio. The Cox model may include 
covariates such as corresponding baseline score, baseline NfL, duration from onset of 
symptoms to the first dose of study treatment, and riluzole or edaravone use. The log-rank 
test may be stratified by median baseline NfL. 
Post-withdrawal or study completion vital status data will also be incorporated into a 
separate analysis of time to death.
 For analysis of 
integrated data from Part 1 and Part 2, data from all cohorts will be analyzed.
Rationale: These changes provide additional detail about planned analyses.
Section 13.4, Interim Analyses
Changes: Language was added to describe early-termination scenarios and permit additional 
interim analyses.
Now reads:
One or more interim analyses of unblinded key safety, secondary, and 
 endpoints 
(including PK, PD, clinical function) may be conducted following the completion of dosing of 1 
or more dose cohorts in Part 1, to allow for the confirmation of dose escalation decisions and/or 
to inform decisions on the BIIB105 clinical development program.
If, based on an interim analysis of Cohort D1 Part 1, the Study Sponsor decides to 
terminate Part 1 of the study for Cohort D2 without terminating Part 2, Cohort D2 
participants who are active in Part 1 at the time of the Sponsor’s decision will have the 
opportunity to end Part 1 and screen and enroll into Part 2. In this scenario, participants 

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screening for Part 2 will not have to meet Section 6.1.2 Part 2 Inclusion Criterion #2 
(having completed Part 1 through Week 25) to be eligible for Part 2.
Additional interim analyses may be performed during the conduct of Part 2, using data 
from Part 2 alone and/or integrated data from Part 1 and Part 2. Specifics will be detailed 
in the statistical analysis plan.
Rationale: This change provides an opportunity for Part 1 participants to continue to Part 2 even 
if an interim analysis leads to termination of Part 1.
This change also affects Section 5.2.1, Study Duration for Participants in Part 1; Section 5.6, End 
of Study; and Section 6.1.2, (Inclusion Criteria) Part 2.

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
Footnote 10 was updated to accommodate participants who may not physically be 
able to lay supine for 5 minutes.

Footnotes 14, 16, 17, and 18 were updated to allow certain predose activities to be 
done up to 24 hours prior to LP.

Footnote 23 was updated to clarify that clinical laboratory samples should be 
collected predose; also, lipid panel and HbA1c should be collected at Screening.
•
Section 3.1.2, Rationale for Starting Dose and Maximum Exposure (and throughout 
protocol), text was updated to reflect that recovery data are available for the 41-week 
NHP toxicology study.
•
Table 4, Predicted ATXN2 mRNA Reduction (Cortex and Spinal Cord), ATXN2 
protein reduction (CSF), and Safety Margins at Steady-state at Proposed Dose Levels; 
the second column (Total Number of Participants per Dose Level) was removed to 
avoid confusion. This information is not crucial to this table and is presented more 
clearly elsewhere in the protocol.
•
Section 15.2.1, Safety Surveillance Team: text was updated to reflect that the SST 
will additionally review the safety and PK data at regular intervals in Part 2 in 
addition to dose escalation in Part 1.

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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
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
ATXN2
ataxin-2 gene or RNA
ATXN2
ataxin-2 protein
AUC0-24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the concentration time curve from time 0 to infinity
AUClast
area under the concentration time curve from time 0 to time of the 
last measurable concentration
Cmax
maximum observed concentration
CSF
cerebrospinal fluid
ECG
electrocardiogram
FAS
full analysis set
FSH
follicle-stimulating hormone
GD
gestation day
HbA1c
hemoglobin A1c
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HHD
handheld dynamometry
HIV
human immunodeficiency virus
ICF
informed consent form
LP
lumbar puncture
NfL
neurofilament light chain
NHP
nonhuman primate
NOAEL
no observed adverse effect level
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
polyQ
polyglutamine 
RNA
ribonucleic acid
SAE
serious adverse event

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SC
subcutaneous
SST
safety surveillance team
SVC
slow vital capacity
t½
elimination half life
Tmax
time to reach maximum observed concentration

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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 275AS101 
 
A Phase 1 Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral 
Sclerosis With or Without Poly-CAG Expansion in the Ataxin-2 Gene  
Version 3.0 
Date: 18 November 2021 
EUDRA CT Number: 2020‐000207‐36 
Version 3.0 of the protocol has been prepared for this amendment, which supersedes Version 2.0. 
 

