PTC Therapeutics Announces Trial for Huntington's Disease

PTC Therapeutics announced the initiation of a Phase 1 clinical trial to evaluate PTC518 in healthy volunteers. PTC518 was identified from PTC's splicing platform and is being developed for the treatment of Huntington's disease (HD). PTC518 is an orally bioavailable molecule with broad central nervous system and systemic distribution and has been designed to target Huntingtin protein  expression with high selectivity and specificity. PTC518 has favorable pharmaceutical properties and has demonstrated uniform lowering of the Huntingtin protein throughout the brain in animal models. Currently there are no approved disease modifying therapies for HD.

"The initiation of the clinical trial to evaluate PTC518 for the Huntington's disease program is an important milestone towards identifying a potential new Huntington's disease treatment that directly targets the underlying cause of the disease," said Stuart W. Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics. "PTC518 is the only orally bioavailable small molecule therapeutic that was identified to selectively and specifically modulate Huntington's disease splicing to reduce huntingtin protein. Analogous to the SMA drug from our splicing platform, this trial is anticipated to establish the appropriate PTC518 dose that reduces HTT protein levels. We believe that the convenient oral administration of PTC518 has the potential to change the treatment landscape for these patients."

The Phase 1 study includes both single and multiple ascending dosing regimens that will help establish the safety, pharmacology, and dose selection for the Phase 2 study. In addition, huntingtin mRNA and protein levels will be measured to gain early proof of splicing mechanism in humans as was done in the risdiplam SMA development program. Data from the Phase 1 study are expected to be available in the first half of 2021.

PTC518 is a small molecule splicing modifier that acts via a unique mechanism to promote the inclusion of a novel pseudoexon containing a premature termination codon, thus triggering HTT mRNA degradation and subsequent reduction in HTT protein levels. In preclinical studies using cells isolated from patients with Huntington's disease (HD), PTC518 reduced both huntingtin mRNA and protein levels with high potency in a dose-dependent manner. In addition, oral administration of PTC518 in the BACHD mouse model of HD achieved dose dependent and equitable lowering of HTT protein throughout the body, including the brain, muscle, and blood.