TRPV3

Phase 1b clinical trial of KM-001 demonstrated favorable safety pro high responder rate of 87% in patients with palmoplantar keratoderma and pachyonychia congenita In vitro and in vivo data of KM-001 and KM-023 demonstrated significant improvements in skin histology and significant reductions in scratching NESS ZIONA, Israel, May 17, 2024 (GLOBE NEWSWIRE) -- Kamari Pharma, a privately-held clinical stage biotechnology company developing first and best-in-class treatments for rare and severe genetic skin diseases, today announced two presentations reporting results for its novel TRPV3 inhibitors, KM-001 (topical) and KM-023 (oral), were given at the 81st Annual Meeting of the Society for Investigative Dermatology (SID) that is taking place May 15-18, 2024 in Dallas, TX, USA. Below are summaries of the presentations: Poster #LB941: “KM-001, a novel TRPV3 inhibitor, demonstrates safety and preliminary efficacy in Phase 1b clinical study for the treatment of palmoplantar keratoderma” presented by Edel O’Toole, M.D., Ph.D. Professor of Molecular Dermatology and Centre Lead of the Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London and lead investigator in the study. Presented results from twelve-week, Phase 1b open-label studies (UK and Israel) assessing 4g/day of KM-001 1% cream applied to each foot twice daily for the treatment of pachyonychia congenita (PC) and punctate palmoplantar keratoderma type 1 (PPPK1). Eight patients in the UK (7 PC;1 PPPK1) and seven patients in Israel (3 PC;4 PPPK1) completed the treatment period. Safety: No drug-related severe adverse events nor systemic side effects were observed. Minimal treatment emergent adverse events occurred (n=11); all were mild and did not lead to patient discontinuation. Efficacy: Responder rate at the end of treatment was 88% (CI 52.9-97.8%) in UK (n=8) and 86% (CI 48.7-97.4%) in Israel (n=7), as defined by an improvement in at least one of six pre-defined disease parameters. Additionally, 47% of patients improved in at least two parameters with a disease severity reduction trend and pain score measured by VAS was reduced in 60% of PC patients; PPPK1 patients do not have pain as a symptom. Presentation #771: “Novel TRPV3 inhibitors developed for the treatment of palmoplantar keratodermas, demonstrate safety and efficacy in preclinical models” presented by Liora Braiman-Wiksman, Ph.D., Chief Scientific Officer at Kamari. Presented preclinical results for KM-001 and KM-023, Kamari’s specific and highly selective TRPV3 inhibitors designed to address both molecular and local damage to the skin by regulating Ca²⁺ influx into the cell. In 3D skin models of PC and PPPK1, KM-001 and KM-023 normalized proliferation and differentiation markers and enhanced epidermal barrier formation. In in vivo efficacy studies performed in DS-Nh mice, a gain-of-function TRPV3 mutation model, KM-001 showed significant improvement in skin histology vs vehicle (70% vs 30%) and exhibited significant reduction in scratching bouts (80%, p>0.04) and KM-023 showed a significant reduction in keratoderma severity score (p=0.003) and reduced scratching significantly (p<0.001) vs vehicle. Based on these results, Kamari plans to initiate Phase 2 development of KM-001 for the treatment of palmoplantar keratoderma and advance KM-023 into first-in-human studies for the oral treatment of Olmstead syndrome, severe keratoderma and Ichthyosis. The full content of these posters is available in the News page of Kamari's corporate website ( ). About Kamari Pharma Kamari Pharma is a privately-held clinical stage biotechnology company developing first and best in class treatments for rare and severe genetic skin diseases. Kamari’s lead molecules, KM-001 (topical) and KM-023 (oral) are novel, highly specific and selective TRPV3 inhibitors that are initially being developed to treat palmoplantar keratodermas, Olmstead syndrome and Ichthyosis. Kamari’s management team is comprised of industry leaders highly experienced in drug discovery, dermatological pharmaceutical development and rare disease drug development. Contact Information Investors and Media Marcy Nanus Managing Partner Trilon Advisors, LLC mnanus@trilonadvisors.com

Late breaking poster presentation includes Phase 1b clinical trial results demonstrating the safety and preliminary efficacy of KM-001, a topical TRPV3 inhibitor, for the treatment of palmoplantar keratoderma Oral presentation highlights favorable in vitro and in vivo safety and efficacy data of novel TRPV3 inhibitors KM-001(topical) and KM-023 (oral) in preclinical 3D skin and mouse models NESS ZIONA, Israel, April 16, 2024 (GLOBE NEWSWIRE) -- Kamari Pharma, a privately-held clinical stage biotechnology company developing first and best-in-class treatments for rare and severe genetic skin diseases, today announced two abstracts reporting results for its novel TRPV3 inhibitors, KM-001(topical) and KM-023 (oral), have been selected for presentation at the 81st Annual Meeting of the Society for Investigative Dermatology (SID), being held May 15-18, 2024 in Dallas, TX, USA. TRPV3 plays a central role in skin disease as it regulates proliferation, differentiation and barrier function of human skin. KM-001 and KM-023 are specific and selective TRPV3 inhibitors that address both molecular and local damage to the skin by regulating Ca²⁺ influx into the cell, thereby reconstructing the skin barrier and reducing inflammation. Kamari is currently developing KM-001 for the treatment of palmoplantar keratoderma and KM-023 for the treatment of Olmstead syndrome, severe keratoderma and Ichthyosis. The details of the presentations are as follows: Title: KM-001, a novel TRPV3 inhibitor, demonstrates safety and preliminary efficacy in Phase 1b clinical study for the treatment of palmoplantar keratodermaFinal ID Number: LB941Session Type: Poster PresentationCategory: Clinical Research - Interventional ResearchSession Date & Time: Thursday, May 16, 2024, 4:30-6:30pm CT Title: Novel TRPV3 inhibitors developed for the treatment of palmoplantar keratodermas, demonstrate safety and efficacy in preclinical modelsFinal ID Number: 771Session Type: Oral PresentationCategory: Translational Studies and Early Preclinical to ClinicalSession Date & Time: Friday, May 17, 2024, 4:30-6:00pm CT About Kamari Pharma Kamari Pharma is a privately-held clinical stage biotechnology company developing first and best in class treatments for rare and severe genetic skin diseases. Kamari’s lead molecules, KM-001 (topical) and KM-023 (oral) are novel, highly specific and selective TRPV3 inhibitors that are initially being developed to treat palmoplantar keratodermas, Olmstead syndrome and Ichthyosis. Kamari’s management team is comprised of industry leaders highly experienced in drug discovery, dermatological pharmaceutical development and rare disease drug development. Contact Information Investors and MediaMarcy NanusManaging PartnerTrilon Advisors, LLCmnanus@trilonadvisors.com

