Tofersen for adults with ALS who do not have SOD1 mutations

A Study to Evaluate the Biological Effect of Tofersen in Adults With Amyotrophic Lateral Sclerosis Without Mutations in SOD1

This study will test whether tofersen given by lumbar puncture over 24 weeks lowers neurofilament light chain and is safe for adults with ALS who do not have SOD1 mutations.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Washington University School of Medicine (Academic / other)
• Locations: 1 site (St Louis, Missouri)
• Trial ID: NCT07294144 on ClinicalTrials.gov

What this trial studies

This Phase 2, single-center trial enrolls adults with confirmed non-SOD1 ALS and symptom onset within 24 months to receive 100 mg tofersen by lumbar puncture at Weeks 0, 2, 4, 8, 12, 16, 20, and 24. The protocol measures neurofilament light chain (NfL) in blood and CSF as a primary biomarker and monitors safety and tolerability throughout dosing and two post-dosing follow-up visits (Weeks 28 and 32). Investigators will also collect clinical outcome measures and quality-of-life questionnaires, along with strength and breathing tests. Prior genetic testing confirming negative SOD1 and FUS is required, and other gene mutations may be allowed at investigator discretion.

Who should consider this trial

Good fit: Adults aged 18 or older with a confirmed diagnosis of ALS, symptom onset within the past 24 months, prior genetic testing negative for SOD1 and FUS, and seated SVC ≥ 50% are the ideal candidates.

Not a fit: Patients with confirmed SOD1 or FUS mutations, symptom onset beyond 24 months, or severely reduced respiratory function (SVC < 50%) are unlikely to be eligible or to benefit from this protocol.

Why it matters

Potential benefit: If successful, tofersen could lower markers of neuronal injury and potentially slow progression or improve clinical outcomes for adults with non-SOD1 ALS.

How similar studies have performed: Tofersen is FDA-approved for SOD1-ALS and has shown biomarker reductions in that population, but its use in non-SOD1 ALS is novel and unproven.

Eligibility criteria

Inclusion Criteria:

* Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use PHI in accordance with national and local participant privacy regulations.
* Aged 18 years or older at the time of informed consent.
* Confirmed diagnosis of ALS.
* Time since onset of weakness due to ALS ≤ 24 months at the time of the screening visit.
* Prior confirmed genetic testing negative for SOD1 and FUS mutations. Participants with mutations in genes other than SOD1 and FUS may be enrolled at the discretion of the Site Investigator.
* SVC ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position).
* Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
* All participants must agree to practice effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment.
* If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and expected to remain at that dose until the final study visit.
* If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study.

Exclusion Criteria:

* Treatment with another investigational drug (including investigational drugs for ALS through compassionate use or expanded access 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 in any other interventional study.
* History of drug abuse or alcoholism within ≤ 6 months of study enrollment that would limit participation in the study, as determined by the Investigator.
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
* Ongoing medical condition (e.g., wasting or cachexia, severe anemia) that according to the Investigator would interfere with the conduct or assessments of 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 neurofilament, in the opinion of the Investigator.
* Female participants who are pregnant or currently breastfeeding.
* Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression ≤ 90 days, as determined by the Investigator.
* History of allergies to a broad range of anesthetics.
* Tracheostomy.
* Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally could place a participant at an increased risk for intraoperative or postoperative bleeding. These could include, but are not limited to, anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or other abnormalities) and underlying disorders of the coagulation cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand's disease, liver disease).
* Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication that cannot be safely held before and/or after an LP procedure according to local or institutional guidelines and/or Investigator determination.
* Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
* Clinically significant abnormalities in hematology or clinical chemistry parameters, as determined by the Investigator, which would render the participant unsuitable for enrollment.
* Inability to comply with study requirements.
* Other unspecified reasons that, in the opinion of the Investigator, make the participant unsuitable for enrollment.

Where this trial is running

St Louis, Missouri

• Washington University ALS Center — St Louis, Missouri, United States (Recruiting)

Conditions ALS; als; amyotrophic lateral sclerosis; tofersen; qalsody