Novel TRPV3 inhibitors developed for the treatment of Palmoplantar keratodermas, demonstrate safety and efficacy in preclinical models

Abstract

Pachyonychia Congenita (PC) and Punctate Palmoplantar Keratoderma type 1 (PPPK1) are rare genetic skin disorders, characterized by hyperkeratosis on the palms and soles, severe pain and disability, with no approved treatment. TRPV3, a Ca⁺² channel is overexpressed in these diseases and its inhibition may present a novel therapeutic pathway. TRPV3 gain-of-function mutation is the cause of Olmsted syndrome. Kamari has developed proprietary first in class TRPV3 topical (KM001) and oral (KM023) inhibitors, exhibiting IC50 of 3-5nM. In keratinocytes these inhibitors reduced Ca⁺² flux, normalized differentiation, and decreased phosphorylation of EGFR and RPS6, in a dose dependent manner (100-500nM). In 3D skin models of PC and PPPK1, KM001 (50-100nM) and KM023 (100-500nM), normalized proliferation and differentiation markers (Ki67, loricrin and invulocrin) and enhanced epidermal barrier formation. In vivo efficacy studies were performed in DS-Nh mice, a gain-of-function TRPV3 mutation model. Treatment (14d) with KM001 showed significant improvement in skin histology vs vehicle (70% vs 30%) and exhibited significant reduction in scratching bouts (80%, p >0.04). Oral treatment (21d) with KM023 10mg/kg led to significant reduction in keratoderma severity score (p=0.003) and reduced scratching significantly (p<0.001) vs vehicle. Both drug candidates exhibit good safety and skin penetration. Two Phase Ib clinical trials treating PC and PPPK1 patients with KM001, currently being concluded, are assessing the safety and preliminary efficacy of KM001. TRPV3 inhibition by KM001 and KM023 may offer a novel treatment modality for Keratoderma patients