Huntington Drug PTC518 Meets Primary End Point in Phase 2 Study

Matthew B. Klein, MD

According to a new announcement from PTC Therapeutics, investigational PTC518 met its primary end point in the phase 2 PIVOT-HD study (NCT05358717), with results showing a statistically significant change in blood Huntingtin (HTT) protein levels over a 12-month period and promising 24-month data as well. Based on the totality of the evidence, PTC plans to work with the FDA on an accelerated approval path for the agent as a potential treatment for Huntington disease (HD).¹

After 12 months of treatment with the small molecule splicing modifier, investigators observed a 23% reduction in blood HTT levels for the 5 mg dose level for both Stage 2 and 3 patients, as well as a 39% and 36% attenuation at the 10 mg dose level for Stage 2 and 3 patients, respectively. More notably, there was a dose-dependent trend of benefit among Stage 2 patients in terms of clinical scales like Composite Unified Huntington’s Disease Rating Scale (cUHDRS) and Total Motor Score (TMS) subscale. This was not the same for Stage 3 patients, as results indicated the 5 mg group was more effective, suggesting that Stage 3 patients may have a different treatment effect than Stage 2.

"These PIVOT-HD results confirm that PTC518 lowers Huntingtin protein and shows early signals of clinical benefit with a favorable safety profile," Matthew B. Klein, MD, chief executive officer at PTC, said in a statement.¹ "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 disease."

The announced data built on previously released results in June 2024, which also revealed dose-dependent effects from PTC518.² In the latest data update, a subgroup of patients on the drug for 24 months (n = 21) continued to show dose-dependent lowering of plasma neurofilament light (NfL), a biomarker of neuroaxonal damage. Overall, there were decreases of –8.9% (nominal P = .12) at the 5 mg dose level and –14% (nominal P = .03) for the 10 mg dose level.¹

PTC518 is an oral small molecule therapy designed to decrease the production of mutated HTT, which contributes to neuronal damage and disease progression. It is selectively bioavailable, able to cross the blood-brain barrier, titratable, and not subject to efflux, distinguishing it from other treatments. At 24 months, treatment with the agent led to signals of dose-dependent trends on the cUHDRS, Total Functional Capacity, and Symbol Digital Modalities Test subscales when compared with a propensity matched natural history cohort from the ENROLL-HD registry.

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PTC noted that the therapy continued to show a favorable safety and tolerability profile. In the previously announced results from 2024, the most common adverse events (AEs) observed with PTC518 were nasopharyngitis, influenza, headache, and falls. There were no dose-limiting toxicities, both dosing and treatment groups had similar safety profiles, and there was 3 serious AEs observed in 3 patients, 2 in the placebo group and 1 in the PCT518 10 mg group.²

In the previous phase 1 study involving healthy volunteers, PTC518 showed a dose-dependent reduction in HTT mRNA and protein levels by 30% to 50%. The agent was well-tolerated, exhibited predictable pharmacokinetics, and had a long half-life, with splicing activity maintained up to 72 hours after the last dose. The results also indicated that steady-state reductions in HTT mRNA levels were achieved within one week, while steady-state reductions in HTT protein levels were expected to take at least six weeks. Furthermore, PTC518 demonstrated its ability to cross the blood-brain barrier and target nerve cells in both human and monkey plasma CSF.³

Finding disease-modifying therapies for HD has been a challenge, mainly because of the complex biology of the disease, lack of early-stage biomarkers, and the irreversible damage caused by the disease. HD is caused by a single gene mutation in the HTT gene, which leads to the production of abnormal huntingtin protein; however, the relationship between the genetic mutation the wide range of symptoms and progression in HD is not fully understood.

REFERENCES
1. PTC518 PIVOT-HD Study Achieves Primary Endpoint. News release. PTC Therapeutics. May 5, 2025. Accessed May 5, 2025. https://www.prnewswire.com/news-releases/ptc518-pivot-hd-study-achieves-primary-endpoint-302445673.html
2. 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 May 5, 2025. https://ir.ptcbio.com/news-releases/news-release-details/interim-pivot-hd-results-demonstrate-evidence-favorable-cns
3. PTC518 Huntington’s Disease Program Update. News release. PTC Therapeutics. September 23, 2021. Accessed May 5, 2025. https://ir.ptcbio.com/static-files/2162ff85-c7ed-4555-8542-52fa2129f7fa