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PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 275AS101 is to extend the Treatment Period 
for Cohorts D1 and D2 from approximately 13 weeks to approximately 25 weeks, and to add a 
second part to the study (Part 2, open-label long-term extension).  
In Part 2, participants who complete 25 weeks in Part 1 of the study will receive up to 104 weeks 
of BIIB105, after which they will have an approximately 12-week Follow-Up Period.    
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 3.1, Study Rationale 
Now reads:  
Given the rapidly progressing, life-threatening, and rare nature of the disease as well as the high 
unmet medical need in ALS, the first-in-human Phase 1 study will be a MAD evaluation of 
BIIB105 in adult participants with ALS and polyQ ALS. two-part evaluation of BIIB105 in 
adult participants with ALS and polyQ-ALS. Part 1 will be a placebo-controlled MAD 
assessment of the safety, tolerability, and pharmacokinetics of BIIB105. Part 2 will be an 
extension study to assess the long-term safety, tolerability, pharmacokinetics, and effect on 
disease progression of BIIB105 in participants who complete Part 1 through Week 25 (Day 
175 Visit for Cohorts A, B, C1, and C2; Day 176 Visit for Cohorts D1 and D2). 
This study design will minimize the number of participants receiving subtherapeutic doses and/or 
dosing durations. The For all cohorts in Part 1, the 72-hour safety data review following 
sentinel dosing of the first 2 participants of each dosing cohort and the 7-day safety review for 
each participant after administration of the first dose and prior to administration of the second 
dose will allow evaluation of potential acute safety and tolerability findings in each participant 
prior to the administration of additional doses, similar to a single-ascending-dose study design. 
Part 2 will provide up to 104 weeks of dosing of BIIB105 for study participants who 
complete 25 weeks in Part 1. The safety, PK, PD, and clinical function data collected from 
Part 2 will allow for the understanding of the long-term effect of BIIB105 in participants 
with ALS and polyQ-ALS.  
Rationale: The Treatment Period duration was extended from 13 to 25 weeks in the 120 mg 
dose cohorts (Cohorts D1 and D2) to evaluate the longer-term safety of BIIB105 versus placebo 
and to enable detection of a biomarker and/or clinical effect of BIIB105 in adults with ALS and 
polyQ-ALS at this dose level. 
The long-term extension portion of the study (Part 2) was added to enable assessment of the 
long-term safety, tolerability, pharmacokinetics, and effect on disease progression of BIIB105 in 
adults with ALS and polyQ-ALS.  
There will be 2 dose levels in Part 2 of the study:  

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• Cohort A, B, C1, and C2 participants will receive 60 mg in Part 2.  
• Cohort D1 and D2 participants will receive 120 mg dosing in Part 2.  
This change also affects the Schedule of Activities, Tables 2 and 3; the Study Design Schematic; 
Section 5.1, Study Overview, Section 5.2, Study Duration for Participants; Section 5.3, Dosing; 
Section 6, Study Population; Section 6.3.1, Screening; Section 7, Study Treatment; Section 7.5, 
Precautions; Section 9.1, Clinical Assessments; and Section 13.5, Sample Size Considerations.  

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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Section 1.1, Synopsis 
The synopsis was revised to reflect changes made throughout the protocol. 
 
 

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Section 1, Schedule of Activities, Table 2, Part 1 Scheduled of Activities: Cohort D1 and D2 
 
Now reads: 
  
Screening1 
Dose 1 
(Inpatient) 
CV 
Dose 
2 
TC 
CV 
Dose 
3 
TC 
CV 
TC 
Doses 
4, 5, 6, 
7 
TC 
CV 
TC 
Dose 
8 
TC 
CV 
TC 
FU Period2 
UV 
CV 
TC 
Final/ 
ET 
Visit 
TC 
Days 
  
  
  
  
  
Assessments5 
-28 to -1 
1 
2 
8 
(±2) 
15 
(±3) 
16 
(+1) 
22 
(±3) 
29 
(±3) 
30 
(+1) 
36 
(±3) 
50 
(±3) 
57, 85, 
113, 
141 
((±3) 
58, 
86, 
114, 
142 
(+1) 
64, 
92, 
120, 
148 
(±3) 
78, 
106, 
134, 
162 
(±3) 
169 
(±3)3 
170 
(+1) 
176 
(±3) 
177 
(+1)4 
214 
(±3) 
215 
(+1) 
259 
(±3) 
260 
(+1) 
Predose 
Dosing/Postdose 
(24 ±1 h) postdose 
 
 

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Section 3.1.2, Rationale for Starting Dose and Maximum Exposure 
Change: New nonclinical study information was added. 
Now reads: 
A single-dose NHP toxicity study (P105-19-06) identified a maximum tolerated dose (
 mg) 
and reversible AEs at 
 mg, which can be monitored clinically. Specifically,  of  animals 
dosed at 
 mg exhibited increased muscle tone, whole body spasms, and tremors that required 
administration of diazepam. The animal fully recovered by 
 hours. Additional nonclinical NHP 
data was obtained from a 13-week study with  doses of BIIB105 administered at 
 mg 
and a 41-week study with 
 doses of BIIB105 administered at 
 mg. 
BIIB105 was tested in 2 pharmacologically relevant species: NHP and mouse. Because BIIB105 
produced no adverse effects at any of the dose levels used in the 
 repeat-dose GLP studies, the 
highest dose of each study was identified as the NOAEL. Specifically, the NOAEL for the 
13-week monkey IT study is 
 mg, the NOAEL for the 41-week monkey IT study is 
 mg 
(pending recovery data), the NOAEL for both the 14-week, and 26-week mouse SC study 
studies is 
 mg/kg, and the NOAEL for the 57-day mouse ICV study is 
 mg. The NHP was 
deemed the most sensitive species because dose-limiting effects were identified in a GLP 
single-dose NHP study at 
 mg, whereas no dose-limiting toxicities have been identified in the 
rodent studies. The At the time of selection of the starting dose for this study, the 13-week 
NHP study also provided the lowest HED, which was calculated to be 
 mg utilizing a CSF 
volumetric scaling factor of 10. This represents represented the most conservative estimate 
based on CSF volume ratio between humans and NHPs and as compared with the HED in the 
mouse ICV (
 mg) and mouse SC (
 mg or 
 mg/kg based on a 
 kg human) toxicity 
studies.  
Therefore, the selection of the starting dose for Part 1 of this study is based on the NOAEL dose 
of 
 mg, established in the 13-week toxicology study in cynomolgus monkeys, and on the 
expected PD of BIIB105 in the brain cortex and spinal cord. The HED value was divided by the 
conventional safety factor of 10 to yield the MRSD of 
 mg. The proposed  mg starting dose is 
below the MRSD, has a 
-fold safety factor over the HED (
 mg) of the NOAEL from the 
13-week toxicology study, and is expected to produce minimal to moderate pharmacologic 
effects in the brain and spinal cord.  
There were 2 chronic toxicology GLP studies conducted to support the dosing duration for 
Part 2 of this study. In the 41-week NHP study BIIB105 was administered IT (
 
