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

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by expanded mutations in the huntingtin (HTT) gene.
• Lowering mutant HTT protein levels is a key therapeutic strategy for HD.
• Branaplam is an orally available HTT messenger RNA splicing modulator designed to reduce HTT protein levels.

Purpose of the Study:

• To evaluate the safety and efficacy of branaplam in individuals with Huntington's disease.
• To assess branaplam's ability to reduce mutant HTT levels in cerebrospinal fluid (CSF).
• To investigate potential neurotoxic effects of branaplam using preclinical and clinical data.

Main Methods:

• A randomized phase 2b study (VIBRANT-HD) was conducted with an innovative design informed by preclinical data.
• Targeted safety monitoring included neurofilament light chain (NfL) measurements and nerve conduction studies.
• Staggered cohorts were used to detect potential neurotoxicity early.

Main Results:

• In the initial cohort, 85.7% of participants receiving branaplam 56 mg weekly showed signs of peripheral neuropathy.
• Branaplam was the first splicing modulator to demonstrate a reduction in CSF mutant HTT levels compared to placebo.
• Elevated NfL levels, indicative of neurotoxicity, were observed but reversed upon treatment discontinuation.

Conclusions:

• The VIBRANT-HD study was terminated early due to a safety signal of peripheral neuropathy associated with branaplam.
• Despite early termination, branaplam successfully lowered mutant HTT levels in the CSF of HD patients.
• Further research is needed to understand and mitigate the neurotoxic potential of HTT splicing modulators.