SOX10

VYN201 demonstrated positive effect on key biomarkers relevant to vitiligo Data supports VYN201’s rapid onset of action and previously announced positive clinical results Program is on track for Phase 2b initiation in Q2 Jan. 10, 2024 (GLOBE NEWSWIRE) -- VYNE Therapeutics Inc. (Nasdaq: VYNE) (“VYNE” or the “Company”), a clinical-stage biopharmaceutical company developing proprietary, innovative and differentiated therapies for the treatment of immuno-inflammatory conditions, today announced new biomarker data from the previously completed Phase 1b trial in patients with nonsegmental vitiligo. The data show that BET inhibitor, VYN201, had a positive effect on multiple disease-associated biomarkers. Positive clinical data from the Phase 1b trial were announced in October 2023. The trial was a 16-week open-label study assessing the safety, tolerability, pharmacokinetics, and exploratory efficacy of once-daily topical VYN201 in 29 patients with a clinical diagnosis of active nonsegmental vitiligo, in three dose cohorts (0.5%, 1.0% and 2.0% strengths). Enrolled subjects had two, non-facial active vitiligo lesions. One lesion, selected for treatment with VYN201, had skin tissue biopsies taken prior to first application of VYN201 and after 8 weeks of treatment. Biopsies were analyzed to quantify the effect of VYN201 on specific biomarkers related to inflammation associated with vitiligo, melanocyte proliferation, and melanogenesis. 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. The magnitude of biomarker modulation was more pronounced in the 2.0% dose cohort than in the 1.0% dose cohort, indicative of an emerging dose-response. Results from the biomarker analyses include the following: Downregulation of Matrix metalloproteinase-9 (MMP-9) levels: VYN201 induced the downregulation of MMP-9 in biopsied lesional skin after 8 weeks of treatment compared to baseline. MMP-9 is an inflammatory biomarker associated with the detachment and subsequent loss of melanocytes from skin in vitiligo and is elevated in patients with vitiligo. At Week 8, there was a median reduction in MMP-9 of 40.8% in lesional skin compared to baseline for subjects in the 2.0% cohort. Upregulation of melanocyte-related transcription factors (MRTFs): VYN201 induced the upregulation of multiple MRTFs, including SRY-box transcription factor 10 (SOX10), Lymphoid-enhancing factor-1 (LEF1), β-Catenin and Microphthalmia associated transcription factor (MITF), after 8 weeks of treatment compared to baseline. Each of these markers are linked to the proliferation of melanocytes, recovery in melanogenesis, and subsequent re-pigmentation of skin. In the 2.0% cohort, SOX10, LEF1, β-Catenin and MITF transcription factors had median increases of 36.1%, 90.2%, 16.5% and 15.2% in their respective expression levels in lesional skin compared to baseline. “VYN201’s potential to reduce melanocyte detachment by downregulating MMP-9 and by upregulating the expression of proteins relevant to melanocyte proliferation and melanogenesis is promising, and I look forward to the continued advancement of VYN201 as a potential differentiated therapy for vitiligo,” said Amit Pandya, M.D., former President of the Global Vitiligo Foundation and Dermatologist, Department of Dermatology, Palo Alto Foundation Medical Group. “We are encouraged by these new biomarker data from the Phase 1b trial for VYN201, building on our recently announced positive clinical results,” said David Domzalski, President and CEO of VYNE. “We’ve made considerable progress in advancing this program, and we look forward to initiating a Phase 2b trial evaluating VYN201 in patients with both active and stable nonsegmental vitiligo in the second quarter of this year.” The loss of functional melanocytes in vitiligo is associated with the generation of inflammatory mediators that facilitate melanocyte detachment in skin.1 This cellular detachment occurs due to the disrupted surface distribution of adhesion molecule E-cadherin and the release of soluble E-cadherin.2 E-cadherin cleavage may be induced by several metalloproteinases including MMP-9. MMP-9 is secreted by the keratinocytes in response to various proinflammatory cytokines such as IFN-γ and TNF-α.3 The Wnt/β-catenin pathway plays an essential role in pigmentation by regulating both melanocyte differentiation and melanogenesis through the action of MITF.4 β-catenin is increased by the binding of Wnt proteins to their receptors, leading to transport of β-catenin into the nucleus, where it regulates transcription of MITF through interactions with several transcription factors that include LEF1 and SOX10. MITF also regulates transcription of downstream genes key for melanin synthesis and melanocyte cell development. 