An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
- Registration Number
- NCT02623699
- Lead Sponsor
- Biogen
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 176
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
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part A-SAD: Combined Placebo Placebo Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively. Part B-MAD: Combined Placebo 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. Part C-Pivotal: Placebo 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. Part A-SAD: Cohort 1: Tofersen 10 mg Tofersen Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1. Part A-SAD: Cohort 3: Tofersen 40 mg Tofersen 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. Part A-SAD: Cohort 2: Tofersen 20 mg Tofersen 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. Part A-SAD: Cohort 4: Tofersen 60 mg Tofersen 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. Part B-MAD: Cohort 5: Tofersen 20 mg Tofersen 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. Part B-MAD: Cohort 6: Tofersen 40 mg Tofersen 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. Part B-MAD: Cohort 7: Tofersen 60 mg Tofersen 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. Part C-Pivotal: Tofersen 100 mg Tofersen 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. Part B-MAD: Cohort 8: Tofersen 100 mg Tofersen 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.
- Primary Outcome Measures
Name Time Method Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities Part A: Up to Day 57; Part B: Up to Day 169 Clinically significant neurological examination abnormalities included hyporeflexia.
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 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: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) Part A: First dose up to Day 63; Part B: First dose up to Day 289 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.
Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities Part A: Up to Day 57; Part B: Up to Day 169 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.
Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities Part A: Up to Day 57; Part B: Up to Day 169 Clinically significant physical examination abnormalities included weight decreased.
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: 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: 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: Number of Participants With Clinically Significant Laboratory Abnormalities Part A: Up to Day 57; Part B: Up to Day 169 Clinical laboratory assessments included hematology, chemistry, and urinalysis.
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 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 Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 Baseline, Week 28 (Day 197) 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.
- Secondary Outcome Measures
Name Time Method Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28 Baseline, Week 28 (Day 197) Vital capacity was measured by means of an SVC test, administered in the upright position.
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline Day 85 Total CSF SOD1 protein ratio to baseline was calculated.
Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline Baseline, Day 197 (Week 28) NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.
Part C: Time to Death or Permanent Ventilation Baseline up to Week 28 (Day 197) 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).
Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline Week 28 (Day 197) Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.
Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28 Baseline, Week 28 (Day 197) 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.
Part C: Time to Death Baseline up to Week 28 (Day 197) Part C: Number of Participants Experiencing AEs and SAEs First dose up to Day 236 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.
Trial Locations
- Locations (31)
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Hopital Pitie Salpetriere
🇫🇷Paris, France
Montreal Neurological Institute
🇨🇦Montreal, Quebec, Canada
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin
🇮🇹Torino, Italy
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
California Pacific Medical Center
🇺🇸San Francisco, California, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Providence ALS Center
🇺🇸Portland, Oregon, United States
Neurology Associates, P.C.
🇺🇸Lincoln, Nebraska, United States
UZ Leuven
🇧🇪Leuven, Belgium
University of Calgary - Health Sciences Centre
🇨🇦Calgary, Alberta, Canada
University of California San Diego Medical Center
🇺🇸La Jolla, California, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
Bioclinica Research
🇺🇸Orlando, Florida, United States
University of Miami School of Medicine
🇺🇸Miami, Florida, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
Mayo Clinic - Rochester
🇺🇸Rochester, Minnesota, United States
Columbia University Medical Center
🇺🇸New York, New York, 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
Research Site
🇬🇧Sheffield, South Yorkshire, United Kingdom
University of Ulm
🇩🇪Ulm, Baden Wuerttemberg, Germany
Bispebjerg Hospital
🇩🇰Copenhagen, Denmark
The University of Tokyo Hospital
🇯🇵Bunkyo-Ku, Japan