PTC Therapeutics Reports Positive 24-Month Data for Votoplam in Huntington's Disease Extension Study
核心洞察
PTC Therapeutics reported positive 24-month interim results from the PIVOT-HD extension study showing dose-dependent benefits of votoplam in slowing Huntington's disease (搜索) progression in Stage 2 patients.
The 10mg dose demonstrated 52% slowing of disease progression on the cUHDRS scale compared to natural history, while the 5mg dose showed 28% slowing.
Novartis has initiated the global Phase 3 INVEST-HD study enrolling approximately 770 early-stage HD patients based on these encouraging long-term extension data.
PTC Therapeutics announced positive topline results from the 24-month interim analysis of the PIVOT-HD long-term extension study, demonstrating dose-dependent benefits of votoplam in slowing Huntington's disease (搜索) progression in Stage 2 patients compared to a matched natural history cohort.
The results showed 52% slowing of disease progression for patients receiving the 10mg dose and 28% slowing for those on the 5mg dose, as measured by the Composite Unified Huntington's Disease (搜索) Rating Scale (cUHDRS). These findings have supported Novartis's decision to initiate the global Phase 3 INVEST-HD study.
Dose-Dependent Efficacy Signals
In Stage 2 participants who received 24 months of votoplam treatment, the study demonstrated evidence of dose-dependent benefit in slowing progression on the cUHDRS relative to a propensity weighted natural history cohort. The 10mg cohort showed signals of favorable treatment effects across the cUHDRS subscales.
"These results give us confidence in the potential for votoplam to deliver long-term meaningful effect on slowing Huntington's disease (搜索) progression," said Matthew B. Klein, M.D., Chief Executive Officer of PTC Therapeutics. "In particular, the evidence of dose-dependent slowing of progression on the cUHDRS disease rating scale in the Stage 2 study participants supports the Novartis-initiated Phase 3 INVEST-HD study."
Biomarker and Safety Profile
The study revealed no treatment-related neurofilament light chain protein (NfL) increases, with mean NfL levels remaining below baseline at 24 months for both high and low dose cohorts. This contrasts with reported natural history showing that NfL levels increase over time in individuals with Huntington's disease (搜索).
In Stage 3 participants, potential signals of slowing of progression were observed at 24 months. The safety data at Month 24 for both dose levels and both stages remained consistent with the previously established evidence of favorable safety.
Phase 3 Study Launch
Based on these extension study results, Novartis announced the initiation of the global Phase 3 INVEST-HD study. This placebo-controlled study will enroll approximately 770 individuals with early-stage HD who will be randomized 3:2 to receive votoplam 10mg or placebo. The primary endpoint will be the change from baseline up to month 36 in the cUHDRS.
Study Design and Mechanism
PIVOT-HD was originally designed as a 12-month placebo-controlled trial assessing pharmacodynamic effect and safety of votoplam at 5mg and 10mg doses relative to placebo. The study initially included Stage 2 patients, with a Stage 3 cohort subsequently added to identify the optimal study population for future trials.
Votoplam is a small molecule splicing modifier that promotes the inclusion of a novel pseudoexon containing a premature termination codon, triggering Huntingtin (搜索) (HTT (搜索)) mRNA degradation and subsequent reduction in HTT protein levels. The drug was discovered from PTC's validated splicing platform and was partnered with Novartis in December 2024.
Unmet Medical Need
Huntington's disease (搜索) is a fatal, hereditary genetic disorder of the central nervous system caused by a defective gene that produces abnormal HTT (搜索) protein, leading to neuron damage and death. The disease typically presents in people in their 30s or 40s and results in abnormal movements, difficulties with speech, swallowing and walking, along with behavioral, cognitive and motor symptoms. Currently, there is no cure for HD and no approved drugs that delay onset or slow disease progression.