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

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

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.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 176
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 1N4
      • University of Calgary - Health Sciences Centre
    • Edmonton, Alberta, Canada, T6G 2G3
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute
• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital
• France
  • Paris, France, 75651
    • Hôpital Pitié Salpetrière
• Germany
  • Baden Wuerttemberg
    • Ulm, Baden Wuerttemberg, Germany, 89081
      • University of Ulm
• Italy
  • Torino, Italy, 10126
    • ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin
• Japan
  • Bunkyo-Ku, Japan
    • The University of Tokyo Hospital
  • Fukuoka-shi, Japan
    • Research Site
  • Kagoshima City, Japan
    • Research Site
  • Shinjuku-ku, Japan
    • Research Site
  • Suita-Shi, Japan
    • Research Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 04763
    • Research Site
  • Gyeongsangnam-do
    • Yangsan-si, Gyeongsangnam-do, Korea, Republic of, 50612
      • Research Site
• Poland
  • Warszawa, Poland, 01684
    • Research Site
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE5 9RS
      • Research Site
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2HQ
      • Research Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego Medical Center
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic in Florida
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine
    • Orlando, Florida, United States, 32806
      • Bioclinica Research
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Neurology Associates, P.C.
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • The Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence ALS Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company
  • Texas
    • Houston, Texas, United States, 77030
      • Methodist Neurological Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 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.	Drug: Placebo; Administered as specified in the treatment arm.
Experimental: Part A-SAD: Cohort 1: Tofersen 10 mg; Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Placebo Comparator: 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.	Drug: Placebo; Administered as specified in the treatment arm.
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY
Placebo Comparator: 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.	Drug: Placebo; Administered as specified in the treatment arm.
Experimental: 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.	Drug: Tofersen; Administered as specified in the treatment arm.; Other Names: BIIB067; QALSODY

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)	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. 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.	Part A: First dose up to Day 63; Part B: First dose up to Day 289
Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities	Clinical laboratory assessments included hematology, chemistry, and urinalysis.	Part A: Up to Day 57; Part B: Up to Day 169
Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities	The criteria for clinically significant vital sign abnormalities include: Temperature: >38 degree Celsius (°C) or an increase from baseline of ≥1°C; Pulse: >120 beats per minute (bpm) or an increase from baseline of >20 bpm, <50 bpm or a decrease from baseline of >20 bpm; Systolic blood pressure (BP): >180 mmHg or an increase from baseline of >40 mmHg, <90 mmHg or a decrease from baseline of >30 mmHg; Diastolic BP: >105 mmHg or an increase from baseline of >30 mmHg, <50 mmHg or a decrease from baseline of >20 mmHg.	Part A: Up to Day 57; Part B: Up to Day 169
Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities	Clinically significant physical examination abnormalities included weight decreased.	Part A: Up to Day 57; Part B: Up to Day 169
Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities	Clinically significant neurological examination abnormalities included hyporeflexia.	Part A: Up to Day 57; Part B: Up to Day 169
Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities		Part A: Up to Day 57; Part B: Up to Day 169
Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)		Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85
Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)		Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)		Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)		Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast)		Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)		Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)		Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28	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 (no function) to 4 (full function), for a total possible score of 48. Scores decline with disease progression. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Higher scores represent better function, negative change from baseline indicates disease progression.	Baseline, Week 28 (Day 197)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline	Total CSF SOD1 protein ratio to baseline was calculated.	Day 85
Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline	Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.	Week 28 (Day 197)
Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline	NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.	Baseline, Day 197 (Week 28)
Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28	Vital capacity was measured by means of an SVC test, administered in the upright position.	Baseline, Week 28 (Day 197)
Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28	Quantitative muscle strength was evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning. Sixteen muscle groups were evaluated in both upper and lower extremities. The muscle strength values were normalized to Z scores as (post-baseline measurements - mean)/SD and averaged to provide HHD overall megascore. The overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. A negative change from baseline indicated decreased muscle strength.	Baseline, Week 28 (Day 197)
Part C: Time to Death or Permanent Ventilation	Time to Death or Permanent Ventilation is defined as the time to the earliest occurrence of one of the following events that were adjudicated by an independent committee: Death; Permanent ventilation (≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days).	Baseline up to Week 28 (Day 197)
Part C: Time to Death		Baseline up to Week 28 (Day 197)
Part C: Number of Participants Experiencing AEs and SAEs	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. 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.	First dose up to Day 236

Collaborators and Investigators

• Sponsor: Biogen
• Collaborators: Ionis Pharmaceuticals, Inc.
• Investigators: Study Director: Medical Director, Biogen

Publications and helpful links

General 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2016
• Primary Completion (Actual): July 16, 2021
• Study Completion (Actual): July 16, 2021

Study Registration Dates

• First Submitted: November 24, 2015
• First Submitted That Met QC Criteria: December 3, 2015
• First Posted (Estimated): December 8, 2015

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 7, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: ALS; SOD1; IONIS-SOD1Rx
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: 233AS101; 2015-004098-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/

Drug and device information, study documents

• 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