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

• ClinicalTrials.gov Identifier: NCT02623699
• Recruitment Status: Completed
• First Posted: December 8, 2015
• Last Update Posted: July 19, 2022
• Sponsor: Biogen
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Biogen

Study Description

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 BIIB067 (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 BIIB067 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 BIIB067 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 BIIB067.

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: BIIB067; Other: Placebo	Phase 3

Detailed Description:

This is a 3-part study to examine the efficacy, safety, tolerability, PK, and PD of BIIB067. Part A is the single ascending dose (SAD) component of the study, Part B is the multiple ascending dose (MAD) component of the 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 15 Jul 2021. In total, the study enrolled 178 participants, of which 108 enrolled in Part C.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 178 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects With Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
• Actual Study Start Date: January 20, 2016
• Actual Primary Completion Date: July 16, 2021
• Actual Study Completion Date: July 16, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Single Ascending Dose; Part A: Randomized single ascending dose	Drug: BIIB067; Part A, B and C; Other Name: Tofersen; Other: Placebo; Part A, B and C
Experimental: Multiple Ascending Dose; Part B: Randomized multiple ascending dose	Drug: BIIB067; Part A, B and C; Other Name: Tofersen; Other: Placebo; Part A, B and C
Experimental: Fixed Dose; Part C: Fixed Dose	Drug: BIIB067; Part A, B and C; Other Name: Tofersen; Other: Placebo; Part A, B and C

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part A and B: Up to Day 169 ]
   An AE is any untoward medical occurrence in a patient 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. A 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.
2. Number of Participants With Clinically Significant Laboratory Assessment Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
3. Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
4. Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
5. Number of Participants With Clinically Significant Neurological Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
6. Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
7. PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) [ Time Frame: Part A and B: Up to Day 169 ]
8. PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) [ Time Frame: Part A and B: Up to Day 169 ]
9. PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) [ Time Frame: Part A and B: Up to Day 169 ]
10. PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) [ Time Frame: Part A and B: Up to Day 169 ]
11. PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
12. PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
13. Change from Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 [ Time Frame: Part C: Baseline to Day 197 ]
    There are 12 questions, each scored from 0 (no function) to 4 (full function). Total possible score is 48. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression.

Secondary Outcome Measures :

1. Change From Baseline in CSF Levels of Total SOD1 Protein. [ Time Frame: Part A and B: Up to Day 169; Part C: up to Day 197 ]
2. Change From Baseline in Slow Vital Capacity (SVC) [ Time Frame: Part C: Baseline to Day 197 ]
   Vital capacity will be measured by means of an SVC test, administered in the upright position.
3. Change From Baseline in Muscle Strength Measured by Handheld Dynamometry (HHD) [ Time Frame: Part C: Baseline to Day 197 ]
   Quantitative muscle strength will be evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning.
4. Time to Death or Permanent Ventilation [ Time Frame: Part C: Baseline up to Day 225 ]
   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)
5. Time to Death [ Time Frame: Part C: Baseline up to Day 225 ]
6. Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part C: Baseline to Day 225 ]
7. Change From Baseline in Neurofilament Light Chain (NfL) Concentration in Plasma [ Time Frame: Part C: Baseline to Day 197 ]
   NfL is a biomarker whose concentration will be assessed in plasma.

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: 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.

Contacts and Locations

Locations

United States, Arizona

Barrow Neurological Institute

Phoenix, Arizona, United States, 85013

United States, California

University of California San Diego Medical Center

La Jolla, California, United States, 92093-0949

California Pacific Medical Center

San Francisco, California, United States, 94115

United States, Florida

Mayo Clinic in Florida

Jacksonville, Florida, United States, 32224

University of Miami School of Medicine

Miami, Florida, United States, 33136

Bioclinica Research

Orlando, Florida, United States, 32806

United States, Georgia

Emory University Hospital

Atlanta, Georgia, United States, 30322

United States, Illinois

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States, 60611

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

Henry Ford Hospital

Detroit, Michigan, United States, 48202

United States, Minnesota

Mayo Clinic - Rochester

Rochester, Minnesota, United States, 55905

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Nebraska

Neurology Associates, P.C.

Lincoln, Nebraska, United States, 68506

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

United States, Ohio

The Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44106

United States, Oregon

Providence ALS Center

Portland, Oregon, United States, 97213

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

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

Knoxville, Tennessee, United States, 37920

United States, Texas

Methodist Neurological Institute

Houston, Texas, United States, 77030

Australia, New South Wales

Westmead Hospital

Westmead, New South Wales, Australia, 2145

Belgium

UZ Leuven

Leuven, Belgium, 3000

Canada, Alberta

University of Calgary - Health Sciences Centre

Calgary, Alberta, Canada, T2N 1N4

Research Site

Edmonton, Alberta, Canada, T6G 2G3

Canada, Ontario

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada, M4N 3M5

Canada, Quebec

Montreal Neurological Institute

Montreal, Quebec, Canada, H3A 2B4

Denmark

Bispebjerg Hospital

Copenhagen, Denmark, 2400

France

Hopital Pitie Salpetriere

Paris, France, 75651

Germany

University of Ulm

Ulm, Baden Wuerttemberg, Germany, 89081

Italy

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

Torino, Italy, 10126

Japan

The University of Tokyo Hospital

Bunkyo-Ku, Japan

Research Site

Fukuoka-shi, Japan

Research Site

Kagoshima City, Japan

Research Site

Shinjuku-ku, Japan

Research Site

Suita-Shi, Japan

Korea, Republic of

Research Site

Yangsan-si, Gyeongsangnam-do, Korea, Republic of, 50612

Research Site

Seoul, Korea, Republic of, 04763

Poland

Research Site

Warszawa, Poland, 01684

United Kingdom

Research Site

London, Greater London, United Kingdom, SE5 9RS

Research Site

Sheffield, South Yorkshire, United Kingdom, S10 2HQ

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.

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.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02623699
• Other Study ID Numbers: 233AS101; 2015-004098-33 ( EudraCT Number )
• First Posted: December 8, 2015
• Last Update Posted: July 19, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
• URL: https://vivli.org/

Keywords provided by Biogen:

IONIS-SOD1Rx; SOD1; ALS

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases