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

NCT04494256 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 275AS1012020-000207-36
• Study Type: interventional
• Target: 99
• Locations: 4 countries
• Sites: 17

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

Conditions

Amyotrophic Lateral Sclerosis

Outcome Measures

Primary Outcomes (2)

• Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

  An AE was 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 was 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. A TEAE/TESAE was defined as any AE/SAE with an onset date that is on or after the first dose of study drug or any pre-existing condition that has worsened in severity after the first dose of study drug.

  From first dose of the study drug in Part 1 up to end of follow up period in Part 1 (up to Day 260)

• Part 2: Number of Participants With TEAEs and TESAEs

  An AE was 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 was 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. A TEAE/TESAE was defined as any AE/SAE with an onset date that is on or after the first dose of study drug or any pre-existing condition that has worsened in severity after the first dose of study drug.

  From first dose of the study in Part 2 up to end of follow up period in Part 2 (up to Day 1184)

Secondary Outcomes (17)

• Part 1: Serum Concentrations of BIIB105

  Pre-dose and 1, 2, 4, 6 hours post-dose on days 1, 15, 29, 57, 85,113, 141, 169 and on days 2, 8, 92, and 176

• Part 1: CSF Concentrations of BIIB105

  Pre-dose on Days 1, 15, 29, 57, 85, 113, 141, 169, and on days 92, 130, 175, and 176

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

  Day 1

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

  Day 1

• Part 1: Maximum Observed Serum Concentration (Cmax)

  Days 1, 15, 29, 57, 85, 113, 141 and 169

Study Arms (9)

Part 1: Cohort A

EXPERIMENTAL

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.

Drug: BIIB105

Part 1: Cohort B

EXPERIMENTAL

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.

Drug: BIIB105

Part 1: Cohort C1

EXPERIMENTAL

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.

Drug: BIIB105

Part 1: Cohort D1

EXPERIMENTAL

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.

Drug: BIIB105

Part 1: Cohort C2

EXPERIMENTAL

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.

Drug: BIIB105

Part 1: Cohort D2

EXPERIMENTAL

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.

Drug: BIIB105

Part 1: Cohorts A-D2: Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Part 2: Cohorts A-C2: Open-Label

EXPERIMENTAL

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.

Drug: BIIB105

Part 2: Cohorts D1, D2: Open-Label

EXPERIMENTAL

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.

Drug: BIIB105

Interventions

BIIB105 DRUG

Administered as specified in the treatment arm.

Part 1: Cohort A; Part 1: Cohort B; Part 1: Cohort C1; Part 1: Cohort C2; Part 1: Cohort D1; Part 1: Cohort D2; Part 2: Cohorts A-C2: Open-Label; Part 2: Cohorts D1, D2: Open-Label

Placebo DRUG

Administered as specified in the treatment arm.

Part 1: Cohorts A-D2: Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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.

You may not qualify if:

• 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:

Sponsors & Collaborators

• Biogen: lead

Study Sites (17)

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

University of California San Diego Medical Center

La Jolla, California, 92037, United States

Location

Stanford Neuromuscular Research Center

Palo Alto, California, 94305, United States

Location

University of Colorado Hospital - Neuroscience Center -Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007-2113, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

Orlando Health

Orlando, Florida, 32806, United States

Location

The Emory Clinic

Atlanta, Georgia, 30322, United States

Location

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

Baltimore, Maryland, 21218, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Washington University, School of Medicine

St Louis, Missouri, 63110, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Houston Methodist Neurological Institute

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Montreal Neurological Institute-Hospital

Montreal, Quebec, H3A 2B4, Canada

Location

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

Torino, Italy

Location

UMC Utrecht

Utrecht, 3584 CX, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 36288714 DERIVED

Related Links

• Biogen Trial Link

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

Study terminated because of sponsor's decision.

Results Point of Contact

• Title: US Biogen Clinical Trial Center
• Organization: Biogen

clinicaltrials@biogen.com

866-633-4636

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2020
• First Posted: July 31, 2020
• Study Start: September 28, 2020
• Primary Completion: August 13, 2024
• Study Completion: August 13, 2024
• Last Updated: October 9, 2025
• Results First Posted: October 9, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

NL (1); US (14); CA (1); IT (1)