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

Amyotrophic Lateral Sclerosis Clinical Trial

— VALOR (Part C)  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02623699
• Other study ID #: 233AS101
• Secondary ID: 2015-004098-33
• Status: Completed
• Phase: Phase 3
• Start date: January 20, 2016
• Est. completion date: July 16, 2021

Study information

• Verified date: July 2023
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 176
• Est. completion date: July 16, 2021
• Est. primary completion date: July 16, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• Tofersen
Administered as specified in the treatment arm.
• Placebo
Administered as specified in the treatment arm.

Locations

Country	Name	City	State
Australia	Westmead Hospital	Westmead	New South Wales
Belgium	UZ Leuven	Leuven
Canada	University of Calgary - Health Sciences Centre	Calgary	Alberta
Canada	Research Site	Edmonton	Alberta
Canada	Montreal Neurological Institute	Montreal	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Denmark	Bispebjerg Hospital	Copenhagen
France	Hopital Pitie Salpetriere	Paris
Germany	University of Ulm	Ulm	Baden Wuerttemberg
Italy	ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin	Torino
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
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Yangsan-si	Gyeongsangnam-do
Poland	Research Site	Warszawa
United Kingdom	Research Site	London	Greater London
United Kingdom	Research Site	Sheffield	South Yorkshire
United States	Emory University Hospital	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	Methodist Neurological Institute	Houston	Texas
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company	Knoxville	Tennessee
United States	University of California San Diego Medical Center	La Jolla	California
United States	Neurology Associates, P.C.	Lincoln	Nebraska
United States	University of Miami School of Medicine	Miami	Florida
United States	Columbia University Medical Center	New York	New York
United States	Bioclinica Research	Orlando	Florida
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	Providence ALS Center	Portland	Oregon
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	California Pacific Medical Center	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Biogen	Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline	Total CSF SOD1 protein ratio to baseline was calculated.	Day 85
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Part C: Time to Death		Baseline up to Week 28 (Day 197)
Secondary	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