A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation

Overview

Official title

A Phase 3 Randomized, Placebo-Controlled Trial With a Longitudinal Natural History Run-In and Open-Label Extension to Evaluate BIIB067 Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation

Brief title

A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation

Registration type

ClinicalTrials.gov

NCT number

NCT04856982

Status

Active, not recruiting

Study category

Interventional, Drug trial, Biomarker, Genetic, Presymptomatic, Prevention, Natural history

Sponsor / center

Biogen

Research center

Not stated in the official study record.

Collaborators

Not stated in the official study record.

Study type

Interventional study

Phase

Phase 3

Enrollment

158

Start date

05-17-2021

Primary completion date

08-07-2027

Estimated / actual completion date

04-30-2028

Last source update

03-30-2026

What is being studied?

The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF). The secondary objectives of this study are to evaluate the safety and tolerability tofersen and to evaluate the effect of tofersen on pharmacodynamics (PD)/treatment response biomarkers when initiated prior to versus at the time of emergence of clinically manifest amyotrophic lateral sclerosis (ALS).

Intervention(s)

Who may be eligible?

This is a simplified summary. The official study team or research center determines eligibility.

Population / disease status

Presymptomatic gene carrier, Diagnosed ALS

Diagnosis / conditions

Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation

Age

18 Years to Not stated in the official study record.

Disease duration

≤ 12 months

Respiratory criteria

Not stated in the official study record.

ALSFRS-R criteria

Not stated in the official study record.

Genetic criteria

The official eligibility criteria include language relevant to this topic; review the full criteria below.

Medication requirements

The official eligibility criteria include language relevant to this topic; review the full criteria below.

Major inclusion and exclusion criteria from the official record

Key Part A Inclusion Criteria:

* Participants should have a protocol-defined rapidly progressive SOD1 mutation, confirmed by a central reader, or a SOD1 mutation that is approved for inclusion by an external mutation adjudication committee.
* Participants with plasma NfL level less than the protocol-defined threshold.
* Participants who are clinically presymptomatic for ALS (i.e., must not have clinically manifest ALS).

Key Part A Exclusion Criteria:

* History or positive test result at screening for human immunodeficiency virus (HIV). The requirement for testing at Screening may be omitted if it is not permitted by local regulations.
* Current hepatitis C infection (defined as positive Hepatitis C Virus (HCV) antibody and detectable HCV RNA). Participants with positive HCV antibody and undetectable HCV Ribonucleic Acid (RNA) are eligible to participate in the study (United States Centers for Disease Control and Prevention).
* Current hepatitis B infection (defined as positive for hepatitis B surface antigen (HBsAg) and/or anti-Hepatitis B Core antibody (HBc)). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-hepatitis B surface antibody (HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti- HBs) are eligible to participate in the study.
* History of systemic hypersensitivity reaction to tofersen, the excipients contained in the formulation, and if appropriate, any diagnostic agents to be administered during the study.
* History of confounding neuromuscular or neurological disorder that is expected to have a progressive (i.e., worsening) course during the study, and/or is expected to be associated with elevations in NF, in the opinion of the Investigator.
* Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally could place a participant at an increased risk for intraoperative or postoperative bleeding.
* Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression

  ≤ 90 days of screening, which in the opinion of the Investigator would interfere with the study procedures.
* Treatment with riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol (also known as ursodoxicoltaurine). If the participant has been on riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol, the medication(s) must be discontinued for at least 5 half-lives prior to Screening.
* Use of off-label treatments for ALS.
* Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed.
* Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication (e.g., clopidogrel) that cannot be safely continued or held for an LP procedure, if necessary, according to local or institutional guidelines and/or Investigator determination.
* Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment, biological agent, device, or approved therapy for investigational use. Participation in a noninterventional study focused on ALS natural history may be allowed at the discretion of the Investigator.

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

Genetics

Gene-specific study?

Yes

Gene or variant

SOD1

Genetic test required?

Not stated in the official study record.

Known carrier required?

Not stated

Confirmed pathogenic variant required?

Not stated in the official study record.

Presymptomatic carriers eligible?

Yes

At-risk relative eligible?

Not stated

Genetic test provided?

Not stated in the official study record.

Genetic counseling provided?

Not stated in the official study record.

Results returned / offered?

Not stated

Family history required?

Not stated in the official study record.

Study design

Randomized?

Not stated in the official study record.

Allocation

Not stated in the official study record.

Intervention model

Not stated in the official study record.

Masking

Not stated in the official study record.

Placebo

Yes

Primary purpose

Not stated in the official study record.

Endpoints

Primary outcome measures

• Parts B and C: Percentage of Participants with Emergence of Clinically Manifest ALS Within 24 Months of Part B Baseline

Secondary outcome measures

• Parts B and C: Time to Emergence of Clinically Manifest ALS
• Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score
• Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC)
• Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on Time to Death or Permanent Ventilation Analysis
• Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis
• Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period
• Parts B, C and D: Change from Baseline in Plasma NfL Concentrations
• Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations

A biomarker outcome should not automatically be interpreted as a clinical outcome.

Locations

Contact

Central contact: Not stated in the official study record.

Study official: Medical Director · Biogen · STUDY_DIRECTOR