Clinical trial NCT05053035
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Alector Inc.
Start date: 2021-09-02; Completion date: 2022-10-28
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A phase 2 double-blind, placebo-controlled study of AL001 in participants with C9orf72-associated ALS.

Detailed description:
This is a phase 2 double-blind, placebo-controlled trial to test the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL001 in participants with C9orf72-associated Amyotrophic Lateral Sclerosis.

Arms: arm 1: AL001 every 4 weeks arm 2: Placebo every 4 weeks
Interventions: intervention 1: AL001 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered via intravenous (IV) infusion intervention 2: Administered via intravenous (IV) infusion

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol AL001-ALS-201, Version 3.0 
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CLINICAL STUDY PROTOCOL 
 
AL001-ALS-201 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in 
C9orf72-Associated Amyotrophic Lateral Sclerosis 
 
Investigational Product: 
AL001, human recombinant anti-human 
sortilin IgG1 monoclonal antibody 
Indication: 
C9orf72-Associated Amyotrophic Lateral 
Sclerosis (C9ALS) 
Study Phase: 
2 
IND Number: 
154279 
Sponsor: 
Alector, Inc. 
131 Oyster Point Boulevard, Suite 600 
South San Francisco, CA 94080, US 
Telephone: +1 650-837-0384 
Vice President,  
Clinical Development: 
Daniel Maslyar, MD 
  
 
Medical Monitor: 
Margherita Torti, MD 
r 
 
 
 
Protocol Version and Date: 
Version 3.0, 11 February 2022 
Version 2.0, 21 April 2021 
Version 1.0, 18 December 2020  
 
CONFIDENTIAL 
This document contains confidential information. This document must not be disclosed to 
anyone other than the site study staff and members of the institutional review board/independent 
ethics committee/institutional scientific review board or equivalent. The information in this 
document cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Alector, Inc. 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL – SPONSOR SIGNATORY ................................................................7 
PROTOCOL APPROVAL – LEAD STATISTICIAN....................................................................8 
PRINCIPAL INVESTIGATOR PROTOCOL APPROVAL SIGNATURE PAGE .......................9 
SITE INVESTIGATOR AGREEMENT SIGNATURE PAGE ....................................................10 
STATEMENT OF COMPLIANCE ...............................................................................................11 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ......................................................12 
SYNOPSIS ....................................................................................................................................17 
LIST OF TERMS AND ABBREVIATIONS ................................................................................26 
1. 
INTRODUCTION ......................................................................................................30 
1.1. 
Study Rationale ...........................................................................................................30 
1.1.1. 
Amyotrophic Lateral Sclerosis ...................................................................................30 
1.1.2. 
C9orf72-Associated ALS ............................................................................................30 
1.1.3. 
Shared Genetics and Pathology of ALS and Frontotemporal Dementia ....................30 
1.2. 
Background .................................................................................................................31 
1.2.1. 
Sortilin and AL001 .....................................................................................................31 
1.2.2. 
Overview of Nonclinical Toxicology Studies ............................................................32 
1.2.3. 
Overview of Clinical Studies with AL001 .................................................................32 
1.2.4. 
Rationale for the Treatment of C9ALS with AL001 ..................................................32 
1.2.5. 
Dose Justification ........................................................................................................33 
1.3. 
Risk/Benefit Assessment of AL001 ............................................................................33 
1.3.1. 
Known Risks of the Drug Class ..................................................................................33 
1.3.2. 
Risks of AL001 and AL001-ALS-201 Study Procedures and Assessments ..............33 
1.3.3. 
Potential Benefits of AL001 .......................................................................................33 
1.3.4. 
Benefit-Risk Assessment for Study AL001-ALS-201 Study Subjects .......................34 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................36 
3. 
STUDY DESIGN .......................................................................................................38 
3.1. 
Overall Design ............................................................................................................38 
3.2. 
End of Study Definition ..............................................................................................38 
4. 
STUDY POPULATION .............................................................................................39 
4.1. 
Inclusion Criteria ........................................................................................................39 
4.2. 
Exclusion Criteria .......................................................................................................40 


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4.3. 
Screening Failures ......................................................................................................43 
5. 
IDENTITY OF INVESTIGATIONAL PRODUCT ...................................................44 
5.1. 
AL001 .........................................................................................................................44 
5.2. 
Dosing and Administration .........................................................................................44 
5.3. 
Storage, Handling, and Stability .................................................................................44 
5.3.1. 
Storage and Handling .................................................................................................44 
5.3.2. 
Stability of Prepared AL001 Solution ........................................................................44 
5.4. 
Formulation, Packaging, and Labeling .......................................................................44 
5.4.1. 
Formulation .................................................................................................................44 
5.4.2. 
Packaging and Labeling ..............................................................................................45 
5.5. 
Drug Accountability ...................................................................................................45 
5.6. 
Randomization and Blinding ......................................................................................45 
5.6.1. 
Randomization ............................................................................................................45 
5.6.2. 
Blinding ......................................................................................................................46 
5.6.2.1. 
Blinded and Unblinded Personnel ..............................................................................46 
5.6.2.2. 
Circumstances for Breaking the Blind ........................................................................46 
5.7. 
Concomitant Therapy .................................................................................................46 
5.8. 
Infusion-Related Reactions .........................................................................................47 
5.8.1. 
Guidance for Management of Infusion-Related Reactions ........................................47 
6. 
STUDY DRUG DISCONTINUATION AND SUBJECT WITHDRAWAL 
FROM THE STUDY ..................................................................................................49 
6.1. 
Study Drug Discontinuation .......................................................................................49 
6.2. 
Subject Withdrawal from the Study ...........................................................................50 
6.3. 
Subject Lost to Follow-Up ..........................................................................................50 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................51 
7.1. 
Efficacy Assessments .................................................................................................51 
7.1.1. 
ALS Functional Rating Scale-Revised .......................................................................51 
7.1.2. 
Combined Assessment of Function and Survival .......................................................51 
7.1.3. 
Vital Capacity .............................................................................................................51 
7.1.4. 
Home Spirometry ........................................................................................................52 
7.1.5. 
ALS Cognitive Behavioral Screen ..............................................................................52 
7.1.6. 
Digital Assessments ....................................................................................................52 
7.1.7. 
Training and Validation ..............................................................................................53 


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7.2. 
Biofluid Collection and Sample Retention .................................................................53 
7.2.1. 
DNA Collection ..........................................................................................................53 
7.2.2. 
Lumbar Puncture ........................................................................................................53 
7.2.3. 
Pharmacokinetic Blood Sample Collection ................................................................54 
7.2.4. 
Anti-Drug Antibodies .................................................................................................54 
7.2.5. 
Blood, Urine, and CSF Pharmacodynamic Assessments ...........................................55 
7.2.6. 
Blood Biomarker Sample Collection ..........................................................................55 
7.2.7. 
Urine Collection ..........................................................................................................55 
7.3. 
Safety and Other Assessments ....................................................................................55 
7.3.1. 
Clinical Variables .......................................................................................................55 
7.3.2. 
Vital Signs and Anthropometrics ................................................................................56 
7.3.3. 
Clinical Safety Laboratory Tests ................................................................................56 
7.3.4. 
12-Lead ECG ..............................................................................................................58 
7.3.5. 
Physical Examination .................................................................................................58 
7.3.6. 
Neurological Examination ..........................................................................................58 
7.3.7. 
Columbia-Suicide Severity Rating Scale ....................................................................58 
8. 
ASSESSMENT OF SAFETY .....................................................................................60 
8.1. 
Definition of Adverse Event .......................................................................................60 
8.2. 
Definition of Serious Adverse Event ..........................................................................61 
8.3. 
Protocol Specific Disease Progression Adverse Event and Serious Adverse 
Event Reporting Requirements ...................................................................................61 
8.4. 
Definition of Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as AE/SAE .............................................................................................62 
8.5. 
Assessment of Adverse Events ...................................................................................62 
8.5.1. 
Assessment of Adverse Event/Serious Adverse Event Severity ................................62 
8.5.2. 
Assessment of Adverse Event/Serious Adverse Event Causality ...............................63 
8.6. 
Recording of Adverse Events .....................................................................................63 
8.6.1. 
Eliciting and Documenting the Adverse Events .........................................................63 
8.6.2. 
Recording the Action Taken with Investigational Products in Response to 
Adverse Events/Serious Adverse Events ....................................................................64 
8.6.3. 
Recording the Outcome and Follow-Up of Subjects Reporting an Adverse 
Event/Serious Adverse Event .....................................................................................64 
8.7. 
Reporting Adverse Events ..........................................................................................64 
8.7.1. 
Adverse Event and Serious Adverse Event Reporting ...............................................64 


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8.8. 
Safety Monitoring .......................................................................................................65 
8.9. 
Follow-Up of AEs and SAEs ......................................................................................66 
8.10. 
General Safety Monitoring .........................................................................................66 
8.10.1. 
Special Situations ........................................................................................................66 
8.10.1.1. 
Pregnancy ...................................................................................................................67 
8.10.1.2. 
Breastfeeding ..............................................................................................................67 
8.10.1.3. 
Reportable Diseases ....................................................................................................67 
9. 
STATISTICAL CONSIDERATIONS .......................................................................68 
9.1. 
Safety ..........................................................................................................................68 
9.2. 
Populations for Analyses ............................................................................................68 
9.3. 
Statistical Analyses .....................................................................................................68 
9.3.1. 
General Approach .......................................................................................................68 
9.3.2. 
Analysis of the Primary Pharmacokinetic Endpoints .................................................68 
9.3.3. 
Analysis of the Primary Pharmacodynamic Endpoints ..............................................68 
9.3.4. 
Analysis of the Primary Immunogenicity Endpoint ...................................................68 
9.3.5. 
Analysis of the Secondary Endpoint(s) ......................................................................69 
9.3.6. 
Safety Analyses ..........................................................................................................69 
9.3.6.1. 
Safety ..........................................................................................................................69 
9.3.6.2. 
Tolerability .................................................................................................................69 
9.3.7. 
Baseline Descriptive Statistics ....................................................................................69 
9.3.8. 
Planned Interim Analyses ...........................................................................................69 
9.3.9. 
Sub-Group Analyses ...................................................................................................69 
9.3.10. 
Tabulation of Individual Subject Data ........................................................................69 
9.3.11. 
Exploratory Analyses ..................................................................................................70 
10. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT .....................................71 
10.1. 
Informed Consent Process ..........................................................................................71 
10.2. 
Study Suspension or Termination ...............................................................................71 
10.3. 
Confidentiality and Privacy ........................................................................................71 
10.4. 
Future Use of Stored Specimens and Data .................................................................72 
10.5. 
Safety Oversight .........................................................................................................72 
10.6. 
Clinical Monitoring ....................................................................................................72 
10.6.1. 
Monitoring Report ......................................................................................................73 
10.7. 
Quality Assurance and Quality Control ......................................................................73 


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10.8. 
Data Handling and Record Keeping ...........................................................................74 
10.8.1. 
Role of Data Management ..........................................................................................74 
10.8.2. 
Data Collection ...........................................................................................................74 
10.8.3. 
Data Entry and Edit Checks ........................................................................................74 
10.8.4. 
Data Collection and Management Responsibilities ....................................................74 
10.9. 
Study Records Retention ............................................................................................75 
10.10. 
Protocol Deviations ....................................................................................................75 
10.11. 
Publication and Data Sharing Policy ..........................................................................75 
10.12. 
Conflict of Interest Policy ...........................................................................................75 
11. 
REFERENCES ...........................................................................................................77 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................80 
APPENDIX 2. ADAPTATION OF TRIAL PROTOCOL DURING THE COVID-19 
PANDEMIC ...............................................................................................................83 
 
LIST OF TABLES 
Table 1: 
Guidelines for Management of Acute Infusion-Related Reactions ............................48 
Table 2: 
Clinical Safety Laboratory Tests ................................................................................57 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................25 
 


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PROTOCOL APPROVAL – SPONSOR SIGNATORY 
Protocol Number: AL001-ALS-201 
Protocol Title: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in 
C9orf72-Associated Amyotrophic Lateral Sclerosis 
Protocol Version and Date: Version 3.0, 11 February 2022 
The undersigned accept the content of this protocol in accordance with the appropriate 
regulations and agrees to adhere to it throughout the execution of the study. 
 
See signature manifest at the end of the document 
Daniel Maslyar, MD 
 
Alector, Inc. 
  
_____________ 
Date 
 
 
 


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PROTOCOL APPROVAL – LEAD STATISTICIAN 
Protocol Number: AL001-ALS-201 
Protocol Title: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in 
C9orf72-Associated Amyotrophic Lateral Sclerosis 
Protocol Version and Date: Version 3.0, 11 February 2022 
The undersigned accept the content of this protocol in accordance with the appropriate 
regulations and agrees to adhere to it throughout the execution of the study. 
 
See signature manifest at the end of the document 
Brian Mangal, MS 
 
  
_____________ 
Date 
 


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PRINCIPAL INVESTIGATOR PROTOCOL APPROVAL SIGNATURE 
PAGE 
Protocol Number: AL001-ALS-201 
Protocol Title: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in 
C9orf72-Associated Amyotrophic Lateral Sclerosis 
Protocol Version and Date: Version 3.0, 11 February 2022 
The undersigned accepts the content of this protocol in accordance with the appropriate 
regulations and agree to adhere to it throughout the execution of the study. 
 
 
 
 
__________________________________ 
Sabrina Paganoni, MD, PhD  
  
 
 
 
 
 


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SITE INVESTIGATOR AGREEMENT SIGNATURE PAGE 
I have read and understood all sections of the protocol specified below and the accompanying 
Investigator’s Brochure. In my formal capacity as Investigator, my duties include ensuring the 
safety of the study subjects enrolled under my supervision and providing Alector with complete 
and timely information, as outlined in the protocol. I will not supply study treatment to any 
person not authorized to receive it. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. Study documents will be stored appropriately to 
ensure their confidentiality. It is understood that all information pertaining to the study will be 
held strictly confidential and that this confidentiality requirement applies to all study staff at this 
site. Furthermore, on behalf of the study staff and myself, I agree to supervise and abide by all 
described protocol procedures. I agree to comply with the International Council for 
Harmonisation (ICH) harmonized tripartite guideline E6(R2): Good Clinical Practice (GCP), 
applicable U.S. Food and Drug Administration (FDA) regulations and guidelines, including 
those identified in Title 21 CFR Parts 11, 50, 54, and 312, central Institutional Review Board 
(IRB) guidelines and policies, and the Health Insurance Portability and Accountability Act 
(HIPAA). 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without written authorization from Alector. 
Protocol Number: AL001-ALS-201 
Protocol Title: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AL001 in 
C9orf72-Associated Amyotrophic Lateral Sclerosis 
Protocol Version and Date: Version 3.0, 11 February 2022 
Investigator Signature 
 
 
Date of Signature 
 
Printed Name and Title 
 
Site Number 
 
Site Name 
 
Site Address 
 
 
 
 


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STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the protocol, International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Guideline 
for Good Clinical Practice (GCP), and applicable regulatory requirements, including United 
States Code of Federal Regulations (CFR) Title 45 CFR Part 46 and Title 21 CFR Parts 50, 56, 
and 312. 
 
 
 


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SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Version 2.0 of the protocol, dated 21 April 2021, has been revised. Typographical changes, 
formatting corrections, minor administrative changes, and minor text clarifications are not listed. 
The protocol synopsis has been revised according to the revisions noted below. 
Important revisions are described below. 
Figure 1: The footnote was corrected to state that “subjects who plan to discontinue the study 
early should be encouraged to return to the investigational site for an Early Termination visit, 
which is 8 weeks after the last dose of study treatment”.   
Synopsis: The text was updated to state that the trial will be conducted at approximately “10-16”, 
instead of 10-12, Northeast ALS Consortium (NEALS) centers in the United States (US). 
Synopsis and Section 1.3.2: Added text to clarify that AL001 is also known as latozinemab. 
Section 1.2.3, Overview of Clinical Studies with AL001: The following text for Study AL001-1 
was deleted “reduction of pro-inflammatory markers, increase in lysosomal proteins, and a trend 
in reduction of neurofilament light chain (NfL)” since subsequent data has revealed a trend for 
lysosomal proteins to decrease and NfL to be unchanged after treatment with AL001.  
Section 1.2.3, Overview of Clinical Studies with AL001: The text was updated to reflect the 
number of subjects enrolled in Study AL001-2 as of 27 August 2021, and the most frequently 
report TEAEs in ongoing studies (AL001-1, AL001-2, AL001-3).  
Section 1.3.2, Risks of AL001 and AL001-ALS-201 Study Procedures and Assessments: Interim 
safety results condensed for clarity.  
Section 3.2, End of Study Definition: The text was corrected to state that “subjects who plan to 
discontinue the study early should be encouraged to return to the investigational site for an Early 
Termination Visit, which is 8 weeks after the last dose of study treatment”.  
Section 4.1, Inclusion Criteria: 
•
The text was revised to clarify the preferred method of measuring vital capacity is by
slow vital capacity (SVC) unless forced vital capacity (FVC) is required due to
pandemic-related restrictions.
•
The text was updated to state that acceptable contraception for male subjects when
having sexual intercourse with a female partner is defined as using a condom or having a
vasectomy.
•
The text was revised to clarify that “In the investigator’s opinion”, subjects must be able
to complete all study procedures, including the IV study drug administration and lumbar
punctures (LPs).
Section 4.3, Screening Failures: The text was revised to clarify that subjects who fail screening 
“may be allowed one rescreen following approval of Alector's Medical Monitor.” The following 
text was deleted: “…there is no time restriction for rescreening”.  
Section 4.4, Strategies for Recruitment and Retention: The section was removed from the 
protocol. 


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Section 5.6.2.1, Blinded and Unblinded Personnel: Text was revised to state that “In addition to 
the iDMC and the independent statistical group supporting the iDMC, safety personnel, and the 
administrative pharmacy personnel will be unblinded as needed.”  
Section 5.7, Concomitant Therapy: Sentence was added to clarify that “Subjects who have not 
started riluzole or edavarone prior to the study will not be allowed to initiate these medications 
during study treatment given their potential to interfere with study endpoint assessments.” 
Section 5.8.1, Guidance for Management of Infusion-Related Reactions,  Section 7.2.4, 
Anti-Drug Antibodies, and Appendix 1 Footnote #13 (previously #12): Text was revised to 
clarify that clinical laboratory samples should be drawn at the site “for central laboratory”; 
however, local laboratories may be utilized, and results assessed for safety by the investigator.  
Section 6.1, Study Drug Discontinuation: Text was revised to clarify that subjects who “plan to” 
discontinue early from the study drug or study should complete an Early Termination Visit 8 
weeks after the last dose of study treatment.  
Section 6.2, Subject Withdrawal from the Study: Text was revised to state that all subjects who 
discontinue the study “during and after the treatment phase but before the final” scheduled Study 
Completion Visit should be encouraged to return to the investigational site for an Early 
Termination Visit 8 weeks after the last dose of study treatment. 
Section 7.1.7 , Training and Validation: Deleted cross-reference to the Manual of Procedures 
(MOP). 
Section 7.2, Biofluid Collection and Sample Retention: Revised cross-reference for instructions 
regarding the collection, processing, storage, and shipment of biosamples from the MOP to the 
central laboratory manual.  
Section 7.2.2, Lumbar Puncture: Text was revised to clarify that “Subjects may only undergo a 
LP if they have a coagulation panel and platelet count performed (using a central or local 
laboratory) within 4 weeks prior to the LP. If the laboratory results are abnormal and warrant 
repeat studies, they should be repeated within a week prior to the LP, and can be repeated at a 
local laboratory as needed. Lumbar puncture at Visit 8 is to be performed prior to study drug 
administration, and at approximately the same time of the day as the Screening LP. The LP is to 
be performed after pulmonary function testing and administration of the ALSFRS-R. For 
subjects who are rescreened, if an LP was previously completed as part of Screening and it is 
within 12 weeks of reconsenting, then a repeat LP is not necessary.” 
Section 7.3.3, Clinical Safety Laboratory Test: Table 2 was revised to exclude “hepatitis B core 
antibody” as a serology test at Screening.  
Section 7.3.5, Physical Examination: Text was revised to clarify that any new or worsened 
clinically significant abnormality does not need to be recorded on the AE eCRF if event is 
related to the patient’s ALS disease progression. 
Section 7.3.7, Columbia-Suicide Severity Rating Scale: Deleted cross-reference to the Manual of 
Procedures (MOP). 
Section 8, Assessment of Safety: Clarified investigator responsibilities for reporting AEs/SAEs. 
Section 8.1, Definition of Adverse Event: Revised list of items that an AE does not include by 
clarifying a previous condition as one that occurs “prior to signing informed consent”, and 


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adding the following: “Note: Any serious procedural complication or hospital-emergent 
conditions (eg, nosocomial infection) would be reported as an SAE.” Deleted item that says “The 
condition that led to the procedure may be an AE and must be reported.” 
Section 8.6.1, Eliciting and Documenting the Adverse Events: Revised text to clarify that 
abnormal laboratory test values or investigational findings reported as AEs or SAEs should be 
followed “until recovered/resolved, until stable, subject withdrawal of consent, lost to follow-up, 
or death, whichever comes first”. 
Section 8.6.3, Recording the Outcome and Follow-Up of Subjects Reporting an AE/SAE: Text 
was corrected for recording the outcome of an AE/SAE on the AE eCRF to be 
“recovered/resolved” instead of “recovered/resolved or attributable to other (defined) cause”, or 
to be “not recovered/not resolved” instead of “not recovered/not resolving up to a 30-day 
follow-up period”. No changes were made to other outcomes. 
Section 8.7.1, Adverse Event and Serious Adverse Event Reporting: Revised the SAE 
information to be collected to add “all applicable seriousness criteria” and to delete “if 
applicable” for collecting seriousness of the SAE. 
Section 8.8, Safety Monitoring: The following paragraph was moved from Section 9.3.6.1 to 
Section 8.8: “Safety will be continuously reviewed by a Medical Monitor in consultation with 
the study investigators. Adverse events will be reported to the Medical Monitor from the study 
EDC system at regular intervals throughout the study, and in real time when SAEs occur or when 
questions arise. The Medical Monitor will have the authority to recommend study 
discontinuation or modification based on medical concerns, including AE or SAE profiles.” 
Section 8.10.1, Special Situations: Text was revised to clarify that special situations 
(ie, non-standard medical conditions) provide valuable information about an investigational 
product and “therefore should be reported”. 
Section 10.1, Informed Consent Process: Text was revised to state that if the ICF is revised 
during the study, active participating subjects “may need to sign the revised consent form as 
determined by the IRB and/or Sponsor” instead of “must sign the revised consent form”.  
Section 10.6, Clinical Monitoring: Deleted cross-reference to the Manual of Procedures (MOP). 
Section 10.6.1, Monitoring Report: Deleted cross-reference to the Manual of Procedures (MOP). 
Section 10.7, Quality Assurance and Quality Control:  
•
Text was clarified to state that no “prospective protocol” waivers will be issued or
approved/pre-approved for changes to the protocol. Deleted “or deviations”.
•
Text was revised to clarify that after “all subjects at the study site have completed the
treatment phase of the study” instead of “at the end of the study site’s participation” any
unused investigational product will be destroyed in accordance with each institution’s
investigational product destruction policy, following the monitor’s authorization of
destruction.
•
Text was revised to delete cross-reference to the MOP and added cross-reference to the
“Pharmacy Manual”, which contains a detailed description of investigational product
storage, accountability, as well as resupply and destruction.


