Background Huntington’s disease (HD) is caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. The mutant protein is ubiquitously expressed and drives HD pathogenesis through a toxic gain-of-function mechanism. Animal models of HD demonstrate that reducing HTT protein levels alleviates HD symptoms. PTC518 is a splicing modifier that acts by promoting the inclusion of a pseudoexon containing a premature stop codon (psiExon), leading to HTT messenger RNA (mRNA) degradation and lowering of HTT levels. Results of a Phase 1 trial demonstrated PTC518’s ability to lower HTT in healthy volunteers, supporting Phase 2 evaluation.

Aims The goal of the randomised, placebo-controlled, dose-ranging PIVOT-HD study (NCT05358717) is to evaluate safety and efficacy of PTC518 in subjects with HD.

Methods/Techniques 162 subjects ≥25 years, with genetically-confirmed HD (42–50 CAG repeats, inclusive), Unified HD Rating Scale (UHDRS)-independence scale score of 100, UHDRS total functional capacity score of 13, and a score of 0.18–4.93 inclusive on the normed HD prognostic index (PINHD) will be enrolled.

Primary outcome measures Number of participants with adverse events through Day 113 and change from baseline in blood total HTT at Day 85. Participants will be randomised 1:1 to part A (5 mg PTC518) or Part B (10 mg PTC518) and then randomised within each Part 2:1 to PTC518 or placebo. A Drug Safety Monitoring Board will undertake an unblinded review of safety data in Parts A and B and provide a recommendation on when Part C (20 mg PTC518) can be initiated.