Long-Term Evaluation of BIIB067 (Tofersen)

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 (tofersen) in participants with amyotrophic lateral sclerosis (ALS) and confirmed superoxide dismutase 1 (SOD1) mutation. The secondary objectives are to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), biomarker effects, and efficacy of BIIB067 administered to participants with ALS and a confirmed SOD1 mutation.

Official Title
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An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to Previously Treated Adults With Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation

Conditions
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ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation

Intervention / Treatment
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* Drug: Tofersen


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must have diagnosis of superoxide dismutase 1-amyotrophic lateral sclerosis (SOD1-ALS), and must have completed the End of Study Visit for either Parts A, B, or C of Study 233AS101 (NCT02623699) (i.e., were not withdrawn). If taking riluzole, participant must be receiving a stable dose for ≥30 days prior to Day 1. If taking edaravone, participant must have initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1. Edaravone may not be administered on dosing days during this study. 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. For female participants of childbearing potential 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. Participants from Study 233AS101 Parts A and B must have a washout ≥16 weeks between the last dose of study treatment received in Study 233AS101 and the first dose of BIIB067 received in the current Study 233AS102. Key Exclusion Criteria: History of allergies to a broad range of anesthetics. Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally and could place a participant at an increased risk for bleeding during or after a Lumbar Puncture (LP) procedure. These risks 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). Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter. Prior or current treatment with small interfering ribonucleic acid (RNA), stem cell therapy, or gene therapy. Treatment with another investigational drug, biological agent (excluding BIIB067), or device within 1 month or 5 half-lives of study agent, whichever is longer. Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period. Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine. Female participants who are pregnant or currently breastfeeding. Current enrollment in any other interventional study. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIIB067<br>Participants who have completed Parts A, B, or C of study 233AS101 will be placed in this arm. | Drug: Tofersen<br>* Participants will receive a loading dose regimen followed by maintenance dosing.<br>* Other names: QALSODY;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. | Up to Week 364 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of BIIB067 in Plasma |  | Up to Week 364 | 
| Levels of BIIB067 in Cerebrospinal Fluid (CSF) |  | Up to Week 360 | 
| Change from Baseline in Total SOD1 Protein in CSF |  | Baseline to Week 360 | 
| Change from Baseline in Neurofilament Light Chain (NfL) Concentration in Plasma |  | Baseline to Week 364 | 
| Change from Baseline in Total ALS Functional Rating Scale - Revised (ALSFRS-R) Score | The ALSFRS-R measures 4 functional domains, including 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. | Baseline to Week 364 | 
| Change from Baseline in Slow Vital Capacity (SVC) | Vital capacity will be measured by means of an SVC test, administered in the upright position. Upright SVC will be determined by performing 3 to 5 measures, in accordance with criteria established by the American Thoracic Society and the European Respiratory Society. | Baseline to Week 364 | 
| Change from Baseline in Handheld Dynamometry (HHD) Megascore and Individual Muscle Strength | Quantitative muscle strength will be evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups will be examined (per each side) in both upper and lower extremities. | Baseline to Week 364 | 
| Time to Death or Permanent Ventilation | Time to death or permanent ventilation is defined as the time to the earliest occurrence of one of the following events: Death; Permanent ventilation [≥22 hours of mechanical ventilation (invasive or noninvasive) per day for ≥21 consecutive days]. | Up to Week 364 | 
| Time to Death |  | Up to Week 364 |