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Section 10.9, Study Records Retention: Text was revised to delete statements that “The 
investigators should retain all study documents and records until they are notified in writing by 
the Sponsor or their representative.” and “No records may be disposed of without the written 
approval of the Sponsor. Written notification should be provided to the Sponsor prior to 
transferring any records to another party or moving them to another location.” 
Appendix 1, Schedule of Assessments:  
• Coagulation was removed from Visit 4 (Week 8).  
• LP was removed from Visit 5 (Week 12). 
Appendix 1 Footnotes: 
• Footnote #2 text was revised to add the following: If necessary, the Baseline Visit may be 
conducted over 2 consecutive days. The following procedures may be performed on the 
first day of the split visit: inclusion/exclusion review, weight, randomization, physical 
examination, neurological examination, ALSFRS-R, ALS-CBS, pulmonary function test, 
C-SSRS, and digital monitoring. The following must be completed on the second day of 
the split visit: collection of safety laboratory samples, serum PK samples (pre-infusion 
and post-infusion as outlined in footnote 11), biomarker samples, serum ADA samples, 
serum pregnancy test, vital signs, and 12-lead ECG. Study drug infusion must always be 
on the second day of a split Baseline Visit. Concomitant medication and AE review 
should be completed on each day.”  
• Footnote #3 was added as follows: “After the Baseline Visit, visit procedures at any 
subsequent visit may be completed over the course of a 48-hour period; however, the 
following must be completed on the day of study drug administration: collection of safety 
laboratory samples, serum PK samples (except for 24-hour post infusion PK at Visit 5, 
see footnote 11), biomarker samples, serum ADA samples, pregnancy test (if applicable), 
vital signs, and 12-lead ECG. The lumbar puncture must be performed prior to infusion 
for all visits where an LP is required (as outlined in footnote 15).”  
• Footnotes #3 through #13 in Amendment 2.0 were renumbered to Footnotes #4 through 
#14 in Amendment 3.0.  
• Footnote #10 (previously #9) was revised to remove the requirement to perform 
coagulation panel at Visit 4.  
• Footnote #11 (previously #10) was revised to clarify serum PK samples drawn pre-
infusion will be done “on the day of the infusion visit”, and PK samples at Visit 5 will be 
collected at 3 hours (±90 minutes) and 24 hours (±6 hours) post end of infusion.  
• Footnotes #14 and #15 were combined and revised as follows: “Subjects may only 
undergo a LP if they have a coagulation panel and platelet count performed (using a 
central or local laboratory) within 4 weeks prior to the LP. If the laboratory results are 
abnormal and warrant repeat studies, they should be repeated within a week prior to the 
LP, and can be repeated at a local laboratory as needed. Lumbar puncture at Visit 8 is to 
be performed prior to study drug administration, and at approximately the same time of 
the day as the Screening LP. The LP is to be performed after pulmonary function testing 
and administration of the ALSFRS-R. For subjects who are rescreened, if a LP was 


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previously completed as part of Screening and is within 12 weeks of reconsenting, then a 
repeat LP is not necessary.”  
•
Footnote #17 was revised to clarify that timing of the home retest spirometry assessment
with virtual coaching by study staff will be conducted 2 days “after” the Baseline visit.
•
Footnote #19 was revised to clarify that C-SSRS “Baseline” Version will be completed at
the “Baseline” visit, not at the Screening visit.
•
Footnote #20 was revised to state that digital monitoring to occur “approximately
weekly” instead of “with a visit window of ±3 days”.
•
Footnote #22 was deleted.
•
Footnote #22 (previously #23) was updated to clarify that in the event of an infusion-
related reaction, blood will be drawn for PK serum and ADA assessment of AL001 or
placebo; the following laboratory tests should be drawn: CRP, ferritin, tryptase, and IL-6
(at 1 to 2 hours after the IRR, then again at 48-72 hours after the IRR). Where possible,
clinical laboratory samples should be drawn at the site for the central laboratory;
however, local laboratories may be utilized and results assessed for safety by the
investigator.
•
Footnote #24 was added: “Subjects may only undergo a LP if they have a coagulation
panel and platelet count performed (using a central or local laboratory) within 4 weeks
prior to the LP. If the laboratory results are abnormal and warrant repeat studies, they
should be repeated within a week prior to the LP, and can be repeated at a local
laboratory as needed. Lumbar puncture is to be performed at approximately the same
time of the day as the Screening LP. The LP is to be performed after pulmonary function
testing and administration of the ALSFRS-R.”
•
Footnote #25 was added: “The Early Termination Visit should occur 8 weeks after the
last dose of study treatment.”
•
Previous Footnote #25 was renumbered to Footnote #26.
Appendix 2, Adaptation of Trial Protocol During the COVID-19 Pandemic: Added text that prior 
to commencing remote source document verification, the following documentation must be 
completed "if required per local regulations”.  


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SYNOPSIS 
Study Title 
Study AL001-ALS-201: A Phase 2, Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of AL001 in 
C9orf72-Associated Amyotrophic Lateral Sclerosis 
Study Description 
This is a phase 2 trial to test the safety, tolerability, pharmacokinetics (PK), 
and pharmacodynamics (PD) of AL001 in subjects with C9orf72-associated 
Amyotrophic Lateral Sclerosis (C9ALS). AL001 is hypothesized to protect 
motor neurons by increasing extracellular progranulin (PGRN) levels and 
thereby reducing TDP-43 pathology in amyotrophic lateral sclerosis (ALS). 
The trial has been designed to confirm elevation of progranulin (PGRN) 
and accumulation of AL001 in cerebrospinal fluid (CSF) and to provide 
proof-of-mechanism target engagement in preparation for a larger trial 
testing the clinical efficacy of AL001 in C9ALS. 
Study Phase 
Phase 2 
Study Population 
Approximately 45 subjects with C9ALS will be randomized in the study. 
Study Sites and 
Coordinating 
(Principal) Investigator 
The trial will be conducted at approximately 10-16 Northeast ALS 
Consortium (NEALS) centers in the United States (US). 
 
Coordinating (Principal) Investigator 
Sabrina Paganoni, MD, PhD 
Massachusetts General Hospital  
The Sean M. Healey & AMG Center for ALS at Massachusetts General 
Hospital 
 
Investigational Product AL001, a human recombinant anti-human sortilin immunoglobulin G 
(IgG)1 monoclonal antibody (also known as latozinemab) that selectively 
binds to sortilin to block the degradation of extracellular PGRN 
Study Drug 
Administration 
AL001 60 mg/kg or matching placebo will be administered intravenously 
(IV) every 4 weeks for 24 weeks. 
Randomization and 
Stratification 
Subjects will be randomly assigned to receive either standard of care + 
AL001 or standard of care + placebo (randomized 2:1) with stratification 
by rs5848 genotype (CC, CT, TT). 
Objectives 
Primary: 
• 
To evaluate the safety of AL001 in C9ALS 
• 
To evaluate the tolerability of AL001 in C9ALS 
• 
To evaluate AL001 PK parameters in serum and CSF 
• 
To evaluate plasma and CSF PGRN levels 
• 
To evaluate anti-drug antibodies (ADA) to AL001 in serum 


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Secondary: 
• 
To evaluate the biological activity of AL001 as measured by 
neurofilament light chain (NfL) levels in the blood and CSF 
Exploratory: 
• 
To evaluate genotype-specific effects of AL001 on PD biomarkers for 
common variants of progranulin gene (GRN) 
• 
To evaluate dipeptide repeat protein (DPR) levels in CSF 
• 
To evaluate the biological activity of AL001 as measured by 
exploratory PD biomarkers of neurodegeneration, inflammation, 
lysosomal function, and glial activation in the blood, urine, and CSF 
• 
To evaluate the effect of AL001 on clinical measures of disease 
progression 
• 
To evaluate the effect of AL001 on ventilation-free survival 
• 
To estimate correlations between fluid PD biomarkers and clinical 
measures of disease progression 
Endpoints 
Primary Outcome Measures: 
• 
Safety: Defined as the occurrence of treatment-emergent adverse 
events (TEAEs), treatment-emergent serious adverse events (SAEs), 
and treatment-emergent clinically significant abnormalities in clinical 
and laboratory values 
• 
Tolerability: Defined as the percentage of subjects who complete the 
study without TEAEs leading to treatment discontinuation 
• 
PK: Serum and CSF concentrations of AL001, and PK parameters 
• 
PD: Changes from baseline in plasma and CSF levels of PGRN 
• 
Immunogenicity: Incidence of ADAs to AL001 
Secondary Outcome Measures: 
• 
Changes in blood and CSF levels of NfL 
Exploratory Outcome Measures: 
• 
Pharmacogenetic effects of AL001 with respect to the following single 
nucleotide polymorphisms (SNPs): rs5848, r
5, 
 
• 
Changes in CSF levels of poly (GP) DPRs 
• 
Changes in PD biomarkers of neurodegeneration, inflammation, 
lysosomal function, and glial activation in the blood, urine, and CSF 
 


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• 
Clinical progression as measured by changes in: 
− 
ALS Functional Rating Scale-Revised (ALSFRS-R) total and 
domain scores 
− 
Combined Assessment of Function and Survival (CAFS) 
− 
Vital capacity (VC) 
− 
ALS Cognitive Behavioral Screen (ALS-CBS) 
− 
Digital home measures of cognition and motor speech 
components 
• 
Permanent assisted ventilation (PAV)-free survival 
• 
Correlations between fluid PD biomarkers and clinical measures of 
disease progression 
Subject Selection 
Inclusion Criteria: 
A prospective subject must meet all the following criteria to be eligible for 
study participation: 
1. Diagnosis of C9orf72-associated ALS with both of the following: 
a. Documentation of a clinical genetic test demonstrating the 
presence of a pathogenic repeat expansion in C9orf72 
and 
b. Must meet possible, laboratory-supported probable, probable, 
or definite criteria for a diagnosis of ALS by revised 
El Escorial criteria (Brooks 2000). 
2. Age 18 or older. 
3. Capable of providing informed consent at the Screening Visit and 
complying with study procedures throughout the study, in the 
investigator's opinion and at the discretion of the Medical Monitor 
and the study sponsor. 
4. If the subject has a participating caregiver, the caregiver must live 
with the subject and, in the investigator's opinion, have adequate 
knowledge of the subject's daily activities and function; 
participating caregivers must sign the caregiver section of the 
informed consent. Not having a caregiver is not exclusionary. 
5. Time since onset of muscle weakness due to ALS ≤36 months at 
the time of the Screening Visit. 
6. Vital capacity ≥50% of predicted capacity at the time of the 
Screening Visit. Vital capacity is preferred to be measured by slow 
vital capacity (SVC) in clinic. If required due to pandemic-related 
restrictions, forced vital capacity (FVC) measured in clinic via 
pulmonary function laboratory may be performed at the discretion 
of the Medical Monitor and the study sponsor. If due to 


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pandemic-related restrictions in clinic vital capacity is not possible, 
then FVC may be performed via home spirometry at the discretion 
of the Medical Monitor and the study sponsor. 
7. Must not be taking riluzole or must be on a stable dose of riluzole 
for at least 30 days prior to the Screening Visit. Riluzole-naïve 
patients are permitted in the study. 
8. Must not be taking edaravone or must have completed at least one 
cycle of edaravone with a plan of continuing edaravone prior to the 
Screening Visit. Subjects must be off cycle and at least 2 days after 
the last dose administration of edaravone at the time of study drug 
infusions. Edaravone-naïve subjects are permitted in the study. 
9. At Screening, women must be non-pregnant (as demonstrated by a 
negative serum pregnancy test at Screening) and non-lactating, and 
one of the following conditions must apply: 
a. Not a woman of childbearing potential (either surgically 
sterilized or physiologically incapable of becoming pregnant, 
or at least 1 year postmenopausal [amenorrhea duration of 
12 consecutive months with no identified cause other than 
menopause]) 
b. Is a woman of childbearing potential and agrees to use an 
acceptable contraceptive method from Screening until 
10 weeks after the last dose of study treatment. Acceptable 
contraception is defined as using hormonal contraceptives 
(eg, combined oral contraceptive pill) or an intrauterine device 
combined with at least one of the following forms of 
contraception: a diaphragm or cervical cap, or a condom. Total 
abstinence, if in accordance with the usual lifestyle of female 
subject, is acceptable. 
A woman of childbearing potential must have a serum pregnancy 
test conducted at Screening. Additional requirements for pregnancy 
testing during and after study intervention are described in the 
Schedule of Assessments (Appendix 1). 
10. Men must agree to use acceptable contraception and not donate 
sperm from Day 0 until 10 weeks after the last dose of study 
treatment. Acceptable contraception for male subjects when having 
sexual intercourse with a female partner is defined as using a 
condom or having a vasectomy. In addition, female partners of 
childbearing potential must agree to use hormonal contraceptives 
(eg, combined oral contraceptive pill) or an intrauterine device. 
Total abstinence, if in accordance with the usual lifestyle of the 
male subject, is acceptable. 
11. In the investigator's opinion, subjects must be able to complete all 
study procedures, including the IV study drug administration and 
lumbar punctures (LPs). 
 


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Exclusion Criteria: 
Prospective subjects who meet any of the following criteria are not eligible 
for study participation: 
1. Clinically significant, unstable, medical condition (other than ALS) 
that would pose a risk to the subject or interfere with the 
interpretation of study data, according to the investigator's 
judgement (eg, cardiovascular disease, systemic infection, 
pulmonary disease, rheumatologic disease, etc.). 
2. Clinically significant laboratory abnormalities including, but not 
limited to: hemoglobin <10 g/dL, white blood cells (WBC) 
<3.0 × 103/mm3, absolute neutrophils ≤1.0 × 103/ mm3, 
eosinophilia (absolute eosinophil count of ≥0.5 × 103/mm3), low 
platelet counts (<150 × 103/mm3), prothrombin time (PT)/activated 
partial thromboplastin time (aPTT)/international normalized ratio 
(INR), lipase ≥1.2 × upper limit of normal (ULN). Out-of-range 
laboratory abnormalities may be repeated during the Screening 
period to reassess for eligibility. 
3. Subject has impaired hepatic function or occult liver injury as 
indicated by Screening: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) greater than 3 times the ULN (bilirubin levels should be 
normal) 
b. Total bilirubin greater than 1.2 × ULN (with exception of 
Gilbert's syndrome) 
c. Alkaline phosphatase (ALP) equal to or higher than 2 × ULN 
unless the ALP elevation is not from a hepatic origin. 
Note: Out-of-range laboratory abnormalities may be repeated 
during the Screening period to reassess for eligibility. 
4.  Subject has significant kidney disease as indicated by either of the 
following: 
a. Estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73m2, according to Modification of Diet in 
Renal Disease (MDRD) Study equation. MDRD equation is 
as follows: 
eGFR (mL/min/1.73 m2) = 175 × (standardized serum 
creatinine)- 1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
black) 
or 
b. Creatinine ≥2 mg/dL. 
Out-of-range laboratory abnormalities may be repeated during the 
Screening period to reassess for eligibility. 


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5. Subject is positive for hepatitis B surface antigen (HbsAg), human 
immunodeficiency virus (HIV)-1 or -2 antibodies or antigen, or 
history of spirochetal infection of the central nervous system (CNS) 
(eg, syphilis, borreliosis, or Lyme disease). Subjects with a positive 
hepatitis C virus antibody will be allowed if hepatitis C RNA is 
negative. 
6. Subject has uncontrolled hypertension (eg, repeated supine systolic 
blood pressure (BP) >140 mm Hg or diastolic BP >90 mm Hg) at 
Screening. 
7. Subject has a history or presence of an abnormal electrocardiogram 
(ECG) that is clinically significant, including atrial fibrillation, 
complete left bundle branch block, second- or third-degree 
atrioventricular block, or evidence of acute or subacute myocardial 
infarction or ischemia. 
8. Presence of unstable psychiatric disease (including suicidality), 
cognitive impairment, dementia, or substance abuse that would 
impair ability of the subject to provide informed consent or 
interfere with the interpretation of study data, in the investigator's 
opinion. 
9. Subject has a history of cancer, except if the subject: 
a. Is considered likely to be cancer-free 
b. Is not being actively treated with anticancer therapy or 
radiation and, in the opinion of the investigator, is not likely to 
require treatment in the ensuing 3 years. Ongoing antihormonal 
adjuvant treatment (eg, tamoxifen) is permitted 
c. Is considered to have low probability of recurrence (with 
supporting documentation from the treating oncologist and at 
the discretion of the investigator and Medical Monitor) 
d. For prostate cancer, has not had significant progression within 
the past 2 years. 
10. Known history of severe allergic, anaphylactic, or other 
hypersensitivity reaction to chimeric, human, or humanized 
antibodies or proteins. 
11. Any prior exposure to an anti-sortilin antibody. 
12. Use of investigational treatments or nutritional supplements 
(off-label use or active participation in a clinical trial) within 5 half-
lives (if known) or 30 days (whichever is longer) prior to the 
Screening Visit, at the discretion of the Medical Monitor and study 
sponsor. 
13. Exposure at any time to any gene therapies under investigation for 
the treatment of ALS (off-label use or investigational) 


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14. Unwilling to forgo donation of blood or blood products for 
transfusion for the duration of the study and for 1 year after final 
dose of study drug. 
15. Anything that would place the subject at increased risk or preclude 
their full compliance with or completion of the study, in the 
investigator's opinion. 
16. Contraindication to undergoing a LP, in the investigator's opinion. 
Subjects undergoing the LP must not be currently taking 
anticoagulation or antiplatelet medications, such as warfarin or 
Plavix®, that would be a contraindication to LP; aspirin and non-
steroidal anti-inflammatories are allowed. 
17. The following medications are prohibited for a pre-specified 
duration prior to study start, as indicated, and during the entire 
period of study participation (subjects who start these medications 
during the study may be discontinued from study drug 
administration): 
a. Any cannabinoids at least 90 days prior to study treatment 
administration unless approved by the Medical Monitor. Use of 
cannabinoids (other than cannabidiol [CBD]) is prohibited 
within 72 hours prior to any cognitive or behavioral assessment 
in the study. 
b. Any passive immunotherapy (immunoglobulin) or other long-
acting biologic agent within 180 days of Screening 
c. Any experimental vaccine. Routinely recommended 
vaccinations are allowed, as well as any vaccine against 
SARS-CoV-2 (COVID-19) either approved or administered 
under an Emergency Use Authorization. 
d. Typical antipsychotic or neuroleptic medication within 
180 days of study drug administration, except as brief treatment 
for a nonpsychiatric indication (eg, emesis). Use of atypical 
antipsychotic medications or use of pimavanserin is allowed if 
treated with a stable regimen for at least 90 days prior to study 
drug administration. Use of certain atypical antipsychotics may 
be allowed for as needed (PRN) or acute use at the discretion of 
the investigator, but must not be initiated within 48 hours of 
cognitive or behavioral assessments. 
e. Systemic immunosuppressive therapy, or the anticipated need 
for systemic immunosuppressive therapy during the study. Use 
of prednisone of ≤10 mg/day or an equivalent corticosteroid is 
allowed if stable for at least 90 days prior to study drug 
administration and hemoglobin >10 g/dL, WBC count 
>3.0 × 103/mm3, absolute neutrophil count >1.0 × 103/mm3, 
and platelet count >150 103/mm3. Brief use of systemic 
corticosteroids (≤7 days) is permitted for treatment of 
intercurrent illness. 


