A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation (ATLAS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Biogen Idec Research Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

27 Jul 2021 → ongoing

Decision date (initial)

2024-08-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Biogen Idec Research Limited

External identifiers

EU CT number

2023-505641-12-00

EudraCT number

2020-004590-51

ClinicalTrials.gov

NCT04856982

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Efficacy, Safety, Pharmacokinetic, Pharmacodynamic

The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF).

Secondary objectives 1

1. The secondary objectives of this study are to evaluate the safety and tolerability tofersen and to evaluate the effect of tofersen on pharmacodynamics (PD)/treatment response biomarkers when initiated prior to versus at the time of emergence of clinically manifest amyotrophic lateral sclerosis (ALS).

Conditions and MedDRA coding

Amyotrophic Lateral Sclerosis (ALS) associated with SOD1 gene mutation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Participants should have a protocol-defined rapidly progressive SOD1 mutation, confirmed by a central reader, or a SOD1 mutation that is approved for inclusion by an external mutation adjudication committee.
2. Participants with plasma NfL level less than the protocol-defined threshold.
3. Participants who are clinically presymptomatic for ALS (i.e., must not have clinically manifest ALS).
4. Note: Other protocol defined Inclusion criteria will apply.

Exclusion criteria 13

1. History or positive test result at screening for human immunodeficiency virus (HIV). The requirement for testing at Screening may be omitted if it is not permitted by local regulations.
2. Current hepatitis C infection (defined as positive Hepatitis C Virus (HCV) antibody and detectable HCV RNA). Participants with positive HCV antibody and undetectable HCV Ribonucleic Acid (RNA) are eligible to participate in the study (United States Centers for Disease Control and Prevention).
3. Current hepatitis B infection (defined as positive for hepatitis B surface antigen (HBsAg) and/or anti-Hepatitis B Core antibody (HBc)). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive antihepatitis B surface antibody (HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti- HBs) are eligible to participate in the study
4. History of systemic hypersensitivity reaction to tofersen, the excipients contained in the formulation, and if appropriate, any diagnostic agents to be administered during the study.
5. History of confounding neuromuscular or neurological disorder that is expected to have a progressive (i.e., worsening) course during the study, and/or is expected to be associated with elevations in NF, in the opinion of the Investigator.
6. Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally could place a participant at an increased risk for intraoperative or postoperative bleeding.
7. Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression ≤ 90 days of Screening, which in the opinion of the Investigator would interfere with the study procedures.
8. Treatment with riluzole, edaravone and/or sodium phenylbutyrate/taurursodiol (also known as ursodoxicoltaurine). If the participant has been on riluzole, edaravone and/or sodium phenylbutyrate/taurursodiol, the medication(s) must be discontinued for at least 5 half-lives prior to screening.
9. Use of-label treatments for ALS.
10. 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.
11. Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication (e.g., clopidogrel) that cannot be safely continued or held for an LP procedure, if necessary, according to local or institutional guidelines and/or Investigator determination.
12. Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment, biological agent, device, or approved therapy for investigational use. Participation in a non-interventional study focused on ALS natural history may be allowed at the discretion of the Investigator.
13. Note: Other protocol defined Exclusion criteria will apply.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Parts B and C: Percentage of Participants with Emergence of Clinically Manifest ALS Within 24 Months of Part B Baseline. [Time Frame: Up to 24 months]

Secondary endpoints 8

1. Parts B and C: Time to Emergence of Clinically Manifest ALS. [Time Frame: Up to 5.6 years].
2. Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score. The ALSFRS-R measures 4 functional domains: respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 to 4, for a total possible score of 48, with higher scores representing better function. [Time Frame: Up to 5.6 years].
3. Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC). [Time Frame: Up to 5.6 years].
4. Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on time to Death or Permanent Ventilation Analysis. Permanent ventilation is defined as ≥22 hours of invasive or non-invasive mechanical ventilation per day for ≥21 consecutive days. [Time Frame: Up to 5.6 years].
5. Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis. [Time Frame: Up to 5.6 years].
6. Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period. [Time Frame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years].
7. Parts B, C and D: Change from Baseline in Plasma NfL Concentrations. [Time Frame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years].
8. Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations. [Time Frame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years].

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Biogen Idec Research Limited

Sponsor organisation

Biogen Idec Research Limited

Address

Building 5 Foundation Park, Roxborough Way Roxborough Way

City

Maidenhead

Postcode

SL6 3UD

Country

United Kingdom

Scientific contact point

Organisation

Biogen Idec Research Limited

Contact name

Clinical Trials Information Desk

Public contact point

Organisation

Biogen Idec Research Limited

Contact name

Clinical Trials Information Desk

Third parties 15

Locations

6 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 46 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications