Long-Term Evaluation of BIIB067 (Tofersen)

Biogen139 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

139

Conditions

ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation

Interventions

TofersenDRUG

Participants will receive a loading dose regimen followed by maintenance dosing.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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must have completed the End of Study Visit for either Parts A, B, or C of Study 233AS101 (NCT02623699) (i.e., were not withdrawn).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

Locations (30)

Research Site

Phoenix, Arizona, United States

Outcomes

Primary Outcomes

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs)

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. TEAEs were defined as any AEs or SAE with an onset date and time that was on or after the first dose of study drug, or any pre-existing condition that worsened in severity after the first dose of study drug.

Time frame: From first dose of the study drug in the current study up to end of follow-up period (up to Week 364)

Secondary Outcomes

Plasma Concentration of BIIB067

Time frame: Week 4

Concentration of BIIB067 in Cerebrospinal Fluid (CSF)

Time frame: Week 4

233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline

This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

Time frame: Baseline, Weeks 52, 104 and 148

233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

Data from ClinicalTrials.gov

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Research Site

La Jolla, California, United States

Research Site

San Francisco, California, United States

Research Site

Jacksonville, Florida, United States

Research Site

Miami, Florida, United States

Research Site

Orlando, Florida, United States

Research Site

Atlanta, Georgia, United States

Research Site

Chicago, Illinois, United States

Research Site

Baltimore, Maryland, United States

Research Site

Boston, Massachusetts, United States

...and 20 more locations

Time frame: Baseline, Weeks 52, 104 and 148

233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis 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 (no function) to 4 (full function). The ALSFRS-R total score was calculated as the sum of the 4 functional domain scores, ranging from 0 to 48, where higher scores representing better function. Negative change from baseline indicates disease progression. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

Time frame: Baseline, Weeks 52, 104 and 148

233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)

Vital capacity was measured by means of an SVC test, administered in the upright position. Upright SVC was determined by performing 3 to 5 measures, in accordance with criteria established by the American Thoracic Society and the European Respiratory Society. The percent predicted SVC was calculated as \[observed SVC divided by predicted SVC\]\*100%. The predicted SVC was adjusted by sex, age, height, which was programmed into and performed by the equipment used. Negative change from baseline indicated worsening of respiratory capacity. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

Time frame: Baseline, Weeks 52, 104 and 148

233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore

Quantitative muscle strength was evaluated using the HHD Megascore, which tests isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups were examined (per each side) in both upper and lower extremities. The muscle strength values were normalized to Z scores as (post-baseline measurements - mean)/SD and averaged to provide HHD overall megascore. The overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. A negative change from baseline indicated decreased muscle strength. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

Time frame: Baseline, Weeks 52, 104 and 148

233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD

Individual muscle strength was evaluated using handheld dynamometer which tests the isometric strength of multiple muscles using standard participant positioning. Eight muscle groups were examined (per each side) in both upper and lower extremities. Negative change from baseline=decreased muscle strength. The analyses was based on observed data. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 \& 233AS102 studies. This is reported as a part of final integrated analyses.

Time frame: Baseline, Weeks 52, 104 and 148

233AS101 and 233AS102 ISE: Time to Death or Permanent Ventilation

Permanent ventilation was defined as ≥ 22 hours of mechanical ventilation \[invasive or noninvasive\] per day for ≥ 21 consecutive days. An event of permanent ventilation was based on an adjudicated event (i.e., adjudicated by the Endpoint Adjudication Committee (EAC) as having met the permanent ventilation criteria defined in the protocol). Time to death or permanent ventilation was defined as the time to the earliest occurrence of death or permanent ventilation. The start date for calculating time to death or permanent ventilation in days was date of first dose. Participants without an event were censored at the last known alive dates. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 \& 233AS102 studies. This is reported as a part of final integrated analyses. Time to permanent ventilation or death was summarized using the Kaplan-Meier product limit method.

Time frame: From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364)

233AS101 and 233AS102 ISE: Time to Death

Time to death was defined as the time from first dose received in 233AS101 to death. Participants who do not meet the endpoint definition were censored at the participant's last known alive date. Only events that were adjudicated by the EAC are included. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 \& 233AS102 studies. This is reported as a part of final integrated analyses. Time to death was summarized using the Kaplan-Meier product limit method.

Time frame: From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364)