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

NCT04856982 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: 233AS3032020-004590-51
• Study Type: interventional
• Target: 158
• Locations: 14 countries
• Sites: 32

Brief Summary

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).

Conditions

Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation

Outcome Measures

Primary Outcomes (1)

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

  Up to 24 months

Secondary Outcomes (8)

• Parts B and C: Time to Emergence of Clinically Manifest ALS

  Up to 5.6 years

• Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score

  Up to 5.6 years

• Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC)

  Up to 5.6 years

• Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on Time to Death or Permanent Ventilation Analysis

  Up to 5.6 years

• Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis

  Up to 5.6 years

Study Arms (4)

Part A: Natural History Run-in

NO INTERVENTION

Participants enrolled in Part A will undergo blood draws approximately once every 28 days to assess neurofilament light chain (NfL) levels.

Part B: Randomized, Double-Blind, Placebo-Controlled

EXPERIMENTAL

Participants from Part A who meet the protocol-defined NfL threshold and remain presymptomatic may be eligible to participate in Part B. During Part B, participants will receive tofersen 100 milligram (mg) or placebo via intrathecal (IT) injection on Days 1, 15, 29, and every 28 days thereafter for up to approximately 5.6 years.

Drug: Tofersen; Drug: Placebo

Part C: Open-Label Extension

EXPERIMENTAL

Participants from Part B who develop clinically manifest ALS may be eligible to participate in Part C. During Part C, participants who received placebo in Part B will receive tofersen 100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter up to the final maintenance dost visit. Participants who received tofersen during Part B will receive tofersen 100 mg on Days 1, 29, and every 28 days thereafter up to the final maintenance dost visit, with a dose of placebo on Day 15 to maintain the study blind. The combined duration of Part B and Part C is up to approximately 5.6 years.

Drug: Tofersen; Drug: Placebo

Part D: Open-Label Treatment

EXPERIMENTAL

Participants from Part A who develop clinically manifest ALS prior to randomization in Part B may be eligible to participate in Part D. During Part D, participants will receive tofersen100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter for up to 2 years.

Drug: Tofersen

Interventions

Tofersen DRUG

Administered as specified in the treatment arm

Also known as: BIIB067, QALSODY

Part B: Randomized, Double-Blind, Placebo-Controlled; Part C: Open-Label Extension; Part D: Open-Label Treatment

Placebo DRUG

Administered as specified in the treatment arm

Part B: Randomized, Double-Blind, Placebo-Controlled; Part C: Open-Label Extension

Eligibility Criteria

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

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Biogen: lead

Study Sites (32)

HonorHealth Neurology

Scottsdale, Arizona, 85258, United States

Location

University of California San Diego Medical Center

La Jolla, California, 92093-0949, United States

Location

California Pacific Medical Center Research Institute

San Francisco, California, 94107, United States

Location

Holy Cross Hospital

Fort Lauderdale, Florida, 33308, United States

Location

University of Miami School of Medicine

Miami, Florida, 33136, United States

Location

The Emory Clinic

Atlanta, Georgia, 30322-4200, United States

Location

Northwestern Medicine

Chicago, Illinois, 60611, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital, MA

Charlestown, Massachusetts, 02129, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University Medical center

New York, New York, 10032, United States

Location

Austin Neuromuscular Center

Austin, Texas, 78756, United States

Location

Macquarie University Hospital

Macquarie Park, New South Wales, 2109, Australia

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Hospital Sao Paulo

São Paulo, São Paulo, 04037-002, Brazil

Location

PSEG Centro de Pesquisa Clinica

São Paulo, 04038-002, Brazil

Location

University of Calgary

Calgary, Alberta, T2N4Z6, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Genge Partners

Montreal, Quebec, H4A 3T2, Canada

Location

Groupe Hospitalier Pitie-Salpetriere

Paris, Paris, 75651, France

Location

Universitaetsklinikum Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Medizinische Hochschule Hannover

Hanover, Lower Saxony, 30625, Germany

Location

Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino

Torino, 10124, Italy

Location

Kagoshima University Hospital

Kagoshima, Kagoshima-ken, 890-8520, Japan

Location

University of Tokyo Hospital

Bunkyō City, Tokyo-To, 113-8655, Japan

Location

NeuroProtect Sp. z o.o.

Warsaw, Masovian Voivodeship, 01-684, Poland

Location

Centrum Medyczne NeuroProtect

Warsaw, 01-684, Poland

Location

Hanyang University Seoul Hospital

Seoul, 04763, South Korea

Location

Hospital Universitari i Politecnic La Fe

Valencia, 46026, Spain

Location

University Hospital of Umea

Umeå, Västerbotten County, 90185, Sweden

Location

Norrlands Universitetssjukhus

Umeå, 90185, Sweden

Location

University of Sheffield

Sheffield, South Yorkshire, S10 2RX, United Kingdom

Location

Related Publications (1)

• Benatar M, Wuu J, Andersen PM, Bucelli RC, Andrews JA, Otto M, Farahany NA, Harrington EA, Chen W, Mitchell AA, Ferguson T, Chew S, Gedney L, Oakley S, Heo J, Chary S, Fanning L, Graham D, Sun P, Liu Y, Wong J, Fradette S. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4. Epub 2022 May 18.

  PMID: 35585374 DERIVED

Related Links

• Disclaimer: Residents in the United States may click here to find out more about participation in this trial.

MeSH Terms

Interventions

tofersen

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: April 20, 2021
• First Posted: April 23, 2021
• Study Start: May 17, 2021
• Primary Completion (Estimated): August 7, 2027
• Study Completion (Estimated): April 30, 2028
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

IT (1); JP (2); KR (1); US (12); PL (2); BR (2); CA (3); AU (1); ES (1); SE (2); GB (1); DE (2); BE (1); FR (1)