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f. Chronic use of opiates or opioids (including long-acting opioid 
medication) within 90 days of study drug administration. 
Intermittent short-term use (<1 week) of short-acting opioid 
medications for pain is permitted except within 2 days or 
5 half-lives (whichever is longer) prior to any clinical outcome 
assessment. 
g. Chronic use of barbiturates, or hypnotics from 90 days prior to 
study drug administration. Intermittent short-term (<1 week) 
use of buspirone or a short-acting hypnotic medication for 
sleep or anxiety is allowed, except within 2 days or 5 half-lives 
(whichever is longer) prior to any clinical outcome assessment. 
Study Duration 
Enrollment is expected to take 8 to 10 months. Total Screening and 
Follow-up duration for each subject is 35 weeks. The time from first 
subject enrolled to last subject completed is expected to be 17 to 19 months. 
Duration of Subject 
Participation 
The expected total duration of a subject's participation is 35 weeks: 
Screening Period: 3 weeks 
Treatment Period: 24 weeks 
Follow-up Period: 8 weeks 


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Figure 1: 
Study Schema 
 
Abbreviations: IV=intravenous. 
Note: Subjects who plan to discontinue the study early should be encouraged to return to the investigational site for 
an Early Termination Visit, which is 8 weeks after the last dose of study treatment.  


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LIST OF TERMS AND ABBREVIATIONS 
Abbreviation 
Term 
ADA 
anti-drug antibody 
ADR 
adverse drug reaction 
AE 
adverse event/adverse experience 
ALP 
alkaline phosphatase 
ALS 
amyotrophic lateral sclerosis  
ALS-CBS 
ALS Cognitive Behavioral Screen 
ALT 
alanine aminotransferase 
aPTT 
activated prothromboplastin time 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BMI 
body mass index 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
AST 
aspartate aminotransferase 
C 
Celsius 
CAFS 
Combined Assessment of Function and Survival 
CC 
Coordination Center 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
COVID-19 
Coronavirus Disease 2019 
C9ALS 
C9orf72-associated amyotrophic lateral sclerosis 
CBD 
cannabidiol 
cm 
centimeter 
CNS 
central nervous system 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
clinical research organization 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
dL 
deciliter 
DLAE 
dose-limiting adverse events 


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Abbreviation 
Term 
DNA 
deoxyribonucleic acid 
DPR 
dipeptide repeat protein 
eCRF 
electronic Case Report Form 
eGRF 
estimated glomerular filtration rate 
ECG 
electrocardiogram  
EDC 
electronic data capture 
EOS 
end of study 
F 
Fahrenheit 
FTD 
frontotemporal dementia 
FTD C9orf72 
frontotemporal dementia with C9orf72 hexanucleotide repeat expansion 
mutations 
FTD-GRN 
frontotemporal dementia with heterozygous progranulin gene mutations 
FDA 
Food and Drug Administration 
FVC 
forced vital capacity 
g 
grams 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GRN 
progranulin gene 
HbsAg 
hepatitis B surface antigen 
Hg 
mercury 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
iDMC 
independent data monitoring committee 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
in 
inches 
IND 
Investigational New Drug 
INR 
international normalized ratio 


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Abbreviation 
Term 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRT 
Interactive Response Technology  
ISF 
investigator site file 
ITT 
intent-to-treat  
IV  
intravenous 
kg 
kilogram 
LFTs 
liver function tests 
LP 
lumbar puncture 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MGH 
Massachusetts General Hospital 
MM 
Medical Monitor 
 
 
mm 
millimeter 
mM 
millimolar 
mmHg 
millimeters of mercury 
NCRI 
Neurological Clinical Research Institute 
NEALS 
Northeast ALS Consortium 
NfL 
neurofilament light chain 
OHRP 
Office for Human Research Protections 
PAV 
permanent assisted ventilation 
PD 
pharmacodynamic 
PGRN 
progranulin 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PRN 
pro re nata, meaning "as needed" 
PT 
partial thrombin 
PTT 
partial thromboplastin time 
QA 
quality assurance 
QC 
quality control 


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Abbreviation 
Term 
RAN 
repeat associated non-AUG 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SI 
Site Investigator 
SNP 
single nucleotide polymorphism 
SOP 
standard operating procedure 
SUSAR 
serious, unexpected, suspected adverse drug reaction 
SVC 
slow vital capacity 
TDP-43 
TAR DNA-binding protein 
TEAE 
treatment-emergent adverse event 
TMF 
Trial Master File 
ULN 
upper limit of normal 
US 
United States 
VC 
vital capacity 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1. 
Study Rationale 
1.1.1. 
Amyotrophic Lateral Sclerosis 
Amyotrophic lateral sclerosis (ALS) is a progressive disorder affecting the motor neurons in the 
brain and spinal cord, ultimately leading to paralysis and death from respiratory failure 
(Brooks 1996). The incidence of ALS is approximately 2/100,000, with a prevalence of only 
5/100,000 due to rapid disease progression (Chiò 2013). Median age of onset is in the mid-to-late 
50s, with survival variable and often dependent on phenotype (Brown 2017). Riluzole and 
edaravone, the two Food and Drug Administration (FDA)-approved disease-modifying 
medications for ALS, confer only a modest survival benefit (Miller 2012; Writing Group; 
Edaravone (MCI-186) ALS 19 Study Group 2017). 
1.1.2. 
C9orf72-Associated ALS 
An expansion of the hexanucleotide intronic repeat GGGGCC in the C9orf72 (C9) gene was first 
described in 2011 and is the most common cause of familial ALS (DeJesus-Hernandez 2011; 
Renton 2011; Gijselinck 2012). Approximately 40-50% of all familial ALS and up to 10% of 
sporadic ALS cases are attributed to this repeat expansion. Patients harboring the C9 repeat 
expansion have an increased predilection for bulbar-onset and the coincidence of frontotemporal 
dysfunction (Ghasemi 2018). The proposed mechanisms by which the C9 repeat expansion 
causes disease are RNA and protein-mediated neurotoxicity through accumulation of dipeptide 
repeat proteins (DPRs) from repeat associated non-AUG (RAN) translation and RNA binding 
protein (eg, TDP-43) sequestration (Brown 2017). TAR DNA-binding protein 43 (TDP-43) is an 
RNA/DNA binding protein important to RNA-related metabolism, found within deposits or 
inclusion bodies in the brains and spinal cords of patients with both sporadic and familial forms 
of ALS and frontotemporal dementia (FTD), including individuals with C9orf72-associated ALS 
(C9ALS) (Prasad 2019; Steinacker 2016). 
1.1.3. 
Shared Genetics and Pathology of ALS and Frontotemporal Dementia 
There is increasing evidence of not only a clinical co-occurrence but a genetic overlap between 
ALS and FTD (Karch 2018). Multiple genes have been identified as causative for both disorders, 
including TARDBP, C9orf72, VCP, and TBK1 (Weishaupt 2016; Smith 2012). The locus of the 
FTD causal gene, progranulin gene (GRN), carries a functional single nucleotide polymorphism 
(SNP) (rs5848) that is linked to survival after disease onset in C9 repeat expansion carriers 
(van Blitterswijk 2014). Furthermore, common variants in GRN (
 
3) were significantly associated with an earlier age of onset and a sho e survival in 
individuals with ALS (Sleegers 2008). These data not only indicate that progranulin (PGRN) 
genetic variability acts as a modifier in ALS, but a common pathway by which C9orf72 and 
PGRN cause disease. 
TDP-43 is an RNA/DNA binding protein important to RNA-related metabolism, found within 
deposits or inclusion bodies in the brain and spinal cord of patients with both sporadic and 
familial forms of ALS and FTD, including individuals with C9ALS (Prasad 2019; 
Steinacker 2016). The prevalence of TDP-43 in most forms of ALS and tau-negative FTD 


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(Van Mossevelde 2018) suggests a pivotal pathogenic role, and thus pathways impacting 
TDP-43 aggregation are potential therapeutic targets in these fatal diseases (Scotter 2015; 
Shenouda 2018). 
Chronic inflammation is another common pathogenic feature seen in ALS and FTD, suggesting 
the importance of central nervous system (CNS) immune cells such as microglia in both 
diseases. GRN and C9orf72 mutations are also both associated with abnormal microglial 
activation (Haukedal 2019). PGRN is a highly expressed protein in microglial cells, with 
multiple functions including modulation of inflammation (Haukedal 2019), regulation of 
lysosomal function (Tanaka 2013), and neurotrophic effects including preservation of neuronal 
survival and axonal growth (Gass 2012, De Muynck 2013). PGRN deficiency results in an 
exaggerated inflammatory response after brain insults (Tanaka 2013; Martens 2012; Yin 2010). 
PGRN was shown to reverse and be protective against TDP-43 pathology in preclinical studies 
(Laird 2010; Tauffenberger 2013, Chang 2017; Beel 2018), which characterizes approximately 
95% of all ALS cases (Prasad 2019). While loss of PGRN was found to be detrimental in 
multiple models of acute and chronic neurodegeneration (Boddaert 2018), overexpression of 
PGRN was protective. Specifically, overexpression of human PGRN was protective against 
TDP-43-induced axonopathy in a zebrafish model (Laird 2010). PGRN was also shown to be 
protective in a C. elegans model of TDP-43 and FUS-induced polyglutamine toxicity 
(Tauffenberger 2013). PGRN overexpression in TDP-43(A315T) mice reduced the levels of 
insoluble TDP-43, decreased the loss of large motor axon fibers, and prolonged survival by 
approximately 130 days (Beel 2018). These findings are consistent with Chang et. al, suggesting 
impaired autophagy contributes to the accumulation of TDP-43 in GRN−/− neurons, and that 
PGRN can stimulate clearance of TDP-43 through autophagy (Chang 2017). In contrast, 
overexpression of PGRN in mutant SOD1 mice, a model of a human ALS form that is not 
associated with TDP-43 pathology, did not affect onset or progression of motor neuron 
degeneration (Herdewyn 2013), indicating that the effect of PGRN is specific to TDP-43 
pathology. 
1.2. 
Background 
1.2.1. 
Sortilin and AL001 
Human and mouse genetic studies identified the transmembrane receptor sortilin, encoded by the 
SORT1 gene, as the major negative regulator of PGRN levels in plasma and the brain 
(Carrasquillo 2010; Hu 2010). Sortilin binds PGRN and targets it for lysosomal degradation 
resulting in a reduction of extracellular PGRN. 
AL001 is an intravenous (IV) recombinant monoclonal antibody (known as latozinemab but 
referred to as AL001 within the protocol) that selectively binds to human and cynomolgus 
monkey sortilin. Sortilin induces the degradation of PGRN (Carrasquillo 2010; Hu 2010), and its 
blockade leads to a chronic, 2–3-fold increase in plasma and cerebrospinal fluid (CSF) levels of 
PGRN in cynomolgus monkeys and in healthy human volunteers. Blocking sortilin/PGRN 
interactions, therefore, provides a therapeutic strategy for sustaining PGRN levels in the CNS. 
Sortilin is not required for PGRN signaling, as evidenced by the fact that SORT1-deficient 
neurons retain a full response to PGRN (Gass 2012), and interestingly, SORT1 knockout is not 
associated with neurodegeneration (Jansen 2007). 


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1.2.2. 
Overview of Nonclinical Toxicology Studies  
To support clinical studies, the toxicology of AL001 was evaluated via single- and repeat-dose 
preliminary and Good Laboratory Practice (GLP) repeat-dose (4-week and 26-week) IV 
toxicology studies in cynomolgus monkeys. Across all the dose levels assessed (up to 
0 mg/kg), there were no significant toxicology findings in the nonclinical studies. 
Refer to the AL001 Investigator’s Brochure for additional information regarding nonclinical 
pharmacology, pharmacokinetic (PK), and toxicology data. 
1.2.3. 
Overview of Clinical Studies with AL001 
AL001 is currently in evaluation for the treatment of FTD with TDP-43 pathology and in 
C9ALS. 
Study AL001-1, Phase 1 FIH Study in Healthy Volunteers and Patients with FTD 
(Completed): The AL001 dose was determined based on the results from a Phase 1 dose-finding 
study in healthy volunteers and in patients with FTD (Study AL001-1). A total of 52 healthy 
volunteers received single doses of AL001 ranging from 2 mg/kg to 60 mg/kg and 12 subjects 
received placebo. AL001 was generally safe and well tolerated through the highest dose assessed 
(60 mg/kg) and demonstrated a favorable safety profile without dose-limiting toxicities or 
concerning apparent trends in adverse events (AEs), with a robust pharmacodynamics (PD) 
effect in plasma and CSF. The second part of Study AL001-1 enrolled asymptomatic FTD-GRN 
patients who received a single dose of 60 mg/kg AL001 by IV, and symptomatic FTD-GRN 
patients who received 3 doses of IV 30 mg/kg AL001 every 2 weeks. Data showed safety and 
tolerability, while demonstrating proof-of-mechanism of action with prolonged post-dose 
increase in plasma PGRN concentration. 
Study AL001-2, A Phase 2 Open-Label Extension Study in Patients with FTD (Ongoing): 
Study AL001-2 is evaluating the long-term safety profile of AL001 in symptomatic and 
asymptomatic FTD-GRN carriers, and in symptomatic carriers of C9orf72 mutations causative of 
FTD (FTD C9orf72). As of 27 August 2021, a total of 16 GRN carriers (5 asymptomatic and 
11 symptomatic with FTD) and 9 symptomatic C9orf72 carriers with FTD have been enrolled; 
study AL001-2 will enroll up to 20 symptomatic FTD C9orf72 repeat expansion carriers. The 
most frequently reported treatment-emergent adverse events (TEAEs) across all study 
populations have been fall and rash. 
Study AL001-3, A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study in 
Patients with FTD: Study AL001-3 is evaluating the efficacy and safety of AL001 in 
individuals with symptomatic FTD and at-risk GRN mutation carriers. The study is ongoing and 
remains blinded. As of the 27 August 2021 data cutoff, 38 subjects have been enrolled. There 
have been no deaths, no drug-related SAEs, and AEs have been predominantly mild in severity. 
One moderate TEAE of flagellate dermatitis led to study discontinuation.  
Refer to the AL001 Investigator's Brochure for additional clinical study data. 
1.2.4. 
Rationale for the Treatment of C9ALS with AL001 
The accumulation of TDP-43 is the most significant pathological finding in approximately 95% 
of ALS cases, such as those associated with the C9 repeat expansion (Prasad 2019). Both data 
from animal models and human genetics support a neuroprotective effect of increasing 


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extracellular PGRN levels by reducing TDP-43-associated pathology in ALS. Taken together, 
these findings suggest that AL001 may be a candidate therapeutic in C9ALS. 
1.2.5. 
Dose Justification 
The AL001 dose was determined based on the AL001-1 Phase 1 study results. AL001 was 
generally safe and well tolerated through the highest dose assessed (60 mg/kg) and demonstrated 
a favorable safety profile without dose-limiting adverse events (DLAEs), with a robust PD effect 
in plasma and CSF. 
1.3. 
Risk/Benefit Assessment of AL001 
Refer to the AL001 Investigator's Brochure for detailed information on safety profile of AL001. 
1.3.1. 
Known Risks of the Drug Class 
Immune Response: Monoclonal antibodies like AL001 may be associated with a potential 
immune response, such as hypersensitivity or hypersensitivity-like reactions, including severe 
anaphylactic reactions. 
1.3.2. 
Risks of AL001 and AL001-ALS-201 Study Procedures and Assessments 
Risks Associated with AL001-ALS-201 Study Procedures and Assessments: The study procedures 
and assessments to be performed are not considered to be of great burden to subjects and are not 
associated with high risk. 
Important Identified Risks: There are no important identified risks for AL001 to date. 
Serious Adverse Drug Reactions: No serious adverse drug reactions (ADRs) have been reported 
in completed and ongoing clinical studies with AL001 to date and there are no expected serious 
ADRs for AL001. 
Immunogenicity: Subjects treated with AL001 have developed anti-drug antibodies (ADAs). The 
preliminary assessment of ADAs has not identified any associations between incident ADAs 
with PK, PD, or clinical safety in subjects receiving single-dose AL001 or three doses of AL001 
administered every 2 weeks. Based on the current information from studies with AL001, the 
impact of immunogenicity on AL001 exposure, PD effects, and clinical safety do not appear 
consequential with short duration of exposure. However, the impact of ADAs continues to be 
assessed in ongoing AL001 clinical studies with longer-term exposure. An ADA assay for 
neutralizing antibodies to AL001 is under development. See the AL001 Investigator's Brochure 
for more information on immunogenicity. 
Adverse Events: AL001 has been generally safe and well tolerated. There have been no deaths, 
no AL001-related serious adverse events (SAEs), and no AL001-related AEs leading to study 
discontinuation in the clinical trials of AL001 to date. AEs have been predominately mild to 
moderate in severity. Refer to the AL001 Investigator's Brochure for a detailed summary of AEs. 
1.3.3. 
Potential Benefits of AL001 
AL001 is a novel recombinant human monoclonal immunoglobulin G (IgG)1 antibody that 
blocks sortilin, decreasing the rate of PGRN clearance, and raising the concentration of PGRN. 
AL001 may therefore decrease the rate of neurodegeneration associated with ALS among 


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patients who carry GRN mutations. Treatment with AL001 represents a promising therapeutic 
strategy for patients with C9ALS and while the efficacy of treatment with AL001 is still under 
investigation, patients with C9ALS may benefit from participating in clinical trials of AL001, 
which are designed to evaluate a potential treatment for a disease for which there are inadequate 
treatments. Subjects will receive either AL001 or placebo in addition to their stable, standard of 
care treatment. All subjects will receive and potentially benefit from close medical monitoring 
and care from qualified professionals throughout their participation in the study. 
1.3.4. 
Benefit-Risk Assessment for Study AL001-ALS-201 Study Subjects 
Participation in Study AL001-ALS-201 offers the possibility of receiving AL001, a novel 
recombinant human monoclonal IgG1 antibody that blocks sortilin, for the treatment of adults 
with C9ALS. By blocking sortilin, decreasing the rate of PGRN clearance and therefore raising 
the concentration of PGRN, AL001 may decrease the rate of neurodegeneration and clinical 
decline associated with ALS among patients who carry C9orf72 mutations. 
More detailed information about the known and expected benefits and risks of AL001 may be 
found in the AL001 Investigator's Brochure. 
The potential benefit of AL001 to subjects is based on the completed Phase 1 study, Study 
AL001-1, which demonstrated that AL001 is associated with significant and dose-dependent 
increases in plasma and CSF PGRN in both healthy volunteers, asymptomatic, and symptomatic 
carriers of GRN mutations causative of FTD. Of note, administration of AL001 to subjects with 
GRN mutations restored CSF and plasma PGRN levels to normal and increased plasma PGRN 
2-3× in FTD subjects with C9orf72 mutations. By blocking sortilin, decreasing the rate of PGRN 
clearance and therefore raising the extracellular concentration, AL001 may reduce TDP-43-
associated pathology and decrease the rate of neurodegeneration and clinical decline associated 
with ALS among patients who carry C9orf72 mutations (C9ALS). 
Any risks to subjects in AL001-ALS-201 will be minimized through a combination of screening 
for appropriate eligibility criteria and rigorous safety monitoring to identify risks, as well as 
careful toxicity management. Adverse event and/or severe AE collection will occur up to 
8 weeks after last dose of study treatment. Frequent safety monitoring will ensure that updated 
safety information is available in a timely manner and that any future changes to the risk/benefit 
profile of AL001 are appropriately reported and managed. Alector will provide careful screening, 
diligent monitoring, and management of patient safety throughout the course of the study. 
Taking the available data on the investigational therapy together with the study design and 
conduct, AL001 is anticipated to be generally safe, well tolerated and provide pharmacological 
effect at the dose of 60 mg/kg being administered in this study. Subjects, regardless of the 
treatment group to which they are randomly assigned, will receive close medical monitoring and 
care from qualified professionals throughout their participation in the study. Periodic safety 
monitoring will ensure that updated safety information is available in a timely manner and that 
any future changes to the benefit-risk profile of AL001 are appropriately assessed. An 
independent data monitoring committee (iDMC) with the capability of reviewing unblinded data 
will provide additional oversight of the study, supplementing the Sponsor’s screening, 
monitoring, and management of patient safety. The assessment procedures included in the 
clinical studies are not considered to be of great burden to patients and are not associated with 
high risk. Informed consent processes are intended to both (1) describe these potential benefits 


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and potential risks from participating in the study and (2) ensure, in accordance with local 
regulation, that a legally authorized representative is identified for subjects who may not have 
legal capacity to provide consent. Therefore, it is plausible to conclude that the anticipated 
benefits of participating in this study outweigh the potential risks or inconveniences. 


