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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation
• Intervention / Treatment: Drug: Placebo; Drug: Tofersen

• Study Type: Interventional
• Enrollment (Actual): 158
• Phase: Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Macquarie Park, New South Wales, Australia, 2109
      • Macquarie University Hospital
• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Brazil
  • São Paulo, Brazil, 04038-002
    • PSEG Centro de Pesquisa Clinica
  • São Paulo
    • São Paulo, São Paulo, Brazil, 04037-002
      • Hospital São Paulo
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N4Z6
      • University Of Calgary
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H4A 3T2
      • Genge Partners
• France
  • Paris
    • Paris, Paris, France, 75651
      • Groupe Hospitalier Pitie-Salpetriere
• Germany
  • Baden-Wurttemberg
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Universitaetsklinikum Ulm
  • Lower Saxony
    • Hanover, Lower Saxony, Germany, 30625
      • Medizinische Hochschule Hannover
• Italy
  • Torino, Italy, 10124
    • Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
• Japan
  • Kagoshima-ken
    • Kagoshima, Kagoshima-ken, Japan, 890-8520
      • Kagoshima University Hospital
  • Tokyo-To
    • Bunkyō City, Tokyo-To, Japan, 113-8655
      • University of Tokyo Hospital
• Poland
  • Warsaw, Poland, 01-684
    • Centrum Medyczne NeuroProtect
  • Masovian Voivodeship
    • Warsaw, Masovian Voivodeship, Poland, 01-684
      • NeuroProtect Sp. z o.o.
• South Korea
  • Seoul, South Korea, 04763
    • Hanyang University Seoul Hospital
• Spain
  • Valencia, Spain, 46026
    • Hospital Universitari i Politècnic La Fe
• Sweden
  • Umeå, Sweden, 90185
    • Norrlands universitetssjukhus
  • Västerbotten County
    • Umeå, Västerbotten County, Sweden, 90185
      • University Hospital of Umeå
• United Kingdom
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2RX
      • University of Sheffield
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • HonorHealth Neurology
  • California
    • La Jolla, California, United States, 92093-0949
      • University of California San Diego Medical Center
    • San Francisco, California, United States, 94107
      • California Pacific Medical Center Research Institute
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322-4200
      • The Emory Clinic
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Massachusetts General Hospital, MA
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Texas
    • Austin, Texas, United States, 78756
      • Austin Neuromuscular Center

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Part A: Natural History Run-in; Participants enrolled in Part A will undergo blood draws approximately once every 28 days to assess neurofilament light chain (NfL) levels.
Experimental: Part D: Open-Label Treatment; 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; Administered as specified in the treatment arm; Other Names: BIIB067; QALSODY
Experimental: Part B: Randomized, Double-Blind, Placebo-Controlled; 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: Placebo; Administered as specified in the treatment arm; Drug: Tofersen; Administered as specified in the treatment arm; Other Names: BIIB067; QALSODY
Experimental: Part C: Open-Label Extension; 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: Placebo; Administered as specified in the treatment arm; Drug: Tofersen; Administered as specified in the treatment arm; Other Names: BIIB067; QALSODY

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	The ALSFRS-R measures 4 functional domains: 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.	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	Permanent ventilation is defined as ≥22 hours of invasive or non-invasive mechanical ventilation per day for ≥21 consecutive days.	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
Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period		Parts B and C: Up to 5.6 years and Part D: Up to 2 years
Parts B, C and D: Change from Baseline in Plasma NfL Concentrations		Parts B and C: Up to 5.6 years and Part D: Up to 2 years
Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations		Parts B and C: Up to 5.6 years and Part D: Up to 2 years

Collaborators and Investigators

• Sponsor: Biogen
• Investigators: Study Director: Medical Director, Biogen

Publications and helpful links

General Publications

• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2021
• Primary Completion (Estimated): August 7, 2027
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: April 20, 2021
• First Submitted That Met QC Criteria: April 20, 2021
• First Posted (Actual): April 23, 2021

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 27, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; tofersen
• Other Study ID Numbers: 233AS303; 2020-004590-51 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No