J002 Twelve-month interim data from PIVOT-HD: a Phase 2, randomized, placebo-controlled study to evaluate the safety and efficacy of PTC518 in participants with Huntington’s disease

<h3>Background</h3> Huntington’s disease (HD) is caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene which leads to the ubiquitous expression of toxic mutant huntingtin protein (mHTT). PTC518 is a splicing modifier that promotes inclusion of a pseudoexon (psiExon) containing a premature stop codon, leading to HTT messenger RNA degradation and lowering HTT levels. PIVOT-HD is a Phase 2, randomized, placebo-controlled, dose-ranging study to evaluate PTC518 in participants with HD (NCT05358717/2021-003852-18). Results from a 12-week interim analysis of 33 patients showed that PTC518 lowered blood mHTT protein in a dose-dependent manner. PTC518 exposure ratios in the cerebrospinal fluid (CSF) were consistent with or higher than the plasma unbound drug levels. Finally, PTC518 treatment was well tolerated, with no treatment-related serious adverse events and no dose-limiting toxicities. There were no treatment-related spikes in CSF and plasma neurofilament light chain protein. <h3>Aims</h3> Here we will present safety, clinical, and biomarker results from the planned interim analysis of PIVOT-HD that includes 12-month data for some participants. <h3>Methods/Techniques</h3> Participants with HD were randomized to receive PTC518 5 or 10 mg or placebo once daily for 12 months at 24 centers across Europe, Asia, and North America. Primary endpoints were the number of participants with adverse events and the change from baseline in blood HTT. <h3>Results/Outcome</h3> Additional interim analysis results will be presented. <h3>Conclusions</h3> These interim results will continue to demonstrate that PTC518 is a potential therapeutic for HD.