Long-Term Evaluation of BIIB067 (Tofersen)

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

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 Overview

• Status: Completed
• Conditions: ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation
• Intervention / Treatment: Drug: Tofersen

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Research Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Research Site
    • Edmonton, Alberta, Canada, T6G 2B7
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H3A2B4
      • Research Site
• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital
• France
  • Puy De Dome
    • Clermont-Ferrand, Puy De Dome, France, 63003
      • Research Site
• Germany
  • Baden-Wurttemberg
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Research Site
• Italy
  • Torino, Italy, 10126
    • Research Site
• Japan
  • Bunkyō City, Japan
    • Research Site
  • Kagoshima, Japan
    • Research Site
  • Shinjuku-ku, Japan
    • Research Site
  • Suita-shi, Japan
    • Research Site
• United Kingdom
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S102HQ
      • Research Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Research Site
  • California
    • La Jolla, California, United States, 92093-0949
      • Research Site
    • San Francisco, California, United States, 94118
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Research Site
    • Miami, Florida, United States, 33136
      • Research Site
    • Orlando, Florida, United States, 32806
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Research Site
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97213
      • Research Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From first dose of the study drug in the current study up to end of follow-up period (up to Week 364)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentration of BIIB067		Week 4
Concentration of BIIB067 in Cerebrospinal Fluid (CSF)		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.	Baseline, Weeks 52, 104 and 148
233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration 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.	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.	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.	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.	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.	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.	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.	From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364)

Collaborators and Investigators

• Sponsor: Biogen
• Collaborators: Ionis Pharmaceuticals, Inc.
• Investigators: Study Director: Medical Director, Biogen

Publications and helpful links

General Publications

• Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2017
• Primary Completion (Actual): August 12, 2024
• Study Completion (Actual): August 12, 2024

Study Registration Dates

• First Submitted: February 28, 2017
• First Submitted That Met QC Criteria: February 28, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 12, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: tofersen
• Other Study ID Numbers: 233AS102; 2016-003225-41 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No