A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis

NCT03626012 | Completed Phase 1 FDA Drug

• 2 other identifiers: 245AS1012017-000294-36
• Study Type: interventional
• Target: 106
• Locations: 6 countries
• Sites: 21

Brief Summary

The primary objective of this study is to evaluate the safety and tolerability of BIIB078 in adults with C9ORF72-Amyotrophic Lateral Sclerosis (ALS). The secondary objectives of this study are to evaluate the pharmacokinetic profile of BIIB078 and to evaluate the effects of BIIB078 on clinical function. As the first-in-human study, the study enrolls a small number of participants in each cohort. Every participant in a cohort is treated with the same dose or placebo. The study is designed to evaluate and confirm the safety of each dose before enrolling and exposing new participants to a higher dose in the next cohort.

Conditions

Amyotrophic Lateral Sclerosis

Outcome Measures

Primary Outcomes (1)

• Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, places participant at immediate risk of death, requires initial or prolonged inpatient hospitalization, results in persistent or significant disability/incapacity, results in congenital anomaly, is a medically important event.

  Baseline through End of Study (Approximately Day 323)

Secondary Outcomes (10)

• Serum BIIB078 Concentration

  Baseline and at multiple time points up to Day 260

• Area Under the Concentration-Time Curve (AUC) from Time 0 to Infinity (AUCinf)

  Baseline and at multiple time points up to Day 260

• AUC from Time 0 to Time of the Last Measurable Concentration (AUClast)

  Baseline and at multiple time points up to Day 260

• Maximum Observed Concentration (Cmax)

  Baseline and at multiple time points up to Day 260

• Time to Reach Cmax (Tmax)

  Baseline and at multiple time points up to Day 260

Study Arms (7)

Cohort 1: BIIB078 First Dosage

EXPERIMENTAL

BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.

Drug: BIIB078

Cohort 2: BIIB078 Second Dosage

EXPERIMENTAL

BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.

Drug: BIIB078

Cohort 3: BIIB078 Third Dosage

EXPERIMENTAL

BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.

Drug: BIIB078

Cohort 4: BIIB078 Fourth Dosage

EXPERIMENTAL

BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.

Drug: BIIB078

Cohort 5: BIIB078 Fifth Dosage

EXPERIMENTAL

BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.

Drug: BIIB078

Cohort 6: BIIB078 Sixth Dosage

EXPERIMENTAL

BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.

Drug: BIIB078

Cohorts 1-6: Placebo

PLACEBO COMPARATOR

Matching placebo will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days (Cohorts 1 through 3) and five maintenance doses on five later days (Cohorts 4 through 6).

Drug: Placebo

Interventions

BIIB078 DRUG

Administered as specified in the treatment arm.

Cohort 1: BIIB078 First Dosage; Cohort 2: BIIB078 Second Dosage; Cohort 3: BIIB078 Third Dosage; Cohort 4: BIIB078 Fourth Dosage; Cohort 5: BIIB078 Fifth Dosage; Cohort 6: BIIB078 Sixth Dosage

Placebo DRUG

Administered as specified in the treatment arm.

Cohorts 1-6: Placebo

Eligibility Criteria

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

You may qualify if:

• Ability of the participant to understand the purpose and risks of the study, to provide signed and dated informed consent, and to authorize the use of confidential health information in accordance with national and local participant privacy regulations; or, in the event of the participant's physical incapacity to sign, to confirm that understanding and consent orally to a legally authorized representative (LAR) for the express purpose of having said informed consent and authorization signed on his/her behalf.
• All participants of childbearing potential must agree to practice highly effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment.
• Must meet the possible, laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria and have documentation of a clinical genetic test demonstrating the presence of a pathogenic mutation in C9ORF72.
• Slow vital capacity (SVC) ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position).
• Participants taking concomitant riluzole at study entry must be on a stable dose for ≥ 30 days prior to the first dose of study treatment (Day 1).
• Participants taking concomitant edaravone at study entry must be on a stable dose for ≥ 60 days prior to the first dose of study treatment (Day 1).
• ALS Cognitive Behavioral Screen (ALS-CBS) score ≥ 11 for the cognitive portion; ≥ 33 for the behavioral portion.
• 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.
• Screening values of coagulation parameters including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) should be within normal ranges.
• Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at Screening.

You may not qualify if:

• History of drug abuse or alcoholism ≤ 6 months of Screening that would limit participation in the study, as determined by the Investigator.
• Tracheostomy.
• Prescreening ALSFRS-R slope less than 0.4 points/month, where prescreening ALSFRS-R slope is defined as follows: (48 - ALSFRS-R score at Screening) / (months from date of symptom onset to date of Screening).
• History of or positive test result at Screening for human immunodeficiency virus. .
• History of, or positive test result at Screening for, hepatitis C virus antibody.
• Treatment with another investigational drug or biological agent within 1 month of Screening or 5 half-lives of study agent, whichever is longer.
• Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for lumbar puncture (LP) according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber.
• Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
• Female participants who are pregnant or currently breastfeeding.

Sponsors & Collaborators

• Biogen: lead

Study Sites (21)

Research Site

La Jolla, California, 92037-0886, United States

Location

Research Site

Los Angeles, California, 90048, United States

Location

Research Site

Palo Alto, California, 94303, United States

Location

Research Site

Jacksonville, Florida, 32224, United States

Location

Research Site

Miami, Florida, 33136, United States

Location

Research Site

Atlanta, Georgia, 30322, United States

Location

Research Site

Baltimore, Maryland, 21287, United States

Location

Research Site

Boston, Massachusetts, 02114, United States

Location

Research Site

St Louis, Missouri, 63110, United States

Location

Research Site

Lincoln, Nebraska, 68506-2960, United States

Location

Research Site

New York, New York, 10032, United States

Location

Research Site

Knoxville, Tennessee, 37920, United States

Location

Research Site

Calgary, Alberta, T2N 1N4, Canada

Location

Research Site

Toronto, Ontario, M4N 3M5, Canada

Location

Research Site

Montreal, Quebec, H3A 2B4, Canada

Location

Research Site

Dublin, DUBLIN 8, Ireland

Location

Research Site

Utrecht, 3508 GA, Netherlands

Location

Research Site

Sankt Gallen, 9007, Switzerland

Location

Research Site

London, Greater London, SE5 9RS, United Kingdom

Location

Research Site

Sheffield, South Yorkshire, S10 2HQ, United Kingdom

Location

Research Site

London, NW1 2PG, United Kingdom

Location

Related Publications (1)

• van den Berg LH, Rothstein JD, Shaw PJ, Babu S, Benatar M, Bucelli RC, Genge A, Glass JD, Hardiman O, Libri V, Mobach T, Oskarsson B, Pattee GL, Ravits J, Shaw CE, Weber M, Zinman L, Jafar-Nejad P, Rigo F, Lin L, Ferguson TA, Gotter AL, Graham D, Monine M, Inra J, Sinks S, Eraly S, Garafalo S, Fradette S. Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study. Lancet Neurol. 2024 Sep;23(9):901-912. doi: 10.1016/S1474-4422(24)00216-3. Epub 2024 Jul 23.

  PMID: 39059407 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

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

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2018
• First Posted: August 10, 2018
• Study Start: September 10, 2018
• Primary Completion: November 17, 2021
• Study Completion: November 17, 2021
• Last Updated: January 14, 2022

Record last verified: 2022-01

Locations

CH (1); GB (3); US (12); NL (1); IE (1); CA (3)