Long-Term Evaluation of BIIB067 (Tofersen)

• ClinicalTrials.gov Identifier: NCT03070119
• Recruitment Status: Active, not recruiting
• First Posted: March 3, 2017
• Last Update Posted: May 22, 2023
• Sponsor: Biogen
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: February 28, 2017
• First Posted Date: March 3, 2017
• Last Update Posted Date: May 22, 2023
• Actual Study Start Date: March 8, 2017
• Estimated Primary Completion Date: June 13, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 2, 2021)

Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 364 ]

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.

Original Primary Outcome Measures (submitted: February 28, 2017)

• Number of participants experiencing AEs and serious adverse events (SAEs) [ Time Frame: Up to 15 months ]
• Number of participants with clinically significant laboratory assessment abnormalities [ Time Frame: Up to 15 months ]
• Number of participants with clinically significant vital sign abnormalities [ Time Frame: Up to 15 months ]
• Number of participants with clinically significant physical examination abnormalities [ Time Frame: Up to 15 months ]
• Number of participants with clinically significant neurological examination abnormalities [ Time Frame: Up to 15 months ]
• Number of participants with clinically significant 12-lead electrocardiograms (ECGs) abnormalities [ Time Frame: Up to 15 months ]

Current Secondary Outcome Measures (submitted: September 2, 2021)

• Levels of BIIB067 in Plasma [ Time Frame: Up to Week 364 ]
• Levels of BIIB067 in Cerebrospinal Fluid (CSF) [ Time Frame: Up to Week 360 ]
• Change from Baseline in Total SOD1 Protein in CSF [ Time Frame: Baseline to Week 360 ]
• Change from Baseline in Neurofilament Light Chain (NfL) Concentration in Plasma [ Time Frame: Baseline to Week 364 ]
• Change from Baseline in Total ALS Functional Rating Scale - Revised (ALSFRS-R) Score [ Time Frame: Baseline to Week 364 ]
  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.
• Change from Baseline in Slow Vital Capacity (SVC) [ Time Frame: Baseline to Week 364 ]
  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.
• Change from Baseline in Handheld Dynamometry (HHD) Megascore and Individual Muscle Strength [ Time Frame: Baseline to Week 364 ]
  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.
• Time to Death or Permanent Ventilation [ Time Frame: Up to Week 364 ]
  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].
• Time to Death [ Time Frame: Up to Week 364 ]

Original Secondary Outcome Measures (submitted: February 28, 2017)

• PK parameter of BIIB067 in plasma: Maximum observed concentration (Cmax) [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in cerebrospinal fluid (CSF): Cmax [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in plasma: Time to reach the maximum observed concentration (Tmax) [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in CSF: Tmax [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in plasma: Area under the concentration-time curve from time 0 to infinity (AUCinf) [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in CSF: AUCinf [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in plasma: Area under the concentration-time curve from time 0 to time of the last measurable (AUClast) [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in CSF: AUClast [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in plasma: Apparent terminal elimination half-life (t½) [ Time Frame: Up to 15 months ]
• PK parameter of BIIB067 in CSF: t½ [ Time Frame: Up to 15 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Long-Term Evaluation of BIIB067 (Tofersen)
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation

Intervention

Drug: Tofersen

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

Other Names:

• BIIB067
• QALSODY

Study Arms

Experimental: BIIB067

Participants who have completed Parts A, B, or C of study 233AS101 will be placed in this arm.

Intervention: Drug: Tofersen

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 2, 2021): 138
• Original Estimated Enrollment (submitted: February 28, 2017): 48
• Estimated Study Completion Date: June 13, 2024
• Estimated Primary Completion Date: June 13, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Germany, Italy, Japan, New Zealand, United Kingdom, United States

Administrative Information

• NCT Number: NCT03070119
• Other Study ID Numbers: 233AS102; 2016-003225-41 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Biogen
• Original Responsible Party: Same as current
• Current Study Sponsor: Biogen
• Original Study Sponsor: Same as current
• Collaborators: Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: May 2023