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)

• ClinicalTrials.gov Identifier: NCT04494256
• Recruitment Status: Active, not recruiting
• First Posted: July 31, 2020
• Last Update Posted: October 5, 2023
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

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

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: BIIB105; Drug: Placebo	Phase 1; Phase 2

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 99 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 28, 2020
• Estimated Primary Completion Date: July 15, 2026
• Estimated Study Completion Date: July 15, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: Cohort A; 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; Administered as specified in the treatment arm.
Experimental: Part 1: Cohort B; 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; Administered as specified in the treatment arm.
Experimental: Part 1: Cohort C1; 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; Administered as specified in the treatment arm.
Experimental: Part 1: Cohort D1; 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; Administered as specified in the treatment arm.
Experimental: Part 1: Cohort C2; 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; Administered as specified in the treatment arm.
Experimental: Part 1: Cohort D2; 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; Administered as specified in the treatment arm.
Placebo Comparator: Part 1: Cohorts A-D2: Placebo; 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; Administered as specified in the treatment arm.
Experimental: Part 2: Cohorts A-C2: Open-Label; 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; Administered as specified in the treatment arm.
Experimental: Part 2: Cohorts D1, D2: Open-Label; 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; Administered as specified in the treatment arm.

Outcome Measures

Primary Outcome Measures :

1. Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 260 ]
   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.
2. Part 2: Number of Participants with AEs and SAEs [ Time Frame: Up to Day 1184 ]
   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.

Secondary Outcome Measures :

1. Part 1: Serum Concentrations of BIIB105 [ Time Frame: Up to Day 176 ]
2. Part 1: CSF Concentrations of BIIB105 [ Time Frame: Up to Day 259 ]
3. Part 1: Area Under the Serum Concentration-Time Curve from Time Zero to Infinity (AUCinf) [ Time Frame: Up to Day 176 ]
4. 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 ]
5. Part 1: Maximum Observed Serum Concentration (Cmax) [ Time Frame: Up to Day 176 ]
6. Part 1: Time to Reach Maximum Observed Serum Concentration (Tmax) [ Time Frame: Up to Day 176 ]
7. Part 1: Elimination Half-Life (t1/2) in Serum [ Time Frame: Up to Day 176 ]
8. Part 1: Change From Baseline in Plasma Levels of Neurofilament Light Chain (NfL) [ Time Frame: Up to Day 259 ]
9. Integrated Parts 1 and 2: CSF Trough PK Concentration of BIIB105 [ Time Frame: Up to Day 1183 ]
10. Integrated Parts 1 and 2: Serum PK Concentration of BIIB105 [ Time Frame: Up to Day 1009 ]
11. Integrated Parts 1 and 2: Change From Baseline in Plasma Levels of NfL [ Time Frame: Up to Day 1183 ]
12. Integrated Parts 1 and 2: Change From Baseline in Slow Vital Capacity (SVC) [ Time Frame: Up to Day 1183 ]
13. Integrated Parts 1 and 2: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score [ Time Frame: Up to Day 1183 ]
    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.
14. Integrated Parts 1 and 2: Change From Baseline in Muscle Strength, as Measured by Handheld Dynamometry (HHD) [ Time Frame: Up to Day 1183 ]
    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.
15. Integrated Parts 1 and 2: Time to Death or Permanent Ventilation [ Time Frame: Up to Day 1184 ]
    Permanent ventilation is defined as ≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days.
16. Integrated Parts 1 and 2: Time to Death [ Time Frame: Up to Day 1184 ]
17. Integrated Parts 1 and 2: Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital Status Data [ Time Frame: Up to Day 1184 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Arizona

Barrow Neurological Institute

Phoenix, Arizona, United States, 85013

United States, California

University of California San Diego Medical Center

La Jolla, California, United States, 92037

Stanford Neuromuscular Research Center

Palo Alto, California, United States, 94305

United States, Colorado

University of Colorado Hospital - Neuroscience Center -Anschutz Medical Campus

Aurora, Colorado, United States, 80045

United States, District of Columbia

Georgetown University

Washington, District of Columbia, United States, 20007-2113

United States, Florida

Mayo Clinic Florida

Jacksonville, Florida, United States, 32224

Orlando Health

Orlando, Florida, United States, 32806

United States, Georgia

The Emory Clinic

Atlanta, Georgia, United States, 30322

United States, Maryland

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

Baltimore, Maryland, United States, 21218

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Missouri

Washington University, School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Houston Methodist Neurological Institute

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

Canada, Quebec

Montreal Neurological Institute-Hospital

Montreal, Quebec, Canada, H3A 2B4

Italy

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

Torino, Italy

Netherlands

UMC Utrecht

Utrecht, Netherlands, 3584 CX

Sponsors and Collaborators

Biogen

Investigators

• Study Director: Medical Director; Biogen

More Information

Additional Information:

Biogen Trial Link 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT04494256
• Other Study ID Numbers: 275AS101; 2020-000207-36 ( EudraCT Number )
• First Posted: July 31, 2020
• Last Update Posted: October 5, 2023
• Last Verified: October 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/
• URL: https://vivli.org/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Disease Progression; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Disease Attributes