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).
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.