TRPV3 novel inhibitor KM-023 as a potential oral treatment for keratodermas

Summary: Abstract Body: TRPV3, a calcium channel which is predominantly expressed in epidermal keratinocytes and promotes differentiation, hyperkeratosis, and elevated inflammation. Gain-of-function variants in TRPV3 underlie Olmsted syndrome (OS), while its overexpression is associated with various palmoplantar keratodermas. Kamari Pharma is developing potent and specific TRPV3 inhibitors for the treatment of rare skin diseases. KM-023 is an oral drug candidate (IC50 ~2nM), which significantly reduced Ca+2 flux in OS keratinocytes, as demonstrated by high throughput calcium imaging and calcium flux cellular assay in human epidermal keratinocytes (nHEK) expressing either WT hTRPV3 or G573S hTRPV3 mutated form. The efficacy of KM-023 was tested in several in-vitro studies, including in OS patient derived keratinocytes. Treatment with KM-023 in a 3D skin equivalent model of Pachyonychia Congenita (PC) led to improvement in the impaired skin barrier and normalization of proliferation and differentiation, as assessed by Ki-67 staining, involucrin and loricrin expression and localization. The in vivo efficacy of orally administered KM-023 (1-100mg/kg/d for 21 days) was assessed in DS-Nh mice with a ‘gain-of-function’ Trpv3 mutation. Doses of 10mg/kg and 20mg/kg significantly reduced keratoderma severity (p < 0.05) (one of the OS symptoms), while also reduced epidermal thickness and normalized differentiation. These doses were also effective in reducing the frequency of episodes of mouse pruritus. Furthermore, in toxicology studies in rats and minipigs, KM-023 was found to be well tolerated, and non-genotoxic. The results suggest that KM-023 can be potentially used to treat OS, PC and other Keratodermas. A Phase 1 study in healthy volunteers and OS patients is planned to be initiated shortly. Ephraim Brener¹, Lucile Marchal², Matthew Caley³, Tal Mashriki¹, Michael McGrath², Boris Vaisman¹, Dayana Michel¹, Shelly Leibman Barak¹, David Aviezer^{1, 4}, Edel O’Toole³, Alain Hovnanian², Liora Braiman¹ 1. Kamari Pharma Ltd., Ness Ziona, Israel. 2. Institut Imagine Institut des Maladies Genetiques, Paris, Île-de-France, France. 3. Queen Mary University of London, London, England, United Kingdom. 4. Bar-Ilan University, Ramat Gan, Tel Aviv District, Israel. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics