PTC Therapeutics Pauses Phase 2 Study of PCT518 in Huntington Disease


After a successful phase 1 study in which PTC518 reduced huntingtin protein by 30% to 50%, the company is pausing the US enrollment of its phase 2 study until additional data is provided to the FDA.

Stuart W. Peltz, chief executive officer, PCT Therapeutics

Stuart W. Peltz

US enrollment for the phase 2 PIVOT-HD trial (NCT05358717) assessing PTC Therapeutics investigational agent PTC518 in patients with Huntington disease (HD) has been paused, according to the company, as the FDA continues to seek more data about the drug. Although stopped in the US, the study of the oral, small molecule splicing modifier is still enrolling participants at sites in several European countries and in Australia.1

The company made it known that there have been no treatment-related adverse events (AEs) reported in the study in the US or outside of the US since its initiation in March 2022. PTC noted that it will continue to work with the FDA in obtaining the data needed to proceed the study, as well as work toward sharing data from the 12-week portion of the study in the first half of 2023.

A 2-part study, PIVOT-HD consists of an initial 12-week placebo-controlled period that focuses on the pharmacological and pharmacodynamic effect of PTC518, followed by a 9-month placebo-controlled period, during which blood, cerebrospinal fluid, and radiographic biomarker data will be collected. The primary outcome of the study is safety, assessed by number of patients with AEs, and change from baseline in total huntingtin protein (tHTT) at day 85.

The study will initially include 2 dose levels—5 mg and 10 mg—with the potential to study a third dose leveraging the titratability of the drug. To date, the approvals for the study have included both the 5-mg and 10-mg dose levels, as well as a potential third dose pending the results of the first 2 dosing cohorts. In addition to safety and changes in tHTT, investigators will assess secondary outcomes such as change in blood HTT messenger RNA (mRNA), mutant HTT and blood mutant HTT.

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When it was first initiated, Stuart W. Peltz, chief executive officer, PCT Therapeutics, said in statement, “In the PIVOT-HD trial, we aim to confirm the dose-dependent lowering of huntingtin protein that was demonstrated in our phase 1 clinical study and gain insight to biomarker data that could provide meaningful evidence of treatment effect."2

In the prior phase 1 study of health volunteers, PTC518 demonstrated a dose-dependent lowering of HTT mRNA and protein by 30% to 50%. Additionally, the agent was well-tolerated, had predictable pharmacology, and showed a long half-life with maintenance of splicing up to 72 hours following last dose. Findings also showed that steady state lowering of HTT mRNA abundance was achieved within 1 week, and that steady state lowering of HTT protein abundance should take at least 6 weeks. In both human and monkey plasma CSF, PTC518 demonstrated the ability to cross the blood-brain barrier and reach its target nerve cells.3

1. PTC provides update on ongoing global PIVOT-HD trial of PTC518. News release. October 18, 2022. Accessed October 19, 2022.
2. PTC Therapeutics announces initiation of PIVOT-HD phase 2 clinical trial to evaluate PTC518 in patients with Huntington disease. News release. PTC Therapeutics. March 30, 2022. Accessed October 19, 2022.
3. PTC518 Huntington’s Disease Program Update. News release. PTC Therapeutics. September 23, 2021. Accessed October 19, 2022.
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