VIBRANT-HD
(2026)Objective
Evaluate safety, tolerability, and CSF mutant huntingtin (mHTT) lowering of oral branaplam, an mRNA splicing modulator, in adults with early manifest Huntington's disease.
Study Summary
• Trial TERMINATED EARLY: 85.7% (18/21) on branaplam developed peripheral neuropathy signs/symptoms vs 0% on placebo
• Sural SNAP amplitude fell ≥50% in 52.4% of branaplam-treated patients; serum NfL elevated in 76.2% (vs 0% placebo)
• Treatment-related SAEs 14.3% (2 subdural hematomas, 1 vestibular neuronitis); all neuropathy partially or fully reversed off drug
• PK-PD modeling: no lower dose could achieve ≥30% mHTT lowering while sparing neurotoxicity → Novartis halted HD development
Intervention
Branaplam 56 mg oral solution once weekly
Inclusion Criteria
Adults >25y with confirmed stage 1 or 2 HD (Shoulson-Fahn), ≥40 CAG repeats, UHDRS-TFC >8, age ≤75y
Study Design
Arms: Branaplam 56 mg PO weekly vs matching placebo (cohort 1 of planned staggered 3-cohort dose-finding)
Patients per Arm: Branaplam 21, Placebo 5 (only cohort 1 completed before termination)
Outcome
• No change in UHDRS-TMS, TFC, IS, cUHDRS or cognition (SDMT, SWRT, MoCA)
• Lateral ventricle volume transiently increased with branaplam, recovered by week 33
• Peripheral neuropathy in 85.7%; treatment-related SAEs 14.3%; all neuropathy reversible after discontinuation
Clinical Question
Can oral branaplam, an mRNA splicing modulator, safely lower CSF mutant huntingtin (mHTT) levels in adults with early manifest Huntington's disease?
Bottom Line
Branaplam 56 mg weekly lowered CSF mHTT by 25.2% (placebo-corrected) at week 17 but caused peripheral neuropathy in 85.7% of treated participants, leading to early termination and discontinuation of Novartis's HD development program.
Major Points
- First oral splicing modulator shown to lower CSF mHTT in people with HD (−25.2% placebo-corrected at week 17)
- Dose-limiting peripheral neuropathy emerged in 18/21 branaplam-treated participants, triggering early study termination
- Serum NfL elevation (≥2× baseline or >100 pg/mL) in 76.2% of branaplam vs 0% placebo participants — confirmed as early biomarker of neurotoxicity
- All peripheral neuropathy signs/symptoms were partially or fully reversible after discontinuation
- Translational PK-PD modeling showed no alternative dose could achieve ≥30% mHTT lowering without neurotoxicity, ending HD development of branaplam
Study Design
- Study Type
- Randomized Controlled Trial (Phase 2b)
- Randomization
- Yes
- Blinding
- Double-blind, placebo-controlled
- Sample Size
- 26
- Follow-up
- Up to 69 weeks (active arm); 33 weeks (placebo)
- Centers
- 12
- Countries
- Canada, France, Germany, Spain, Hungary
Primary Outcome
Definition: Percent change in CSF mutant huntingtin (mHTT) from baseline to week 17
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −1.4% (SE 10.26, n=4) | −26.6% (SE 7.45, n=9) | - | Descriptive only — planned MCP-Mod analysis voided by early termination |
Limitations & Criticisms
- Early termination after only Cohort 1 (n=26) — planned 75 participants across three dose levels never reached; higher doses not tested
- Severe arm imbalance: only 5 placebo participants vs 21 active; placebo follow-up just 33 weeks vs 69 weeks active
- Primary endpoint analysis (MCP-Mod) voided — efficacy reported only descriptively
- No cohorts at lower doses, so safety-efficacy threshold for branaplam in HD was inferred from translational PK-PD modeling rather than tested clinically
- External TRACK-HD control used post hoc to address imbalance — propensity matching has residual confounding risk
- CSF NfL not measured after treatment discontinuation, limiting CNS recovery characterization
Citation
Nat Med. 2026 Jan 5;DOI:10.1038/s41591-025-04117-4