 mg) on Days 
, then 
 until Day 
. The dosing period of the study has 
completed and recovery period is ongoing.  In the 26-week mouse study BIIB105 was 
administered SC (
 mg/kg/dose) every 
 from Day  through 
Day 
.  NOAEL for both of the studies was considered to be the highest dose tested 
(pending recovery data in the NHP study). The 41-week NHP chronic toxicology study 
provided the lowest HED, which was calculated to be 
 mg utilizing a CSF volumetric 
scaling factor of 10. These chronic toxicology studies support the proposed dose levels and 
dosing duration in the study. 

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… 
The predicted ATXN2 mRNA reductions in the target CNS regions and safety margins after 
 dose administrations at steady state at the proposed dose levels planned in this study are 
shown in Table 4. The MRSD of 
 mg is estimated to reduce ATXN2 mRNA levels 
approximately 
% in the cortex and approximately 
% in the spinal cord after  doses. 
reaching steady state. In consideration of the higher reduction of ATXN2 mRNA in the spinal 
cord, a starting dose of  mg is proposed, which is anticipated to reduce ATXN2 mRNA levels by 
approximately % in the cortex and 
% in the spinal cord. A maximum dose of 
 mg is 
proposed at this time and is estimated to reduce ATXN2 mRNA levels in the cortex by 
approximately 
% and in the spinal cord by approximately 
% at steady state and will provide 
an approximately 
-fold safety margin to the HED (
 mg) of the 13-week NHP IT 
toxicology study NOAEL (
 mg). and an approximately 
-fold safety margin to the HED 
(
 mg) of the 41-week NHP IT toxicology study NOAEL (
 mg- pending recovery data). 
Postmortem tissue analyses from the 13-week and 41-week toxicology study studies in NHP 
showed that the CNS tissue ATXN2 protein levels are reflective of CNS tissue ATXN2 mRNA 
levels.  
 
   
The length of the dosing interval during the 28-day loading period (3 doses administered once 
every 2 weeks) will potentially is designed to yield a rapid onset of steady-state exposure. After 
by the third dose on Day 29. Following the loading period, the MAD design, with 2 
maintenance doses administered once dosing every 4 weeks, will allow for the evaluation of 
longer term tolerability at is projected to maintain steady-state exposure based on the whole-
body physiologically based PK model.

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Table 4: 
Predicted ATXN2 mRNA Reduction (Cortex and Spinal Cord), ATXN2 Protein 
Reduction (CSF), and Safety Margins After 5 Administrations at Steady-state at Proposed Dose 
Levels 
Indication 
Cohort 
Dose 
(mg) 
Total 
Number of 
Participants 
per Cohort 
Dose Level 
Fold 
Increase 
% Decrease 
in Cortex 
Average 
(maximum) 
% Decrease 
in Spinal 
Cord 
Average 
(maximum) 
% Decrease 
in CSF 
(approximate 
median) 
Safety 
Margin1 
13 week/ 
41 week 
 
A 
5  
8 
B 
20 
8 
  
C1 
60 
12 
  
D1 
120 
20 
 
C2 
60 
416 
D2 
120 
1838 
1Safety margins are based in HED of the NOAEL 13 week and 41 weeks NHP IT toxicology studies using CSF 
volumetric scaling. 
 
During Part 1 of the study, the SST will review safety, tolerability, and available PK data before 
each dose escalation. 
   
Rationale: This section was updated to reflect new data from the 41-week NHP chronic 
toxicology study, which resulted in a NOAEL of 
 mg (pending data from the recovery portion 
of the study, which is ongoing at the time of this protocol amendment). The rationale for 
maximum exposure was updated to reflect the revised safety margins of doses tested in Study 
275AS101 to the 41-week NHP NOAEL at steady state.  
This change also affects Section 3.2.3.1, Nonclinical Experience.

