In this study, researchers will learn more about the effects of a drug called tofersen, also known as BIIB067 and QALSODY®, in adults with amyotrophic lateral sclerosis (ALS) who have a superoxide dismutase 1 (SOD1) gene mutation. One of the causes of ALS is a change (or mutation) in the SOD1 gene, which causes abnormal SOD1 protein to be made. This abnormal protein can cause the motor neurons in people with ALS to break down and die. When neurons are damaged, they release a protein called neurofilament light chain, also known as NfL. Previous studies have shown that NfL levels are higher in people with SOD1-ALS, even before any ALS symptoms appear. In this study, researchers will look at the effect of tofersen treatment in the earlier stages of the disease, even before ALS symptoms appear. Researchers believe that giving tofersen to patients as early as possible may slow the onset of ALS symptoms and the progression of the disease. This study will have 4 parts. In Part A, participants will have their health monitored and NfL levels tested on a monthly basis, but they will not receive any study drug. Tofersen or placebo will be given to participants in Parts B, while all participants will receive tofersen in Parts C and D. The main question that researchers want to answer is: • How long does it take for ALS symptoms to appear? Researchers will also learn more about: - How many participants develop ALS symptoms within 24 months of the start of Part B - Changes in participants' ability to perform their daily activities - Changes in participants' ability to breathe - How many participants die or need long-term breathing support - Changes in NfL levels in the blood - Changes in SOD1 protein levels in the fluid around the brain and spinal cord - How many participants have adverse events or serious adverse events. Adverse events are health problems that may or may not be caused by the study drug. The study will be done as follows: - Participants will first be screened to check if they can join the study. The screening period will be up to 6 weeks. Participants will join the study only after reading and signing an informed consent form, also known as an ICF. - In Part A, participants with presymptomatic ALS will not get any study drugs. Researchers will check the levels of NfL in their blood. Participants will be closely checked for any signs or symptoms of ALS. - Once a participant's NfL levels rise to a certain amount, they will move onto Part B. - In Part B, participants will be randomly assigned to get either tofersen or a placebo. Neither participants nor researchers will know who gets tofersen or the placebo during Part B. A placebo looks like the study drug but contains no medicine. - Participants will get the first 3 doses of tofersen once every 14 days. Afterwards, they will continue getting maintenance doses every 28 days. - All doses will be given through an intrathecal (IT) injection done through a lumbar puncture procedure. This involves injecting the drug into the fluid surrounding the spinal cord in the lower back. - Participants who develop ALS symptoms during Part B will move to Part C to receive tofersen. - Participants who develop ALS symptoms during Part A will move to Part D to receive tofersen. - In both Parts C and D, participants will know they are receiving tofersen. - Throughout the study, doctors will measure any changes to the participants' function and quality of life using different questionnaires. Doctors will also take blood and urine samples. They will also check the participants' overall health and ask how they are feeling. - Participants will have a follow-up visit 28 days after their last dose of study drug. - Participants will be in this study for up to about 6.5 years.
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 of 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 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 ribonucleic acid (RNA)]. Participants with positive HCV antibody
and undetectable HCV 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 a Lumbar Puncture (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.