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2. 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
• To evaluate the safety of AL001 
in C9ALS 
• To evaluate the tolerability of 
AL001 in C9ALS 
• To evaluate changes in plasma 
and CSF PGRN levels after 
AL001 treatment 
• To evaluate AL001 PK 
parameters in serum and CSF 
• To evaluate ADAs to AL001 in 
serum 
• Safety: Defined as the occurrence of 
TEAEs, treatment-emergent SAEs, 
and treatment-emergent clinically 
significant abnormalities in clinical 
and laboratory values 
• Tolerability: Defined as the 
percentage of subjects who complete 
the trial without TEAEs leading to 
treatment discontinuation 
• PK: Serum and CSF concentrations of 
AL001, and PK parameters 
• PD: Changes from baseline in plasma 
and CSF levels of PGRN 
• Immunogenicity: Incidence of ADAs 
to AL001 
Safety, tolerability, 
immunogenicity, PK, CSF 
penetration of AL001, and 
PD have not yet been 
evaluated in patients with 
C9ALS. 
Secondary 
 
 
• To evaluate the biological 
activity of AL001 as measured 
by NfL levels in the blood and 
CSF 
• Changes in blood and CSF levels of 
NfL 
The level of neurofilament, a 
marker of neurodegeneration, 
is believed to be relatively 
stable over time and thus, a 
change from baseline may 
demonstrate biological 
evidence of a disease 
modifying effect. 
Exploratory  
 
 
• To evaluate genotype-specific 
effects of AL001 on PD 
biomarkers for common variants 
of GRN  
• To evaluate dipeptide repeat 
protein (DPR) levels in CSF 
• To evaluate the biological 
activity of AL001 as measured 
by exploratory PD biomarkers of 
neurodegeneration, lysosomal 
• Pharmacogenetic effects of AL001 
with respect to the following single 
nucleotide polymorphisms (SNPs): 
rs5848, r
 
r
3 
• Changes in CSF levels of poly (GP) 
DPRs 
• Changes in PD biomarkers of 
neurodegeneration, lysosomal 
These endpoints have been 
chosen to provide a greater 
understanding of ALS and 
may provide opportunities for 
identification of surrogate 
endpoints that are reasonably 
likely to predict clinical 
benefit and that might serve 
as a basis for accelerated 
approval in future trials. 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
function, and glial activation in 
the blood, urine, and CSF 
• To evaluate the effect of AL001 
on clinical measures of disease 
progression 
• To evaluate the effect of AL001 
on ventilator-free survival 
• To estimate correlations between 
fluid PD biomarkers and clinical 
measures of disease progression 
function, and glial activation in the 
blood, urine, and CSF 
• Clinical progression as measured by 
changes in: 
− 
ALS Functional Rating Scale-
Revised (ALSFRS-R) total and 
domain scores 
− 
Combined Assessment of 
Function and Survival (CAFS) 
− 
Vital capacity (VC) 
− 
ALS Cognitive Behavioral 
Screen (ALS-CBS) 
− 
Digital home measures of 
cognition and motor speech 
components 
• Permanent assisted ventilation 
(PAV)-free survival 
• Correlations between fluid PD 
biomarkers and clinical measures of 
disease progression 
Abbreviations: ADA=anti-drug antibody; AE=adverse event; ALS=amyotrophic lateral sclerosis; ALS-CBS=ALS 
Cognitive Behavioral Screen; ALSFRS-R=ALS Functional Rating Scale-Revised; CSF=cerebrospinal fluid; 
DPR=dipeptide repeat protein; IV= intravenous; NfL=neurofilament light chain; PAV=permanent assisted 
ventilation; PGRN=progranulin; PD=pharmacodynamic; PK=pharmacokinetic; SAE=serious adverse event; 
SNP=single nucleotide polymorphism; TEAE=treatment-emergent adverse event; VC=vital capacity.  
 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a Phase 2, multicenter, randomized clinical trial evaluating the safety, tolerability, and 
biological effect of AL001 compared to placebo in approximately 45 adults with C9ALS.  
The study consists of a Screening Period (within 3 weeks prior to Day 0), a 24-week Treatment 
Period, and an 8-week Safety Follow-Up Period, concluding with the Study Completion Visit 
(8 weeks after last study drug administration). 
Informed consent will be obtained prior to the conduct of any study-related procedures. Any 
individual who gives written informed consent to participate in the study is considered a subject 
in the study. Subject eligibility will be assessed at the Screening Visit and during the Screening 
Period. Upon determination of subject eligibility, Day 0 will occur within 3 weeks of Screening. 
Subjects will be randomly assigned to receive either standard of care + AL001 or standard of 
care + placebo (randomized 2:1 with stratification by rs5848 genotype [CC, CT, TT]). AL001 
60 mg/kg or matching placebo will be administered via IV infusion every 4 weeks for 24 weeks. 
An iDMC will review the progress of the study and perform safety reviews to evaluate potential 
safety and tolerability issues. The iDMC will be governed by an approved charter. The roles and 
responsibilities of the iDMC are summarized in Section 10.5. 
Refer to the Schedule of Assessments (Appendix 1) for the assessments to be performed at each 
study visit. 
3.2. 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of 
Assessments (Appendix 1). 
Subjects can withdraw from the study at any time. Subjects who plan to discontinue the study 
early should be encouraged to return to the investigational site for an Early Termination Visit, 
which is 8 weeks after the last dose of study treatment.  
Information on whether a subject has died may be obtained from the subject’s family, from clinic 
notes, or from a publicly available data source like the Centers for Disease Control and 
Prevention (CDC) National Death Index or the Social Security Death Index. The vital status 
determination, defined as a determination of date of death or death equivalent or date last known 
alive, can be determined for each subject at the end of their study participation. If the subject is 
alive at the end of their study participation, their vital status may be determined again at a later 
time after study participation has ended but before the final data lock from clinic notes or using 
publicly available resources. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
A prospective subject must meet all the following criteria to be eligible for study participation: 
1. Diagnosis of C9orf72-associated ALS with both of the following: 
a. Documentation of a clinical genetic test demonstrating the presence of a pathogenic 
repeat expansion in C9orf72 
and 
b. Must meet possible, laboratory-supported probable, probable, or definite criteria for a 
diagnosis of ALS by revised El Escorial criteria (Brooks 2000). 
2. Age 18 or older. 
3. Capable of providing informed consent at the Screening Visit and complying with study 
procedures throughout the study, in the investigator's opinion and at the discretion of the 
Medical Monitor and the study sponsor. 
4. If the subject has a participating caregiver, the caregiver must live with the subject and, in 
the investigator's opinion, have adequate knowledge of the subject's daily activities and 
function; participating caregivers must sign the caregiver section of the informed consent. 
Not having a caregiver is not exclusionary. 
5. Time since onset of muscle weakness due to ALS ≤36 months at the time of the 
Screening Visit. 
6. Vital capacity (VC) ≥50% of predicted capacity at the time of the Screening Visit. Vital 
capacity is preferred to be measured by slow vital capacity (SVC) in clinic. If required 
due to pandemic-related restrictions, forced vital capacity (FVC) measured in clinic via 
pulmonary function laboratory may be performed at the discretion of the Medical 
Monitor and the study sponsor. If due to pandemic-related restrictions in clinic vital 
capacity is not possible, then FVC may be performed via home spirometry at the 
discretion of the Medical Monitor and the study sponsor. 
7. Must not be taking riluzole or must be on a stable dose of riluzole for at least 30 days 
prior to the Screening Visit. Riluzole-naïve patients are permitted in the study. 
8. Must not be taking edaravone or must have completed at least one cycle of edaravone 
with a plan of continuing edaravone prior to the Screening Visit. Subjects must be off 
cycle and at least 2 days after the last dose administration of edaravone at the time of 
study drug infusions. Edaravone-naïve subjects are permitted in the study. 
9. At Screening, women must be non-pregnant (as demonstrated by a negative serum 
pregnancy test at Screening) and non-lactating, and one of the following conditions must 
apply: 
a. Not a woman of childbearing potential (either surgically sterilized or physiologically 
incapable of becoming pregnant, or at least 1 year postmenopausal [amenorrhea 
duration of 12 consecutive months with no identified cause other than menopause]) 


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b. Is a woman of childbearing potential and agrees to use an acceptable contraceptive 
method from Screening until 10 weeks after the last dose of study treatment. 
Acceptable contraception is defined as using hormonal contraceptives (eg, combined 
oral contraceptive pill) or an intrauterine device combined with at least one of the 
following forms of contraception: a diaphragm or cervical cap, or a condom. Total 
abstinence, if in accordance with the usual lifestyle of female subject, is acceptable. 
A woman of childbearing potential must have a serum pregnancy test conducted at 
Screening. Additional requirements for pregnancy testing during and after study 
intervention are described in the Schedule of Assessments (Appendix 1). 
10. Men must agree to use acceptable contraception and not donate sperm from Day 0 until 
10 weeks after the last dose of study treatment. Acceptable contraception for male 
subjects when having sexual intercourse with a female partner who is not currently 
pregnant is defined as using a condom. In addition, female partners of childbearing 
potential must agree to use hormonal contraceptives (eg, combined oral contraceptive 
pill) or an intrauterine device. Acceptable contraception for male subjects when having 
sexual intercourse with a female partner is defined as using a condom or having a 
vasectomy. Total abstinence, if in accordance with the usual lifestyle of the male subject, 
is acceptable. 
11. In the investigator’s opinion, subjects must be able to complete all study procedures, 
including the IV study drug administration and lumbar punctures (LPs). 
4.2. 
Exclusion Criteria 
Prospective subjects who meet any of the following criteria are not eligible for study 
participation: 
1. Clinically significant, unstable, medical condition (other than ALS) that would pose a 
risk to the subject or interfere with the interpretation of study data, according to the 
investigator's judgement (eg, cardiovascular disease, systemic infection, pulmonary 
disease, rheumatologic disease, etc.). 
2. Clinically significant laboratory abnormalities including, but not limited to: hemoglobin 
<10 g/dL, white blood cells (WBC) <3.0 × 103/mm3, absolute neutrophils ≤1.0 × 103/ 
mm3, eosinophilia (absolute eosinophil count of ≥0.5 × 103/mm3), low platelet counts 
(<150 × 103/mm3), prothrombin time (PT)/activated partial thromboplastin time 
(aPTT)/international normalized ratio (INR), lipase >1.2 × upper limit of normal (ULN). 
Out-of-range laboratory abnormalities may be repeated during the Screening period to 
reassess for eligibility. 
3. Subject has impaired hepatic function or occult liver injury as indicated by Screening: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 
3 times the ULN (bilirubin levels should be normal) 
b. Total bilirubin greater than 1.2 × ULN (with exception of Gilbert's syndrome) 
c. Alkaline phosphatase (ALP) equal to or higher than 2 × ULN unless the ALP 
elevation is not from a hepatic origin. 


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Note: Out-of-range laboratory abnormalities may be repeated during the Screening period 
to reassess for eligibility. 
4.  Subject has significant kidney disease as indicated by either of the following: 
a. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2, according to 
Modification of Diet in Renal Disease (MDRD) Study equation. MDRD equation is 
as follows: 
eGFR (mL/min/1.73 m2) = 175 × (standardized serum creatinine)- 1.154 × (Age)-0.203 × 
(0.742 if female) × (1.212 if black) 
or 
b. Creatinine ≥2 mg/dL. 
Out-of-range laboratory abnormalities may be repeated during the Screening period to 
reassess for eligibility. 
5. Subject is positive for hepatitis B surface antigen (HbsAg), human immunodeficiency 
virus (HIV)-1 or -2 antibodies or antigen, or history of spirochetal infection of the CNS 
(eg, syphilis, borreliosis, or Lyme disease). Subjects with a positive hepatitis C virus 
antibody will be allowed if hepatitis C RNA is negative. 
6. Subject has uncontrolled hypertension (eg, repeated supine systolic blood pressure (BP) 
>140 mm Hg or diastolic BP >90 mm Hg) at Screening. 
7. Subject has a history or presence of an abnormal electrocardiogram (ECG) that is 
clinically significant, including atrial fibrillation, complete left bundle branch block, 
second- or third-degree atrioventricular block, or evidence of acute or subacute 
myocardial infarction or ischemia. 
8. Presence of unstable psychiatric disease (including suicidality), cognitive impairment, 
dementia, or substance abuse that would impair ability of the subject to provide informed 
consent or interfere with the interpretation of study data, in the investigator's opinion. 
9. Subject has a history of cancer, except if the subject: 
a. Is considered likely to be cancer-free 
b. Is not being actively treated with anticancer therapy or radiation and, in the opinion of 
the investigator, is not likely to require treatment in the ensuing 3 years. Ongoing 
antihormonal adjuvant treatment (eg, tamoxifen) is permitted. 
c. Is considered to have low probability of recurrence (with supporting documentation 
from the treating oncologist and at the discretion of the investigator and Medical 
Monitor). 
d. For prostate cancer, has not had significant progression within the past 2 years. 
10. Known history of severe allergic, anaphylactic, or other hypersensitivity reaction to 
chimeric, human, or humanized antibodies or proteins. 
11. Any prior exposure to an anti-sortilin antibody. 
12. Use of investigational treatments or nutritional supplements (off-label use or active 
participation in a clinical trial) within 5 half-lives (if known) or 30 days (whichever is 


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longer) prior to the Screening Visit, at the discretion of the Medical Monitor and study 
sponsor. 
13. Exposure at any time to any gene therapies under investigation for the treatment of ALS 
(off-label use or investigational). 
14. Unwilling to forgo donation of blood or blood products for transfusion for the duration of 
the study and for 1 year after final dose of study drug. 
15. Anything that would place the subject at increased risk or preclude their full compliance 
with or completion of the study, in the investigator's opinion. 
16. Contraindication to undergoing a LP, in the investigator's opinion. Subjects undergoing 
the LP must not be currently taking anticoagulation or antiplatelet medications, such as 
warfarin or Plavix®, that would be a contraindication to LP; aspirin and non-steroidal 
anti-inflammatories are allowed. 
17. The following medications are prohibited for a pre-specified duration prior to study start, 
as indicated, and during the entire period of study participation (subjects who start these 
medications during the study may be discontinued from study drug administration): 
a. Any cannabinoids at least 90 days prior to study treatment administration unless 
approved by the Medical Monitor. Use of cannabinoids (other than cannabidiol 
[CBD]) is prohibited within 72 hours prior to any cognitive or behavioral assessment 
in the study. 
b. Any passive immunotherapy (immunoglobulin) or other long-acting biologic agent 
within 180 days of Screening. 
c. Any experimental vaccine. Routinely recommended vaccinations are allowed, as well 
as any vaccine against SARS-CoV-2 (COVID-19) either approved or administered 
under an Emergency Use Authorization. 
d. Typical antipsychotic or neuroleptic medication within 180 days of study drug 
administration, except as brief treatment for a nonpsychiatric indication (eg, emesis). 
Use of atypical antipsychotic medications or use of pimavanserin is allowed if treated 
with a stable regimen for at least 90 days prior to study drug administration. Use of 
certain atypical antipsychotics may be allowed for as needed (PRN) or acute use at 
the discretion of the investigator, but must not be initiated within 48 hours of 
cognitive or behavioral assessments. 
e. Systemic immunosuppressive therapy, or the anticipated need for systemic 
immunosuppressive therapy during the study. Use of prednisone of ≤10 mg/day or an 
equivalent corticosteroid is allowed if stable for at least 90 days prior to study drug 
administration and hemoglobin >10 g/dL, WBC count >3.0 × 103/mm3, absolute 
neutrophil count >1.0 × 103/mm3, and platelet count >150 103/mm3. Brief use of 
systemic corticosteroids (≤7 days) is permitted for treatment of intercurrent illness. 
f. Chronic use of opiates or opioids (including long-acting opioid medication) within 
90 days of study drug administration. Intermittent short-term use (<1 week) of 
short-acting opioid medications for pain is permitted except within 2 days or 
5 half-lives (whichever is longer) prior to any clinical outcome assessment. 


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g. Chronic use of barbiturates, or hypnotics from 90 days prior to study drug 
administration. Intermittent short-term (<1 week) use of buspirone or a short-acting 
hypnotic medication for sleep or anxiety is allowed, except within 2 days or 
5 half-lives (whichever is longer) prior to any clinical outcome assessment. 
4.3. 
Screening Failures 
Individuals who give informed consent to participate in the clinical trial, but who do not meet 
one or more criteria required for participation in the trial during the screening assessments, are 
considered screening failures. Minimal information for subjects who fail screening is collected in 
the Interactive Response Technology (IRT) system; this information includes basic demography 
and the reason(s) the subject failed Screening. 
Subjects who fail screening may be allowed one rescreen if an identifiable cause for screen 
failure is appropriately managed following approval of Alector's Medical Monitor. Subjects who 
are to be rescreened must be reconsented and given a new screening number, and the screening 
assessments must be repeated. The subject may not be required to repeat LP, if performed within 
12 weeks prior to study treatment administration, with approval from Alector's Medical Monitor. 
Repeat pharmacogenomic sampling is not required. 


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5. 
IDENTITY OF INVESTIGATIONAL PRODUCT 
5.1. 
AL001 
AL001 is a human recombinant anti-human sortilin monoclonal IgG1 G1m17,1 [or G1m (z,a)] 
kappa monoclonal antibody). 
5.2. 
Dosing and Administration 
Dosing solution preparation instructions will be provided separately in a Pharmacy Manual. 
AL001 or placebo will be administered IV over 60 minutes (±15 minutes) by trained site 
personnel under the supervision of the investigator or their designee. Study treatment 
administration will be recorded in the source documentation and in the electronic Case Report 
Form (eCRF). 
The investigator or a qualified designee must be present during the administration of study 
treatment. Subjects should be monitored for at least 60 minutes post infusion for the first 
2 infusions of AL001. After the first 2 infusions, post-infusion monitoring may be reduced to 
30 minutes. On treatment days, subjects will be discharged after the post-infusion monitoring 
period and after completion of all activities scheduled for that visit day at the discretion of the 
investigator or qualified designee. 
5.3. 
Storage, Handling, and Stability 
5.3.1. 
Storage and Handling 
The AL001 and placebo will be shipped and stored at a controlled temperature of 2°C to 8°C. 
Upon receipt at the investigational site, the AL001 and placebo shall be stored securely under 
controlled conditions in a refrigerator set to maintain 2°C to 8°C. The AL001 and placebo vials 
should be protected from light and remain in the cartons provided until use. Specific instructions 
about the preparation and administration of investigational drug are provided in the Pharmacy 
Manual. 
The investigators will be fully responsible for the security, accessibility, and storage of the 
AL001 and placebo while the vials are at their investigational facility. 
5.3.2. 
Stability of Prepared AL001 Solution 
From preparation of dosing solution to administration at the investigational site, dosing solution 
storage time will be limited to 4 hours at ambient temperature and no more than 24 hours at 2°C 
to 8°C. 
5.4. 
Formulation, Packaging, and Labeling 
5.4.1. 
Formulation 
AL001 is provided as a sterile solution formulated at a concentration of 5  mg AL001/mL in an 
aqueous formulation containing 
 
0
. 


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The placebo shares the same formulation as the study drug but lacks the AL001 antibody. 
AL001 and placebo vials provided for this study will be manufactured under current Good 
Manufacturing Practice (GMP) and will be suitable for human use. 
5.4.2. 
Packaging and Labeling 
The container closure system for both AL001 and placebo consists of a 20R Type I (European 
Pharmacopoeia compliant) clear glass vial with a coated bromobutyl rubber stopper and a 
flip-off type aluminum crimp seal with blue cap. Each single use vial will contain at least 2  mL 
of AL001 or 
 mL of placebo intended for IV use only. 
AL001 and placebo will be manufactured for Alector under contractual and quality agreements 
at a qualified contract manufacturing organization and per current GMP. Alector will ensure that 
the products are labeled in accordance with all local regulatory requirements. 
5.5. 
Drug Accountability 
The investigational site will maintain accurate records of receipt of all AL001 and placebo, 
including dates and condition of receipt. In addition, accurate records will be kept regarding 
when and how much AL001 or placebo is dispensed and used by each subject in the study. At 
the completion of the study, all AL001 and placebo will be reconciled and retained or destroyed 
according to applicable regulations. 
Study product supplies, including partially used or empty vials, should be disposed of at the 
investigational site per local standard operating procedures (SOPs). If study product supplies 
cannot be destroyed on site, they may be shipped back to the return depot. Please see Pharmacy 
Manual for additional instructions. 
AL001 and placebo are supplied for use only in this clinical study and may not be used for any 
other purpose. 
5.6. 
Randomization and Blinding 
5.6.1. 
Randomization 
Eligible subjects will be randomized to AL001 or placebo in a 2:1 ratio with stratification by 
rs5848 genotype (3 levels: CC, CT, TT). Randomization schedules for each stratum will be 
computer generated using permuted blocks. 
Subjects who sign the informed consent form and are randomized, but who do not receive study 
drug, may be replaced. Subjects who sign the informed consent form, are randomized, receive 
study drug, and who subsequently withdraw or are withdrawn from the study, will not be 
replaced. 
Eligible subjects will be randomly assigned to AL001 or placebo based on a randomization 
schedule prepared by the clinical research organization (CRO) before the start of the study. An 
IRT system will be used to administer the randomization schedule.  
The IRT will be used to maintain a central log documenting screening, to implement 
randomization, to assess current inventories of AL001 and placebo, to initiate any necessary 
resupply of AL001 or placebo, and to document discontinuation of study treatment. 