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Section 4, Study Objectives and Endpoints 
. 
Now reads: 
To evaluate the effect of BIIB105 on measures of clinical function. 
Changes from baseline in the following assessments: 
•         SVC 
•         ALSFRS-R score 
•         Muscle strength, as measured by HHD 
•         
 
•         
 
•         
  
•         
 
 
          
 
 
         
 
 
 
 
 
 
  
 
Section 5.1, Study Overview 
Change: The natural history run-in period for Cohort D2 was removed from the protocol.   
Now reads: 

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Adult participants with ALS will be randomized at a ratio of 3:1 (active drug:placebo) in 
Cohorts A, B, C1, and D1. Adult participants with polyQ-ALS will be randomized at a ratio of 
3:1 in Cohort C2 and at a ratio of 2:1 in Cohort D2. Cohorts C1 and C2 can dose concurrently. 
Cohorts D1 and D2 can dose concurrently, but participants with polyQ ALS (Cohort D2) must 
complete a 4 month or longer Natural History Run in Period (inclusive of the Screening Period) 
prior to dosing. Participants with polyQ ALS (Cohort D2) may be enrolled (i.e., sign the main 
ICF) in the study and enter the Natural History Run in Period prior to the SST approving the 
safety of Cohort C2 and allowing the dosing of Cohort D2; dosing of Cohort D2 will not begin 
until after SST approval is obtained as described in Section 5.3. The Natural History Run in 
Period will be included to gain a better understanding of the natural history of polyQ ALS and an 
enhanced ability to detect clinical changes in a small population with limited ease of access. 
Rationale: Given the potential importance of early treatment initiation in ALS, the natural 
history run-in period for Cohort D2 was removed to allow investigation of the effect of BIIB105 
initiated approximately 4 months earlier in polyQ-ALS. PolyQ-ALS participants may begin 
dosing immediately after screening is completed and eligibility is confirmed. PolyQ-ALS 
participants who are actively enrolled in the Cohort D2 natural history run-in period at the time 
that the protocol amendment is approved will not have to complete the full run-in period and 
may immediately enter the screening period for the study.  
This change also affects Section 5.2.1, Study Duration for Participants in Part 1; Section 12.3, 
Monitoring and Recording Events. 
 
Section 5.2.2, Study Duration for Participants in Part 2 
Change: Language was added allowing follow-up of health status after withdrawal from or end 
of study, if a participant consents to data collection after withdrawal or study completion. 
 
Now reads: 
… 
After a participant’s end of study date, follow-up on vital status and date of death (if 
deceased) will be performed for participants who provide optional consent for data 
collection after study completion. 
Rationale: This text was added to enable follow-up of health status, such as vital status and date 
of death (if deceased) after participant withdrawal from study or study completion for analyses of 
BIIB105 effect on survival. 
This change also affects Section 5.6, End of Study; Section 8.3, Withdrawal of Participants From 
the Study.  
 
Section 5.3.1, Dose Escalation (Part 1) 

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Change: Safety surveillance team review criteria for Cohorts D1 and D2 was separated from the 
criteria for Cohorts A, B, C1, and C2.  
… 
For Cohorts D1 and D2, the safety review for each cohort will occur after the cohort is fully 
randomized, and at least 92 days after the randomization of the 12th participant. The SST 
will review all blinded safety data from all randomized participants, which must include a 
minimum of 12 evaluable participants (those who completed all of the first 5 dosing visits 
as well as the Day 92 clinic visit) in each cohort.  This review will be for a final safety 
review for Cohorts D1 and D2.  Cohorts D1 and D2 can be reviewed concurrently or in 
separate SSTs, depending on when the cohorts have reached the minimum evaluable 
patients. 
… 
In addition to the review of all safety data, there will be a review of available PK data collected 
through 6 hours after the third dose on Day 29 prior to dosing of the next dose cohort for 
Cohorts A, B, C1, and C2.  For Cohorts D1 and D2, there will be a review of all available 
PK data for a minimum of 12 evaluable participants.  
Rationale: Criteria to initiate SST safety reviews for Cohorts D1 and D2 were updated to reflect 
the longer length of the study for these two cohorts. 
 
Section 5.4.1, Cohort Suspension 
Change: Cohort study stopping rules were updated to include additional information on the role 
of the SST.  
Now reads: 
If 1 participant experiences either an SAE or a medically unacceptable AE (as defined by the 
Investigator or the Sponsor), the Sponsor Medical Director and Global Medical Safety Physician 
will discuss the event with review relevant safety information and obtain more information 
from the Investigator and review the SAE form (if applicable). necessary. If the AE is assessed 
as unrelated to study treatment by both the Investigator and the Sponsor (e.g., is a known sign or 
symptom of ALS or is a known effect of the LP procedure), dose suspension is not necessary. 
If the SAE or medically unacceptable AE (as determined by the Investigator or the Sponsor) is 
assessed as related to study treatment by the Investigator or the Sponsor, all then dosing at and 
above the dose level at which the event occurred will be suspended until the event has been 
fully evaluated by the SST. 
… 
Following the SST review of safety and PK data for Cohort D1 (Part 1), if there is 
agreement that the current emerging safety, tolerability, and PK data support continued 

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dosing at 120 mg, the abovementioned dose suspension rules will no longer apply. The 
Sponsor may still determine that a dose suspension is required at any time due to emerging 
safety data. 
 
