A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease

NCT05111249 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: CLMI070C122032020-000105-92
• Study Type: interventional
• Target: 26
• Locations: 5 countries
• Sites: 12

Brief Summary

This is the first study of branaplam in adults with Huntington's Disease (HD) to determine the correct dose required to lower mutant huntingtin protein (mHTT) levels in the cerebrospinal fluid (CSF) to a degree expected to be efficacious over longer periods of time.

Conditions

Early Manifest Huntington Disease

Keywords

Early Manifest; Huntington Disease; Branaplam; LMI070; Dose Range Finding; Safety; HD; mHTT; Pharmacokinetics; oral; Adult

Outcome Measures

Primary Outcomes (2)

• Percentage Change From Baseline to Week 17 in mHTT Protein in CSF

  Mutant Huntingtin (mHTT) protein was measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. The percentage change from baseline to Week 17 in mHTT protein in CSF was calculated with the following formula: (mHTTweek17 - mHTTbaseline)/ mHTTbaseline \* 100. Baseline value for mHTT is the last evaluable measurements prior to the first administration of study drug.

  Baseline, Week 17

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

  Incidence of AEs (any AEs regardless of seriousness) and SAEs, including changes in vital signs, neurological examination, electrocardiograms (ECGs) and laboratory parameters qualifying and reported as AEs. Participants received study treatment up to maximum Week 20 (placebo) and Week 22 (branaplam).

  From first dose of study treatment up to Week 69

Secondary Outcomes (20)

• Percentage Change From Baseline in Total Brain Volume

  Baseline, Week 17, Week 33, Week 53, Week 69

• Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma

  Baseline, Week 17, Week 33, Week 53, Week 69

• Percentage Change From Baseline in Lateral Ventricles Volume

  Baseline, Week 17, Week 33, Week 53, Week 69

• Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma

  Baseline, Week 17, Week 33, Week 53, Week 69

• Percentage Change From Baseline in Left Caudate Volume

  Baseline, Week 17, Week 33, Week 53, Week 69

Other Outcomes (1)

• Number of Participants With NfL Increase and Recovery

  From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum)

Study Arms (4)

Treatment Arm A

EXPERIMENTAL

Branaplam 56 mg oral solution once weekly

Drug: Branaplam

Treatment Arm B

EXPERIMENTAL

Branaplam 112 mg oral solution once weekly

Drug: Branaplam

Treatment Arm C or X or Y

EXPERIMENTAL

(C) Branaplam 154 mg oral solution once weekly, OR (X) Branaplam 84 mg oral solution once weekly OR (Y) Branaplam 28 mg oral solution once weekly

Drug: Branaplam

Placebo

PLACEBO COMPARATOR

Matching placebo oral solution once weekly

Drug: Placebo

Interventions

Branaplam DRUG

messenger ribonucleic acid (RNA) splicing modifier. Branaplam was administered as an oral solution once weekly.

Also known as: LMI070

Treatment Arm A; Treatment Arm B; Treatment Arm C or X or Y

Placebo DRUG

Matching placebo oral solution once weekly

Placebo

Eligibility Criteria

• Age: 25 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent must be obtained prior to participation in the study.
• Clinically diagnosed Stage 1 or 2 Huntington's disease with a diagnostic confidence level (DCL) = 4 and a United Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) \>8 at screening.
• Genetically confirmed Huntington's disease, with presence of ≥40 cytosine-adenineguanine (CAG) repeats in the huntingtin gene.
• Male and female participants between 25 to 75 years of age, inclusive, on the day of Informed Consent signature.

You may not qualify if:

• Prior participation in clinical trial investigating a huntingtin-lowering therapy (unless participant received only placebo).
• Participants taking medications prohibited by the protocol.
• Any medical history, lumbar surgery or condition that would interfere with the ability to complete the protocol specified assessments.
• Participant has other severe, acute or chronic medical conditions including unstable psychiatric conditions, or laboratory abnormalities that in the opinion of the Investigator may increase the risk associated with study participation, or that may interfere with the interpretation of the study results.
• Any surgical or medical condition which might put the participant at risk in case of participation in the study. The Investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence at the Screening visit.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (12)

Novartis Investigative Site

Montreal, Quebec, H2W 1T8, Canada

Location

Novartis Investigative Site

Angers, 49933, France

Location

Novartis Investigative Site

Créteil, 94010, France

Location

Novartis Investigative Site

Lille, 59037, France

Location

Novartis Investigative Site

Bochum, 44791, Germany

Location

Novartis Investigative Site

Münster, 48149, Germany

Location

Novartis Investigative Site

Ulm, 89081, Germany

Location

Novartis Investigative Site

Budapest, H-1083, Hungary

Location

Novartis Investigative Site

Szeged, 6720, Hungary

Location

Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

Location

Novartis Investigative Site

Barcelona, 08041, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Related Publications (3)

• Borowsky B, Ramos H, Caputo A, Hartmann A, Faller T, Peters T, Sui Y, Liu F, Meadowcroft M, David OJ, Laisney M, Kinhikar A, Marder KS, Tabrizi SJ, Landwehrmeyer GB, Leavitt BR. Oral splicing modulator branaplam in Huntington's disease: a phase 2 randomized controlled trial. Nat Med. 2026 Jan;32(1):103-112. doi: 10.1038/s41591-025-04117-4. Epub 2026 Jan 5.

  PMID: 41491108 DERIVED

• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: March 2024. J Huntingtons Dis. 2024;13(1):1-14. doi: 10.3233/JHD-240017.

  PMID: 38489195 DERIVED

• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: November 2022. J Huntingtons Dis. 2022;11(4):351-367. doi: 10.3233/JHD-229006.

  PMID: 36463457 DERIVED

Related Links

• A Plain Language Trial Summary is available on www.novctrd.com

MeSH Terms

Conditions

Huntington Disease

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This was a randomized double blind study. Participants were planned to be randomized in an equal randomization rate among the open treatment arms, and then in a 4:1 ratio for active vs. placebo within each arm.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: The study design used a staggered cohort approach, allowing safety and tolerability of lower doses to be assessed before randomizing subjects to higher doses. At the time of the Cohort Gating Assessments (CGAs), all available data was reviewed from a safety and dose finding perspective by an independent Sponsor team to support the decision to open the next cohort. The independent Data Monitoring Committee (DMC) reviewed the data separately. The decision to open a new cohort was planned to be made by the Sponsor in consultation with the DMC.

Study Record Dates

• First Submitted: October 15, 2021
• First Posted: November 8, 2021
• Study Start: December 8, 2021
• Primary Completion: October 27, 2023
• Study Completion: October 27, 2023
• Last Updated: May 16, 2025
• Results First Posted: November 4, 2024

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

FR (3); DE (3); HU (2); CA (1); ES (3)