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The IRT will assign carton and vial numbers and provide instructions for dispensing study 
treatment (AL001 or placebo). 
5.6.2. 
Blinding 
Blind maintenance procedures for the study are detailed in the Blind Maintenance Plan. 
5.6.2.1. 
Blinded and Unblinded Personnel 
Research subjects, investigators, and anyone involved in the conduct of, final analysis of, or with 
any other interest in the trial, with the exception of the iDMC and the independent statistical 
group supporting the iDMC, will be blinded to randomized treatment assignments. The 
randomized treatment assigned for subjects will be kept secure until final database lock.  
In addition to the iDMC and the independent statistical group supporting the iDMC, safety 
personnel, and the administrative pharmacy personnel will be unblinded as needed. 
The Sponsor may be unblinded to a participant’s treatment assignment, if necessary, for safety 
(see Section 5.6.2.2).  
5.6.2.2. 
Circumstances for Breaking the Blind 
In the event of a medical emergency, an investigator may be unblinded to the treatment 
assignment of a single subject in order to safely provide care to that participant. Emergency 
unblinding for a subject will only be undertaken when knowing the participant's treatment 
assignment is essential to treating the subject safely or otherwise ensure the safety of other 
participants or others exposed to investigational products. The investigator may unblind an 
individual participant's treatment allocation through the IRT. Reasons for treatment unblinding 
must be clearly explained and justified in the source documents. The date on which the code was 
broken, together with the identity of the person responsible, must also be documented. Alector 
recommends but does not require that the investigator contact the Medical Monitor before 
breaking the blind. Treatment assignment should not be disclosed to the Medical Monitor. 
Maintaining blinded treatment is critical for the integrity of the clinical study, and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will be discontinued 
from study treatment, but will continue with study follow-up assessments and procedures, if 
possible. 
Alector pharmacovigilance personnel may independently unblind a subject for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs) or other events requiring 
expedited regulatory reporting. In addition, in the event of SUSARs, which are subject to 
expedited reporting, Alector pharmacovigilance staff or their designee will unblind the affected 
cases in order to fulfill reporting requirements. For such cases, unblinding will be performed 
according to documented procedures and the unblinded information will be kept to authorized 
pharmacovigilance personnel. 
5.7. 
Concomitant Therapy 
Throughout the study, subjects may be prescribed concomitant medications deemed necessary by 
their treating clinician to provide adequate care. Subjects should not receive other investigational 
products during the study. This includes marketed agents at experimental dosages that are being 


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tested for the treatment of ALS. Subjects who have not started riluzole or edavarone prior to the 
study will not be allowed to initiate these medications during study treatment given their 
potential to interfere with study endpoint assessments. All concomitant medications and 
significant non-drug therapies, including supplements, received by a subject should be recorded 
from the point of screening forward on the appropriate source document and eCRF. Medications 
that are prohibited for a pre-specified duration prior to study start, and during the entire period of 
study participation are listed in Section 4.2, Item 17.  
5.8. 
Infusion-Related Reactions 
5.8.1. 
Guidance for Management of Infusion-Related Reactions 
All subjects will be monitored for infusion-related reactions (IRR) or injection-related reactions 
during the infusion and immediately afterwards for at least 60 minutes post infusion for the first 
2 infusions, and at least 30 minutes for subsequent infusions. Injection-related reactions can be 
localized at the site of the injection or systemic and should be treated per institutional guidelines. 
Acute IRRs typically occur within 24 hours of infusion and may manifest as erythema, pruritis, 
fever, or chills and progress to an anaphylactic-type reaction. Clinical sites should be prepared to 
manage any acute hypersensitivity or hypersensitivity-like events. Table 1 provides guidelines on 
management of acute infusion reactions as well as management of subsequent AL001 dosing. 
In addition, in the event of an IRR, blood samples should be obtained for serum PK and ADA 
assessments of AL001 or placebo, and blood samples should be drawn for assessment by the 
laboratory: C-reactive protein (CRP), ferritin, tryptase, and IL-6 (at 1 to 2 hours after the IRR, 
then again at 48-72 hours after the IRR). Where possible, clinical laboratory samples should be 
drawn at the site for central laboratory; however, local laboratories may be utilized, and results 
assessed for safety by the investigator. 
Further details regarding IRRs are provided in the Investigator Brochure. 


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Table 1: 
Guidelines for Management of Acute Infusion-Related Reactions 
WHO Toxicity Criteria 
Treatment 
Pre-Medication at 
Subsequent Dosing 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention 
not indicated 
Stop infusion and monitor symptoms. If symptoms resolve 
without intervention, the infusion may be restarted at 50% 
of the original infusion rate. 
None 
Grade 2 
Therapy or infusion 
interruption indicated 
but responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hours 
Stop infusion and monitor symptoms. Additional 
appropriate medical therapy may include but is not limited 
to IV fluids, antihistamines, and antipyretics. Increase 
monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of 
the investigator. 
 
If symptoms resolve following supportive treatment, the 
infusion may be restarted at 50% of the original infusion 
rate. Otherwise, dosing will be held until symptoms 
resolve and the participant should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
pre-medication and infusion rate reduction should be 
permanently discontinued from further trial treatment 
administration. 
Subject should be 
premedicated prior to 
next dose of study drug 
with antihistamine 
(eg, diphenhydramine 
50 mg po) and 
antipyretic 
(eg, acetaminophen / 
paracetamol 
500-1000 mg po). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequalae 
 
Grade 4: 
Life-threatening 
consequences; urgent 
intervention indicated 
Stop infusion and increase monitoring of vital signs as 
medically indicated. Additional appropriate medical 
therapy may include but is not limited to IV fluids, IV 
steroids (eg, hydrocortisone 100-200 mg or corticosteroid 
equivalent), IV antihistamines, vasopressors, and 
antipyretics. Hospitalization may be indicated. 
Subjects with signs or symptoms that may be consistent 
with cardiac etiology should be assessed by ECGs, cardiac 
enzymes (eg, creatinine-MB isoenzyme, troponins, brain 
natriuretic peptide) to rule out myocardial infarction, and 
echocardiogram should be performed unless cardiac 
failure is ruled out by preceding investigations. 
Subject is permanently discontinued from further trial 
treatment administration. 
Any subject with a 
serious Grade 3 or any 
Grade 4 event will not 
be permitted to re-dose. 
Any subsequent 
redosing of nonserious 
Grade 3 events must be 
discussed an approved 
with the Medical 
Monitor. 
Abbreviations: ECG=electrocardiogram; IV=intravenous; MB=myocardial band; NSAIDs=non-steroidal 
anti-inflammatory drugs; po=orally; WHO=World Health Organization. 


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6. 
STUDY DRUG DISCONTINUATION AND SUBJECT 
WITHDRAWAL FROM THE STUDY 
6.1. 
Study Drug Discontinuation 
An investigator may discontinue study drug or a subject may also choose to discontinue study 
drug at any time. Subjects who plan to discontinue early from the study drug or study should 
complete an Early Termination Visit 8 weeks after the last dose of study treatment.  
The following is a list of possible reasons for study drug discontinuation: 
1. Subject is noncompliant with the protocol 
2. Subject is lost to follow-up 
3. Subject withdraws consent 
4. Subject has a serious or intolerable AE that, in the opinion of the investigator, requires 
withdrawal from the study treatment 
5. Occurrence of an intercurrent illness that, in the opinion of the investigator, will affect 
assessments of clinical status or safety to a significant degree 
6. Use of a nonpermitted concomitant medication  
7. Pregnancy 
8. Discretion of the investigator and Medical Monitor 
9. Serum transaminases (ALT or AST) >3 × ULN and total bilirubin >2 × ULN without an 
alternative explanation 
10. Anaphylaxis 
11. Infusion-related or injection-related reaction despite adequate pre-medication for an 
initial occurrence of a moderate to severe infusion related reaction or if the subject 
experiences any of the following events: mucosal tissue involvement, airway 
compromise, or symptomatic hypotension with systolic BP <90 mm Hg measured in the 
supine position. 
If a subject is withdrawn from study treatment due to an AE or a SAE, the subject will be 
followed up by the investigator until the abnormal parameter or symptom has resolved or 
stabilized (if applicable). Additional clinical work-up to further evaluate an AE or SAE may be 
recommended by the site investigator, in conjunction with the Medical Monitor, and the 
subject’s treating ALS physician. It is recommended that the investigator consult with the 
Medical Monitor prior to removing the subject from study treatment for any reason except 
subject withdrawal of consent. Any subject may withdraw his or her consent at any time for any 
reason. 
For all research subjects, the reason for permanent discontinuation of study drug must be 
recorded in the electronic eCRF. These data will be included in the trial database and reported. 


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6.2. 
Subject Withdrawal from the Study 
Subjects may withdraw from the study at any time for any reason. An investigator should only 
withdraw a subject from the study if required to ensure the subject's safety even after 
discontinuation of study drug. The following is a list of possible reasons for subject withdrawal 
from the study: 
1. Subject withdraws of consent 
2. Subject is lost to follow-up 
3. Subject is withdrawn from the study at the discretion of the investigator 
4. Subject is withdrawn due to administrative or other reasons (eg, termination of the study 
by Alector) 
All subjects who discontinue the study during and after the treatment phase, but before the final 
scheduled Study Completion Visit should be encouraged to return to the investigational site for 
an Early Termination Visit 8 weeks after the last dose of study treatment. 
Reasonable attempts will be made by the investigator to obtain reasons for subject withdrawal 
(eg, 2 documented telephone calls on different days, followed by 1 registered letter). The reason 
for subject withdrawal from the study will be recorded on the eCRF. 
6.3. 
Subject Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled study visits and is unable to be contacted by the study site staff. 
The following actions must be taken and documented if a subject fails to return to the clinic for a 
required study visit: 
• The site will attempt to contact the subject and reschedule the missed visit within the 
study window and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain if the subject wishes to continue or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the subject (where possible, 3 telephone calls and 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record or study file. 
• Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of "lost to follow-up". 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Efficacy Assessments 
7.1.1. 
ALS Functional Rating Scale-Revised 
The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale used to determine the 
patient's assessment of their capability and independence in 12 functional activities 
(Cedarbaum 1999). All ALSFRS-R evaluators must be certified by the Northeast ALS 
Consortium (NEALS). Each functional activity is rated 0–4 for a total score that ranges from 0 to 
48. Higher scores indicate better function. Initial validity in ALS patients was established by 
documenting that change in ALSFRS-R scores correlated with change in strength over time, was 
closely associated with quality-of-life measures, and predicted survival. The test-retest reliability 
is greater than 0.88 for all test items. The advantages of the ALSFRS-R are that all 12 functional 
activities are relevant to ALS, it is a sensitive and reliable tool for assessing activities of daily 
living function in those with ALS, and it is quickly administered. With appropriate training the 
ALSFRS-R can be administered with high inter-rater reliability and test-retest reliability. 
When required due to pandemic-related restrictions, the ALSFRS-R can be administered via 
phone or web-based interface. The ALSFRS-R can be administered by phone with good 
inter-rater and test-retest reliability. The equivalency of phone versus in-person testing, and the 
equivalency of study subject versus caregiver responses have also been established. Additionally, 
the ALSFRS-R can also be obtained using a web-based interface with good concordance with 
in-person assessment. 
7.1.2. 
Combined Assessment of Function and Survival 
The Combined Assessment of Function and Survival (CAFS) (Berry 2013) evaluates treatment-
dependent differences in disease progression as measured by survival time or change in 
function. CAFS ranks each pair of subjects' clinical outcomes based on survival time if 
evaluable or based on change in the ALSFRS-R total score if a comparison based on survival 
time is not evaluable. A subject's CAFS score is the sum of their ranking with respect to all other 
subjects. A higher CAFS score indicates a better outcome. CAFS scores are nonparametric and 
thus do not rely on statistical assumptions required for many of the standard techniques, such as 
linearity of disease progression or imputation of missing data. 
7.1.3. 
Vital Capacity 
Vital capacity will be determined using the upright SVC method. All evaluators performing 
SVC, must be NEALS certified*. The SVC will be measured using the study-approved* portable 
spirometer, and assessments will be performed using a face mask. A printout from the spirometer 
of all VC trials will be retained. Three VC trials are required for each testing session, however up 
to 5 trials may be performed if the variability between the highest and second highest VC is 10% 
or greater for the first 3 trials. Only the 3 best trials are recorded on the eCRF. The highest VC 
recorded is utilized for eligibility. At least 3 measurable VC trials must be completed to score 
VC for all visits after Screening. Predicted VC values and percent-predicted VC values will be 
calculated using the Quanjer Global Lung Initiative equations. 


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*Note: Exceptions to the requirement of NEALS evaluator certification and study-approved 
spirometer will be permitted if performed in a pulmonary function lab (including FEV1) during 
the Screening Visit as needed during the pandemic. 
7.1.4. 
Home Spirometry 
Remote/home-based FVC will be measured with the MIR Spirobank Smart spirometer within 2 
days of each in-person study visit. A mask will be provided to each subject for FVC assessment 
throughout the study. FVC assessments will be conducted remotely with the subject at home and 
connected with the evaluator via the Zephyrx Breathe Easy application (app) on the subject’s 
mobile device and telemedicine platform (or phone, if telemedicine is not available). The app 
will enable video interaction between the subject and evaluator. The evaluator will observe the 
assessment and will provide instruction and coaching in real time. Three FVC trials are required 
for each testing session, however up to 5 trials may be performed if the variability between the 
highest and second highest VC is 10% or greater for the first 3 trials. The evaluator will print out 
the assessments via a secure online portal. At least 3 measurable FVC trials must be completed 
to score FVC for all visits after Screening. Predicted FVC values and percent-predicted FVC 
values will be calculated using the Quanjer Global Lung Initiative equations. 
7.1.5. 
ALS Cognitive Behavioral Screen 
The ALS Cognitive Behavioral Screen (ALS-CBS™) (Woolley 2010a) is a short measure of 
cognition and behavior in patients with ALS. The cognitive section includes commonly used 
elements of standard testing batteries, consisting of 8 tasks, with a total possible score of 20. It 
can be administered by a physician or other clinical care staff and takes approximately 5 minutes 
to complete. 
The optional behavioral section (ALS Caregiver Behavioral Questionnaire) is composed of 
questions sensitive to organic brain changes. It consists of a set of questions that compare 
changes in personality and behavior since the onset of ALS, as well as yes/no questions about 
mood, pseudobulbar affect, and fatigue. It is completed by a caregiver, defined as an individual 
who lives with the subject and in the investigator's opinion has adequate knowledge of their daily 
activities and function. The caregiver completes the questionnaire during the same time that the 
subject completes the cognitive portion. The questionnaire typically takes about 2 minutes to 
complete. If a caregiver is not present during a visit, this section of the questionnaire will not be 
performed. 
7.1.6. 
Digital Assessments 
Voice samples and cognitive assessments will be collected once per week, using an app installed 
on either an android or iOS-based smartphone. Combined these estimates take about 10 minutes 
or less to complete. 
For speech analysis, the app characterizes ambient noise, then asks the subject to perform a set of 
speaking tasks: reading 5 fixed sentences and 5 sentences chosen at random from a large 
sentence bank, repeating a consonant-vowel sequence (diadochokinetic rate), producing a 
sustained phonation, and counting on a single breath. 
In cognitive evaluation the app asks the subject to view and listen to a story and repeat the story 
verbatim (story recall), describe a picture of a complex scene in their own words (complex 


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picture description), name as many items as possible within a provided category in 15 seconds 
(category naming), name objects as many shown objects as possible (object recall), describe their 
emotions associated with a picture provided (affect assessment), and rate their ability to 
communicate with others in various situations (social participation). 
Voice signals and cognitive assessments are securely uploaded to a Health Insurance Portability 
and Accountability Act (HIPAA)-compliant web server, where an artificial intelligence (AI)-
based analysis identifies relevant vocal attributes. Quality control (QC) of individual samples 
will occur by evaluation of voice records by trained personnel. 
7.1.7. 
Training and Validation 
All evaluators must be certified to perform the ALSFRS-R, ALS-CBS and VC assessments. 
Certification occurs via a formal evaluation of reliability and accuracy of performance of these 
measures. It is strongly preferred that a single evaluator performs all measures throughout the 
study, as much as possible. 
7.2. 
Biofluid Collection and Sample Retention 
All biosamples will be labeled with a unique identifying code. The code will not include any 
personal identification information. The code will be linked to a specific subject, visit, and 
sample by data entry of the code into the electronic data capture (EDC) system. Unused portions 
of PK, PD, and/or exploratory PD biomarker samples remaining after all applicable protocol-
defined tests have been performed may be retained and maintained for future use, if the subject 
agrees and provides consent separately. For subjects who have provided consent, these samples 
may be used for testing including the following: further evaluation of PD biomarkers 
(eg, associated with efficacy, AEs, or disease progression), further clarification or 
characterization of the disease, further evaluation of the study, and future testing not described in 
this protocol. 
Specific instructions regarding the collection, processing, storage, and shipment of these samples 
will be provided in the central laboratory manual. 
7.2.1. 
DNA Collection 
All subjects will provide blood samples for repeat primed polymerase chain reaction (PCR) 
evaluation of the C9orf72 repeat expansion and for DNA extraction for genotype determination 
of the rs5848 polymorphism at the Screening Visit. The same samples will be used for 
genotyping 
 polymorphisms and may be used for whole 
genome sequencing or DNA microarray analysis with the goal of, but limited to, identifying 
common and rare genetic variants that are predictive of response to study treatment, are 
associated with progression to a more severe disease state, are associated with susceptibility to 
developing AEs, or can increase the knowledge and understanding of disease biology. 
7.2.2. 
Lumbar Puncture 
LP will be performed to collect CSF as specified in the Schedule of Assessments. CSF will be 
collected at each visit for analysis of AL001 concentration and PD biomarkers. 


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Subjects may only undergo a LP if they have a coagulation panel and platelet count performed 
(using a central or local laboratory) within 4 weeks prior to the LP. If the laboratory results are 
abnormal and warrant repeat studies, they should be repeated within a week prior to the LP, and 
can be repeated at a local laboratory as needed. Lumbar puncture at Visit 8 is to be performed 
prior to study drug administration, and at approximately the same time of the day as the 
Screening LP. The LP is to be performed after pulmonary function testing and administration of 
the ALSFRS-R.  For subjects who are rescreened, if an LP was previously completed as part of 
Screening and it is within 12 weeks of reconsenting, then a repeat LP is not necessary.  
Specific information on the collection, processing, storage, and shipment of CSF samples will be 
provided in a separate manual. 
The investigator will discuss all potential LP risks to the subjects including: 
• Local pain at injection site 
• Reaction to anesthetic agents 
• Bleeding at needle entrance site 
• Infection at needle entrance site 
• Post-LP low-pressure headache 
Extensive experience with research LP in Alzheimer’s disease reveals a very low incidence of 
complication, including the incidence of post-LP headache (Woolley 2010b). Fewer than 2.6% 
of patients in a memory disorder clinic developed post-LP headache, and only a single patient in 
a cohort of over 1,000 patients had a headache lasting more than 5 days (Woolley 2010b). No 
other local or generalized complications occurred. 
Atraumatic needles will be used to further reduce the risk of post-LP headache (Quinn 2013). 
The procedure must be performed by the investigator or another licensed practitioner with 
experience and training in performing LPs, and must be listed on the site delegation log. 
7.2.3. 
Pharmacokinetic Blood Sample Collection 
Blood serum samples will be collected for assessment of serum concentrations of AL001 as 
specified in the Schedule of Assessments (Appendix 1) for the evaluation of AL001 
concentrations. 
7.2.4. 
Anti-Drug Antibodies 
Blood serum samples will be collected for the determination of ADAs as specified in the 
Schedule of Assessments (Appendix 1). Samples should be collected prior to infusion. 
Additional ADA samples should be collected in subjects with signs and symptoms of IRRs. In 
the event of an infusion reaction, blood samples should be obtained for serum PK and ADA 
assessments of AL001 or placebo, and the following laboratories should be drawn for assessment 
by the laboratory: CRP, ferritin, tryptase, and IL-6 (at 1 to 2 hours after the IRR, then again at 
48–72 hours after the IRR). Where possible, clinical laboratory samples should be drawn at the 
site for the central laboratory; however, local laboratories may be utilized and results assessed 
for safety by the investigator. 


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7.2.5. 
Blood, Urine, and CSF Pharmacodynamic Assessments 
As specified in the Schedule of Assessments (Appendix 1), blood, urine and CSF samples will be 
collected for the evaluation of PD biomarkers as follows: 
Blood-Based Biomarkers: 
• Plasma samples will be collected for evaluation of PGRN levels 
• Plasma samples will be collected for evaluation of NfL levels 
• Other exploratory PD biomarkers 
CSF-Based Biomarkers: 
• CSF samples collection will be evaluated for levels of PGRN and NfL 
• Other exploratory PD biomarkers 
Urine-Based Biomarkers: 
• Urine samples will be collected for evaluation of p
 and creatinine 
• Other exploratory PD biomarker 
Timing and frequency of all PD biomarker assessments are presented in the Schedule of 
Assessments (Appendix 1). 
7.2.6. 
Blood Biomarker Sample Collection 
All subjects will provide blood samples for biomarker assessments at every study visit. Specific 
information on clinical laboratory, ADA, PK, PD biomarker, and pharmacogenomic sample 
collection, processing, storage, and shipment will be provided in separate manuals. 
7.2.7. 
Urine Collection 
Urine samples will be collected at all study visits starting at the Baseline Visit. 
7.3. 
Safety and Other Assessments 
7.3.1. 
Clinical Variables 
In addition to the assessments listed above, the following clinical variables will be collected at 
the Screening Visit: 
• Demographic data 
• ALS disease history and genetic status 
• Family history of ALS 
• Medical history 
• Concomitant medications  
Assessment for changes in clinical variables will occur at every follow-up visit. 