Rationale: Cohort study stopping rules were updated to reflect the addition of Part 2. Because 
some participants may be dosed with 60 mg in Part 2 while other participants are being dosed 
with 120 mg (in Part 1 or 2), there may be more than one active dose level in the study at the 
time of a potential SAE or medically unacceptable AE. The dosing suspension rules were 
updated to specify that dose suspension would apply to any dose at or above the dose level at 
which an SAE or medically unacceptable AE was assessed as related to study treatment. The 
automatic dose suspension rules will end after SST evaluation of Cohort D1 (Part 1), if the SST 
agrees with continued 120 mg dosing in the study, because benefit/risk profile of BIIB105 at the 
top dose will have been assessed, and because participants in the study will be moving from the 
first-in-human portion of the study into the long-term extension portion of the study without 
further dose escalation.  
 
Section 5.4.3, Study Termination 
Changes: Study termination criteria were clarified. 
Now reads: 
... 
If, in light of emerging data, the Sponsor decides to continue testing, evaluation, or 
development of the product only for a specific subpopulation of ALS (for example, polyQ-
ALS), the study may be terminated for participants who do not meet criteria for the 
subpopulation.  
Rationale: The study termination rules were updated to reflect that a decision for BIIB105 
development to proceed only for a subpopulation of ALS would result in the study continuing 
only for that subpopulation of ALS. 
Section 6.1, Inclusion Criteria 
Change: Part 1 inclusion criteria 1, 10, and 11 were updated. 
Now reads: 
6.1.1 Part 1 
1. 
Ability of the participant and/or his/her legally authorized representative (e.g., parent, 
spouse, or legal guardian), as appropriate and applicable, to understand the purpose and risks of 
the study, to provide  and indicate informed consent, and to authorize the ability of the 
participant or the participant’s legally authorized representative, to provide signed and 

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dated informed consent and authorization to use of confidential protected health information 
in accordance with national and local privacy regulations. 
… 
10. 
Screening values of coagulation parameters including platelet count, INR, PT, and APTT 
should be within normal ranges. Coagulation tests done at a local laboratory may be used for 
screening purposes, in order to reduce participant burden. Coagulation tests may be repeated 
once at the local laboratory if, in the opinion of the Investigator, values of the initial tests are out 
of range but not clinically significant. Participants with nonclinically significant and stable 
out-of-range values may be eligible to enroll in the study at the discretion of the Investigator and 
after a consultation with the Sponsor. 
11. 
Has an informant/caregiver who, in the Investigator’s judgment, has frequent and 
sufficient contact with the participant as to be able to provide accurate information about the 
participant’s cognitive and functional abilities at Screening. An informant/caregiver should be 
available at Screening (or at the Day 113 Visit for participants in Cohort D2), and theThe 
participation of the same informant/caregiver for the duration of the study is encouraged. 
… 
Rationale: The change to inclusion criterion 1 was made to clarify that, while the participant’s 
representative may sign the consent form on the participant’s behalf, the representative may not 
provide informed consent on the participant’s behalf. The participant must have the ability to 
understand the purpose and risks of the study and indicate consent. 
The change to inclusion criterion 10 was made to clarify that coagulation tests completed at a 
local laboratory may be used for screening purposes, thereby reducing participant burden. 
For inclusion criterion 11, there is no longer a requirement for a caregiver at Day -113 because 
the natural history portion of the study for Cohort D2 participants was removed.  
 
Section 6.3.3, Screen Failures 
Change: A rescreening option was added for screen failures.  
Now reads: 
If a participant is considered a screen failure, the reasons for exclusion must be documented in 
the participant’s source documents and on the screening log. Participants who fail screening 
may be permitted to be rescreened once at the Investigator’s discretion after discussion 
with the Sponsor.  
... 
Rationale: This language was added to clarify procedures for re-screening in the case of screen 
failures.  

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Section 7.7.1.2, Disallowed Concomitant Medication 
Change: Text was updated to state that indwelling injection ports/catheters are prohibited only 
during Part 1 of the study. 
Now reads: 
...  
Use of a diaphragm pacing system, indwelling injection ports/catheters, investigational drugs 
other than the investigational product (including drugs for ALS through compassionate use 
programs), or ASOs is prohibited for the duration of the study.  
Use of indwelling injection ports/catheters are prohibited during Part 1 of the study.  
Rationale: Because indwelling injection ports/catheters are becoming more commonly used in 
the clinical care of ALS patients, injection ports/catheters will be allowed only during Part 2 of 
the study for participants from all cohorts.  
Indwelling injection ports/catheters will remain prohibited during Part 1 of the study to ensure 
that participants from Cohorts D1 and D2 are comparable to those in Cohorts A, B, C1, C2 (who 
were also prohibited from having indwelling injection ports/catheters during Part 1), for the 
purposes of safety monitoring and pooling of placebo data.  
This change also affects Section 6.2, Part 1 exclusion criterion 16. 
 
