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A Study to Assess the Safety, Tolerability, and Effect on Disease Progression of BIIB105 in Participants With Amyotrophic Lateral Sclerosis (ALS) and Participants With the ALS Ataxin-2 (ATXN2) Genetic Mutation (ALSpire)

Primary Purpose

Amyotrophic Lateral Sclerosis

Status

Active

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

BIIB105

Placebo

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

Part 1:

Ability of the participant to understand the purpose and risks of the study and indicate informed consent, and the ability of the participant or the participant's legally authorized representative, to provide signed and dated informed consent and authorization to use protected health information in accordance with national and local privacy regulations.
All women of childbearing potential and all men must ensure that highly effective contraception is used during the study and for at least 6 months for female participants and 8 months for male participants after their last dose of study treatment.
No known presence or family history of mutations in the superoxide dismutase 1 (SOD1) or fused in sarcoma (FUS) genes.
Participants in Cohorts A, B, C1 and D1, must meet the laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria (revised according to the Airlie House Conference 1998 [Brooks 2000]). Participants in Cohort C2 and D2, must meet any of the prior conditions, but may also only meet clinically possible criteria for diagnosing ALS, or exhibit weakness attributable to ALS in the presence of ataxin-2 protein (ATXN2) intermediate repeats.
In participants in Cohorts C2 and D2, confirmed intermediate cytosine-adenine-guanine/cytosine-adenine-adenine (CAG/CAA) repeat expansion in the ataxin-2 gene or RNA (ATXN2) gene as defined by at least 1 allele carrying 30 to 33 CAG/CAA repeats.
Slow vital capacity (SVC) criteria:
In participants in Cohorts A, B, C1, and D1, SVC ≥60% of predicted value as adjusted for sex, age, and height (from the sitting position).
In participants in Cohort C2 and D2, SVC ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position).
If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study.
Participants taking concomitant edaravone at study entry must be on a stable dose for ≥60 days prior to the first dose of study treatment (Day 1). Participants taking concomitant edaravone must be willing to continue with the same dose regimen throughout the study, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study.
Screening values of coagulation parameters including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be within normal ranges.
Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at screening.

Part 2:

Ability of the participant to understand the purpose and risks of the study and indicate informed consent, and the ability of the participant or the participant's legally authorized representative to provide signed and dated informed consent and authorization to use protected health information in accordance with national and local privacy regulations
Participants must have completed Study NCT04494256 Part 1 through Week 25 (Day 175 Visit for Cohorts A, B, C1, C2; Day 176 Visit for Cohorts D1, D2). This inclusion criterion does not apply to a participant if Part 1 was terminated by the Sponsor before the participant reached Week 25.
Participants from Cohorts A, B, C1, and C2 must have a washout of ≥16 weeks between the last dose of study treatment received in Study NCT04494256 Part 1 and the first dose of BIIB105 received in Study NCT04494256 Part 2. Participants from Cohorts D1 and D2 do not require a washout period.
If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study.
Participants taking concomitant edaravone at study entry must be on a stable dose for ≥60 days prior to the first dose of study treatment (Day 1). Participants taking concomitant edaravone must be willing to continue with the same dose regimen throughout the study, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study.
Screening values of coagulation parameters including platelet count, INR, PT, and aPTT should be within normal ranges.

Key Exclusion Criteria

Part 1:

History or positive test result at Screening for human immunodeficiency virus (HIV).
Current hepatitis C infection.
Current hepatitis B infection.
History of alcohol or substance abuse ≤6 months of Screening that would limit participation in the study, as determined by the Investigator.
Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
Presence of tracheostomy.
In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as determined by the Investigator.
In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥8% during Screening.
In participants in Cohorts A, B, and C1, prescreening ALSFRS-R slope >-0.4 points/month, where prescreening ALSFRS-R slope is defined as: (ALSFRS-R score at Screening - 48) / (months from date of symptom onset to date of Screening). This criterion is not applicable for Cohorts C2, D1, and D2.
Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs) or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before Screening.
Treatment with an approved disease-modifying therapy for ALS other than riluzole or edaravone within 1 month or 5 half-lives of therapy, whichever is longer, before screening.
Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for lumbar puncture (LP) according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber.
Female participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study.

