PTC-518 Hits HD Study Endpoint

Initially, the study included only Stage 2 patients. A Stage 3 cohort of similar size was subsequently added to help identify the best study population for future studies. The primary endpoints of PIVOT-HD were total blood Huntingtin (HTT) lowering at 12 weeks and safety events. Secondary endpoints included 12-month blood HTT levels, and other blood-and central nervous system (CNS) biomarkers as well as changes in Composite Unified Huntington's Disease Rating Scale (cUHDRS). Following 12 months, patients were eligible to enroll in a long-term extension study in which all subjects would receive PTC 518. Those originally randomized to 5mg and 10mg would continue at that dose level; those initially randomized to placebo would be randomized 1:1 to 5mg or 10mg. All subjects and investigators remain blinded to initial treatment assignment.

 The study met its primary endpoint of reduction in blood Huntingtin (HTT) protein levels (p<0.0001) at Week 12 and favorable safety and tolerability. In addition, the 12-month data from the Stage 2 patients are consistent with the previously reported dose-dependent lowering of HTT protein and dose-dependent trends across clinical scales.

Results from the full 12-month cohort demonstrate dose-dependent lowering in blood HTT levels, with 23% at the 5mg dose level for both Stage 2 and 3 patients and 39% and 36% at the 10mg dose level for Stage 2 and 3 patients, respectively. For Stage 2 patients, there were dose-dependent trends of benefit on clinical scales including the Composite Unified Huntington's Disease Rating Scale (cUHDRS) and Total Motor Score (TMS) subscale. For Stage 3 patients, there were trends favoring the 5mg dose group relative to placebo, but not the 10mg dose group, suggesting that treatment effect may differ in Stage 3 patients relative to Stage 2 patients. For all dose levels and disease stages, PTC 518 showed a favorable safety and tolerability profile with no treatment-related serious adverse events or neurofilament light chain protein (NfL) spikes.

In addition, 24-month treatment data from the patients on whom data were shared last year (N=21) demonstrate signals of dose-dependent trends on the cUHDRS, Total Function Capacity (TFC) and Symbol Digit Modalities Test (SDMT) subscales when compared to a propensity matched natural history cohort from the ENROLL-HD Registry. At Month 24, there was also dose-dependent lowering of plasma NfL from baseline of -8.9% (nominal p=0.12) for the 5mg dose level and -14% (nominal p=0.03) for 10mg dose level.

Presentation of study results is expected at a scientific meeting later in the year.

"These PIVOT-HD results confirm that PTC518 lowers Huntingtin protein and shows early signals of clinical benefit with a favorable safety profile," said Dr. Matthew B. Klein,  Chief Executive Officer, PTC Therapeutics. "In addition, at 24 months, we observed favorable dose-dependent trends on the cUHDRS and the TFC and SDMT subscales relative to natural history as well as dose-dependent lowering of neurofilament light chain protein. We look forward to discussions on the next development and regulatory steps including the potential for accelerated approval as we work to potentially bring the first disease-modifying therapy to those affected by Huntington's disease."