Oral splicing modulator branaplam in Huntington's disease: a phase 2 randomized controlled trial.

Lowering mutant huntingtin (HTT) gene products is a promising approach for slowing the progression of Huntington's disease (HD), a monogenic neurodegenerative disease caused by an expansion mutation in the HTT gene (NCBI Gene ID: 3064). Branaplam, an orally available HTT messenger RNA splicing modulator, reduces HTT protein levels in vitro and in animal models, and is the first splicing modulator to be evaluated in individuals with HD. Here we present the design and results of VIBRANT-HD, a randomized phase 2b study of branaplam in HD, along with preclinical findings in nonhuman primates. VIBRANT-HD utilized an innovative study design informed by our preclinical data, including targeted safety monitoring measures (for example, neurofilament light chain measurements in blood, nerve conduction studies), and staggered cohorts to capture potential neurotoxic effects early. Of the 21 participants in the initial cohort receiving branaplam 56 mg weekly, 18 (85.7%) showed at least one sign or symptom of peripheral neuropathy. This safety signal, along with dose-modeling results triggered the early termination of VIBRANT-HD. The primary outcome, a decrease in cerebrospinal fluid mutant HTT levels versus placebo, was summarized descriptively, making branaplam the first splicing modulator to lower mutant HTT levels in the cerebrospinal fluid of individuals with HD. Increased neurofilament light chain levels observed in most participants reversed after treatment discontinuation. ClinicalTrials.gov identifier: NCT05111249.