Clinical trial NCT02623699: An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Keywords: IONIS-SOD1Rx
SOD1
ALS
Lead sponsor: Biogen
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2015-12-08
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Part A: First dose up to Day 63; Part B: First dose up to Day 289
measure: Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities
timeFrame: Part A: Up to Day 57; Part B: Up to Day 169
measure: Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: Part A: Up to Day 57; Part B: Up to Day 169
measure: Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities
timeFrame: Part A: Up to Day 57; Part B: Up to Day 169
measure: Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities
timeFrame: Part A: Up to Day 57; Part B: Up to Day 169
measure: Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities
timeFrame: Part A: Up to Day 57; Part B: Up to Day 169
measure: Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)
timeFrame: 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
measure: Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)
timeFrame: 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
measure: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)
timeFrame: Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1
measure: Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)
timeFrame: 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
measure: Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)
timeFrame: 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
measure: Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28
timeFrame: Baseline, Week 28 (Day 197)
Secondary outcomes:
measure: Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
timeFrame: Day 85
measure: Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
timeFrame: Week 28 (Day 197)
measure: Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
timeFrame: Baseline, Day 197 (Week 28)
measure: Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28
timeFrame: Baseline, Week 28 (Day 197)
measure: Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28
timeFrame: Baseline, Week 28 (Day 197)
measure: Part C: Time to Death or Permanent Ventilation
timeFrame: Baseline up to Week 28 (Day 197)
measure: Part C: Time to Death
timeFrame: Baseline up to Week 28 (Day 197)
measure: Part C: Number of Participants Experiencing AEs and SAEs
timeFrame: First dose up to Day 236
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Orlando
country: United States
facility: Bioclinica Research
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lincoln
country: United States
facility: Neurology Associates, P.C.
state: Nebraska
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Providence ALS Center
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Knoxville
country: United States
facility: New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company
state: Tennessee
city: Houston
country: United States
facility: Methodist Neurological Institute
state: Texas
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Leuven
country: Belgium
facility: UZ Leuven
city: Calgary
country: Canada
facility: University of Calgary - Health Sciences Centre
state: Alberta
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Institute
state: Quebec
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Ulm
country: Germany
facility: University of Ulm
state: Baden Wuerttemberg
city: Torino
country: Italy
facility: ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin
city: Bunkyo-Ku
country: Japan
facility: The University of Tokyo Hospital
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Kagoshima City
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Suita-Shi
country: Japan
facility: Research Site
city: Yangsan-si
country: Korea, Republic of
facility: Research Site
state: Gyeongsangnam-do
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
state: Greater London
city: Sheffield
country: United Kingdom
facility: Research Site
state: South Yorkshire
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.