PTC518 is an oral, small molecule RNA splicing modifier under investigation for the treatment of Huntington’s disease. Amy-Lee Bredlau, MD; Lee Golden, MD; and Brian Beers, BSc; PTC Therapeutics, Inc., New Jersey, share an update on the clinical development of PTC518. In a Phase I healthy volunteer study, PTC518 demonstrated dose-dependent huntingtin (HTT) splicing and lowering of HTT protein of 30-50%. The agent was well tolerated, with no safety-related findings. Having shown proof of mechanism, the team is conducting a larger scale trial, hoping to replicate the HTT lowering effects seen in Phase I. The newly launched Phase II PIVOT-HD study (NCT05358717) aims to evaluate the efficacy of PTC518 in patients with HD ISS stage 2 disease. The initial 12-week placebo-controlled phase will focus on pharmacology and pharmacodynamic effect, with participants receiving 5mg PTC518 once daily. This will be followed by a 9-month phase (PTC518 10mg daily versus placebo) focused on biomarker effect, including change in blood HTT mRNA, blood total HTT protein, and CSF mutant HTT protein levels. This interview took place during the European Huntington’s Disease Network 2022 Plenary Meeting.
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