PTC518 Shows Dose-Dependent Effect on Huntington Disease in Interim Analysis of PIVOT-HD Study


Overall, the treatment resulted in dose-dependent trends of improvement on key clinical measures including Total Functional Capacity and Composite Unified Hungtinton's Disease Rating Scale.

Matthew B. Klein, MD, chief executive officer at PTC Therapeutics

Matthew B. Klein, MD

New 12-month, interim data from the phase 2 PIVOT-HD study (NCT05358717) showed that treatment with PTC518 resulted in dose-dependent lowering of huntingtin (HTT) mRNA and protein levels in blood cells of patients with Huntington disease (HD). Overall, the investigational agent was considered safe and well tolerated, with treated patients achieving desired cerebrospinal fluid (CSF) exposure and stable neurofilament light (NfL) levels.1,2

In the 2-part study, patients were randomly assigned to doses of PTC518 at 5 (n = 10) or 10 mg (n = 12) or placebo (n = 10), for 12 weeks, followed by an additional 9-months to end of study. After 12 weeks, results showed a –30% decrease in HTT protein in the 10 mg group, –21% decrease in the 5 mg group, and +12% increase in those on placebo.

The therapy continued to show a durable, dose-dependent effect on mTT protein lowering at month 12. All told, investigators reported lowering of –43% and –22% in the PTC518 10 mg and 5 mg groups, respectively, compared with increases of 14% in the placebo group. Overall, the dose-dependent lowering of such protein with steady state reached at 6-9 months into the study. At the same time point, PTC518-treated patients demonstrated lowering of –43% and –22% in CSF protein, respectively, relative to a –9% decrease observed in placebo.

"The evidence of both CNS biomarker and early clinical effects at Month 12 along with the continued favorable tolerability profile supports the promise of PTC518 to address the need for an effective and safe disease-modifying therapy for patients living with Huntington's disease,” Matthew B. Klein, MD, chief executive officer at PTC Therapeutics, said in a statement.1 "With these data in hand, we look forward to the next steps in the PTC518 development program."

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Throughout the trial, NfL levels remained consistent across treatment groups with no evidence of treatment-related spikes. Across the PTC518 5 mg and 10 mg groups, investigators observed changes of –4% and –3% vs changes of –7% for those on placebo. For context, plasma NfL increases typically around 10-12% per year based on natural history data. In addition, results at 12 months showed consistent change in striatum brain volume, with decreases of –5.4%, –5.2%, and –5.8% in the placebo, PTC518 5 mg, and 10 mg groups, respectively.

PTC518 was considered well tolerated, with no dose-limiting toxicities and an adverse event (AE) profile that was similar across all treatment groups, including placebo. Overall, PTC518-treated patients experienced mostly AEs of nasopharyngitis, influenza, headache, and falls. Serious AEs were observed in 3 patients, 2 in the placebo group and 1 in the PTC518 10 mg group. Treatment-related AEs were observed in 50% (n = 5), 50% (n = 6), and 10% (n = 1) of those in the PTC518 10 mg, 5 mg, and placebo groups, respectively.

Investigators also observed a dose-dependent trend of improvement in Total Motor Score (TMS) with PTC518. In the study, those in the 10 and 5 mg groups showed worsening scores of 1.33 and 2.00, respectively, compared with those on placebo, who showed decreases of 4.90 at 12 months. In addition, treatment with the agent resulted in improvement on Composite Unified Huntington’s Disease Rating Scale as well as Total Functional Capacity.

PTC518, a small molecule therapy taken orally, aims to reduce the production of mutated HTT that leads to injury and death of the neuron, which results in disease progression. The orally bioavailable small molecule penetrates the blood brain barrier, is selective, titratable, and not effluxed – which are key differentiation properties. Towards the end of its presentation, PTC Therapeutics noted that based on these results, the company will begin preparations for a phase 3 clinical trial, as well as continue the PIVOT-HD and PIVOT-HD open label extension studies.

1. Interim PIVOT-HD Results Demonstrate Evidence of Favorable CNS Biomarker and Clinical Effects at Month 12 in Huntington's Disease Patients. News release. June 20, 2024. Accessed June 21, 2024.
2. Klein MB. PIVOT-HD Interim Results. June 20, 2024. Accessed June 21, 2024.
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