Huntington Agent PTC518 Demonstrates Significant Reduction in Key Biomarker in Phase 2 Study


Over a 12-week period, PTC518 showed a safe and tolerable profile, with significant reductions in mutant huntingtin protein and an overall trend towards lowering of neurofilament light levels.

Matthew Klein, chief executive officer at PTC Therapeutics

Matthew Klein

Newly announced interim data from the phase 2 PIVOT study (NCT05358717) of PTC518 (PTC Therapeutics), an agent in development for Huntington disease (HD), showed a dose-dependent lowering of huntingtin protein (HTT) levels after 12 weeks of treatment. HD, a rare, hereditary, genetic disorder of the central nerve system, is caused by a defective gene that produces HTT, which is involved in the functioning of the nerve cells in the brain.1

PTC518, a small molecule administered orally, resulted in a 30% reduction in mutant HTT levels when given in doses of 10 mg. In addition, the therapy showed a safe and tolerable profile, with exposure in cerebrospinal fluid (CSF) that was consistent with or higher than plasma unbound drug levels. There were no reports of serious treatment-related adverse events (AEs), as well as no peripheral neuropathy or dose-limiting toxicities.

"We are very pleased with the encouraging data from the PIVOT-HD interim analysis demonstrating dose-dependent HTT lowering, desired CSF exposure and a favorable tolerability profile without evidence of treatment-related serious adverse events or CSF NfL spikes," Matthew Klein, chief executive officer at PTC Therapeutics, said in a statement.1

After 12 weeks, those treated with PTC518 started to see trends toward lowering of CSF neurofilament light levels, a marker of neuroaxonal damage. 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, CSF, and radiologic biomarker data is collected. The primary outcome of the study is safety, assessed by number of patients with AEs, and change from baseline in total HTT.

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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.

In October 2022, US enrollment for the study was paused as the FDA continued to seek more data about the drug. The stoppage, which was not because of treatment-related AEs reported in the study, continued enrollment for several sites across European countries and in Australia. At the time, PTC noted that it will continue to work with the FDA to obtain the data needed to proceed with the study.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 Therapeutics shares positive interim data from PIVOT-HD clinical trial in Huntington’s disease patients. News release. June 21, 2023. Accessed June 21, 2023.
2. PTC provides update on ongoing global PIVOT-HD trial of PTC518. News release. October 18, 2022. Accessed June 21, 2023.
3. PTC518 Huntington’s Disease Program Update. News release. PTC Therapeutics. September 23, 2021. Accessed June 21, 2023.
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