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 0.5-2.0% of the world population.5 There is currently only one FDA-approved product for the treatment of vitiligo. Nonsegmental vitiligo is the most common type of vitiligo. VYN201 is a pan-bromodomain 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. To date, VYN201 has produced consistent reductions in pro-inflammatory and disease-related biomarkers and improvements in disease severity, and demonstrated local activity in several preclinical models (using several different routes of administration). 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 with additional potential in myeloproliferative neoplastic disorders. 1. Picardo, M. et al. Nat. Rev. Dis. Primer 1, 15011 (2015). 2. Delmas, V. & Larue, L. Exp. Dermatol. 28, 662–666 (2019). 3. Boukhedouni, N. et al. JCI Insight 5, 133772 (2020). 4. Zhao SJ et al, Clin Cosmet Investig Dermatol. Sep 1;14:1089-11031 (2021). 5. Rosmarin et al, Lancet (2020);396:110-120. 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 bromodomain & extra-terminal (BET) domain inhibitors, which comprise its InhiBET™ platform, include a locally administered pan-BD BET inhibitor (VYN201) and an orally available BD2-selective BET inhibitor (VYN202) that were licensed from Tay Therapeutics Limited. 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TORONTO--( BUSINESS WIRE )--Today, Breast Cancer Canada , a national charity dedicated to saving lives through breast cancer research, announced a new research grant in collaboration with AstraZeneca Canada , a global, science-led biopharmaceutical company and Illumina , a global leader in DNA sequencing and array-based technologies. Breast Cancer Canada also announced the recipients of its annual Precision Oncology Research Grants. Breast Cancer Canada and AstraZeneca Canada will together award $200,000 to Canadian research teams using precision diagnostics and AI technology to advance the screening and detection of breast cancer. Illumina will help fuel the collaboration by providing in-kind donations of sequencing consumables. Eligible research teams must be focused on the discovery and development of advancing quality testing and analysis techniques for the general population in screening for breast cancer, accelerating the new age of personalized medicine. Breast Cancer Canada and AstraZeneca Canada will be looking for researchers that utilize new precision or personalized technology, including blood tests or imaging that identify breast cancer during screening, and machine learning that assists clinicians with more accurate breast cancer detection. The submission period will open on July 3, 2023. "By investing in Canadian breast cancer screening research, Breast Cancer Canada and AstraZeneca Canada are advancing innovation technology to diagnose the disease earlier, faster and ahead of symptoms. We are looking for research teams to revolutionize breast cancer detection," said Kimberly Carson, CEO of Breast Cancer Canada. "The progress we seek will address higher quality, less invasive and more accessible test techniques for Canadians.” “At AstraZeneca, we’re committed to unlocking what science can do to redefine cancer care and set new standards for patient outcomes. That includes helping identify cancers earlier so patients have the best chance at a cure,” says Brian Seguin, AstraZeneca Canada, Head – Breast Cancer. “We’re proud to join forces with Breast Cancer Canada to support research that will not only help improve health outcomes for people with breast cancer, but also contribute to strengthening healthcare capabilities and capacity in the areas of screening and early diagnosis." “Illumina is pleased to join this effort and support research to leverage genomics