Part 2:

History or positive test result at Screening for HIV. If participants from Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive for HIV during screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the discretion of the Investigator.
Current hepatitis C infection. If participants from Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive for hepatitis C during screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the discretion of the Investigator.
Current hepatitis B infection. If participants from Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive for hepatitis B during screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the discretion of the Investigator.
History of alcohol or substance abuse ≤ 6 months of Screening that would limit participation in the study, as determined by the Investigator.
Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as determined by the Investigator.
In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes mellitus defined as HbA1c ≥8% during Screening.
Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs; excluding BIIB105) or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before Screening.
Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for LP according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber.
Female participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Sites / Locations

Barrow Neurological Institute
University of California San Diego Medical Center
Stanford Neuromuscular Research Center
University of Colorado Hospital - Neuroscience Center -Anschutz Medical Campus
Georgetown University
Mayo Clinic Florida
Orlando Health
The Emory Clinic
ALS Clinic - Department of Neurology, Neuromuscular Division, Johns Hopkins University, School of Medicine
Massachusetts General Hospital
Washington University, School of Medicine
University of Pennsylvania
Houston Methodist Neurological Institute
University of Utah
Montreal Neurological Institute-Hospital
A.O.U. Città della salute e della scienza di Torino
UMC Utrecht

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Placebo Comparator

Experimental

Arm Label

Part 1: Cohort A

Part 1: Cohort B

Part 1: Cohort C1

Part 1: Cohort D1

Part 1: Cohort C2

Part 1: Cohort D2

Part 1: Cohorts A-D2: Placebo

Part 2: Cohorts A-C2: Open-Label

Part 2: Cohorts D1, D2: Open-Label

Arm Description

Participants with ALS will receive BIIB105 Dose 1, intrathecally (IT), as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Participants with ALS will receive BIIB105 Dose 2, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Participants with ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Participants with ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.

Participants with polyQ-ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Participants with polyQ-ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.

Participants with ALS and polyQ-ALS for Cohorts A, B, C1 and C2 will receive matching placebo to BIIB105 as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days, and participants with ALS and polyQ-ALS for Cohorts D1 and D2 will receive matching placebo to BIIB105 as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.

Participants who complete Cohorts A, B, C1, and C2 will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed up to thirty-eight maintenance doses, on up to thirty-eight later days.

Participants who complete Cohorts D1 and D2 will have a blinded Loading Dose Period, during which those who received placebo in Part 1 will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, while those who received BIIB105 in Part 1 will receive 2 loading doses of BIIB105 Dose 4, IT, on Days 1 and one later day, and placebo on Day 15. After the blinded Loading Dose Period, participants will receive BIIB105 Dose 4 up to thirty-eight maintenance doses, on up to thirty-eight later days.

Outcomes

Primary Outcome Measures

Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event.

Part 2: Number of Participants with AEs and SAEs

Secondary Outcome Measures

Part 1: Serum Concentrations of BIIB105

Part 1: CSF Concentrations of BIIB105

Part 1: Area Under the Serum Concentration-Time Curve from Time Zero to Infinity (AUCinf)

Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast)

Part 1: Maximum Observed Serum Concentration (Cmax)

Part 1: Time to Reach Maximum Observed Serum Concentration (Tmax)

Part 1: Elimination Half-Life (t1/2) in Serum

Part 1: Change From Baseline in Plasma Levels of Neurofilament Light Chain (NfL)

Integrated Parts 1 and 2: CSF Trough PK Concentration of BIIB105

Integrated Parts 1 and 2: Serum PK Concentration of BIIB105

Integrated Parts 1 and 2: Change From Baseline in Plasma Levels of NfL

Integrated Parts 1 and 2: Change From Baseline in Slow Vital Capacity (SVC)

Integrated Parts 1 and 2: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score

The ALSFRS-R is used to predict survival. The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 to 4, for a total possible score of 48, with higher scores representing better function.

