VYNE Reports Positive Preclinical Data for Lead BET Inhibitor in Human Skin Model of Vitiligo

VYNE Therapeutics Inc. recently announced positive preclinical data in an ex vivo skin model of vitiligo. In the preclinical model, pan-bromodomain and extra-terminal (BET) inhibitor VYN201 reduced the expression of key pro-inflammatory biomarkers relevant to the pathogenesis of vitiligo, and demonstrated marked reduction in melanocyte loss.

Vitiligo is a chronic autoimmune depigmenting disorder of the skin. There are currently no FDA approved drug therapies for the treatment of vitiligo. It is the most common depigmenting skin condition, with a prevalence estimated at 0.5-2% of the world population. Vitiligo is characterized by increased MMP-9 secretion and soluble E-cadherin², resulting in a loss of pigment in the skin.

The objectives of this study were to evaluate the potential of VYN201 to (i) reduce Matrix Metalloproteinase-9 (MMP-9) secretion (reducing the secretion of MMP-9 allows for melanocyte stabilization and limits loss of melanocytes/depigmentation in vitiligo); (ii) reduce soluble adhesion molecule, E-cadherin (soluble E-cadherin is a biomarker of melanocyte loss due to degradation of matrix-bound E-cadherin by MMP-9); (iii) minimize the loss of melanocytes by assessing melanin pigment content and (iv) affect the expression of genes commonly associated with melanogenesis (melanin synthesis, melanosome maturation and transport).

In the study, reconstituted human epithelial skin cultures were stimulated with Tumor Necrosis Factor alpha (TNF-α) and Interferon gamma (IFN-ɣ) cytokines to induce a vitiligo phenotype (loss of melanin, increased MMP-9 secretion and increased soluble E-cadherin). The stimulated cultures were topically treated with vehicle, VYN201 at varying concentrations ranging from 0.001% – 1%, or an active control, topical ruxolitinib cream, 1.5%, at 3 mg/cm². The topical treatments were applied to the skin cultures 24 hours prior to, and concomitantly with, cytokine induction.

Key findings from the study:

• VYN201 produced a dose dependent reduction in MMP-9 and soluble E-cadherin:
  • Applications with VYN201 at each of the 0.1% and 1% concentrations resulted in statistically significant reductions in MMP-9 when compared to vehicle, with a 94.7% reduction in secreted MMP-9 for the VYN201 1% treatment (p<0.0001).
  • Applications with VYN201 at each of the 0.1% and 1% concentrations resulted in statistically significant reductions in the release of soluble E-cadherin relative to vehicle, with a 32.6% reduction in soluble E-cadherin for the VYN201 1% concentration (p<0.01).
  • VYN201 0.1% and 1% were both numerically superior to topical ruxolitinib cream, 1.5% in reducing the secretion of MMP-9 and soluble E-cadherin.
• VYN201 at each of the 0.1% and 1% concentrations substantially reduced the loss of melanin pigment in the basal layers of skin:
  • Quantified melanin levels for VYN201 1% treated skin cultures were approximately 10-fold higher as compared to VYN201 vehicle treated skin cultures (p=0.03).
• VYN201 positively impacted the expression of several genes implicated in the pathogenesis of vitiligo:
  • VYN201 0.1% and 1% resulted in a statistically significant reduction in the expression of inflammatory cytokines IL1-α and IL1-β relative to vehicle (VYN201 1%, p<0.0005). These cytokines are well recognized as significant contributors to inflammation in vitiligo and their over-expression correlates with disease progression.
  • VYN201 significantly upregulated the WNT signaling pathway at the 0.1% and 1% concentrations relative to vehicle, with a 10-fold increase observed at the 1% concentration (p<0.01). The WNT family of proteins and its signalling pathway is recognized as an important indicator of melanocyte regeneration.

“We are encouraged by the evolving therapeutic potential of our locally-administered pan-BET inhibitor, VYN201,” said David Domzalski, VYNE’s Chief Executive Officer. “This latest set of pre-clinical data in vitiligo reflects the potential broad utility for this molecule. We look forward to providing additional updates as we continue to advance this program toward in-human clinical trials later this year.”

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. Inhibiting BET proteins blocks cytokine transcription and therefore may have significant therapeutic potential across a wide variety of immuno-inflammatory/fibrotic and myeloproliferative neoplastic disorders. A locally administered pan-BET inhibitor has the possibility to positively impact diseases involving multiple, diverse inflammatory cell signaling pathways that are active in many immune-inflammatory diseases.

VYNE’s mission is to improve the lives of patients by developing proprietary, innovative, and differentiated therapies for the treatment of immuno-inflammatory conditions. The company’s unique and proprietary pipeline includes FMX114 for the potential treatment of mild-to-moderate atopic dermatitis, and access to a library of bromodomain & extra-terminal (BET) domain inhibitors licensed from In4Derm Limited. The BET inhibitor platform includes lead programs VYN201 (pan-BETi) and VYN202 (selective-BETi) and access to a library of (BET) domain inhibitors for the potential treatment of immuno-inflammatory conditions. For more information, visit www.vynetherapeutics.com.