A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB105 in Participants With Amyotrophic Lateral Sclerosis With or Without Poly-cytosine-adenine-guanine (CAG) Expansion in the Ataxin-2 Gene

• ClinicalTrials.gov Identifier: NCT04494256
• Recruitment Status: Recruiting
• First Posted: July 31, 2020
• Last Update Posted: January 13, 2021
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: July 30, 2020
• First Posted Date: July 31, 2020
• Last Update Posted Date: January 13, 2021
• Actual Study Start Date: September 28, 2020
• Estimated Primary Completion Date: February 28, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 30, 2020)

Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 175 ]

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 SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 30, 2020)

• Serum Concentration of BIIB105 [ Time Frame: Predose and at multiple timepoints upto 6 hours postdose, from Day 1 up to Day 92 ]
• Area Under the Concentration-Time Curve from Time Zero to Infinity (AUCinf) [ Time Frame: Predose and at multiple timepoints upto 6 hours postdose, from Day 1 up to Day 92 ]
• Area Under the Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast) [ Time Frame: Predose and at multiple timepoints upto 6 hours postdose, from Day 1 up to Day 92 ]
• Maximum Observed Concentration (Cmax) [ Time Frame: Predose and at multiple timepoints upto 6 hours postdose, from Day 1 up to Day 92 ]
• Time to Reach Maximum Observed Concentration (Tmax) [ Time Frame: Predose and at multiple timepoints upto 6 hours postdose, from Day 1 up to Day 92 ]
• Elimination Half-Life (t1/2) [ Time Frame: Predose and at multiple timepoints upto 6 hours postdose, from Day 1 up to Day 92 ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB105 in Participants With Amyotrophic Lateral Sclerosis With or Without Poly-cytosine-adenine-guanine (CAG) Expansion in the Ataxin-2 Gene
• Official Title: A Phase 1 Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral Sclerosis With or Without Poly-CAG Expansion in the Ataxin-2 Gene
• Brief Summary: The primary objective is to evaluate the safety and tolerability of BIIB105 in participants with amyotrophic lateral sclerosis (ALS) or poly-CAG expansion (polyQ)-ALS. The secondary objective is to assess the pharmacokinetic (PK) profile of BIIB105 in serum of participants with ALS or poly-CAG expansion (polyQ)-ALS.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis

Intervention

• Drug: BIIB105
  Administered as specified in the treatment arm.
• Drug: Placebo
  Administered as specified in the treatment arm.

Study Arms

• Experimental: Cohort A
  Participants with ALS will receive BIIB105 Dose 1, intrathecally (IT), as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
  Intervention: Drug: BIIB105
• Experimental: Cohort B
  Participants with ALS will receive BIIB105 Dose 2, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
  Intervention: Drug: BIIB105
• Experimental: Cohort C1
  Participants with ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
  Intervention: Drug: BIIB105
• Experimental: Cohort C2
  Participants with polyQ-ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
  Intervention: Drug: BIIB105
• Experimental: Cohort D1
  Participants with ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
  Intervention: Drug: BIIB105
• Experimental: Cohort D2
  Participants with polyQ-ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
  Intervention: Drug: BIIB105
• Placebo Comparator: Cohorts A-D2
  Participants with ALS and polyQ-ALS will receive matching placebo to BIIB105 as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 30, 2020): 70
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 28, 2023
• Estimated Primary Completion Date: February 28, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Ability of the participant and/or his/her legally authorized representative (e.g., parent, spouse, or legal guardian), as appropriate and applicable, to understand the purpose and risks of the study, to provide informed consent, and to authorize the use of confidential health information in accordance with national and local privacy regulations.
• All women of childbearing potential and all men must ensure that highly effective contraception is used during the study and for at least 6 months for female participants and 8 months for male participants after their last dose of study treatment.
• No known presence or family history of mutations in the superoxide dismutase 1 (SOD1) or fused in sarcoma (FUS) genes.
• Participants in Cohorts A, B, C1 and D1, must meet the laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria (revised according to the Airlie House Conference 1998 [Brooks 2000]). Participants in Cohort C2 and D2, must meet any of the prior conditions, but may also only meet clinically possible criteria for diagnosing ALS, or exhibit weakness attributable to ALS in the presence of ataxin-2 protein (ATXN2) intermediate repeats.
• In participants in Cohorts C2 and D2, confirmed intermediate cytosine-adenine-guanine/cytosine- adenine-adenine (CAG/CAA) repeat expansion in the ataxin-2 gene or RNA (ATXN2) gene as defined by at least 1 allele carrying 30 to 33 CAG/CAA repeats.
• Slow vital capacity (SVC) criteria:

• In participants in Cohorts A, B, C1, and D1, SVC

  • 60% of predicted value as adjusted for sex, age, and height (from the sitting position).
• In participants in Cohorts C2 and D2, SVC ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position).

• 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, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study.
• 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).
• 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.

Key Exclusion Criteria

• History or positive test result at Screening for HIV.
• Current hepatitis C infection.
• Current hepatitis B infection.
• History of alcohol or substance abuse ≤6 months of Screening that would limit participation in the study, as determined by the Investigator.
• Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
• Presence of tracheostomy.
• In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as determined by the Investigator.

• In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes mellitus defined as HbA1c

  • 8% during Screening.
• Prescreening Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) slope > -0.4 points/month, where prescreening ALSFRS-R slope is defined as: (48 - ALSFRS-R score at Screening) / (months from date of symptom onset to date of Screening) in participants from Cohorts A, B, C1, and D1.
• Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs) or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before Screening.
• 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.
• Female participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: US Biogen Clinical Trial Center; 866-633-4636; clinicaltrials@biogen.com

Contact: Global Biogen Clinical Trial Center; clinicaltrials@biogen.com

• Listed Location Countries: Canada, Netherlands, United States

Administrative Information

• NCT Number: NCT04494256
• Other Study ID Numbers: 275AS101; 2020-000207-36 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
• URL: http://www.biogenclinicaldatarequest.com/

• Responsible Party: Biogen
• Study Sponsor: Biogen
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: January 2021