Integrated Parts 1 and 2: Change From Baseline in Muscle Strength, as Measured by Handheld Dynamometry (HHD)

Quantitative muscle strength will be evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups will be examined (per each side) in both upper and lower extremities.

Integrated Parts 1 and 2: Time to Death or Permanent Ventilation

Permanent ventilation is defined as ≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days.

Integrated Parts 1 and 2: Time to Death

Integrated Parts 1 and 2: Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital Status Data

Full Information

NCT ID

NCT04494256

First Posted

July 30, 2020

Last Updated

October 3, 2023

Sponsor

Biogen

1. Study Identification

Unique Protocol Identification Number

NCT04494256

Brief Title

A Study to Assess the Safety, Tolerability, and Effect on Disease Progression of BIIB105 in Participants With Amyotrophic Lateral Sclerosis (ALS) and Participants With the ALS Ataxin-2 (ATXN2) Genetic Mutation

Acronym

ALSpire

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

September 28, 2020 (Actual)

Primary Completion Date

July 15, 2026 (Anticipated)

Study Completion Date

July 15, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Biogen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The ALSpire Study is a clinical trial evaluating the investigational drug BIIB105 in adults living with amyotrophic lateral sclerosis (ALS). The ALSpire Study consists of two parts: Part 1: 6-month placebo-controlled study. During Part 1, participants are randomly assigned to receive either BIIB105 or placebo in a 3:1 or 2:1 ratio (depending on the participant's assigned Cohort). Part 2: up to 3-year long-term open-label extension. During Part 2, all participants receive BIIB105. The objectives of the study are to evaluate: The safety and tolerability of BIIB105 in people with ALS What the body does to BIIB105 (also called "pharmacokinetics") What BIIB105 does to the body (also called "pharmacodynamics") Whether BIIB105 can slow the worsening of clinical function

Detailed Description

About BIIB105: - BIIB105 is an investigational drug designed to reduce the levels of a protein called ATXN2. It is administered intrathecally (via a procedure called lumbar puncture).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Amyotrophic Lateral Sclerosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

99 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Cohort A

Arm Type

Experimental

Arm Description

Participants with ALS will receive BIIB105 Dose 1, intrathecally (IT), as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Arm Title

Part 1: Cohort B

Arm Type

Experimental

Arm Description

Participants with ALS will receive BIIB105 Dose 2, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Arm Title

Part 1: Cohort C1

Arm Type

Experimental

Arm Description

Participants with ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Arm Title

Part 1: Cohort D1

Arm Type

Experimental

Arm Description

Participants with ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.

Arm Title

Part 1: Cohort C2

Arm Type

Experimental

Arm Description

Participants with polyQ-ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.

Arm Title

Part 1: Cohort D2

Arm Type

Experimental

Arm Description

Participants with polyQ-ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.

Arm Title

Part 1: Cohorts A-D2: Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

Part 2: Cohorts A-C2: Open-Label

Arm Type

Experimental

Arm Description

Arm Title

Part 2: Cohorts D1, D2: Open-Label

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

BIIB105

Intervention Description

Administered as specified in the treatment arm.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Administered as specified in the treatment arm.

Primary Outcome Measure Information:

Title

Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Description

Time Frame

Up to Day 260

Title

Part 2: Number of Participants with AEs and SAEs

Description

Time Frame

Up to Day 1184

Secondary Outcome Measure Information:

Title

Part 1: Serum Concentrations of BIIB105

Time Frame

Up to Day 176

Title

Part 1: CSF Concentrations of BIIB105

Time Frame

Up to Day 259

Title

Part 1: Area Under the Serum Concentration-Time Curve from Time Zero to Infinity (AUCinf)

Time Frame

Up to Day 176

Title

Part 1: Area Under the Serum Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast)

