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EHDN 2022 | PTC518: oral 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, introduce PTC518 as a new investigational agent in the Huntington’s disease (HD) space. PTC518 is an oral RNA splicing modifier, which acts to incorporate a pseudoexon into the huntingtin (HTT) pre-mRNA, creating a nonsense mutation that truncates the mRNA production. The consequential degradation of HTT mRNA leads to lowering of HTT protein. Brian Beers highlights that PTC518 is uniformly distributed throughout the brain and the body, giving it the potential to tackle peripheral manifestations of disease as well as acting in key brain regions. Preclinical studies have demonstrated the ability of PTC518 to promote splicing and lower HTT protein levels in human cells and mouse models, in a dose-dependent manner. Additionally, efforts to reduce efflux have resulted in balanced peripheral versus brain HTT lowering, increasing the therapeutic window. PTC518 is now in Phase II development (PIVOT-HD; NCT05358717) in patients with HD ISS Stage 2 disease, after the Phase I program provided promising safety and pharmacology data, and early proof of splicing mechanism in healthy volunteers. This interview took place during the European Huntington’s Disease Network 2022 Plenary Meeting.

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