J003 PIVOT-LTE: a Phase 2, double-blind, randomized extension study to evaluate the long-term 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 (<i>HTT</i>) 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 <i>HTT</i> levels. PTC518 is being evaluated in Phase 2 studies: the 12-month PIVOT-HD study (NCT05358717/2021-003852-18) and the PIVOT-long-term extension (LTE) study (NCT06254482). <h3>Aims</h3> PIVOT-LTE is a Phase 2, double-blind, randomized extension study to evaluate the long-term safety and efficacy of PTC518 in participants with HD. <h3>Methods/Techniques</h3> PIVOT-HD is an ongoing Phase 2, placebo-controlled study to evaluate the safety and biomarker effects of PTC518. After completing treatment, all participants have the option to rollover into PIVOT-LTE. The primary outcome measures of the LTE are safety profile of PTC518 through Month 30 and change from baseline in blood HTT over time. The effects of PTC518 on blood and cerebrospinal fluid biomarkers will also be determined. Participants will receive PTC518 in PIVOT-LTE at the same dose level they received in PIVOT-HD. Those who received placebo in PIVOT-HD will receive active treatment (PTC518) at the dose level corresponding to their randomly-assigned treatment group in PIVOT-HD. <h3>Conclusions</h3> Early data indicate PTC518 treatment is well tolerated, with no treatment-related serious adverse events and no reports of dose-limiting toxicities. Enrollment of patients for PIVOT-LTE is ongoing and data will be presented at a later timepoint.