Section 9.1, Clinical Assessments 
Change: Information was updated to clearly reflect Part 1 and Part 2 assessment requirements.  
Now reads: 
The following clinical assessments will be performed to evaluate the safety profile of BIIB105: 
•         ... 
•         C-SSRS:  
−        In Part 1, the “Since Last Visit” version of C-SSRS will be used from Day 8 onward. 
−        In Part 2, participants from Cohorts D1 and D2 will use "Since Last Visit" version of 
C-SSRS on Day 1 onward. Participants from Cohorts A, B, C1, and C2 will use the “Since 
Last Visit” version of the C-SSRS from Day 15 onward.  

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Rationale: Details about the C-SSRS versions to be used at visits were updated to reflect the 
addition of Part 2.  
 
Section 11.2, Clinical Functional Assessments 
 
  
Now reads: 
 
 
•         SVC 
•         ALSFRSR (standard) 
         
  
         
 
         
 
•         HHD 
         
  
         
 
         
  
         
 
         
 
•         Ventilation diary 
11.2.2  
ALS Functional Rating Scale-Revised (standard) 
The ALSFRS-R has been demonstrated to predict survival. The ALSFRS-R measures 
4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor 
skills. There are 12 questions, each scored from 0 to 4, for a total possible score of 48, with 
higher scores representing better function [Cedarbaum 1999]. At each study site, the same 
qualified and trained study site staff member will consistently perform the ALSFRS-R for a 
participant. A qualified and trained backup ALSFRS-R rater will be identified in case the 
primary rater is unavailable. This In Part 1, this study site staff member will remain blinded to 
participants’ treatment assignments and to the results of other assessments. In Part 2, this study 
site staff member will remain blinded to participants' treatment assignments and to the 

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results of other assessments during the blinded loading dose period for participants in 
Cohorts D1 and D2.  
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  

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. 
Section 11.2, Clinical Functional Assessments 
Change: Text was added specifying that participants will complete a weekly ventilation e-diary. 
Now reads: 
11.2.10 
Participant Ventilation Diary 
Participants will be given diaries to record use of ventilation. This diary will be reviewed 
with study site staff at each visit. Refer to the Study Reference Guide for details. 
Rationale: The ventilation diary was added to enable analyses of the effect of BIIB105 on time 
to death or permanent ventilation (i.e., survival without permanent ventilation). 
This change also affects Section 1, Schedule of Activities Tables 2 and 3. 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section 13.2, Analysis Populations 
Change: Text was added defining the analysis populations.   
Now reads: 
The full analysis population is defined as all randomized participants. 
The intent-to-treat (ITT) population is defined as all randomized subjects who receive at 
least 1 dose of study treatment. 
The safety analysis population is defined as all randomized participants who receive at least 
1 dose of study treatment. 
The PK analysis population is defined as all randomized participants who receive at least 1 dose 
of study treatment and have at least 1 postdose serum and/or CSF BIIB105 measurement.  
The PD population is defined as subjects who have received at least 1 dose of study 
treatment and have at least 1 available post-dose evaluation of the respective PD endpoint 
in the study. 
The clinical function set is defined as the subset of the ITT population who have at least 1 
post-dose measurement. 
Any additional details will be specified in the statistical analysis plan. 
Rationale: This section was updated to reflect the planned analysis populations for the study. 
 
Section 13.3.1.1, Adverse Events 
Change: Details were added to clarify the planned statistical analyses of AEs. 
Now reads: 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
incidence of treatment-emergent AEs, SAEs, deaths and AEs leading to treatment 
discontinuation, at minimum, will be tabulated by dose level, with placebo data pooled across 
cohorts summarized by system organ class and preferred term. The AEs level of severity 
and relationship to study treatment will also be similarly summarized. For the summary of 
AEs by severity, if a subject has multiple events occurring in the same body system, then 
the event with the highest severity will be counted. The relationship to study treatment will 
be classified as related or not related. 

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Rationale: This section was updated to reflect the planned statistical analyses for the study. 
 
Section 13.3.1.2, Laboratory Results 
Change: Details for planned laboratory analyses were added.  
Now reads:  
Laboratory data includes hematology, coagulation, blood chemistry, CSF assessments, and 
urinalysis, and will be summarized, with placebo data pooled across cohorts. Summary statistics 
for actual values and changes from baseline will be presented for quantitative laboratory data. In 
addition, shift tables will be used to tabulate the shifts from baseline to high/low status for each 
laboratory test. 
Rationale: This section was updated to clarify details of the planned statistical analyses for the 
study. 
 
Section 16.6, Public Health Emergencies 
Change: Details on contingency plans were added for potential site closure, travel restrictions, 
or other events resulting from a public health emergency. 
 