and AI technologies to further innovate screening and detection capabilities for breast cancer,” said Nicki Berry, Head of Americas Region at Illumina. “We look forward to what these efforts will unlock towards improving personalized medicine for patients.” The AstraZeneca Canada and Illumina partnership comes on the heels of Breast Cancer Canada’s second annual Precision Oncology Research Grants. Researchers from across Canada were invited to submit projects last December for funding consideration in 2023. The selected projects focus on one of the four divisions of precision oncology research identified by the Scientific Advisory Committee: basic science, screening and detection, personalized treatment, and patient-reported outcomes. All projects must also include an artificial intelligence (AI) component and a patient advocate actively participating in the research. The following are the researchers that have been selected by Breast Cancer Canada for funding: $75,000 Dr. Saima Hassan Centre de Recherche de Centre Hospitalier de l’Université de Montréal (CRCHUM) Disentangling the immune landscape to predict response to immunotherapy and PARP inhibition in breast cancer $75,000 Dr. Katarzyna Jerzak Sunnybrook Odette Cancer Centre Identifying microRNA predictive biomarkers for breast to brain metastasis $75,000 Dr. Joanne Kotsopoulos Women’s College Hospital University of Toronto Improving long-term outcomes following the diagnosis and treatment of BRCA1-associated breast cancer $75,000 Dr. Hermann Nabi Quebec City University Hospital Research Centre Personalized risk-stratified breast cancer follow-up care $50,000 Dr. Luc Sabourin Ottawa Hospital Research Institute Targeting Sox10 activity in HER2+ breast cancers $50,000 Dr. Mohammad Reza Akbari Women’s College Hospital University of Toronto Gene expression profiling in young-onset breast cancer patients with ER+/HER2- breast cancer (prognosis and chemotherapy) Driven by their vision to end breast cancer, Breast Cancer Canada is committed to funding research projects that will directly impact Canadian patients, focusing on the rapid movement of research findings from lab bench to bedside. Grant recipient Dr. Katarzyna Jerzak, researcher at Sunnybrook Odette Cancer Centre will use her funding for the microRNA biomarkers. Dr. Jerzak and her team will focus on identifying predictive biomarkers for brain metastasis in patients with breast cancer. Breast Cancer Canada’s Scientific Advisory Committee led the selection process and is committed to listening to breast cancer patients. All funded project teams are required to include a breast cancer patient advocate or a local breast cancer advocacy group as part of their research. For more information on Breast Cancer Canada and the research projects they fund, please visit, breastcancerprogress.ca . About Breast Cancer Canada Breast Cancer Canada is a national charity dedicated to saving lives through breast cancer research. With a focus on precision oncology (personalized care), it is the only national breast cancer organization in Canada that has a clear mandate to raise money for research. The organization receives no government funding, meaning all research is funded through the generosity of donors. For more information visit, breastcancerprogress.ca . About AstraZeneca Canada AstraZeneca is a global, innovation-driven biopharmaceutical business with a focus on the discovery, development, and commercialization of medicines that transform lives, with a core scientific focus in the areas of Oncology; Cardiovascular, Renal and Metabolic (CVRM) disease; Rare Disease; Respiratory & Immunology; and Vaccine & Immune Therapies. AstraZeneca operates in more than 100 countries and its innovative medicines are used by millions of patients worldwide. About Illumina Illumina is improving human health by unlocking the power of the genome. In 2023 we celebrate 25 years of innovation, which has established us as a global leader in DNA sequencing and array-based technologies, serving customers in the research, clinical, and applied markets. Our products are used for applications in the life sciences, oncology, reproductive health, agriculture, and other emerging segments. To learn more, visit illumina.com .

