VYNE Therapeutics Inc. announced positive first-in-human pharmacokinetic and hematology data from its Phase 1a single and multiple ascending dose trial for its investigational novel BET inhibitor, VYN201. In February 2023, the Company announced positive preliminary safety and tolerability data from the trial. The Phase 1a portion of the trial included comprehensive pharmacokinetic sampling to ascertain the exposure to topically-applied VYN201 from single and repeat treatment of VYN201 over five ascending dose cohorts.

Results have shown that there were no quantifiable VYN201 plasma concentrations above the assay lower limit of quantification (0.25ng/ml). Inhibiting the functionality of the bromodomain 1 (BD1) subunit of BET proteins is believed to disrupt homeostatic gene regulation. This can lead to potential clinical safety concerns such as thrombocytopenia (low platelet count), a known dose-limiting adverse event for systemically administered pan-BD BET inhibitors.

In the Phase 1a trial, there was no evidence of low or lower platelet counts at any timepoint for any dose cohort. The assay lower limit of quantification (LLOQ) of 0.25ng/ml is 720-fold below the free half maximal effective concentration (EC50) for VYN201 against the BD1 domain of the BET protein, BRD4. There was no effect on other assessed clinical hematological parameters.

Enrollment in the Phase 1b portion of the trial is ongoing and the Company expects to report topline results in mid-2023. About the Phase 1a/b Trial in Healthy Volunteers and Patients with Nonsegmental Vitiligo: In the Phase 1a portion of the study, single ascending and multiple ascending doses of VYN201 were applied topically once daily to 30 healthy volunteers in five dose cohorts (0.025%, 0.1%, 0.5%, 1.0% and 2.0% ointment strengths) over a two-week treatment period with a one-week safety follow-up visit to evaluate the safety, tolerability and pharmacokinetics of VYN201. The safety and tolerability results are summarized: There were no serious adverse events and no dose adjustments were required.

There were no clinically relevant treatment emergent adverse events, abnormal clinical laboratory results or electrocardiogram findings. No healthy volunteers withdrew from the trial for any reason. Based on the Phase 1a results, VYNE selected 0.5%, 1.0% and 2.0% ointment strengths for evaluation in the ongoing Phase 1b study.

In this portion of the study, up to 30 patients with a clinical diagnosis of non-segmental vitiligo will receive VYN201 once daily in three dose cohorts. The primary objective of the Phase 1b portion of the study will be to evaluate the safety and pharmacokinetics of VYN201. Exploratory efficacy of VYN201 in non-segmental vitiligo patients will also be evaluated, including F-VASI, pharmacodynamic biomarkers and clinical photography.

YN201 and Vitiligo: VYN201 is a locally-administered pan-bromodomain BET inhibitor, designed as a “soft” drug to address diseases involving multiple, diverse inflammatory cell signaling pathways while providing low systemic exposure. To date, VYN201 has produced consistent reductions in pro-inflammatory and disease-related biomarkers, improvements in disease severity and a demonstrated local activity through several preclinical models. The Company believes that these data suggest potential broad utility for VYN201 across multiple routes of administration.

Vitiligo is a chronic autoimmune depigmenting disorder of the skin, characterized by the loss of pigment producing cells known as melanocytes. Vitiligo is the most common depigmenting skin condition, with a prevalence estimated at 0.5-2% of the world population. There is currently only one FDA-approved product for the treatment of vitiligo.

Non-segmental vitiligo is the most common type of vitiligo. BET proteins play a key role in regulating gene transcription via epigenetic interactions (“reading”), and recent research has determined a key role for these BET proteins in regulating B cell and T cell activation and subsequent inflammatory processes. As epigenetic readers, BET proteins regulate the recruitment of transcriptional factors that are key to the production of several pro-inflammatory cytokines.

BET inhibitors (BETi) have the potential to treat a range of immuno-inflammatory and fibrotic diseases by blocking pro-inflammatory cytokine transcription with additional potential in myeloproliferative neoplastic disorders.