LEO 29102 / LEO Pharma - LARVOL DELTA

Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies. (PubMed, Pharm Res) - "Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution."

Journal • PK/PD data

Discovery of LEO 39652 a novel PDE4 inhibitor for topical treatment of atopic dermatitis (SID 2019) - "...Previously we have described the discovery of LEO 29102, a “soft” PDE4 inhibitor designed to achieve high local skin concentrations but low systemic exposure upon topical application, due to a high systemic clearance driven by rapid liver metabolism.[1] In the end, the clinical development of this compound was however discontinued in part due to safety concerns related to the systemic exposure of the candidate drug...Here we report the discovery of a novel series of PDE4 inhibitors and our efforts to optimize the in vitro pharmacokinetics of these using phenotypic screening models of skin and blood stability. Eventually LEO 39652 was selected as a clinical development candidate and a characterization of its metabolism, pharmacokinetic profile as well as the early clinical efficacy data obtained with this compound will be presented in this poster."