A member of an important class of ion channel proteins can transiently rearrange itself into a larger structure with dramatically altered properties, according to a new study. The discovery is a significant advance in cell biology, likely solves a long-standing mystery about an unusual feature of some ion channels and has implications for the development of drugs targeting these proteins and for drug delivery. A member of an important class of ion channel proteins can transiently rearrange itself into a larger structure with dramatically altered properties, according to a study led by researchers at Weill Cornell Medicine. The discovery is a significant advance in cell biology, likely solves a long-standing mystery about an unusual feature of some ion channels and has implications for the development of drugs targeting these proteins and for drug delivery. Ion channels are ubiquitous in the cell membranes of higher organisms. They conduct small, charged molecules called ions into or out of cells, in order to regulate cell activity. They are necessary for most biological functions, from sensation to cognition to heartbeat. Although about 15 percent of pharmaceuticals work by targeting ion channels, scientists could target them more effectively if they knew more about the dynamics of their complex structures. In the study, published Aug. 30 in Nature, the researchers examined the structural dynamics of an ion channel called TRPV3. They discovered an uncommon but striking structural rearrangement in which TRPV3, normally a "tetramer" made of four identical protein subunits, becomes a five-protein "pentamer." The researchers found strong evidence that this structural rearrangement underlies a hitherto unexplained ion-channel phenomenon called pore dilation. "These findings open up a broad new avenue of research on the workings of ion channels," said study senior author Dr. Simon Scheuring, a professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. The study's first author was Dr. Shifra Lansky, a postdoctoral research associate in the Scheuring lab in the Department of Anesthesiology. The work was performed in collaboration with Dr. Crina Nimigean's lab in the Department of Anesthesiology at Weill Cornell Medicine. TRPV3 is an ion channel that is involved in the sensing of warm temperatures, skin health, itch, hair growth, and other functions throughout the body. It belongs to the larger family of TRP ion channels, which have numerous biological roles in higher organisms. Drs. Scheuring and Lansky and their colleagues initially set out to map TRPV3's structural dynamics -- how its structure changes as it opens and closes its channel -- using an advanced tool called high-speed atomic-force microscopy. To the researchers' surprise, they soon discovered that TRPV3, normally a tetramer, occasionally assembles itself into a pentamer, and can exist in this uncommon state for only about three minutes. The scientists recognized that this substantial enlargement of the TRPV3 structure might account for the phenomenon of ion channel pore dilation, an oddity first reported in another ion channel in 1999, and in TRPV3 in 2005. Pore dilation is an unusual, transient state in which an ion channel opens to an abnormal extent, admitting much larger ions than usual, and becomes insensitive to its normal activators and inactivators. Whether pore dilation serves an evolved biological function isn't clear, though it can be triggered by prolonged ion channel activation, and the researchers suspect it works as a protective mechanism against excessive exposure to a stimulus. "If you bite on a strong chili pepper, for example, your mouth will be insensitive and in pain for a few minutes, during which you won't want to take another bite," Dr. Scheuring said. "Maybe that kind of protective alteration of sensitivity is what ion channel pore dilation is for." Pore dilation is also of interest to drug developers -- inhibiting it may be therapeutic in some cases and activating it may provide a way to get large, water-soluble drug molecules into cells that would otherwise be impermeable to them. Subsequently, the team used electron microscopy to obtain a high-resolution 3D structure of TRPV3 in its pentameric state. They showed that the pore of the TRPV3 pentamer is indeed much larger than the pore of the tetramer, corresponding to increased ion conductance and the ability to transport molecules. These features are associated with the pore dilation phenomenon. They also found that a compound known to make pore dilation more likely destabilizes the TRPV3 tetramer, making it about twice as likely to turn into a pentamer. Thus, they concluded, pore dilation is related to this transient pentameric state of ion channels that are normally tetramers. Pore dilation appears to be a quite common property of ion channels, functionally reported in at least seven channels from two different families, and so the discovery is expected to lead to much further research in this area, with the goal of understanding exactly how it occurs and how it can be controlled, perhaps for treating diseases. "There are genetic diseases linked to mutations in TRPV channels, and we suspect that some of these mutations cause disease by increasing pentamer formation," Dr. Lansky said. "If we can prove that, it would be a big step towards curing these diseases." Dr. Scheuring also noted that the process in which TRPV3 subunits diffuse through the cell membrane to turn tetramers into pentamers, and back again, represents a previously undiscovered mechanism for how proteins reshape their structures to modulate their functions. "This is a completely novel way of thinking about protein conformational change," he said.