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7.3.2. 
Vital Signs and Anthropometrics 
Vital signs include weight in kilograms (kg), systolic and diastolic blood pressure in mmHg, 
pulse rate (radial artery)/minute, respiratory rate/minute, and temperature in °C. Height in 
centimeters (cm) will be measured and recorded at the Screening Visit (Visit 1) only. This 
one-time height measurement must be used throughout the duration of the study. 
7.3.3. 
Clinical Safety Laboratory Tests 
The laboratory tests to be performed for safety at Screening to determine eligibility and pre-
infusion at every subsequent visit are listed in Table 2. 
For any screening laboratory test value outside the reference range that the investigator considers 
clinically significant, repeat testing will be obtained through the central laboratory. For all other 
visits, any laboratory test value outside the reference range that the investigator considers 
clinically significant will be repeated either through a central or local laboratory, as deemed 
appropriate by the investigator. 
All subjects will have clinical safety laboratory tests at the designated visits outlined in the 
Schedule of Assessments (Appendix 1). All laboratory samples will be analyzed at a central 
laboratory, with the exception of urine pregnancy testing or medically indicated laboratory tests 
to further assess an AE which will be done at local laboratories. The investigator may order 
additional local testing, if needed, to further assess an AE, or if there is any suspicion that a 
subject may be pregnant, throughout the course of the study. 
 
 


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Table 2: 
Clinical Safety Laboratory Tests 
Chemistry 
Coagulation 
Hematology 
Serology5 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
gammaGT 
AST 
ALT 
LDH 
Creatine kinase 
Creatinine 1 
Urea 
Uric acid 
Cholesterol 
HDL 
LDL 
Triglycerides 
Total protein 
Albumin 
Glucose 
Bicarbonate 
Inorganic phosphate 
Sodium 
Potassium 
Calcium 
Chloride 
Magnesium 
Lipase 
PT 
INR 
aPTT 
HbA1c 5  
Leukocytes 
Erythrocytes 
Hemoglobin 
Hematocrit 
Thrombocytes (platelets) 
MCV 
MCH 
MCHC 
 
Partial automated 
differentiation: 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Neutrophils 2 
ANC 2 
anti-HCV 
anti-HIV  
HIV antigen 
HBsAg 
 
Urinalysis 
Pregnancy Test 
Hemoglobin (blood urine) 
Ketones 
Glucose 
Protein 
Leukocyte esterase 
Nitrite 
pH 
Specific gravity 
Microscopic analysis 4 (sediment, erythrocytes, 
leukocytes, casts, crystals, epithelial cells, and bacteria) 
Serum β-hCG or urine 
pregnancy test 3 
Abbreviations: ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial 
thromboplastin time; AST=aspartate aminotransferase; β-hCG=β-human chorionic gonadotropin; gamma 
GT=gamma glutamyl transferase; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HDL=high-density 
lipoprotein cholesterol; HIV=human immunodeficiency virus; INR=international normalized ratio; LDH=lactate 
dehydrogenase; LDL=low-density lipoprotein cholesterol; MCH=mean corpuscular hemoglobin; MCHC=mean 
corpuscular hemoglobin concentration; MCV=mean corpuscular volume; PT=prothrombin time. 
1 Creatinine (and calculation of glomerular filtration rate). 
2ANC will be calculated at Screening only. Neutrophils will be assessed at all other time points. 
3 All women of childbearing potential will have a serum pregnancy test at Screening. Urine pregnancy tests will be 
performed at specified subsequent visits prior to study drug administration. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
4 Microscopic examination of the sediment if blood, protein, leukocytes esterase, or nitrite are positive on the 
dipstick. 
5 Screening only. 


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7.3.4. 
12-Lead ECG 
12-lead ECGs will be obtained after the subject has been in the supine position for at least 
5 minutes to determine eligibility and for safety as outlined in the Schedule of Assessments 
(Appendix 1). Tracings will be reviewed by an ECG reader and a copy of the tracings will be 
kept on site as part of the source documents. Additional ECG monitoring must be performed 
during the treatment period, if clinically indicated. 
7.3.5. 
Physical Examination 
Complete physical examinations will include evaluation of the head, eyes, ears, nose, and throat 
and the cardiovascular, dermatological, musculoskeletal, respiratory, and gastrointestinal 
systems. Breast, genital, and rectal examinations are not required, unless warranted in the 
opinion of the examiner. 
Record physical examination abnormalities observed at Screening on the General Medical 
History and Baseline Conditions eCRF. At subsequent visits, record new or worsened clinically 
significant abnormalities on the AE eCRF, unless the new or worsened event is related to the 
patient’s ALS disease progression. 
7.3.6. 
Neurological Examination 
A complete neurologic examination will include the evaluation of consciousness, orientation, 
cranial nerves, motor and sensory system, coordination and gait, and reflexes. 
Record neurological examination abnormalities observed at Screening on the General Medical 
History and Baseline Conditions eCRF. At subsequent visits, record new or worsened clinically 
significant abnormalities on the AE eCRF. 
7.3.7. 
Columbia-Suicide Severity Rating Scale 
Suicidality will be assessed with the C-SSRS. The C-SSRS involves a series of probing 
questions to inquire about possible suicidal thinking and behavior. 
At the Baseline Visit, the C-SSRS baseline version will be administered. This version is used to 
assess suicidality over the subject’s lifetime. 
At all other visits, the Since Last Contact version of the C-SSRS will be administered. This 
version of the scale assesses suicidality since the subject’s last visit. 
If there is a positive response to question 4 or 5 on the severity of ideation subscale or any 
positive response on the suicidal behavior subscale of suicide attempt or suicidal ideation by the 
subject during the administration of the C-SSRS during the treatment period, the appropriately 
qualified clinician will be notified during the study visit to determine the appropriate actions 
required to ensure the subject’s safety. The site must ensure that the subject is seen by a licensed 
physician (or other qualified individual as required by local institutional policy) before leaving 
the study site. The investigator will determine whether the subject should remain on study drug. 
Reference to the Clinical Triage Guidelines Using the C-SSRS can be found here 
https://cssrs.columbia.edu/wp-content/uploads/C-SSRStriageexampleguidelines.pdf. 


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It is recommended that a medically licensed physician, nurse, nurse practitioner, or physician 
assistant to assess suicidality with the C-SSRS. All evaluators must be certified to perform the 
C-SSRS. Certification is required prior to performing the C-SSRS. 


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8. 
ASSESSMENT OF SAFETY 
The investigator is responsible for reporting all AEs and SAEs that are observed or reported 
during the study, from the time a subject provides consent until the completion of their study 
participation, regardless of their relationship to study treatment or their clinical significance. 
The investigator’s assessment of the relationship of an AE or SAE to study treatment is part of 
the documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE/SAE, and the event is 
not a sign or symptom of another reported AE/SAE, the observation should be reported as an 
AE/SAE. All AEs/SAEs that are observed or reported during the study, from the time a 
prospective participant provides consent until the completion of their study participation, must be 
reported, regardless of their relationship to study treatment or their clinical significance. 
8.1. 
Definition of Adverse Event 
Adverse events are any untoward medical occurrence in a subject enrolled into this study, 
including side effects, injury, toxicity, sensitivity reaction, intercurrent illnesses, clinically 
significant physical exam signs, or sudden death, whether or not it is considered related to the 
study treatment. Subjects will be instructed to contact the investigator at any time after informed 
consent if any symptoms develop. Subjects will be instructed to report all AEs to the 
investigator. All AEs must be appropriately documented in the subject’s original source 
documents and on the eCRFs. Investigators should report the diagnosis rather than list 
symptoms, whenever possible. 
A treatment-emergent AE (TEAE) is defined as any event not present before first administration 
of study treatment or any event already present that worsens in either intensity or frequency after 
first administration of study treatment. 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported within the 
established time frames. 
An AE does not include the following: 
• Elective medical or surgical procedures planned prior to the start of study treatment 
(eg, hip replacement surgery) that did not result from a worsening of a previous 
condition (ie, prior to signing informed consent). Note: Any serious procedural 
complication or hospital-emergent conditions (eg, nosocomial infection) would be 
reported as an SAE.  
• Any medical condition or clinically significant laboratory abnormality that has an 
onset date before the consent form is signed, and that is not related to a protocol-
associated procedure, is not an AE. Such conditions are considered to be pre-existing 
and should be documented on the medical history eCRF. A pre-existing condition 
should be reported as an AE only if its frequency, intensity, or symptoms worsen 
during the course of the study. 
• Situations where an untoward medical occurrence has not occurred 
(eg, hospitalization for study treatment administration per institutional guidelines, 
elective surgery, social and/or convenience admissions). 


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• Overdose without adverse event. 
• Disease progression within expected parameters for the study population is not 
considered an AE. See Section 8.3 for Protocol Specific Disease Progression Adverse 
Event and Serious Adverse Event Reporting Requirements. 
8.2. 
Definition of Serious Adverse Event 
An SAE is defined as any adverse event that fulfill one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization: 
− Social hospitalization, defined as inadequate family support or care at the 
subject’s primary residence resulting in subject hospitalization, will not be 
considered an SAE 
− Any pre-planned hospitalization for a condition that did not worsen while the 
subject was on study is not considered an SAE; however, any events that cause 
prolongation of the hospitalization would be captured as such. Similarly, elective 
surgical procedures performed during the study that are intended to treat pre-
existing conditions are not considered adverse events. 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
Important medical events that may not meet one of the above criteria could be considered a SAE 
by the investigator when, based upon appropriate medical judgment, they are considered 
clinically significant and may jeopardize the subject, or may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
An AE is considered “life-threatening” if, in the opinion of either the investigator or the sponsor, 
its occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
8.3. 
Protocol Specific Disease Progression Adverse Event and Serious 
Adverse Event Reporting Requirements 
Disease progression in this study is measured via the ALSFRS-R and VC. Changes in these 
scores that are consistent with the expected rate of progression of the underlying disease should 
not be recorded as AEs. 
However, symptomatic deterioration or events that are judged by the investigator to be 
inconsistent with normal disease progression or are considered related to study treatment should 
be reported as AEs, and if any of the “serious” criteria are met, it must be reported as an SAE. 


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Please note that the term “disease progression” should not be reported, but rather the clinical 
manifestation(s) with applicable descriptors should be captured on the Adverse Event eCRF 
page. 
8.4. 
Definition of Clinical Laboratory Abnormalities and Other 
Abnormal Assessments as AE/SAE 
Abnormal laboratory findings (hematology, coagulation, chemistry, and urinalysis) or other 
abnormal assessments (ECG, vital signs) per se are not reported as AEs. However, those 
abnormal findings that are deemed clinically significant or are associated with signs and/or 
symptoms must be recorded as AEs if they meet the definition of an AE (or recorded as an SAE 
if they meet the criteria of being serious) as previously described. Clinically significant abnormal 
laboratory or other abnormal findings that are detected after consent or that are present at 
baseline and worsen after consent are included as AEs (and SAEs if serious). 
The investigator should exercise medical and scientific judgment in deciding whether an 
abnormal laboratory finding, or other abnormal assessment is clinically significant. Usually, the 
abnormality should be associated with a clinically evident sign or symptom or be likely to result 
in an evident sign or symptom in the near term, to be considered clinically significant. 
A clinically significant laboratory abnormality in the absence of clinical symptoms may 
jeopardize the subject and may require intervention to prevent immediate consequences. For 
example, a markedly low serum glucose concentration may not be accompanied by coma or 
convulsions, yet be of a magnitude to require glucose administration to prevent such sequelae. 
8.5. 
Assessment of Adverse Events 
8.5.1. 
Assessment of Adverse Event/Serious Adverse Event Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s daily 
activities. Severity will be graded according to the World Health Organization (WHO) Toxicity 
Grading Scale, March 2020 or later. If an AE is not specified within the WHO Toxicity Grading 
Scale, then the AE will be graded according to the following definitions: 
Grade 
Severity 
Description 
1 
Mild 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
2 
Moderate 
Mild to moderate limitation in activity; no or minimal medical 
intervention or therapy required. 
3 
Severe* 
Marked limitation in activity; medical intervention or therapy 
required; hospitalizations possible. 
4 
Life-Threatening 
The subject is at risk of death due to the AE as it occurred. 
This does not refer to an AE that hypothetically might have 
caused death if it were more severe. 
5 
Death 
Any AE where the outcome is death. 
Abbreviation: AE=adverse event. 
*Note that the term “severe” is a measure of intensity and that a severe AE is not necessarily serious. 


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Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. AEs characterized as intermittent do not 
require documentation of onset and duration of each episode. When the intensity of an AE 
changes more than once a day, the maximum severity for the event should be listed. If the 
intensity changes over a number of days, these changes should be recorded separately (ie, as 
having distinct onset dates). 
8.5.2. 
Assessment of Adverse Event/Serious Adverse Event Causality 
The relationship or association of the study treatment in causing or contributing to the AE/SAE 
will be characterized by the investigator using the following classification and criteria: 
Relationship to Study Treatment 
Comment 
Related 
There is reasonable possibility that the event may have 
been caused by study treatment (eg; confirmation by 
positive rechallenge test). 
Not Related 
The event can be readily explained by the subject’s 
underlying medical condition, concomitant therapy, or 
other causes, and therefore, the investigator believes no 
relationship exists between the event and study 
treatment. 
The investigator should assess causality by answering either “related” or “not related” to the 
question “Is there a reasonable possibility that the event may have been caused by the study 
treatment?” The following factors may be used in consideration of causality assessment: 
• Challenge/rechallenge: Did the event abate after study treatment was reduced or 
interrupted? Did the event reappear after study treatment was reintroduced? 
• Temporal relationship and time to onset plausibility 
• Confounding risk factors 
• Amount and duration of study treatment exposure 
• Concomitant medications 
8.6. 
Recording of Adverse Events 
8.6.1. 
Eliciting and Documenting the Adverse Events 
At every study visit, subjects will be asked a standard nonleading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had 
any accidents (eg, falls), used any new medications, or changed concomitant medication 
regimens (prescription drugs, herbal products, vitamins, minerals, vaccines, topical medications, 
and over-the-counter medications). 
Laboratory test values or investigational findings (eg, findings on ECGs, imaging, or 
examination) outside the normal reference range that meet any of the following criteria should be 
reported as an AE: 
• Is confirmed and the investigator considers it clinically significant 


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• Requires a subject to discontinue study drug 
• Requires a subject to receive treatment 
Abnormal laboratory test values or investigational findings reported as AEs or SAEs should be 
followed until recovered/resolved, until stable, subject withdrawal of consent, lost to follow-up, 
or death, whichever comes first. 
8.6.2. 
Recording the Action Taken with Investigational Products in Response to 
Adverse Events/Serious Adverse Events 
Should the investigator need to alter the administration of the investigational product from the 
procedure described in the protocol in response to an AE/SAE, then the action taken will be 
recorded on the AE eCRF page as one of the following options: 
• 
 Dose reduced 
• Dose interrupted 
• Dose withdrawn 
• Not applicable 
• Unknown 
8.6.3. 
Recording the Outcome and Follow-Up of Subjects Reporting an Adverse 
Event/Serious Adverse Event 
Outcome of an AE/SAE will be recorded on the AE eCRF as follows: 
• Recovered/Resolved  
• Recovered/Resolved with Sequelae (with sequelae being a condition that is the 
consequence of the reported event, and not the event in a lower grade/ severity) 
• Not Recovered/Not Resolved 
• Fatal 
• Unknown (or subject lost to follow-up after 4 attempts to contact over a period of 
30 days since last information has been received). 
8.7. 
Reporting Adverse Events 
8.7.1. 
Adverse Event and Serious Adverse Event Reporting 
All AEs and SAEs must be recorded and reported, regardless of cause or relationship, that occur 
after the subject signs informed consent through the end of study (EOS) visit. After this period, 
Alector should be notified if the investigator becomes aware of any SAE that is believed to be 
related to prior study drug treatment. Alector will follow any unresolved AEs and/or SAEs 
through satisfactory clinical resolution. Additionally, SAEs considered related to study treatment 
that occur at any time should be reported to Alector by the investigator. 
In the event of any SAE reported or observed during the study, the investigational site is required 
to complete the AE eCRF within the EDC system, indicating the AE is serious, within 24 hours 


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of becoming aware of the event or aware of new information relating to the event. In the event 
that the EDC system is not available, a paper SAE Report Form should be used and emailed to 
drugsafety@alector.com, according to the instructions provided in the Study-Specific Regulatory 
Binder. 
SAE information to be collected includes the following: 
• Event term 
• Date of onset of event 
• Investigator-specified assessment of severity and relationship to study drug 
• Date of resolution of the event 
• Seriousness  
• All applicable seriousness criteria 
• Any required treatment or evaluations 
• Event outcome 
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or later will be used 
by Alector to code all AEs. 
If additional visits are required before EOS, the subject will be asked to return to the 
investigational site for further follow‐up. As additional information becomes available, such as 
hospital discharge notes and subject medical records, the investigator will be notified and 
provided with all relevant information. It is the investigator’s responsibility to report all SAEs to 
Alector (covered in this section), and it is Alector’s responsibility to ensure that all safety 
reporting obligations are carried out in compliance with current legislation for expedited 
reporting of SAEs (including SUSARs). 
8.8. 
Safety Monitoring 
Safety will be continuously reviewed by a Medical Monitor in consultation with the study 
investigators. Adverse events will be reported to the Medical Monitor from the study EDC 
system at regular intervals throughout the study, and in real time when SAEs occur or when 
questions arise. The Medical Monitor will have the authority to recommend study 
discontinuation or modification based on medical concerns, including AE or SAE profiles. 
For medical emergencies, contact: 
Study Medical Monitor 
Margherita Torti, MD 


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The Medical Monitor will review AE reports, compiled by Data Management, as described in the 
Safety Monitoring Plan. The Medical Monitor will review blinded study data on enrollment, 
abnormal laboratory results and protocol deviations. These reports will collectively be known as 
the Medical Monitoring Report. 
Alector will be responsible for notifying the applicable regulatory agencies of any unexpected 
fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later than 
7 calendar days after the sponsor’s initial receipt of the information. In addition, Alector must 
notify the applicable regulatory agencies and all participating investigators in an Investigational 
New Drug safety report of potential serious risks, from clinical trials or any other source, as soon 
as possible, but in no case later than 15 calendar days after Alector determines that the 
information qualifies for reporting. 
8.9. 
Follow-Up of AEs and SAEs 
All AEs and SAEs that are deemed related to the investigational product must be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until the 
subject dies or is lost to follow-up. The investigator is responsible for ensuring that follow-up 
includes any supplemental investigations that may be indicated to elucidate as completely as 
practical the nature and/or causality of the AE/SAE. This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals. 
Alector may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations. If a subject dies during participation in the study or during a 
recognized follow-up period, the sponsor should be provided with a copy of any post-mortem 
findings, including histopathology. 
8.10. 
General Safety Monitoring 
8.10.1. 
Special Situations 
Special situations are non-standard medical conditions that provide valuable information about 
an investigational product and therefore should be reported. All special situations associated with 
an AE or SAE should be recorded in the EDC system in the applicable AE/SAE eCRF within 
24 hours of becoming aware of the special situation. Special situations are defined as below: 
Overdose: This refers to the administration of a quantity of an investigational product given 
per administration or cumulatively, which is above the maximum recommended dose 
according to the authorized product information. Clinical judgement should always be 
applied. 
Misuse: This refers to situations where the investigational product is intentionally and 
inappropriately used not in accordance with the prescribed or authorized dose, route of 
administration, and/or the indication(s) or within legal status of its supply. 
Abuse: This corresponds to the persistent or sporadic, intentional excessive use of an 
investigational product, which is accompanied by harmful physical or psychological effects. 
Medication Error: A medication error is any dose of study treatment given to a subject or 
taken by a subject that differs from the dose described in the protocol. Medication errors are 


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not likely in the study, as the study treatment is administered by IV infusion by trained 
personnel under the supervision of the investigator or their designee. 
Occupational exposure: This corresponds to an investigational product for human use as a 
result of one’s occupation. 
8.10.1.1. Pregnancy 
Female subjects must be instructed to discontinue all study treatments and inform the 
investigator immediately if they become pregnant during the study. The investigator must report 
any pregnancy within 24 hours of becoming aware of it using the Pregnancy Report form. 
The investigational site should email the Pregnancy Report Form to drugsafety@alector.com, 
according to the instructions provided in the Study-Specific Regulatory Binder. An 
uncomplicated pregnancy will not be considered an AE or SAE, but all pregnancies will be 
followed up through term. 
Pregnancies are captured if they occur in female subjects or in the sexual partners of male 
subjects from the time the subject is first exposed to the study treatment until 10 weeks after the 
last dose of study drug. Any SAE occurring in association with a pregnancy, brought to the 
investigator’s attention after the subject has completed the study, and considered by the 
investigator as possibly related to the study treatment, must be promptly reported to Alector. 
Any congenital abnormalities noted at birth in the offspring of a subject who received study drug 
or in the female sexual partner of a male subject who received study drug will be reported as an 
SAE. The outcome of any pregnancy and the presence or absence of any congenital abnormality 
in offspring will be recorded in the source documentation and reported using the Pregnancy 
Report Form. 
8.10.1.2. Breastfeeding 
Adverse events that occur in infants following exposure to an investigational product from breast 
milk should be reported. 
8.10.1.3. Reportable Diseases 
In the case a subject has or manifests any clinical signs characteristic of a reportable disease or 
condition, eg, HIV, tuberculosis, SARS, COVID-19, it is the responsibility of the investigator to 
notify Alector after becoming aware of the information. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Safety 
Using the calculation power = 1-(1-p)n, where p is probability of an event and n is the number of 
subjects in a treatment arm, with 30 subjects exposed to the treatment (45 total study subjects 
randomized 2:1, treatment:placebo), there will be a >80% chance of seeing at least one 
occurrence of any SAE resulting from treatment with AL001 for which the expected frequency is 
at least 5.2% of exposed subjects, a rate of 8.5 events per 100-patient years, assuming uniform 
risk over 32 weeks. 
9.2. 
Populations for Analyses 
Full Data: All subjects who receive at least one dose of AL001 or placebo will be included in the 
analysis datasets for safety, tolerability, immunogenicity, clinical outcomes, and PD. 
PK Data: All subjects who receive at least one dose of AL001 or placebo, and from whom at 
least one serum or CSF sample is analyzed for AL001 concentration, will be included in PK 
analyses. 
9.3. 
Statistical Analyses 
9.3.1. 
General Approach 
Details of the planned analyses will be specified in a separate statistical analysis plan (SAP). As 
this is an exploratory study, no adjustments for multiplicity will be made. Data from all centers 
will be pooled for analysis purposes. 
9.3.2. 
Analysis of the Primary Pharmacokinetic Endpoints 
Pharmacokinetic measures will be summarized using descriptive statistics and AL001 
concentrations in serum and CSF will be summarized using descriptive statistics by treatment 
group, visit, and time point. 
9.3.3. 
Analysis of the Primary Pharmacodynamic Endpoints 
Plasma and CSF levels of PGRN will be summarized using descriptive statistics for each 
treatment group at each visit. A
 
9.3.4. 
Analysis of the Primary Immunogenicity Endpoint 
Immunogenicity test results for ADA to AL001 will be summarized using descriptive statistics 
by treatment group and visit. 


