Phase 2 Trial of Oral Therapy PTC518 Launched in US

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A Phase 2 trial evaluating PTC518, an investigational treatment for Huntington’s disease, has started in the U.S., PTC Therapeutics announced.

The trial, called PIVOT-HD, will run across clinical sites worldwide and is divided into two parts. First, participants will be randomly assigned to a placebo or PTC518 and followed for 12 weeks (approximately three months). This first part will assess PTC518’s pharmacology and pharmacodynamic effect — or the interactions between the body and a given compound.

In the second part, participants will be followed for nine months and researchers will assess the impact of PTC518 on disease biomarkers.

“We are excited to advance our Huntington’s disease program,” Stuart W. Peltz, PhD, CEO of PTC Therapeutics, which is developing the therapy, said in a press release.

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PTC518 is an oral small molecule designed to specifically reduce mutant huntingtin (mHTT) protein that triggers the death of nerve cells in Huntington’s. It works by modifying a natural process in cells called RNA splicing.

The genetic information contained in DNA is translated into proteins. Several steps mediate this process.

One of the first steps is the generation of a pre-messenger RNA, or pre-mRNA, from DNA. This is then processed into a mature mRNA molecule that will serve as a template for protein production.

The transformation of a pre-mRNA into a mature mRNA is called RNA splicing. During splicing, sequences called introns that do not code for proteins are removed, while those that code, called exons, are stitched together. RNA splicing allows for a single gene to give rise to many different proteins.

PTC518 works by introducing a “stop” signal during the splicing process, triggering the mutant huntingtin mRNA for degradation. As a result, mHTT protein production is reduced.

In a Phase 1 trial with healthy volunteers, results showed that PTC518 reduced the HTT mRNA and protein by 30% to 50%. This was achieved in a dose-dependent manner, with higher doses leading to more pronounced reductions.

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PTC518 also was able to cross the blood-brain barrier — a highly selective membrane that shields the brain and spinal cord from general blood circulation — and reach its target nerve cells.

“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,” Peltz said.