The palmoplantar keratoderma (PPK) group of skin disorders results from various mutations in several epidermal genes and is characterized by thickening of the skin on the palms and soles.~Punctate palmoplantar keratoderma (PPKP1) is a rare autosomal, dominant, inherited skin disease characterized by bilateral asymptomatic, tiny, hyperkeratotic punctate papules and plaques on the palmoplantar surface.~Pachyonychia congenita (PC) is a rare group of autosomal dominant skin disorders that are caused by a mutation in one of five different keratin genes. PC is often associated with thickened toenails, plantar keratoderma, and plantar pain. Its manifestations include bilateral PPK on palms and soles pattern with sharp margins and a yellow tone.~A common characteristic of these skin diseases is the impaired differentiation of keratinocytes, often caused by defective calcium homeostasis. Normal calcium homeostasis is regulated by calcium ion channels, including the transient receptor potential cation channel subfamily V, member 3 (TRPV3), which has been implicated in regulation of keratinocyte proliferation, differentiation, and apoptosis. As a result, it has been suggested as a drug target for a variety of dermatological conditions and itch. It has therefore been suggested that inhibition of TRPV3 by specific antagonists can address the above-mentioned conditions.KM-001, developed by Kamari Pharma, is a potent and selective TRPV3 antagonist. Kamari has demonstrated that KM-001 reduces Ca+2flux in keratinocytes and decreases cell proliferation accompanied by normalization of keratinocyte differentiation markers. Efficacy was demonstrated in in vivo studies, using the DS-Nh mice model, where it was able to normalize epidermal hyperkeratosis. In addition, the compound significantly reduced pruritus which is characteristic of this model and of many types of PPK.~KM-001 topical formulation demonstrates favorable safety profile in rodents and minipigs and significant efficacy in animal models.
In this phase 1 open label study, up to 10 eligible patients with type I punctate palmoplantar keratoderma or pachyonychia congenital will be recruited to be treated twice daily, for 12 weeks, with 1% topical KM-001.~Treatment safety and efficacy will be assessed in the clinic on Days 7, 21, 42, 56, 70 and 84 after initiation of treatment. In between visits, safety will also be assessed by phone on Days 14, 28, 35, 49, 63 and 77 of treatment.~At the in-clinic visits, treatment efficacy (lesion clearance - IGA) will also be assessed.~PK blood samples will be collected on Days 1, 7, 84 One week after the end of treatment (EoT) visit, patients will return to the clinic for final safety, efficacy and PK evaluations.