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

Biogen

Status and phase: Completed; Phase 3

Conditions: Amyotrophic Lateral Sclerosis

Treatments: Drug: Tofersen; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02623699

2015-004098-33 (EudraCT Number)

233AS101

Details and patient eligibility

About

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.

Full 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.

Enrollment: 176 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria: Part A and B

• 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.

Key Exclusion Criteria: Part A and B

• 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.

Key Inclusion Criteria: Part C

• 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.

Key Exclusion Criteria: Part C

• 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.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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176 participants in 12 patient groups, including a placebo group

Part A-SAD: Combined Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo

Part A-SAD: Cohort 1: Tofersen 10 mg

Experimental group

Description:

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

Treatment:

Drug: Tofersen

Part A-SAD: Cohort 2: Tofersen 20 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen

Part A-SAD: Cohort 3: Tofersen 40 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen

Part A-SAD: Cohort 4: Tofersen 60 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen

Part B-MAD: Combined Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Part B-MAD: Cohort 5: Tofersen 20 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen

Part B-MAD: Cohort 6: Tofersen 40 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen

Part B-MAD: Cohort 7: Tofersen 60 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen

Part B-MAD: Cohort 8: Tofersen 100 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen

Part C-Pivotal: Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Part C-Pivotal: Tofersen 100 mg

Experimental group

Description:

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.

Treatment:

Drug: Tofersen