Now reads: 
16.6 
 Public Health Emergencies 
In the event of a public health emergency that results in site closure, travel restrictions, 
and/or the study being deprioritized at the site such that clinic visit(s) cannot occur, a 
protocol deviation would be incurred for any deviation from the protocol-specified visits 
and assessments, with additional notation that this protocol deviation is due to the public 
health emergency. If a protocol-specified clinical visit cannot occur because of a public 
health emergency, the following mitigating options should be pursued (if allowed per local 
regulations), in order of preference (in which the highest preference option that is feasible 
should be done): 1) transfer to another active study site that is open, 2) home visit, 3) 
telemedicine visit (e.g., by telephone or web conference), and 4) local laboratory visit. These 
mitigating options only apply in the setting of a public health emergency in which a 
protocol-specified clinic visit cannot occur and should not be pursued solely because of a 
participant’s preference. If the participant does not participate in one of these options, a 
Safety Telephone call must be conducted within 14 days of the last dosing visit. 
A third-party vendor has been engaged to perform assessments at the study participant’s 
home, which may include but are not limited to: 
•         Limited neurological examination 

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•         Physical examination 
•         Vital signs 
•         Height and body weight collection 
         
 
         
 
         
 
•         C-SSRS 
•         SVC 
•         Biological sample collection 
•         Pregnancy test (if applicable) 
•         HHD 
•         Collection/shipment of ventilation diary records 
The following assessments will be performed via telephone (telemedicine) by the site staff: 
•         ALSFRS-R 
•         Review of concomitant medications and AEs 
 
 
Rationale: In the event of a public health emergency, mitigating options provide flexibility with 
respect to the collection of data in the interest of participant safety and to protect the integrity of 
the data when participants are unable to attend a clinic visit. 
 

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Section 15.1.4, Digital Clinical Outcomes Data Capture 
Change: A section was added to account for the digital data collected by participants.  
Now reads: 
15.1.4  
Digital Clinical Outcomes Data Capture 
Participant information, including 
 and ventilation 
diary logs, will be captured electronically to assess clinical outcomes.  
Rationale: 
 and the ventilation e-diary will be accessible 
via digital devices given to the participants.  
 
 

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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. 
• Typographical errors and formatting were corrected. 
• Section 1, Schedule of Activities, Table 1, a safety telephone call was added after the 
final or early termination visit. Information in the Notes column was moved to the 
footnotes.  The title of the table was also updated to reflect that the assessments were 
only for Cohorts A, B, C1, and C2 in Part 1. 
• Section 1, Schedule of Activities, Table 2:  
− Footnote 11 was updated to include specific days a limited physical examination 
will take place. 
− Footnote 12 was updated to provide sites an appropriate time window (±15 
minutes) to complete study assessments on dosing days.   
− Footnote 14 was updated to provide sites an appropriate time window (±15 
minutes) to complete ECG and vital signs on dosing days. Text was also added to 
clarify how vital signs and ECGs should be administered. 
− Footnote 25 was updated to add Day 259 to HbA1c and lipid panel assessment. 
− Footnote 26 was updated to clarify time window for serum sampling for PK 
postdose on dosing days. Text was also added to clarify that remaining serum may 
be used for 
. 
− Footnote 27 was added to clarify that assessment should take place on Day 85 
visit only. 
− Footnote 29 was updated to clarify that remaining CSF sample may be used for 
. 
• Section 3.2.3, Profile of Previous Experience with BIIB109, and Section 3.2.3.2, 
Clinical Experience, text was updated to reflect that clinical data are available for 
BIIB105. 
• 
 
 

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• Section 13.3.1.3, Vital Signs; Section 13.3.1.4, C-SSRS; and Section 13.3.1.5, 
Electrocardiogram, text was edited to remove the term “dose level” from the 
description of these assessments.  
• Section 13.3.3, Pharmacodynamics, text was updated to clarify analysis for 
pharmacodynamics. 
 

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24 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
 
 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised 
APTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
CAG 
cytosine-adenine-guanine  
CNS 
central nervous system 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
clinic visit 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
 
 
ET 
early termination 
HbA1c 
hemoglobin A1c 
HED 
human equivalent dose 
HHD 
handheld dynamometry 
ICF 
informed consent form 
INR 
international normalized ratio 
 
 
IT 
intrathecal(ly) 
LP 
lumbar puncture 
MAD 
multiple-ascending dose 
mRNA 
messenger ribonucleic acid 
MRSD 
maximum recommended starting dose 
NHP 
nonhuman primate 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
polyQ 
polyglutamine  
PT 
prothrombin time 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SST 
safety surveillance team 
SVC 
slow vital capacity 
TC 
telephone contact 
UV 
Unscheduled Visit 

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CONFIDENTIAL
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Biogen MA Inc.
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 275AS101
A Phase 1 Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral 
Sclerosis With or Without Poly-CAG Expansion in the Ataxin-2 Gene
Version 2
Date: 02 March 2021
EUDRA CT Number: 2020‐000207‐36
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1.