Time Frame

Up to Day 176

Title

Part 1: Maximum Observed Serum Concentration (Cmax)

Time Frame

Up to Day 176

Title

Part 1: Time to Reach Maximum Observed Serum Concentration (Tmax)

Time Frame

Up to Day 176

Title

Part 1: Elimination Half-Life (t1/2) in Serum

Time Frame

Up to Day 176

Title

Part 1: Change From Baseline in Plasma Levels of Neurofilament Light Chain (NfL)

Time Frame

Up to Day 259

Title

Integrated Parts 1 and 2: CSF Trough PK Concentration of BIIB105

Time Frame

Up to Day 1183

Title

Integrated Parts 1 and 2: Serum PK Concentration of BIIB105

Time Frame

Up to Day 1009

Title

Integrated Parts 1 and 2: Change From Baseline in Plasma Levels of NfL

Time Frame

Up to Day 1183

Title

Integrated Parts 1 and 2: Change From Baseline in Slow Vital Capacity (SVC)

Time Frame

Up to Day 1183

Title

Integrated Parts 1 and 2: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score

Description

Time Frame

Up to Day 1183

Title

Integrated Parts 1 and 2: Change From Baseline in Muscle Strength, as Measured by Handheld Dynamometry (HHD)

Description

Time Frame

Up to Day 1183

Title

Integrated Parts 1 and 2: Time to Death or Permanent Ventilation

Description

Permanent ventilation is defined as ≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days.

Time Frame

Up to Day 1184

Title

Integrated Parts 1 and 2: Time to Death

Time Frame

Up to Day 1184

Title

Integrated Parts 1 and 2: Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital Status Data

Time Frame

Up to Day 1184

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria: Part 1: Ability of the participant to understand the purpose and risks of the study and indicate informed consent, and the ability of the participant or the participant's legally authorized representative, to provide signed and dated informed consent and authorization to use protected health information in accordance with national and local privacy regulations. No known presence or family history of mutations in the superoxide dismutase 1 (SOD1) or fused in sarcoma (FUS) genes. Participants in Cohorts A, B, C1 and D1, must meet the laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria (revised according to the Airlie House Conference 1998 [Brooks 2000]). Participants in Cohort C2 and D2, must meet any of the prior conditions, but may also only meet clinically possible criteria for diagnosing ALS, or exhibit weakness attributable to ALS in the presence of ataxin-2 protein (ATXN2) intermediate repeats. In participants in Cohorts C2 and D2, confirmed intermediate cytosine-adenine-guanine/cytosine-adenine-adenine (CAG/CAA) repeat expansion in the ataxin-2 (ATXN2) gene as defined by at least 1 allele carrying 30 to 33 CAG/CAA repeats. Slow vital capacity (SVC) criteria: In participants in Cohorts A, B, C1, and D1, SVC ≥60% of predicted value as adjusted for sex, age, and height (from the sitting position). In participants in Cohort C2 and D2, SVC ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study. Participants taking concomitant edaravone at study entry must be on a stable dose for ≥60 days prior to the first dose of study treatment (Day 1). Participants taking concomitant edaravone must be willing to continue with the same dose regimen throughout the study, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study. Screening values of coagulation parameters including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be within normal ranges. Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at screening. Part 2: Ability of the participant to understand the purpose and risks of the study and indicate informed consent, and the ability of the participant or the participant's legally authorized representative to provide signed and dated informed consent and authorization to use protected health information in accordance with national and local privacy regulations Participants must have completed Study NCT04494256 Part 1 through Week 25 (Day 175 Visit for Cohorts A, B, C1, C2; Day 176 Visit for Cohorts D1, D2). This inclusion criterion does not apply to a participant if Part 1 was terminated by the Sponsor before the participant reached Week 25. Participants from Cohorts A, B, C1, and C2 must have a washout of ≥16 weeks between the last dose of study treatment received in Study NCT04494256 Part 1 and the first dose of BIIB105 received in Study NCT04494256 Part 2. Participants from Cohorts D1 and D2 do not require a washout period. If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study. Participants taking concomitant edaravone at study entry must be on a stable dose for ≥60 days prior to the first dose of study treatment (Day 1). Participants taking concomitant edaravone must be willing to continue with the same dose regimen throughout the study, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study. Screening values of coagulation parameters including platelet count, INR, PT, and aPTT should be within normal ranges. Key Exclusion Criteria Part 1: History or positive test result at Screening for human immunodeficiency virus (HIV). Current hepatitis C infection. Current hepatitis B infection. History of alcohol or substance abuse ≤6 months of Screening that would limit participation in the study, as determined by the Investigator. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period. Presence of tracheostomy. In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as determined by the Investigator. In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥8% during Screening. In participants in Cohorts A, B, and C1, prescreening ALSFRS-R slope >-0.4 points/month, where prescreening ALSFRS-R slope is defined as: (ALSFRS-R score at Screening - 48) / (months from date of symptom onset to date of Screening). This criterion is not applicable for Cohorts C2, D1, and D2. Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs) or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before Screening. Treatment with an approved disease-modifying therapy for ALS other than riluzole or edaravone within 1 month or 5 half-lives of therapy, whichever is longer, before completion of screening. Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for lumbar puncture (LP) according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber. Female participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study. Part 2: History or positive test result at Screening for HIV. If participants from Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive for HIV during screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the discretion of the Investigator. Current hepatitis C infection. If participants from Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive for hepatitis C during screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the discretion of the Investigator. Current hepatitis B infection. If participants from Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test positive for hepatitis B during screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the discretion of the Investigator. History of alcohol or substance abuse ≤ 6 months of Screening that would limit participation in the study, as determined by the Investigator. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period. In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as determined by the Investigator. In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes mellitus defined as HbA1c ≥8% during Screening. Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs; excluding BIIB105) or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before Screening. Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for LP according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber. Female participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Biogen

