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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation	Drug: Tofersen	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 138 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 8, 2017
• Estimated Primary Completion Date: June 13, 2024
• Estimated Study Completion Date: June 13, 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. Levels of BIIB067 in Plasma [ Time Frame: Up to Week 364 ]
2. Levels of BIIB067 in Cerebrospinal Fluid (CSF) [ Time Frame: Up to Week 360 ]
3. Change from Baseline in Total SOD1 Protein in CSF [ Time Frame: Baseline to Week 360 ]
4. Change from Baseline in Neurofilament Light Chain (NfL) Concentration in Plasma [ Time Frame: Baseline to Week 364 ]
5. 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.
6. 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.
7. 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.
8. 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].
9. Time to Death [ Time Frame: Up to Week 364 ]

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Arizona

Research Site

Phoenix, Arizona, United States, 85013

United States, California

Research Site

La Jolla, California, United States, 92093-0949

Research Site

San Francisco, California, United States, 94118

United States, Florida

Research Site

Jacksonville, Florida, United States, 32224

Research Site

Miami, Florida, United States, 33136

Research Site

Orlando, Florida, United States, 32806

United States, Georgia

Research Site

Atlanta, Georgia, United States, 30322

United States, Illinois

Research Site

Chicago, Illinois, United States, 60611

United States, Maryland

Research Site

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02114

United States, Minnesota

Research Site

Rochester, Minnesota, United States, 55905

United States, Missouri

Research Site

Saint Louis, Missouri, United States, 63110

United States, Nebraska

Research Site

Lincoln, Nebraska, United States, 68510

United States, Ohio

Research Site

Cleveland, Ohio, United States, 44106

United States, Oregon

Research Site

Portland, Oregon, United States, 97213

United States, Tennessee

Research Site

Knoxville, Tennessee, United States, 37920

Belgium

Research Site

Leuven, Belgium, 3000

Canada, Alberta

Research Site

Calgary, Alberta, Canada, T2N 4Z6

Research Site

Edmonton, Alberta, Canada, T6G 2B7

Canada, Ontario

Research Site

Toronto, Ontario, Canada, M4N 3M5

Canada, Quebec

Research Site

Montreal, Quebec, Canada, H3A2B4

France

Research Site

Clermont-Ferrand cedex, Puy De Dome, France, 63003

Germany

Research Site

Ulm, Baden Wuerttemberg, Germany, 89081

Italy

Research Site

Torino, Italy, 10126

Japan

Research Site

Bunkyo-ku, Japan

Research Site

Kagoshima-shi, Japan

Research Site

Shinjuku-ku, Japan

Research Site

Suita-shi, Japan

New Zealand

Research Site

Christchurch, New Zealand, 8011

United Kingdom

Research Site

Sheffield, South Yorkshire, United Kingdom, S102HQ

Sponsors and Collaborators

Biogen

Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director; Biogen

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT03070119
• Other Study ID Numbers: 233AS102; 2016-003225-41 ( EudraCT Number )
• First Posted: March 3, 2017
• Last Update Posted: May 22, 2023
• Last Verified: May 2023

• 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