PTC Therapeutics (PTCT) Study result summary

Study design and methodology

• PIVOT-HD was a phase II, 12-month placebo-controlled study of votoplam at 5 mg and 10 mg in Stage 2 and 3 Huntington's disease, followed by a long-term extension where all participants received votoplam for up to 24 months, remaining blinded to initial assignment.

• The primary endpoint was reduction in blood HTT protein at week 12; secondary endpoints included biomarker changes and cUHDRS scores, with the extension assessing long-term efficacy, safety, and biomarker effects versus a propensity-matched natural history cohort from Enroll-HD.

• Placebo participants were re-randomized to votoplam after 12 months, and matching variables ensured comparability between the natural history and treated groups.

• Baseline characteristics such as age, CAG repeats, and functional scores were similar across groups, ensuring comparability.

Efficacy and clinical outcomes

• At 24 months, votoplam showed dose-dependent slowing of disease progression in Stage 2 patients: 52% slowing at 10 mg and 28% at 5 mg versus natural history on cUHDRS.

• Benefit signals were observed in Stage 3 participants, particularly on the TFC subscale, with trends toward slowing progression at both dose levels.

• Favorable treatment effects were observed across cUHDRS subscales, including TFC, TMS, SDMT, and SWRT, especially in the 10 mg group.

• Curves for treated groups continued to diverge from natural history between months 12 and 24, suggesting increasing treatment effect over time.

Biomarker and safety findings

• No evidence of treatment-related NfL spikes was observed; mean plasma NfL levels remained below baseline at 24 months for both dose groups, contrary to expected natural history increases.

• Dose-dependent reductions in blood HTT levels were maintained, supporting a link between HTT lowering and clinical benefit.

• Votoplam maintained a favorable safety profile at 24 months in both Stage 2 and 3 participants, with no new adverse event signals and consistent safety across doses and disease stages.

• Grade 3 and 4 adverse events and serious adverse events were not treatment-related; rates of serious adverse events and discontinuations were low.

• High adherence and low dropout rates were reported, with as-observed data used for efficacy analyses.