Votoplam
Votoplam is an investigational oral small molecule drug being developed by PTC Therapeutics for the treatment of Huntington's disease. The compound functions as a huntingtin gene modulator and splicing factor modifier, designed to selectively reduce huntingtin mRNA and protein levels.
Mechanism of action
Votoplam functions as a splicing modulator of the HTT gene by promoting the inclusion of a pseudoexon that harbors a premature termination codon, leading to degradation of HTT mRNA and a consequent decrease in HTT protein expression. It exhibits strong potency in lowering huntingtin protein levels, with an IC50 of ≤ 0.1 μM.The drug is an orally bioavailable small molecule that specifically targets the huntingtin gene through splicing modification, leading to selective reduction of both mutant and wild-type huntingtin mRNA and protein.
Clinical development
PIVOT-HD Phase 2 trial
The primary clinical evaluation of votoplam has been conducted through the Phase 2 PIVOT-HD study, which enrolled patients with Stage 2 and Stage 3 Huntington's disease. The study was initially designed to include only Stage 2 patients, but a Stage 3 cohort was subsequently added to help identify the optimal study population for future trials.The trial achieved its primary endpoint of reducing blood huntingtin protein levels at 12 weeks, demonstrating statistically significant efficacy. Dose-dependent reductions in HTT protein were observed, with a 23% reduction at the 5 mg dose for both Stage 2 and Stage 3 patients, increasing to 39% and 36% respectively at the 10 mg dose.