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

UK Chief Investigator

Professor Dame Pamela Shaw

Research summary

Amyotrophic lateral sclerosis (ALS), is a rapidly progressive and fatal neurological disease that attacks the nerve cells (neurons) that control voluntary muscles such as those in the arms, legs, and face.

Although the majority of patients suffer from sporadic ALS without family history, approximately 2%, have an inherited form of ALS caused by a variety of genetic mutations known as superoxide dismutase 1 mutations (SOD1-ALS).

This study is being carried out to find out more about the study drug, BIIB067 as a potential treatment for people with SOD1 ALS. The optimum timing for starting BIIB067 in this group of people is currently unknown (i.e., prior to or after the appearance of clinically manifested disease). This study will involve people who have 1 of a limited number of possible SOD1 gene mutations and who are not showing any signs or symptoms of ALS.

The study consists of 4 parts. In Part A (run-in period) the participant’s neurofilament (NF) level will be monitored. NF is a protein with many functions in the body. This study will use NF as a biomarker (naturally occurring substances in the body that change as a result of disease). No study treatment will be given. If NF levels increase and the participant is not showing signs or symptoms of ALS, the participant will be screened to enter Part B (randomised placebo-controlled in pre-symptomatic participants with elevated NfL). If the participant shows signs or symptoms of ALS during Part B, they will be screened and entered into Part C of the study (open-label extension phase). If the participant shows signs or symptoms of ALS during Part A of the study or during screening for Part B of the study, they may be eligible to enter Part D of the study (randomised placebo-controlled in participants with clinically manifested ALS).

Around 150 participants will be enrolled in Part A, of which around 28 will be enrolled in Part B/C and approximately 6 will be enrolled in Part D. Approximately 30 sites are planned globally.

Inclusion / exclusion criteria

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 adjudicated 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 manifested 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 antihepatitis 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.

  • 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.

  • 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.

  • 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 non-interventional study focused on ALS natural history may be allowed at the discretion of the Investigator. NOTE: Other protocol defined Inclusion/Exclusion criteria will apply.

Current status

Open to recruitment


  • Royal Hallamshire Hosptial, Sheffield

Information about study sites

Contact details


Recruitment group(s)

Pre-symptomatic participants with SOD1 mutations

Recruitment target(s)

Up to 150 participants globally (4 participants in the UK)

Key dates

Actual opening date: May 2022

Recruitment planned end date: 17 September 2022





Study design

Interventional; multi-arm, multi-stage, adaptive, randomised controlled trial

Intervention (if applicable)

  • Drug: BIIB067 (Tofersen)

  • Placebo

Phase (if applicable)


Outcome measures

Primary outcome measure

  • Parts B and C: Percentage of Participants with Emergence of Clinically Manifest ALS Within 12 Months of Part B Baseline

Secondary outcome measures

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

  • 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

Publications / Results reports

Links will be provided when papers are published.