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9.3.5. 
Analysis of the Secondary Endpoint(s) 
Neurofilament light levels in the blood and CSF will be summarized using descriptive statistics 
by treatment group and visit and analyzed using the same approach as outlined for PGRN levels. 
9.3.6. 
Safety Analyses 
9.3.6.1. 
Safety 
Safety will be assessed by the occurrence of TEAEs, treatment-emergent SAEs, and treatment-
emergent clinically significant abnormalities in clinical and laboratory values. AEs will be coded 
to system organ class and preferred term using the MedDRA Version 22.0 or later and 
summarized as counts of events and proportions of subjects experiencing a given type of event, 
by treatment group. 
Summaries by severity, relationship to the study intervention, action taken with respect to study 
intervention, and outcome of all TEAEs will also be provided, by treatment group. 
9.3.6.2. 
Tolerability 
Tolerability will be defined as the percentage of subjects who complete the trial without 
treatment-emergent AEs leading to treatment discontinuation. Exact confidence bounds on the 
estimated percentage within each treatment group and the risk difference will be reported. 
9.3.7. 
Baseline Descriptive Statistics 
Baseline characteristics including age, sex, weight, site of symptom onset, time from symptom 
onset to diagnosis, time from symptom onset to first AL001 infusion, riluzole use, edaravone 
use, noninvasive ventilation use, forced vital capacity prior to first AL001 infusion, and 
measures of disease burden (ALSFRS-R, ALS-CBS) prior to first AL001 infusion will be 
summarized using appropriate descriptive statistics. 
9.3.8. 
Planned Interim Analyses 
There are no planned interim analyses for efficacy.  
9.3.9. 
Sub-Group Analyses 
Subgroups defined by the SNPs rs5848, 
3 will be tested for 
pharmacogenomics effects on PD biomarkers. For each SNP, 
 
d
Subgroup-specific effects of AL001 will also be tested for subgroups defined by baseline use of 
edaravone and baseline use of riluzole using the same extension of the model. 
9.3.10. 
Tabulation of Individual Subject Data 
Individual subject data will be listed by measure and visit. 


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9.3.11. 
Exploratory Analyses 
Exploratory outcomes will be summarized using appropriate descriptive statistics. Outcomes for 
which a consistent rate of progression is expected over 28 weeks, e
 
al


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10. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT  
10.1. 
Informed Consent Process 
A written informed consent in compliance with US Title 21 CFR Part 50 and any other 
applicable regulatory authority regulations shall be obtained from each subject before entering 
the study or performing any unusual or nonroutine procedure that involves risk to the subject. An 
informed consent template may be provided by Alector to investigational sites. If any site-
specific modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by Alector (or designee) or both before Institutional Review Board (IRB) 
submission. Once reviewed, the consent will be submitted by the investigator to the IRB for 
review and approval before the start of the study. If the informed consent form (ICF) is revised 
during the course of the study, active participating subjects may need to sign the revised form as 
determined by the IRB and/or Sponsor. 
Before recruitment and enrollment, each prospective subject and caregiver (if applicable) will be 
given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the subject understands the implications of participating in the study, 
the subject will be asked to give consent to participate in the study by signing the ICF. The 
subject’s caregiver, if applicable, will also be asked to give consent to participate in the optional 
caregiver portion of the ALS-CBS by signing an ICF. 
Prior to agreeing to samples being retained for future testing outside of the main study, subjects 
will provide informed consent in accordance with the SOPs of the investigational sites. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject, or caregiver (if applicable). 
10.2. 
Study Suspension or Termination 
Although Alector has every intention of completing the study, Alector reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes follow‑up visit). 
10.3. 
Confidentiality and Privacy 
Subject confidentiality and privacy are strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
subjects. Therefore, the study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study, or the data will be 
released to any unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
IRB/Independent Ethics Committee (IEC), regulatory agencies or pharmaceutical company 
supplying study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 


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pharmacy records for the subjects in this study. The clinical study site will permit access to such 
records. 
The study subject’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB/IEC, Institutional policies, or 
sponsor requirements. 
Data generated by this study must be available for inspection by representatives of the United 
States (US) FDA, the Office for Human Research Protections (OHRP), the sponsor, all pertinent 
national and local health and regulatory authorities, the Coordinating Center or their 
representative, study monitoring personnel, and the central IRB. 
10.4. 
Future Use of Stored Specimens and Data 
Unused portions of PK, PD, and/or exploratory PD biomarker samples remaining after all 
applicable protocol-defined tests have been performed may be retained and maintained for future 
use, if the subject agrees and provides consent. For subjects who have provided consent, the 
samples may be used for testing including the following: further evaluation of PD biomarkers 
(eg, associated with efficacy, AEs, or disease progression), further clarification or 
characterization of the disease, further evaluation of the study drug’s effects, and/or development 
of assays (eg, PD biomarker or diagnostic assays), and for future testing not described in this 
protocol. 
10.5. 
Safety Oversight 
Safety oversight will be under the direction of the Alector Medical Monitor. 
An iDMC for the AL001-ALS-201 study will be established by the Sponsor to review 
accumulating study data in order to monitor the safety of all participants on an ongoing basis. No 
Alector employee or investigator involved in the AL001 clinical studies will be a member of the 
iDMC or participate in closed iDMC sessions; however, representatives from Alector may attend 
the open meeting sessions and will be able to provide additional information, as requested. 
The iDMC will review the progress of the study and perform interim reviews to evaluate 
potential safety and tolerability issues for AL001.  
The iDMC will act in an advisory capacity to the sponsor. The iDMC responsibilities will be 
detailed in an iDMC charter.  
The iDMC membership and responsibilities will be further outlined in the iDMC Charter, which 
will be maintained separately from the protocol. 
10.6. 
Clinical Monitoring 
Study monitors will review source documentation, ICF, and the clinical facilities to ensure the 
study is conducted in accordance with the study protocol and compliance with ICH/GCP and 
regulatory guidelines. Investigators are responsible for allowing access to all source documents 
and medical records related to the subject’s participation in the study. Monitoring visits will 
occur at defined intervals per the Clinical Monitoring Plan (CMP). Study monitor(s) will identify 
study noncompliance and if appropriate, the study monitor(s) will assist the site with developing 


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a corrective and preventative action plan. All significant noncompliance will be communicated 
to the Sponsor. 
Specific monitoring activities, including remote data verification, will be outlined in the CMP. 
10.6.1. 
Monitoring Report 
The Study Monitors will provide monitoring reports to the Study Team and, will provide reports 
of protocol compliance to the Study Sponsor and other applicable parties as detailed in the CMP. 
10.7. 
Quality Assurance and Quality Control 
Protocol procedures are reviewed with the investigator and associated personnel prior to the 
study to ensure the accuracy and reliability of data. Each investigator must adhere to the protocol 
detailed in this document and agree that any changes to the protocol must be approved by the 
IRB prior to implementing the change unless it is to address immediate subject safety. No 
prospective protocol waivers will be issued or approved/pre-approved. 
Quality control procedures will be implemented beginning with the data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are 
generated and biological specimens are collected, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), and applicable regulatory requirements (eg, GLP, GMP). 
The investigational site will provide direct access to all trial related sites (including pharmacy), 
source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities. Specifics regarding pharmacy visits will be 
outlined in the Pharmacy Manual. 
The investigational product and associated documentation will be monitored during interim, 
remote, and final on-site visits. The unblinded clinical research associate (CRA) will review the 
investigational product inventory on-site and associated pharmacy inventory documentation 
during on-site visits; this also includes shipping receipts, temperature logs, and the study storage 
area. After all subjects at the site have completed the treatment phase of the study, any unused 
investigational product will be destroyed in accordance with each institution’s investigational 
product destruction policy, following the monitor’s authorization of destruction. It is acceptable 
for the unblinded CRA to verify and authorize all returned study investigational product for 
destruction during interim monitoring visits if permitted by the site’s investigational product 
destruction policy. A copy of each site’s Drug Destruction SOP or policy shall be provided to the 
Project Manager and filed in the Pharmacy Binder. All pharmacy documentation should be kept 
on file at the site. A detailed description of investigational product storage, accountability, as 
well as resupply and destruction, can be found in the Pharmacy Manual. 


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10.8. 
Data Handling and Record Keeping 
10.8.1. 
Role of Data Management 
Data management is the development, execution and supervision of plans, policies, programs, 
and practices that control, protect, deliver, and enhance the value of data and information assets. 
The EDC system will facilitate the collection, management, monitoring, and reporting of study 
data. 
10.8.2. 
Data Collection 
Site personnel will collect data onto paper source documents as appropriate and into electronic 
source documents (eg, voice sample data). Values from paper source documents will be 
transcribed into the corresponding eCRFs in the EDC system by site personnel; electronically 
captured data will be transmitted to their respective vendors for consolidation and reconciliation 
with the study EDC system. Clinical sites will be monitored to ensure compliance with the study 
protocol, data management requirements, and GCP. 
10.8.3. 
Data Entry and Edit Checks 
Site personnel are instructed to enter collected data into the EDC system within 5 days of a visit. 
Please note: SAEs must be entered into the EDC system and reported to the Coordination Center 
(CC) within 24 hours of site awareness of the SAE. Data collection is the responsibility of the 
staff at the site under the supervision of the investigator as specified in the delegation log for that 
site. During the study, the investigator must maintain complete and accurate documentation for 
the study. 
To ensure accuracy and completeness of the data set, logic and range checks as well as in-form 
rules will be built into the EDC system, and electronic queries will be created to track potential 
data issues. The sites will only have access to the queries concerning their own subjects. 
10.8.4. 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Data recorded in the eCRF derived from source documents should be consistent with the data 
recorded on the source documents. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into the EDC a 21 CFR Part 11-compliant data capture 
system. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 


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10.9. 
Study Records Retention 
US FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drugs, including CRFs (if 
applicable), consent forms, laboratory test results, and medical inventory records, must be 
retained by the investigator for two years after marketing application approval. If no application 
is filed, these records must be kept for two years after the investigation is discontinued and the 
US FDA and the applicable national and local health authorities are notified. The CC or their 
representative will notify the investigators of these events. 
10.10. 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source documentation 
any deviation from the approved protocol. The investigator may implement a deviation from, or 
a change of, the protocol to eliminate an immediate hazard to study subjects without prior 
IRB/IEC approval. As soon as possible after such an occurrence, the implemented deviation or 
change, the reasons for it, and any proposed protocol amendments should be submitted to the 
IRB/IEC for review and approval, to Alector for agreement, and to the regulatory authorities, if 
required. 
A protocol deviation occurs when the subject, investigator, or Alector (or designee) fails to 
adhere to protocol requirements. Major protocol deviations are the ones that affect the subjects' 
safety or the primary endpoint (safety). Major protocol deviations for this study include, but are 
not limited to, the following: 
• Failure to meet inclusion/exclusion criteria 
• Failure to comply with GCP guidelines will result in a major protocol deviation; 
Alector will determine if a major protocol deviation will result in withdrawal of a 
subject. 
10.11. 
Publication and Data Sharing Policy 
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, Alector will be responsible for these 
activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. Alector has final approval authority over all such issues. 
Data are the property of Alector and cannot be published without prior authorization from 
Alector, but data and publication thereof will not be unduly withheld. 
10.12. 
Conflict of Interest Policy 
Investigators are required to provide financial disclosure information to allow Alector to submit 
the complete and accurate certification or disclosure statements required under 21 CFR 54. In 
addition, the investigator must provide to Alector a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study. 


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Alector is not financially responsible for further testing or treatment of any medical condition 
that may be detected during the screening process. In addition, in the absence of specific 
arrangements, Alector is not financially responsible for further treatment of the subject’s disease. 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership at Massachusetts General Hospital (MGH), in 
conjunction with Neurological Clinical Research Institute (NCRI), has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 


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11. 
REFERENCES 
1. 
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2. 
Berry JD, Miller R, Moore DH, et al. The Combined Assessment of Function and 
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3. 
Boddaert J, Wils H, Kumar-Singh S. Methods to Investigate the Molecular Basis of 
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4. 
Brooks BR, Miller RG, Swash M, et al. El Escorial revisited: revised criteria for the 
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5. 
Brooks BR. Natural history of ALS: symptoms, strength, pulmonary function, and 
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6. 
Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 
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7. 
Carrasquillo MM, Nicholson AM, Finch N, et al. Genome-wide screen identifies 
rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am J Hum 
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8. 
Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional 
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9. 
Chang MC, Srinivasan K, Friedman BA, et al. Progranulin deficiency causes impairment 
of autophagy and TDP-43 accumulation. J Exp Med. 2017;214(9):2611-2628. 
10. Chiò A, Logroscino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral 
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11. De Muynck L, Herdewyn S, Beel S, et al. The neurotrophic properties of progranulin 
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12. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC 
hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked 
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13. Gass J, Lee WC, Cook C, et al. Progranulin regulates neuronal outgrowth independent of 
sortilin. Mol Neurodegener. 2012;7:33. 
14. Ghasemi M, Brown RH. Genetics of Amyotrophic Lateral Sclerosis. Cold Spring Harb 
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15. Gijselinck I, Van Langenhove T, van der Zee J, et al. A C9orf72 promoter repeat 
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16. Haukedal H, Freude K. Implications of Microglia in Amyotrophic Lateral Sclerosis and 
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17. Herdewyn S, De Muynck L, Van Den Bosch L, et al. Progranulin does not affect motor 
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18. Hu F, Padukkavidana T, Vægter CB, et al. Sortilin-mediated endocytosis determines 
levels of the frontotemporal dementia protein, progranulin. Neuron. 2010;68(4):654-667. 
19. Jansen P, Giehl K, Nyengaard JR, et al. Roles for the pro-neurotrophin receptor sortilin in 
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20. Karch CM, Wen N, Fan CC, et al. Selective Genetic Overlap Between Amyotrophic 
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21. Laird AS, Van Hoecke A, De Muynck L, et al. Progranulin is neurotrophic in vivo and 
protects against a mutant TDP-43 induced axonopathy. PLoS One. 2010;5(10):e13368. 
22. Martens LH, Zhang J, Barmada SJ, et al. Progranulin deficiency promotes 
neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest. 
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23. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis 
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24. Prasad A, Bharathi V, Sivalingam V, et al. Molecular Mechanisms of TDP-43 Misfolding 
and Pathology in Amyotrophic Lateral Sclerosis. Front Mol Neurosci. 2019;12:25. 
25. Quinn C, Macklin EA, Atassi N, et al. Post-lumbar puncture headache is reduced with use 
of atraumatic needles in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 
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27. Scotter EL, Chen HJ, Shaw CE. TDP-43 Proteinopathy and ALS: Insights into Disease 
Mechanisms and Therapeutic Targets. Neurotherapeutics. 2015;12 (2):352-363. 
28. Shenouda M, Zhang AB, Weichert A, et al. Mechanisms Associated with TDP-43 
Neurotoxicity in ALS/FTLD. Adv Neurobiol. 2018;20:239-263. 
29. Sleegers K, Brouwers N, Maurer-Stroh S, et al. Progranulin genetic variability contributes 
to amyotrophic lateral sclerosis. Neurology. 2008;71(4):253-259. 
30. Smith KR, Damiano J, Franceschetti S, et al. Strikingly different clinicopathological 
phenotypes determined by progranulin-mutation dosage. Am J Hum Genet. 
2012;90(6):1102-1107. 
31. Steinacker P, Feneberg E, Weishaupt J, et al. Neurofilaments in the diagnosis of 
motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry. 
2016;87(1):12-20. 
32. Tanaka Y, Matsuwaki T, Yamanouchi K, et al. Increased lysosomal biogenesis in 
activated microglia and exacerbated neuronal damage after traumatic brain injury in 
progranulin-deficient mice. Neuroscience. 2013;250:8-19. 
33. Tauffenberger A, Chitramuthu BP, Bateman A, et al. Reduction of polyglutamine toxicity 
by TDP-43, FUS and progranulin in Huntington's disease models. Hum Mol Genet. 
2013;22(4):782-794. 
34. van Blitterswijk M, Mullen B, Wojtas A, et al. Genetic modifiers in carriers of repeat 
expansions in the C9orf72 gene. Mol Neurodegener. 2014;9:38. 
35. Van Mossevelde S, Engelborghs S, van der Zee J, et al. Genotype-phenotype links in 
frontotemporal lobar degeneration. Nat Rev Neurol. 2018;14(6):363-378. 
36. Weishaupt JH, Hyman T, Dikic I. Common Molecular Pathways in Amyotrophic Lateral 
Sclerosis and Frontotemporal Dementia. Trends Mol Med. 2016;22 (9):769-783. 
37. Woolley H, Tullhög K, Hansson O, et al. Low incidence of post-lumbar puncture 
headache in 1,089 consecutive memory clinic patients. Eur Neurol. 2010b;63(6):326-330. 
38. Woolley SC, York MK, Moore DH, et al. Detecting frontotemporal dysfunction in ALS: 
utility of the ALS Cognitive Behavioral Screen (ALS-CBS). Amyotroph Lateral Scler. 
2010a;11(3):303-311. 
39. 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. 
40. Yin F, Banerjee R, Thomas B, et al. Exaggerated inflammation, impaired host defense, 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Visit Name26 
Visit 1 
Screening1 
Visit 2 
Baseline2  
Visit 33 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 94 
Visit 10 
Study 
Completion 
Visit  
Early 
Termination 
Visit25  
Visit Timing (Visit Window) 
Week -3 to 
Day 0 
Week 0 
Day 0 
Week 4  
(± 7 days) 
Week 8  
(± 7 days) 
Week 12 
(± 7 days) 
Week 16 
(± 7 days) 
Week 20 
(± 7 days) 
Week 24 
(± 7 days) 
Week 28 
(±7 days) 
Week 32 
(± 7 days) 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Review 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History/ 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
ALS Diagnosis History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Neurological Examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Height & Weight6 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-Lead ECG7 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Screening Laboratory 
Tests8 
X 
 
 
 
 
 
 
 
 
 
 
Safety Laboratory Tests9 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Coagulation10  
X 
 
 
 
 
 
X 
 
 
 
 
Whole Blood Sample for 
Targeted Genomic Variants 
X 
 
 
 
 
 
 
 
 
 
 
Serum PK Samples11 
 
X 
X 
X 
X11 
X 
X 
X 
 
X 
X 
Biomarker Samples12 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Serum ADA Samples13 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pregnancy Test14 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Lumbar Puncture15 
X 
 
 
 
 
 
 
X 
 
 
X24 
ALSFRS-R16 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary Function 
Testing17 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ALS-CBS18 
 
X 
 
 
 
 
X 
 
 
X 
X 
Suicide Assessment 
(C-SSRS)19 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Digital Monitoring20 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Review21 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
AL001/Placebo Intravenous 
Infusion22 
 
X23 
X 
X 
X 
X 
X 
X 
 
 
 