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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 275AS101 is to clarify the dosing of the 
sentinel pair in cohort C2 to avoid the possible unblinding of study participants’ treatment 
assignment. 
New text is shown in bold type; deleted text is shown with a strikethrough.
5.1, Study Overview
Now reads:
[…]
The first 2 participants within each in all cohorts, except cohort C2, will be randomized at a 
ratio of 1:1 (active:placebo) and dosed as a sentinel group. No other participants within the 
cohort will be dosed until the Investigators have reviewed 72 hours of safety data after dosing the 
first 2 participants and communicated with the Sponsor Medical Director and Global Medical 
Safety Physician. Based on this safety evaluation, the Sponsor will determine if the rest of the 
cohort can be dosed. For the remainder of participants in the all cohorts, except for cohort C2, 
no more than 2 participants will receive their first dose of study treatment on the same day 
throughout the study. For cohort C2, the participants will be randomized 3:1 
(active:placebo). Treatment will be staggered by 72 hours for the first 2 participants. The 
first 2 participants will be dosed as a sentinel group, and no other participant will be dosed 
until the Investigators have reviewed safety data after dosing the first 2 participants and 
communicated with the Sponsor Medical Director and Global Medical Safety Physician. 
This phone call will occur 72 hours after the dosing of the second participant. Based on this 
safety evaluation, the Sponsor will determine if the rest of the cohort can be dosed. If 
approved, the third and fourth participants may receive their first dose of study treatment 
on the same day. 
For each participant, a review of all available safety and tolerability data will be performed 
approximately 7 days after the first dose is administered and before administration of the second 
dose on Day 15. This single-dose review will be performed by the site’s Principal Investigator or 
designee and communicated to the Sponsor Medical Director and Global Medical Safety 
Physician, or their appropriate designees. The Sponsor Medical Director and Safety Physician 
will determine if each participant can proceed with subsequent doses. The second dose cannot be 
administered until this review is complete.

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Rationale: Cohort C2 is designed to enroll 4 participants with polyQ-ALS who will be 
randomized 3:1 (BIIB105:placebo). To maintain the blinding of the treatment assignment, the 
sentinel pair for cohort C2 will not be randomized 1:1 (BIIB105:placebo) but instead will be 
randomly assigned drug or placebo with a minimum of 1 participant receiving drug. To maintain 
all safety features of the sentinel pair without unblinding, the C2 sentinel pair will have 72 hours 
between their first doses as described in section 5.1, Study Overview.
This change also affects Section 1.1, Synopsis and Section 3.1, Study Rationale.

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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.
1.3, Schedule of Activities
Change: The Note associated with the C-SSRS Questionnaire was corrected to indicate that the 
“since last visit” version of the C-SSRS should be used from Day 8 forward, as indicated in the 
corresponding row in the Schedule of Activities.
Now reads: 

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Table 1:
Schedule of Activities: Cohorts A, B, C1, C2, and D1
Follow-Up 
Period
Screening
Dose 1 (Inpatient)
CV
Dose 2
TC
CV
Dose 3
TC
CV
TC
Dose 4
TC
CV
TC
Dose 5
TC
CV
TC
CV
TC
Final/ 
ET Visit
Notes
1
2
Days
Assessments
-28 to -1
Predose
Dosing/ 
Postdose
(24 ±1 h) 
postdose
8
(±2)
15
(±3)
16 
(+1)
22
(±3)
29
(±3)
30 
(+1)
36
(±3)
50
(±3)
57
(±3)
58 
(+1)
64
(±3)
78
(±3)
85
(±3)
86 
(+1)
92
(±3)
93 
(+1)
130
(±3)
131 
(+1)
175
(±3)
UV Screening assessments 
can be performed on 
multiple days (up to 
7 days) for ease of 
participant burden.
C-SSRS 
Questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
Use “Since Last Visit” 
version of C-SSRS 
from Day 158 onward.
Done predose on 
dosing days.
At UV may be assessed 
per the Investigator’s 
discretion.
[…]
Table 2:
Schedule of Activities: Cohort D2
[…]
16Use “Since Last Visit” version of C-SSRS from Day 158 onward. Done predose on dosing days. At UV, may be assessed per the Investigator’s discretion.

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Rationale: The Note in Table 1 and the footnote in Table 2 were corrected to fix a discrepancy 
in the protocol between the Schedule of Activities row indicating the schedule of C-SSRS 
questionnaire completion and the Note and footnote indicating when the “since last visit” version 
of the questionnaire should be used.
This change also affects Section 9.1, Clinical Assessments.
6.2, Exclusion Criteria 
Change: The definition of the ALSFRS-R slope calculation was corrected.
Now reads: 
19.
Prescreening ALSFRS-R slope > -0.4 points/month, where prescreening ALSFRS-R 
slope is defined as follows: (48- ALSFRS-R score at Screening - 48) / (months from date of 
symptom onset to date of Screening) in participants from Cohorts A, B, C1, and D1.
Rationale: The order of the components in the equation to calculate the ALSFRS-R slope at 
prescreening was incorrect. The change provides clarification in the protocol to ensure correct 
calculation of the ALSFRS-R slope when determining participant eligibility for the trial.

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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

The Sponsor Signature Page was updated.

The sentence describing the option to extend the screening period to 42 days for 
eligible participants was added to Section 6.3.1, Screening. This addition was made to 
clarify that this extension does not only apply to instances of retesting participants 
who have a nonclinically significant out-of-range laboratory result.

Section 6.3.2, Retesting was revised to clarify that the screening period may also be 
extended to 42 days for retesting of genetic sequencing results.

Typographical errors and formatting were corrected.

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LIST OF ABBREVIATIONS
ALS
amyotrophic lateral sclerosis
ASLFRS-R
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised
C-SSRS
Columbia Suicide Severity Rating Scale
CV
clinic visit
ET
early termination
MAD
multiple-ascending dose
polyQ
polyglutamine
TC
telephone contact
UV
Unscheduled Visit