Scientists have uncovered the underlying cause of deafness caused by swelling of the chambers in the inner ear. Using a mouse model of a human congenital disorder that displays deafness, the researchers identified two master genes controlling hearing function, which opened a new pathway for diagnosis of deafness and balance problems, and possibly to the effects on stem cells in other tissues and syndromes. An international team of scientists led by the LKS Faculty of Medicine, the University of Hong Kong (HKUMed) has uncovered the underlying cause of deafness caused by swelling of the chambers in the inner ear. Using a mouse model of a human congenital disorder that displays deafness, the researchers identified two master genes controlling hearing function, which opened a new pathway for diagnosis of deafness and balance problems, and possibly to the effects on stem cells in other tissues and syndromes. This exciting advance is described in their paper published in the Proceedings of the National Academy of Sciences. Background Hearing and balance require a functioning inner ear, which houses the sensory organs, and a system that mediates the transmission of sound through a fluid filled chamber called the endolymphatic system, composed of the endolymphatic duct and sac. These tissues help to control the amount of ions within the fluid (called endolymph) in the inner ear and thereby enable sound and balance signals to be transmitted to the nerves and the brain. Impairment of the endolymphatic system is a common cause of deafness. The endolymph is essential for hearing function. Dysfunction of this fluid results in swelling of the endolymphatic sac (called hydrops) causing hearing loss, vertigo, aural fullness and pain. HKUMed scientists, leading an international research team, generated and studied mouse models of a human disorder called campomelic dysplasia (CD), a syndrome characterised in part by deafness of unknown etiology. The team found that the underlying cause of the deafness is deficiency for two master regulatory factors, called SOX9 and SOX10 (collectively called SOXE genes). These factors were found to orchestrate the generation of stem cells in the development of the inner ear. When these SOXE genes were deficient, the result is insufficient supply of mature cells that are responsible for ensuring proper ionic composition of the endolymph and a functioning endolymphatic system. As a consequence, the chambers of the inner ear become swollen, causing deafness. Significance Human hearing loss leads to physical disabilities and generates difficulties in education, employment and social life. One in 10 people is estimated to experience hearing loss by 2050 and 1-3 newborns per thousand are hearing impaired, of which 50% are due to genetic causes. Malfunction affecting the ionic composition in the endolymph is the most common causes of deafness. Because SOXE genes are master controllers of many other genes, a further importance of the study is that it provides a rich resource for the discovery of other candidate congenital deafness genes or identify disease genes regulated by the SOXE factors. The resource could be a guide for diagnosis of deafness and balance problems. Since SOXE genes have many roles in development and in stem cells, the principles found could be applicable to effects on stem cells in general in other tissues and syndromes. Professor Kathryn Cheah Song Eng, Jimmy and Emily Tang Professor of Molecular Genetics and Chair Professor of Biochemistry, School of Biomedical Sciences, HKUMed, who led the study said, "Being deaf can have deep psychological and social impact on the affected individual. Discovering the master controllers of the sound conducting system in the inner ear provides insights into the disease mechanism that will help development of treatment that will have enormous impact on the many people with hearing loss." Dr Brian Chung Hon-yin, Clinical Geneticist/Clinical Associate Professor, Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, HKUMed, also commented, "Congenital deafness is an important indication of referral in clinical genetics. Patients with both syndromic and non-syndromic hearing loss are frequently encountered. Despite recent studies suggesting a genetic diagnosis in up to 50% of patients, the underlying pathophysiology remains complex and poorly understood. This exciting work shows convincing evidence of the partnership between SOX9 and SOX10 in controlling the development of the endolymphatic system. It sheds light on the future direction for research of clinical geneticists and scientists in deciphering other conditions of hearing impairment." About the research team This collaborative study was led by Professor Kathryn Cheah, Jimmy and Emily Tang Professor in Molecular Genetics and Chair Professor of Biochemistry, School of Biomedical Sciences, HKUMed and involved postdoctoral fellows, research postgraduates and scientists from The Chinese University of Hong Kong (CUHK) and international research institutions. Other scientists contributing to the research included Professor Chan Ying-shing, Dr Ralf Jauch and Professor Sham Mai-har (currently in CUHK), of the School of Biomedical Sciences, HKUMed; Professor Chan Wood-yee of the School of Biomedical Science, CUHK. International collaborators were Professor Robin Lovell-Badge of the Francis Crick Institute in London, the United Kingdom and Professor Bernd Fritsch of the University of Iowa, the United States. Acknowledgements The work was supported by funding from the University Grants Committee Areas of Excellence Scheme, Research Grants Council General Research Fund, Theme-Based Research Schemes (HKU7222/97M, HKU2/02C, HKU4/05C, AoE/M-04/04, T12-708/12N) and the Jimmy and Emily Tang Professorship.