Vyne Therapeutics’ attempt to develop a safer, more tolerable BET inhibitor has hit turbulence. The FDA slapped a clinical hold on a phase 1b plaque psoriasis trial after testicular toxicity was reported in dogs from a nonclinical test.
Research into the use of BET inhibitors to treat cancer has shown the mechanism can cause hematologic and gastrointestinal adverse effects. Seeking to avoid those outcomes, Vyne designed VYN202 to be selective for the BD2 portion of the protein. The choice reflected evidence that BD2 regulates gene expression of pro-inflammatory mediators while BD1 modulates cell-cycling and homeostatic functions.
Vyne shared phase 1a data late last year, generating early support for the hypothesis and emboldening the biotech to start a phase 1b trial in plaque psoriasis in February. The FDA slammed the brakes on the phase 1b study Friday, sending Vyne’s share price down 20% to $1.50 in premarket trading.
In a statement, Vyne said “the clinical hold determination was made following a recent observation of testicular toxicity in dogs from a non-clinical toxicology study with VYN202.” The biotech has stopped all screening, enrollment and dosing in the phase 1b while it works with the FDA to resolve the clinical hold. No patients in the study have experienced serious adverse events.
Testicular toxicity torpedoed Gilead Sciences and Galapagos’ plans for filgotinib. The FDA restricted the maximum dose of the JAK inhibitor for a period during clinical development, based on data in rats and dogs, and in 2020 rejected a request for approval in rheumatoid arthritis.
Vyne is looking to find a speedy resolution to the clinical hold and get back to advancing an asset that it has pitched as a promising prospect. Talking at an H.C. Wainwright investor event last month, Vyne CEO David Domzalski said the team was “thrilled” with the phase 1a results and looking to emerge from the phase 1b trial with data that could unlock opportunities for the program.
“This is primarily a safety study. We want to get as much exposure data as possible. We want to come out of this with a clean safety profile, take any kind of ‘halo effect’ out of the equation for our drug and then, obviously, hopefully get some meaningful efficacy signals,” Domzalski said. “Assuming we do that, I think the optionality for this product is quite substantial.”
Vyne’s phase 2b trial of repibresib in nonsegmental vitiligo isn’t affected by the clinical hold. Repibresib is a pan-BD BET inhibitor. While the molecule inhibits BD1, the topical gel delivery format sidesteps safety concerns associated with the systemic use of pan-BD BET inhibitors.