Clinical evaluation of a novel AKT/PDK1 inhibitor, PHT-427, for the treatment of multi-field actinitc keratoses

ABSTRACT Actinic keratosis (AK) is the premalignant dysplastic proliferation of keratinocytes on sun-exposed skin affecting more than 58 million individuals in the US, that can progress in up to 10% of cases to cutaneous squamous cell carcinoma (cSCC), with 1.8 million cases diagnosed annually and 15,000 dying from the disease. Because of the risk of progression AK should not be left untreated. For isolated lesions surgery, cryotherapy and photodynamic therapy are used, having to be repeated as additional lesions inevitably occur. Field ablation for multiple lesions uses topical creams containing 5FU or imiquimod but they have significant toxicity and lesion clearance rates are low and not much greater than placebo. The leaves a large unmet medical need for less toxic and more efficacious treatments for AK. Sun-exposed skin has a high incidence of UV DNA damage leading to mutations in AK and cSCC that are remarkably similar. While tumor suppressor loss-of-function mutations are most common they are difficult to treat. Oncogenic PI-3-kinase is mutated in half of AK and cSCC making it an attractive target. PHusis Therapeutics has developed PHT-427 as a lipophilic, dual inhibitor of AKT1/2/3 and PDPK1 downstream PI-3-kinase signaling that specifically blocks membrane binding of their pleckstrin homology (PH) domains. PHT-427 applied topically to mice with UV-B induced AK significantly decreases the size and number of AK lesions by readily permeating the stratum corneum to give high skin concentrations, but with low transdermal absorption into the blood stream and minimal toxicity in mice, or rabbit skin as a model for human skin. The hypothesis being tested is that the dual AKT/PDK1 inhibitor PHT-427 applied topically will be a convenient, effective and low toxicity treatment of human AK and cSCC caused by activated PI-3-kinase signaling. In this Direct to Phase II SBIR application, PHusis Therapeutics proposes to perform a Phase IA clinical trial to study safety and PK of topical PHT-427 as a treatment for AK in human subjects.