VYNE Therapeutics recently presented preclinical data on positive preclinical and Phase 1b data of VYN201 in nonsegmental vitiligo at the Society for Investigative Dermatology’s (SID) annual meeting in Dallas, TX. Iain Stuart, PhD, Chief Scientific Officer at Vyne Therapeutics, sat down with the Dermatology Digest to discuss the results, the company’s pipeline, and what we can expect from Vyne in the future.
TDD: What is Vyne’s mission statement?
Iain Stuart, PhD: “Our mission is to improve the lives of patients by developing proprietary, innovative, and differentiated therapies for the treatment of immuno-inflammatory conditions.”
TDD: Please provide an overview of your pipeline.
Dr. Stuart: “VYNE has a leading early-stage pipeline to address unmet needs in autoimmune conditions. Our pipeline of bromodomain and extra-terminal (BET) domain protein inhibitors includes two separate candidates. VYN201 is a locally administered “soft” pan-bromodomain (BD) BET inhibitor. A topical gel formulation is being studied in nonsegmental vitiligo. Following successful Phase 1b proof-of-concept data, VYNE is advancing VYN201 into a Phase 2b study to further explore optimal dosing and peak efficacy. The trial is anticipated to begin this quarter. VYN202 is a BD2-selective BET inhibitor that is orally delivered. We believe VYN202 has significant potential as a treatment option for autoimmune diseases. We anticipate initiating Phase 1a single ascending dose (SAD) and multiple ascending dose (MAD) studies this quarter.”
TDD: How may VYN201 help treat vitiligo?
Dr. Stuart: “Currently, there’s only one drug approved for nonsegmental vitiligo, a topical JAK inhibitor, and the few late-stage treatments in development are also JAK inhibitors. BET inhibition provides a differentiated treatment strategy for those with nonsegmental 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 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 have the potential to treat a range of immuno-inflammatory and fibrotic diseases by blocking pro-inflammatory cytokine transcription. VYN201 is a pan-BD BET inhibitor designed to be locally administered as a “soft” drug to address diseases involving multiple, diverse inflammatory cell signaling pathways while providing low systemic exposure. As a topical therapy, VYN201 has demonstrated clinical proof-of-concept in nonsegmental vitiligo, showing promising onset of action and F-VASI response as well as competitive efficacy data at 16 weeks as compared to the JAK class at 24 weeks.”
TDD: Can you summarize the two SID presentations?
Dr. Stuart: “Presentations at SID highlighted positive preclinical and Phase 1b data of VYN201 in nonsegmental vitiligo. The preclinical study found that VYN201 inhibits CD8+ T-cell expansion and activity in vitro at a lower IC50 than ruxolitinib without being cytotoxic to these cells. At a 1% topical strength, VYN201 reduces melanocytorrhagy by decreasing MMP-9 and E-cadherin release, prevents melanocyte loss in a vitiligo model, and up-regulates the wingless-related integration site (WNT) pathway, supporting melanogenesis and melanocyte differentiation. The Phase 1b trial was a 16-week open-label trial assessing the safety, tolerability, pharmacokinetics, and exploratory efficacy of a once-daily topical formulation of VYN201 in 29 patients with active nonsegmental vitiligo in three dose cohorts (0.5%, 1.0%, and 2.0% concentrations). The study showed significant clinical improvement was observed in the 1.0% and 2.0% cohorts, with rapid onset of action and a dose-dependent response. The mean percentage reduction in facial vitiligo area index score from baseline after 16 weeks of treatment was 7.5%, 30.2%, and 39.0% for the 0.5%, 1.0%, and 2.0% cohorts, respectively. Additionally, exploratory data from the 1.0% and 2.0% cohorts showed that VYN201 treatment demonstrated biological activity and a positive effect on certain key biomarkers relevant to vitiligo disease severity and progression. VYN201 was generally well tolerated with no clinically relevant treatment-emergent adverse events across all dose cohorts.”
TDD: What are the next steps with VYN201?
Dr. Stuart: “The data support the advancement of VYN201 as a differentiated therapy for the potential treatment of nonsegmental vitiligo. We believe the results from the Phase 1b trial are the first clinical demonstration of a BET inhibitor’s effect in any autoimmune disease and has positioned us to move VYN201 into a Phase 2b study for nonsegmental vitiligo. The VYN201 Phase 2b trial is expected to enroll approximately 160 people with either active or stable nonsegmental vitiligo and will evaluate VYN201 gel in 1%, 2%, and 3% concentrations compared to vehicle for 24 weeks, followed by a 28-week active treatment extension. We expect to start the trial this quarter and report top-line results from the 24-week double-blind portion of the trial in mid-2025.”
TDD: Please provide an overview of VYN202.
Dr. Stuart: “VYNE’s second clinical development candidate, VYN202, is an innovative, oral BD2-selective BET inhibitor. Slated for Phase 1 clinical initiation this quarter, VYN202 has exhibited potent anti-inflammatory activity across diverse relevant preclinical models and demonstrated significant down-regulation of key pro-inflammatory and disease-related biomarkers corresponding with improvements in disease severity. VYN202 has the potential to be a more conveniently administered non-biologic treatment option for both acute control and chronic management of immuno-inflammatory indications, where the damaging effects of unrestricted inflammatory signaling activity is common. In in vivo psoriasis models, VYN202 treatment reduced production of key cytokines associated with psoriasis pathogenesis and led to marked improvement of disease clinical outcome, as measured by reduced dermal inflammation. In in vivo RA models, VYN202 demonstrated highly potent anti-inflammatory activity, with near-normal joint histopathology achieved at 10 mg/kg dosing once a day.
If the Phase 1a trial is successfully completed, we plan to initiate Phase 1b trials in subjects with moderate-to-severe plaque psoriasis and moderate-to-severe adult-onset rheumatoid arthritis, with top-line results anticipated in the second half of 2025.”
TDD: Why did you decide to focus on vitiligo, psoriasis, and rheumatoid arthritis (RA)?
Dr. Stuart: “It started with the rationale that BET inhibition could positively impact aberrant immune-inflammatory processes in these diseases. Both VYN201 and VYN202 have demonstrated significant anti-inflammatory effects across multiple diverse preclinical models of autoimmune disease. Of note, these effects have led to positive improvements in both disease severity with corresponding reductions in key pro-inflammatory biomarkers of disease. In particular, our data in vitiligo, psoriasis, and RA were quite compelling and these diseases have large patient populations, unmet need, and strong market potential. They also enable us to efficiently and effectively demonstrate the platform’s potential value and broad utility for patients and other stakeholders. Additionally, initial proof-of-concept studies in these disease areas allow for potential expansion into other large, growing, and underserved patient populations.”
TDD: Where do you hope to see the company and its pipeline in 5-10 years?
Dr. Stuart: “We believe our pipeline provides great opportunity for both acute control and chronic management of immuno-inflammatory indications, where the damaging effects of unrestricted inflammatory signaling activity is common. At VYNE, we hold the view that our treatment candidates can impact multiple inflammatory pathways, unlocking potential for a broad development strategy across a range of high-need, immune-mediated diseases.”
