Votoplam
Small molecule drug
From Wikipedia, the free encyclopedia
Votoplam (also known as PTC518) is an investigational oral small molecule drug being developed by PTC Therapeutics for the treatment of Huntington's disease (HD).[1] The compound functions as a huntingtin (HTT) gene modulator and splicing factor modifier, designed to selectively reduce huntingtin mRNA and protein levels.[2]
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| Other names | PTC518 |
| Routes of administration | Oral |
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| Formula | C21H25N9O |
| Molar mass | 419.493 g·mol−1 |
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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.[3] It exhibits strong potency in lowering huntingtin protein levels, with an IC50 of ≤ 0.1 μM.[4]
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.[5]
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.[6][7][8][9] 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.[9]
The trial achieved its primary endpoint of reducing blood huntingtin (HTT) protein levels at 12 weeks (p<0.0001), demonstrating statistically significant efficacy.[9] 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.[10]
Regulatory status
Votoplam has received orphan drug designation for the treatment of Huntington's disease from both the European Medicines Agency (December 13, 2024) and the Food and Drug Administration (October 25, 2024).[11] As of September 2025, the drug is in Phase 2 clinical development, representing the highest research and development status globally for this compound.[1]