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Abbreviations: ADA=anti-drug antibody; AE=adverse event; ALS=amyotrophic lateral sclerosis; ALS-CBS=ALS Cognitive Behavioral Screen; 
ALSFRS-R=ALS Functional Rating Scale-Revised; aPTT=activated prothromboplastin time; CBC=complete blood count; CRP=C-reactive protein; 
C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; FVC=forced vital capacity; IL-6=interleukin 6; INR=international normalized ratio; 
IRR=infusion-related reaction; LP=lumbar puncture; PK=pharmacokinetic; PFT=Pulmonary Function Testing; PT=prothrombin time; SVC=slow vital capacity; 
VC=vital capacity. 
1 Screening procedures must be completed within 21 days prior to the Baseline Visit.  
2 If necessary, the Baseline Visit may be conducted over 2 consecutive days. The following procedures may be performed on the first day of the split visit: 
inclusion/exclusion review, weight, randomization, physical examination, neurological examination, ALSFRS-R, ALS-CBS, pulmonary function test, C-SSRS, 
and digital monitoring. The following must be completed on the second day of the split visit: collection of safety laboratory samples, serum PK samples 
(pre-infusion and post-infusion as outlined in footnote 11), biomarker samples, serum ADA samples, serum pregnancy test, vital signs, and 12-lead ECG. 
Study drug infusion must always be on the second day of a split Baseline Visit. Concomitant medication and AE review should be completed on each day.  
3 After the Baseline Visit, visit procedures at any subsequent visit may be completed over the course of a 48-hour period; however, the following must be 
completed on the day of study drug administration: collection of safety laboratory samples, serum PK samples (except for 24-hour post infusion PK at Visit 5, 
see footnote 11), biomarker samples, serum ADA samples, pregnancy test (if applicable), vital signs, and 12-lead ECG. The lumbar puncture must be 
performed prior to infusion for all visits where an LP is required (as outlined in footnote 15).  
4 Visit 9 will be a telephone visit and will include the ALSFRS-R, a review of concomitant medications, and a review of adverse events.  
5 Vital signs include systolic and diastolic pressure in mmHg, respiratory rate/minute, heart rate/minute and temperature. For Visits 2-8 vital signs will be 
performed pre-dose and within 15 minutes after the end of the infusion. 
6 Height measured at Screening Visit only. Weight to be performed prior to infusion for Visits 2-8. 
7 12-lead ECGs will be obtained after the subject has been in the supine position for at least 5 minutes. Additional ECG monitoring must be performed during the 
treatment period, if clinically indicated. On dosing days, the ECG will be obtained within 60 minutes after the end of infusion. 
8 Screening laboratory tests include hematology (CBC with differential), complete chemistry panel (to include liver function tests), hepatitis B surface antigen, 
hepatitis C viral antibodies, HIV-1/2 antibodies and antigen, urinalysis. Serum pregnancy test will be performed in women of childbearing potential. 
9 Safety laboratory tests will be performed pre-infusion and include hematology (CBC with differential), complete chemistry panel (to include liver function 
tests), and urinalysis. Urine pregnancy test will be performed in women of childbearing potential. 
10 A coagulation panel including PT/INR, aPTT is to be performed at Screening and Visit 7. 
11 Serum PK samples will be drawn pre-infusion on the day of the infusion visit and within 15 minutes after the end of infusion (including the line flush). 
Additional serum PK samples will be collected at Visit 5 at 3 hours (± 90 minutes) post end of infusion. Subjects will also be required to return to the study site 
for the Visit 5 at 24 hours (±6 hours) post end of infusion for additional serum PK samples. 
12 Biomarker samples include plasma and urine at Visits 2-10 and Early Termination. At the Screening Visit, only plasma will be collected.   
13 Blood serum samples will be collected prior to infusion for determination of ADA. In the event of an infusion reaction, blood samples should be obtained for 
serum PK and ADA assessments of AL001 or placebo, and the following assessments should be performed: CRP, ferritin, tryptase, and IL-6 (at 1 to 2 hours 
after the IRR, then again at 48-72 hours after the IRR). Where possible, clinical laboratory samples should be drawn at the site for the central laboratory; 
however, local laboratories may be utilized and results assessed for safety by the investigator. 
14 All women of childbearing potential will have a serum pregnancy test at Screening. Urine pregnancy tests will be performed at all subsequent visits. If a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
15 Subjects may only undergo a LP if they have a coagulation panel and platelet count performed (using a central or local laboratory) within 4 weeks prior to the 
LP. If the laboratory results are abnormal and warrant repeat studies, they should be repeated within a week prior to the LP, and can be repeated at a local 
laboratory as needed. Lumbar puncture at Visit 8 is to be performed prior to study drug administration, and at approximately the same time of the day as the 


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AL001 
Alector, Inc. 
Confidential 
Page 82 of 85 
Screening LP. The LP is to be performed after pulmonary function testing and administration of the ALSFRS-R. For subjects who are rescreened, if a LP was 
previously completed as part of Screening and is within 12 weeks of reconsenting, then a repeat LP is not necessary.  
16 ALS Functional Rating Scale-Revised. 
17 Pulmonary function testing (PFT) includes slow vital capacity (SVC) at in-clinic study visits and FVC and forced expiratory volume in one second (FEV1) 
when conducted in a PFT lab. In addition to this in-clinic assessment, home spirometry will be performed with virtual coaching by study staff within 2 days of 
each in-clinic study visit. The initial home spirometry assessment will be performed in clinic with study staff at the Baseline visit with retest at home with 
virtual coaching by study staff within 2 days after the Baseline visit.  
18 ALS Cognitive Behavioral Scale. 
19 C-SSRS Baseline Version to be completed at Baseline Visit only. C-SSRS Since Last Contact version to be completed at all other visits. 
20 Digital monitoring to occur approximately weekly. Subjects will undergo set up of digital monitoring smartphone application and initial use with study staff 
during the Baseline Visit. All subsequent weekly digital monitoring should occur at home and before noon, if possible, to minimize the potential effects of 
fatigue. At every in-person visit after Baseline study staff will check-in on subject use and app-related questions. 
21 Adverse events that occur AFTER signing consent form will be recorded. 
22 AL001 should be infused over 60 minutes, with a 60 minutes observation period following infusion completion for the first 2 infusions (30 minutes for 
subsequent infusions). In the event of an infusion-related reaction, blood will be drawn for PK serum and ADA assessment of AL001 or placebo; the following 
laboratory tests should be drawn: CRP, ferritin, tryptase, and IL-6 (at 1 to 2 hours after the IRR, then again at 48-72 hours after the IRR). Where possible, 
clinical laboratory samples should be drawn at the site for the central laboratory; however, local laboratories may be utilized and results assessed for safety by 
the investigator. 
23 Administer first dose of study drug AFTER Baseline Visit procedures are completed. 
24 Subjects may only undergo a LP if they have a coagulation panel and platelet count performed (using a central or local laboratory) within 4 weeks prior to the 
LP. If the laboratory results are abnormal and warrant repeat studies, they should be repeated within a week prior to the LP, and can be repeated at a local 
laboratory as needed. Lumbar puncture is to be performed at approximately the same time of the day as the Screening LP. The LP is to be performed after 
pulmonary function testing and administration of the ALSFRS-R.  
25 The Early Termination Visit should occur 8 weeks after the last dose of study treatment. 
26 If the assessment cannot be performed at the scheduled visit due to the COVID-19 pandemic, the assessments may be performed remotely or at a future on-site 
visit with approval from the Medical Monitor. Refer to Appendix 2 for additional details on trial adaptations due to COVID. 
 


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APPENDIX 2. ADAPTATION OF TRIAL PROTOCOL DURING THE 
COVID-19 PANDEMIC 
Background 
The COVID-19 pandemic has caused significant disruption globally and is a public health 
emergency that has an impact on the conduct of global clinical research activities. The safety of 
patients and site staff continues to be paramount, and Alector has made the decision to continue 
patient participation in the AL001-ALS-201 study at the discretion of the investigator, and in 
accordance with each site’s regional or country health authority guidelines and recommendations 
regarding the COVID-19 pandemic. 
Alector, in collaboration with the CRO, is committed to performing pandemic-related risk 
reviews of study procedures and mitigating the effect of the pandemic on the conduct of this 
study. These ongoing collaborative risk reviews include analysis of COVID-19 restrictions as 
they impact patient safety, study, and data integrity, and the impact on program timelines 
continues to be assessed. The review has been and will continue to be conducted regularly and 
will take into consideration any new information regarding the pandemic, including continuous 
assessment of adverse events reported in the study. 
Implementation of COVID-19 Adaptations 
The implementation of adaptations to study visits and procedures described in this appendix 
applies only to the exceptional circumstances of the COVID-19 pandemic. Procedure adaptations 
apply to those sites that have been impacted by the pandemic through restrictions to 
movement/travel, study site restrictions, and where the safety of the patient may be adversely 
impacted by on-site visits. 
The implementation of these adaptations will be determined on a site-by-site basis dependent on 
local requirements, and will be reviewed on a regular basis with Alector to confirm the continued 
need for implementation. 
Essential On-Site Assessments and Remote Visits (Via Phone or Video) 
Continuation of the study during the pandemic does, and will continue, to impact the ability of 
some sites to conduct all protocol assessments per the Schedules of Assessments. This is due to 
reduced time for on-site visits, limited or no availability of some services on site, and the need to 
conduct visits remotely via telephone or via televisit (if approved locally). 
The primary objective with any change to the study schedule is to ensure ongoing monitoring of 
patient safety. 
On-Site Essential Assessments 
Where possible, all protocol assessments and treatments should be completed. 
To accommodate reduced time on-site during study visits, the following reduced assessments 
schedule should be completed as a minimum: 
• Vital signs, weight, physical, and neurological examinations 
• Phlebotomy and urinalysis, including pregnancy test 


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• ECGs 
• Collection of AEs and concomitant medications 
• C-SSRS 
• Study drug administration 
Remote Essential Assessments 
If patients or raters are not able to come to the study site for a visit, the following assessments 
should be completed by telephone or video (if locally approved/allowed): 
• Review of AEs and concomitant medications 
• Review of medical history 
• ALSFRS-R 
• C-SSRS 
On-Site Assessments that Cannot be Completed at Scheduled Visits 
In the event that a scheduled assessment cannot be completed at the site, eg, limited 
availability/restriction of equipment, patient has limited time on-site, or because a remote visit 
was completed, the missed assessments may be completed at a future on-site visit, as determined 
and approved by the Medical Monitor. 
The approval of the Medical Monitor must be obtained prior to completion of these rescheduled 
assessments. 
COVID-19 Reporting 
In the event that a study subject is diagnosed with COVID-19 infection, the local health authority 
recommendations regarding treatment should be followed and the event should be reported as an 
AE/SAE, depending on the severity of infection and diagnosis. 
Remote Consent 
Where it is allowed by country/site regulations, a remote eConsent will be provided that allows a 
patient to be physically remote from the study site and participate in the consent process. 
Remote Source Document Verification 
Remote source document verification will be employed in the following circumstances: 
• International law, regulatory authorities, and the IRB/IEC permit this process and on-
site CRA visits are not permitted due to continued COVID-19 restrictions 
• There is a need to complete source document verification for the following reasons: 
− Study data assessment review of critical study milestones (eg, database lock) 
− Patient safety 
− A significant backlog of data monitoring that could impact data integrity or 
patient safety 


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Prior to commencing remote source document verification, the following documentation must be 
completed, if required per local regulations: 
• The site CRA will complete a confidentiality agreement committing to the following: 
− To securely destroy any copies of documents received from sites (paper or 
electronic) 
− Not to take any recording during video access 
• Remote SDV will only be completed for subjects who have consented to allow access 
to their health records remotely 
Home Visits 
To allow for collection of safety and protocol assessment data, and continuity of study drug 
administration, a home health service may be employed. A home visit for the purposes of this 
appendix is a visit to a patient’s home or an alternative convenient location, such as an alternate 
site. 
In event of home visits being employed, appropriate regulatory and ethics approval will be 
obtained prior to implementation. 
The following MUST be completed as on-site visits: 
• Screening Visit 
• Randomization Visit 
• First study drug infusion 
• Second study drug infusion 
All other visits may be completed as home visits. 


Document Approvals
Approval Task
Verdict:  Approve
Brian Mangal,
(b
al@alector.com)
SME Approval
11-Feb-2022 17:03:46 GMT+0000
Approval Task
Verdict:  Approve
Daniel Maslyar,
(d
el.maslyar@alector.com)
SME Approval
14-Feb-2022 17:31:30 GMT+0000
Number: GCP-00124            Status: Approved
Alector AL001-ALS-201 Protocol Amendment 3.0               86  of  86


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SAP_001.pdf: 
 
Alector, Inc. 
131 Oyster Point Blvd, Suite 600 
South San Francisco, CA 94080 
 
alector.com 
 
STATISTICAL ANALYSIS PLAN 
AL001-ALS-201 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of AL001 in C9orf72-Associated Amyotrophic Lateral 
Sclerosis 
SPONSOR: 
Alector, Inc. 
131 Oyster Point Boulevard, Suite 600 
South San Francisco, CA 94080, US 
Telephone: +1 650-837-0384 
PROTOCOL DATE: 
v3.0, 11 February 2022 
SAP DATE: 
v1.0, 29 November 2022 
 


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Clinical Study Protocol: AL001-ALS-201 
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Version 1.0 
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STATISTICAL ANALYSIS PLAN 
ALECTOR APPROVAL SIGNATURE PAGE 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of AL001 in C9orf72-Associated Amyotrophic Lateral 
Sclerosis 
 
This statistical analysis plan has been reviewed and approved by: 
 
 
 
See signature manifest at the end of the document. 
 
 
Brian Mangal, MSc. 
Date 
 
Alector, Inc. 
 
 
 
See signature manifest at the end of the document. 
 
 
Lawrence Carter, Ph.D. 
Date 
V
 
Alector, Inc
 


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Version 1.0 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................4 
1. 
INTRODUCTION ........................................................................................................5 
2. 
STUDY DESIGN .........................................................................................................5 
2.1. 
Design Overview ..........................................................................................................5 
3. 
STATISTICAL METHODS .........................................................................................6 
3.1. 
General Considerations .................................................................................................6 
3.1.1. 
Baseline Definition .......................................................................................................6 
3.2. 
Analysis Populations ....................................................................................................6 
3.2.1. 
Safety Analysis Set .......................................................................................................6 
4. 
LISTINGS .....................................................................................................................7 
4.1. 
Subject Disposition, Demographics ..............................................................................7 
4.2. 
Exposure to Study Drug ................................................................................................7 
4.3. 
Protocol Deviations ......................................................................................................7 
4.4. 
Adverse Events .............................................................................................................7 
4.5. 
Laboratory Assessments and Laboratory Abnormalities ..............................................7 
4.6. 
Vital Signs and 12-lead ECGs ......................................................................................8 
4.7. 
ALSFRS-R ....................................................................................................................8 
 


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Version 1.0 
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LIST OF ABBREVIATIONS 
aPTT 
activated partial thromboplastin time 
AE 
adverse event/adverse experience 
ALP 
alkaline phosphatase 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
C9ALS 
C9orf72-associated amyotrophic lateral sclerosis 
CRP 
C-Reactive Protein 
CSF 
cerebral spinal fluid 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
GCP 
Good Clinical Practice 
INR 
international normalized ratio 
IRR 
infusion-related reaction 
IV 
intravenous 
kg 
kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic 
PGRN 
progranulin 
PK 
pharmacokinetic 
PT 
preferred term/prothrombin time 
sCSR 
Synoptic clinical study report 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TDP-43 
TAR DNA-binding protein 43 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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Version 1.0 
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1. 
INTRODUCTION 
Study AL001-ALS-201 titled “A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics 
of AL001 in C9orf72-Associated Amyotrophic Lateral Sclerosis” was halted early after 
5 participants were enrolled. The study was not halted for safety reasons. Due to the limited 
number of patients enrolled, a synoptic clinical study report (sCSR) will be produced. 
This statistical analysis plan (SAP) provides a brief description of the planned analysis and 
reporting to support the development of the sCSR. This SAP is based on Protocol version 3.0 
dated 11 February 2022. 
2. 
STUDY DESIGN 
2.1. 
Design Overview 
This is a Phase 2, multicenter, randomized clinical trial evaluating the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of AL001 compared to placebo in 5 adults 
with C9orf72-associated Amyotrophic Lateral Sclerosis (C9ALS). AL001 is hypothesized to 
protect motor neurons by increasing extracellular progranulin (PGRN) levels and thereby 
reducing TAR DNA-binding protein 43 (TDP-43) pathology in amyotrophic lateral sclerosis 
(ALS). The trial has been designed to confirm elevation of PGRN and accumulation of AL001 in 
cerebral spinal fluid (CSF) and to provide proof-of-mechanism target engagement in preparation 
for a larger trial testing the clinical efficacy of AL001 in C9ALS. 
The study consists of a Screening Period (within 3 weeks prior to Day 0), a 24-week Treatment 
Period, and an 8-week Safety Follow-Up Period, concluding with the Study Completion Visit 
(8 weeks after last study drug administration). Day 0 is defined as the baseline, the first date of 
study drug administration. 
Subjects will be randomly assigned to receive either standard of care + AL001 or standard of 
care + placebo in a 2:1 ratio with stratification by rs5848 genotype (3 levels: CC, CT, and TT). 
Randomization will use each stratum specific computer-generated permuted block randomization 
schedule with an undisclosed block size. Seven doses of AL001 60 mg/kg or matching placebo 
are planned to be administered via intravenous (IV) infusion every 4 weeks for 24 weeks (Visit 2 
through Visit 8). Overview of Study Schema is shown below: 
 


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A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedures shown in the Schedule of 
Assessments. Subjects can withdraw from the study at any time. Subjects who plan to 
discontinue the study early should be encouraged to return to the investigational site for an Early 
Termination Visit, which is 8 weeks after the last dose of study treatment. 
3. 
STATISTICAL METHODS 
3.1. 
General Considerations 
No formal statistical analyses are planned. Key data will be provided in listings. All listings will 
be produced at the completion of the study for the sCSR using SAS® software version 9.4. 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 25.0 for system organ class (SOC) and preferred term (PT). Severity AEs 
will be graded according to the World Health Organization (WHO) Toxicity Grading Scale, 
March 2020 or later. If an AE is not specified within the WHO Toxicity Grading Scale, then the 
AE will be graded according to the following definitions: 
Grade 
Severity 
Description 
1 
Mild 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign or 
symptom but tolerates it reasonably well. 
2 
Moderate 
Mild to moderate limitation in activity; no or minimal medical intervention 
or therapy required. 
3 
Severe1 
Marked limitation in activity; medical intervention or therapy required; 
hospitalizations possible. 
4 
Life-Threatening 
The subject is at risk of death due to the AE as it occurred. This does not 
refer to an AE that hypothetically might have caused death if it were more 
severe. 
5 
Death 
Any AE where the outcome is death. 
1 Note that the term “severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Relatedness of each AE to the study treatment is assessed by the investigator as ‘Related’ or ‘Not 
Related’. 
3.1.1. 
Baseline Definition 
Unless otherwise specified, baseline value of a variable is defined as the last non-missing value 
prior to the first study treatment (Day 0). 
3.2. 
Analysis Populations 
3.2.1. 
Safety Analysis Set 
All subjects who receive at least one dose of AL001 or placebo will be included in the Safety 
Analysis Set. 


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Version 1.0 
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4. 
LISTINGS 
All listings will use the Safety Analysis Set. 
4.1. 
Subject Disposition, Demographics 
Subject demographics and rs5848 genotype (age, sex, ethnicity, race, screening weight, 
genotype) and disposition (study drug completion status, and study completion status) will be 
listed. 
4.2. 
Exposure to Study Drug 
Doses of AL001 or placebo are planned to be administered IV over 60 minutes (±15 minutes) by 
trained site personnel under the supervision of the investigator or their designee. Study treatment 
administration are recorded in the source documentation and in the electronic Case Report Form 
(eCRF), in particular planned infusion volume, actual infusion volume, and start and stop times 
of infusion, if the infusion was interrupted and if yes, reason for interruption. 
Exposure to study drug will be listed for the Safety Analysis Set. 
4.3. 
Protocol Deviations 
A protocol deviation occurs when the subject, investigator, or Alector (or designee) fails to 
adhere to protocol requirements. Important protocol deviations are the ones that affect the 
subjects' safety or the primary endpoint (safety). Important protocol deviations for this study 
include, but are not limited to, the following: 
• Failure to meet inclusion/exclusion criteria 
• Failure to comply with Good Clinical Practice (GCP) guidelines will result in an 
important protocol deviation; Alector will determine if an important protocol 
deviation will result in withdrawal of a subject from the trial. 
All important protocol deviations will be listed. 
4.4. 
Adverse Events 
AEs are collected regardless of cause or relationship that occur after signing of informed consent 
through end of study visit. Treatment emergent adverse events are those AEs with a start date on 
or after the date of first administration of investigational product. All AEs will be listed with a 
flag to indicate if an AE is treatment emergent. 
In addition, all serious adverse events (SAEs) and AEs leading to discontinuation of study 
medication will be listed, with a flag to indicate if an AE is treatment emergent. 
4.5. 
Laboratory Assessments and Laboratory Abnormalities 
Laboratory assessments include: hematology, chemistry, urinalysis, and coagulation. On dosing 
days, in the event of an infusion-related reaction (IRR), blood will also be drawn for PK serum 
and ADA assessments, and blood will also be drawn at 1 to 2 hours and 48-72 hours after the 
IRR to assess C-reactive protein (CRP), ferritin, tryptase, and IL-6 levels. 


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Laboratory assessments will be listed. Any values that are outside of normal ranges will be 
flagged in the listings. 
All laboratory assessments collected in the case of an IRR will be listed separately. 
4.6. 
Vital Signs and 12-lead ECGs 
All vital signs and 12-lead ECG data will be listed. 
4.7. 
ALSFRS-R 
ALSFRS-R total scores and changes from baseline will be listed. 


Document Approvals
Approval Task
Verdict:  Approve
Brian Mangal,
(b
m)
Author Approval
30-Nov-2022 17:25:55 GMT+0000
Approval Task
Verdict:  Approve
Lawrence Carter,
(lawrence.carter@alector.com)
Management Approval
30-Nov-2022 18:08:33 GMT+0000
Number: GCP-01731            Status: Approved
AL001-ALS-201 Synoptic CSR SAP v1.0               9  of  9