Characterization of LY2775240, a selective phosphodiesterase‐4 inhibitor, in nonclinical models and in healthy subjects

ABSTRACT: LY2775240 is a highly selective, potent and orally‐administered inhibitor of phosphodiesterase 4 (PDE4), and is being investigated as a treatment option for inflammatory disorders, such as psoriasis. LY2775240 was investigated in rodent and rhesus monkey nonclinical models. Treatment with LY2775240 led to significant reductions in TNFα production, a marker of PDE4 engagement upon immune activation, in both nonclinical models. In the first part of a 2‐part first‐in‐human randomized study, a wide dose range of LY2775240 was safely evaluated and found to be well‐tolerated with common adverse events (AEs) of nausea, diarrhea, and headache. No serious AEs were reported. The pharmacokinetic profile of LY2775240 was well‐characterized, with a half‐life that can support once‐a‐day dosing. An ex vivo pharmacodynamic (PD) assay demonstrated dose‐dependent PDE4 target engagement as assessed by reduction in TNFα production. A 20 mg dose of LY2775240 led to near‐maximal TNFα inhibition in this PD assay in the first part of the study and was selected for comparison with the clinical dose of apremilast (30 mg) in the crossover, second part of this study. The 20 mg dose of LY2775240 demonstrated sustained maximal (50%–80%) inhibition of TNFα over all timepoints over the 24‐h duration. The comparator apremilast achieved peak inhibition of ~ 50% at only 4 h postdose with a return to about 10% inhibition within 12 h of dosing. In summary, the nonclinical data and safety, tolerability, and PK/PD data in healthy subjects supports further investigation of LY2775240 in inflammatory indications. STUDY HIGHLIGHTS: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? WHAT QUESTION DID THIS STUDY ADDRESS? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This is the first report of an ex vivo PD assay that has been systematically implemented in a PDE4 inhibitor Phase 1 study. Early investigation of exposure‐response relationships versus a comparator can support evaluation of clinically meaningful doses of investigational agents.