Votoplam Shows Dose-Dependent Slowing of Disease Progression in Stage 2 Huntington Disease

In a new company update, PTC Therapeutics reported positive topline findings from an interim analysis of a long-term extension study (NCT06254482) from the phase 2 PIVOT-HD trial (NCT05358717) of investigational votoplam. All told, the results indicated dose-dependent effects on disease progression in patients with stage 2 Huntington disease (HD) treated with votoplam, formally known as PTC518, for 24 months when compared with an external natural history cohort.¹

After 24 months of treatment with votoplam, data from the analysis showed evidence of dose-dependent benefit in slowing progression on the Composite Unified Huntington's Disease Rating Scale (cUHDRS) relative to a propensity weighted natural history cohort in stage 2 participants, with 52% and 28% slowing for 10 mg and 5 mg participants, respectively. The company also noted that additional signals suggesting potential treatment effects relative to natural history were observed across cUHDRS subscales in the 10 mg cohort.

"These results give us confidence in the potential for votoplam to deliver long-term meaningful effect on slowing Huntington's disease progression," Matthew B. Klein, MD, chief executive officer at PTC Therapeutics, said in a statement.¹ "In particular, the evidence of dose-dependent slowing of progression on the cUHDRS disease rating scale in the Stage 2 study participants supports the Novartis-initiated Phase 3 INVEST-HD study. We look forward to continuing to review the data and aligning on potential regulatory interactions based on the results with our partner Novartis."

For context, PIVOT-HD study is a 12-month, placebo-controlled trial evaluating 2 dose levels of votoplam in participants with stage 2 and stage 3 HD. The study previously met its primary end point of reducing blood huntingtin protein at 12 weeks, with continued dose-dependent reductions observed through month 12.²

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Following the core period, participants subsequently enrolled in the PIVOT-HD extension study. There, individuals originally assigned to votoplam 5 mg or 10 mg continue on their assigned dose, whereas those initially randomized to placebo are re-randomized to receive 5 mg or 10 mg.

In the latest data update, treatment-related increases in neurofilament light chain (NfL) were observed with votoplam, and mean NfL levels remained below baseline at 24 months in both the high- and low-dose cohorts, in contrast to the expected natural history of HD, in which NfL levels typically increase over time. In stage 3 participants, signals suggestive of slowed disease progression were observed at 24 months. Furthermore, safety data at 24 months across both dose levels and disease stages were consistent with previously reported findings indicating a favorable safety profile.

In additional news, Novartis has announced the initiation of the global phase 3 INVEST-HD study (NCT07326709), a placebo-controlled trial expected to enroll approximately 770 participants with early-stage HD testing the therapeutic benefit of votoplam. The study, which randomizes patients in a 3:2 ratio to receive votoplam 10 mg or placebo uses 36-month change in the cUHDR as the primary end point. The study is sponsored and funded by Novartis. Novartis and PTC Therapeutics plan to continue evaluating the data on votoplam and to discuss potential next steps, including possible regulatory interactions.

REFERENCES
1. PTC Therapeutics Reports Positive Topline Results from Month 24 Interim Analysis of PIVOT-HD Extension Study of Votoplam. PTC Therapeutics. April 28, 2026. Accessed April 29, 2026. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-reports-positive-topline-results-month-24
2. PTC518 PIVOT-HD Study Achieves Primary Endpoint. News release. PTC Therapeutics. May 5, 2025. Accessed April 29, 2026. https://www.prnewswire.com/news-releases/ptc518-pivot-hd-study-achieves-primary-endpoint-302445673.html