Official's Role

Study Director

Facility Information:

Facility Name

Barrow Neurological Institute

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85013

Country

United States

Facility Name

University of California San Diego Medical Center

City

La Jolla

State/Province

California

ZIP/Postal Code

92037

Country

United States

Facility Name

Stanford Neuromuscular Research Center

City

Palo Alto

State/Province

California

ZIP/Postal Code

94305

Country

United States

Facility Name

University of Colorado Hospital - Neuroscience Center -Anschutz Medical Campus

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Georgetown University

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20007-2113

Country

United States

Facility Name

Mayo Clinic Florida

City

Jacksonville

State/Province

Florida

ZIP/Postal Code

32224

Country

United States

Facility Name

Orlando Health

City

Orlando

State/Province

Florida

ZIP/Postal Code

32806

Country

United States

Facility Name

The Emory Clinic

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

ALS Clinic - Department of Neurology, Neuromuscular Division, Johns Hopkins University, School of Medicine

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21218

Country

United States

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

Washington University, School of Medicine

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

University of Pennsylvania

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Houston Methodist Neurological Institute

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84132

Country

United States

Facility Name

Montreal Neurological Institute-Hospital

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H3A 2B4

Country

Canada

Facility Name

A.O.U. Città della salute e della scienza di Torino

City

Torino

Country

Italy

Facility Name

UMC Utrecht

City

Utrecht

ZIP/Postal Code

3584 CX

Country

Netherlands

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/

IPD Sharing URL

https://vivli.org/

Citations:

PubMed Identifier

36288714

Citation

Kim G, Nakayama L, Blum JA, Akiyama T, Boeynaems S, Chakraborty M, Couthouis J, Tassoni-Tsuchida E, Rodriguez CM, Bassik MC, Gitler AD. Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2. Cell Rep. 2022 Oct 25;41(4):111508. doi: 10.1016/j.celrep.2022.111508.

Results Reference

derived

Links:

URL

https://www.biogentriallink.com/en-us/home.html

Description

Biogen Trial Link

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