An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)

NCT ID: NCT02623699

Last Updated: 2023-07-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 176 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-20
• Study Completion Date: 2021-07-16

Brief Summary

The primary objectives of Parts A and B of this study are to evaluate the safety, tolerability, and pharmacokinetics (PK) of ascending doses of tofersen in adults with ALS and a documented superoxide dismutase 1 (SOD1) mutation. The primary objective of Part C of this study is to evaluate the clinical efficacy of tofersen administered to adults with ALS and a confirmed SOD1 mutation.

The secondary objective of Parts A and B of this study is to evaluate the effects of tofersen on levels of total SOD1 protein in the cerebrospinal fluid (CSF). The secondary objectives of Part C are to evaluate the safety, tolerability, pharmacodynamic (PD), and biomarker effects of tofersen.

Detailed Description

This is a 3-part study to examine the efficacy, safety, tolerability, PK, and PD of tofersen. Part A is the single ascending dose (SAD) component of the study, Part B is the multiple ascending dose (MAD) component of study and Part C is the fixed dose component of the study. Hence, the overall phase of development of the study is 1/2/3.

The study completed on 16 Jul 2021. In total, the study enrolled 176 participants, of which 108 enrolled in Part C.

Conditions

Amyotrophic Lateral Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Part A-SAD: Combined Placebo

Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part A-SAD: Cohort 1: Tofersen 10 mg

Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part A-SAD: Cohort 2: Tofersen 20 mg

Participants will be administered tofersen 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part A-SAD: Cohort 3: Tofersen 40 mg

Participants will be administered tofersen 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part A-SAD: Cohort 4: Tofersen 60 mg

Participants will be administered tofersen 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part B-MAD: Combined Placebo

Participants will be administered tofersen-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part B-MAD: Cohort 5: Tofersen 20 mg

Participants will be administered tofersen 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part B-MAD: Cohort 6: Tofersen 40 mg

Participants will be administered tofersen 40 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety and PK review of Cohort 5.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part B-MAD: Cohort 7: Tofersen 60 mg

Participants will be administered tofersen 60 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 6.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part B-MAD: Cohort 8: Tofersen 100 mg

Participants will be administered tofersen 100 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 7.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part C-Pivotal: Placebo

Participants will be administered tofersen-matching placebo, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Administered as specified in the treatment arm.

Part C-Pivotal: Tofersen 100 mg

Participants will be administered tofersen 100 mg, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm.

Interventions

Tofersen

Administered as specified in the treatment arm.

Intervention Type: DRUG

Placebo

Administered as specified in the treatment arm.

Intervention Type: DRUG

Other Intervention Names

BIIB067; QALSODY

Eligibility Criteria

Inclusion Criteria

• Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2.
• A forced vital capacity (FVC) ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). Participants with stable FVC <50% but ≥45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator.
• If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• 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.

• Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit.
• If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• If taking edaravone, participant must have initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of 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.

Exclusion Criteria

• History of or positive test result for human immunodeficiency virus.
• History of, or positive test result at Screening, for hepatitis C virus antibody.
• Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study.
• Treatment with another investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed.
• Current enrollment in any other interventional study.
• 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.
• Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.

• History of or positive test result for human immunodeficiency virus.
• Current hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody and detectable HCV ribonucleic acid [RNA]). Participants with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study (United States Centers for Disease Control and Prevention).
• Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
• Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed.
• Current enrollment in any other interventional study.
• 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.
• Current or anticipated need, in the opinion of the Investigator, of a DPS during the study period.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ionis Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Biogen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Biogen

Locations

Barrow Neurological Institute

Phoenix, Arizona, United States

University of California San Diego Medical Center

La Jolla, California, United States

California Pacific Medical Center

San Francisco, California, United States

Mayo Clinic in Florida

Jacksonville, Florida, United States

University of Miami School of Medicine

Miami, Florida, United States

Bioclinica Research

Orlando, Florida, United States

Emory University Hospital

Atlanta, Georgia, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Henry Ford Hospital

Detroit, Michigan, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Neurology Associates, P.C.

Lincoln, Nebraska, United States

Columbia University Medical Center

New York, New York, United States

The Cleveland Clinic Foundation

Cleveland, Ohio, United States

Providence ALS Center

Portland, Oregon, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company

Knoxville, Tennessee, United States

Methodist Neurological Institute

Houston, Texas, United States

Westmead Hospital

Westmead, New South Wales, Australia

UZ Leuven

Leuven, , Belgium

University of Calgary - Health Sciences Centre

Calgary, Alberta, Canada

Research Site

Edmonton, Alberta, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Montreal Neurological Institute

Montreal, Quebec, Canada

Bispebjerg Hospital

Copenhagen, , Denmark

Hopital Pitie Salpetriere

Paris, , France

University of Ulm

Ulm, Baden-Wurttemberg, Germany

ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin

Torino, , Italy

The University of Tokyo Hospital

Bunkyō City, , Japan

Research Site

Fukuoka, , Japan

Research Site

Kagoshima, , Japan

Research Site

Shinjuku-ku, , Japan

Research Site

Suita-Shi, , Japan

Research Site

Warsaw, , Poland

Research Site

Yangsan, Gyeongsangnam-do, South Korea

Research Site

Seoul, , South Korea

Research Site

London, Greater London, United Kingdom

Research Site

Sheffield, South Yorkshire, United Kingdom

Countries

United States; Australia; Belgium; Canada; Denmark; France; Germany; Italy; Japan; Poland; South Korea; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 36129998 (View on PubMed)

Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, Maragakis NJ, McDermott CJ, Pestronk A, Ravits J, Salachas F, Trudell R, Van Damme P, Zinman L, Bennett CF, Lane R, Sandrock A, Runz H, Graham D, Houshyar H, McCampbell A, Nestorov I, Chang I, McNeill M, Fanning L, Fradette S, Ferguson TA. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.

Reference Type: DERIVED

PMID: 32640130 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-004098-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

233AS101

Identifier Type: -

Identifier Source: org_study_id