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

NCT02623699 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 233AS1012015-004098-33
• Study Type: interventional
• Target: 176
• Locations: 12 countries
• Sites: 40

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.

Conditions

Amyotrophic Lateral Sclerosis

Keywords

IONIS-SOD1Rx; SOD1; ALS

Outcome Measures

Primary Outcomes (14)

• 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 Outcomes (8)

• Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

  Day 85

• Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline

  Week 28 (Day 197)

• Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

  Baseline, Day 197 (Week 28)

• Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28

  Baseline, Week 28 (Day 197)

• Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28

  Baseline, Week 28 (Day 197)

Study Arms (12)

Part A-SAD: Combined Placebo

PLACEBO COMPARATOR

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

Part A-SAD: Cohort 1: Tofersen 10 mg

EXPERIMENTAL

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

Drug: Tofersen

Part A-SAD: Cohort 2: Tofersen 20 mg

EXPERIMENTAL

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

Part A-SAD: Cohort 3: Tofersen 40 mg

EXPERIMENTAL

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

Part A-SAD: Cohort 4: Tofersen 60 mg

EXPERIMENTAL

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

Part B-MAD: Combined Placebo

PLACEBO COMPARATOR

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

Part B-MAD: Cohort 5: Tofersen 20 mg

EXPERIMENTAL

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

Part B-MAD: Cohort 6: Tofersen 40 mg

EXPERIMENTAL

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

Part B-MAD: Cohort 7: Tofersen 60 mg

EXPERIMENTAL

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

Part B-MAD: Cohort 8: Tofersen 100 mg

EXPERIMENTAL

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

Part C-Pivotal: Placebo

PLACEBO COMPARATOR

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

Part C-Pivotal: Tofersen 100 mg

EXPERIMENTAL

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

Interventions

Tofersen DRUG

Administered as specified in the treatment arm.

Also known as: BIIB067, QALSODY

Part A-SAD: Cohort 1: Tofersen 10 mg; Part A-SAD: Cohort 2: Tofersen 20 mg; Part A-SAD: Cohort 3: Tofersen 40 mg; Part A-SAD: Cohort 4: Tofersen 60 mg; Part B-MAD: Cohort 5: Tofersen 20 mg; Part B-MAD: Cohort 6: Tofersen 40 mg; Part B-MAD: Cohort 7: Tofersen 60 mg; Part B-MAD: Cohort 8: Tofersen 100 mg; Part C-Pivotal: Tofersen 100 mg

Placebo DRUG

Administered as specified in the treatment arm.

Part A-SAD: Combined Placebo; Part B-MAD: Combined Placebo; Part C-Pivotal: Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2.
• 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.

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• Biogen: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (40)

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

University of California San Diego Medical Center

La Jolla, California, 92093, United States

Location

California Pacific Medical Center

San Francisco, California, 94115, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224, United States

Location

University of Miami School of Medicine

Miami, Florida, 33136, United States

Location

Bioclinica Research

Orlando, Florida, 32806, United States

Location

Emory University Hospital

Atlanta, Georgia, 30322, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Neurology Associates, P.C.

Lincoln, Nebraska, 68506, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

The Cleveland Clinic Foundation

Cleveland, Ohio, 44106, United States

Location

Providence ALS Center

Portland, Oregon, 97213, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

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

Knoxville, Tennessee, 37920, United States

Location

Methodist Neurological Institute

Houston, Texas, 77030, United States

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

UZ Leuven

Leuven, 3000, Belgium

Location

University of Calgary - Health Sciences Centre

Calgary, Alberta, T2N 1N4, Canada

Location

Research Site

Edmonton, Alberta, T6G 2G3, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Montreal Neurological Institute

Montreal, Quebec, H3A 2B4, Canada

Location

Bispebjerg Hospital

Copenhagen, 2400, Denmark

Location

Hopital Pitie Salpetriere

Paris, 75651, France

Location

University of Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

Location

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

Torino, 10126, Italy

Location

The University of Tokyo Hospital

Bunkyō City, Japan

Location

Research Site

Fukuoka, Japan

Location

Research Site

Kagoshima, Japan

Location

Research Site

Shinjuku-ku, Japan

Location

Research Site

Suita-Shi, Japan

Location

Research Site

Warsaw, 01684, Poland

Location

Research Site

Yangsan, Gyeongsangnam-do, 50612, South Korea

Location

Research Site

Seoul, 04763, South Korea

Location

Research Site

London, Greater London, SE5 9RS, United Kingdom

Location

Research Site

Sheffield, South Yorkshire, S10 2HQ, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 36129998 DERIVED

• 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.

  PMID: 32640130 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

tofersen

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: US Biogen Clinical Trial Center
• Organization: Biogen

clinicaltrials@biogen.com

866-633-4636

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 24, 2015
• First Posted: December 8, 2015
• Study Start: January 20, 2016
• Primary Completion: July 16, 2021
• Study Completion: July 16, 2021
• Last Updated: July 28, 2023
• Results First Posted: July 28, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); CA (4); BE (1); IT (1); DE (1); PL (1); FR (1); GB (2); DK (1); KR (2); JP (5); US (20)