PHASE 1 INVESTIGATION INTO THE SAFETY, TOLERABILITY, PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF E2027, A SELECTIVE PHOSPHODIESTERASE-9 (PDE9) INHIBITOR

To investigate the safety, tolerability and pharmacokinetics (PK) of E2027, a selective PDE9 inhibitor, in healthy volunteers (HV), and to establish pharmacodynamic (PD) proof-of-target engagement for development of a PK/PD model to drive dose determination in subsequent studies. This was a 4-part randomized double blind, placebo-controlled, single ascending dose, Phase 1 study. In Part A, cohorts of adult subjects were randomized to single ascending doses of E2027 or placebo (6:2 ratio). Further cohorts underwent serial CSF collection for 32 h postdose to measure CSF cGMP after single doses of E2027/placebo (Part B), effect of food on PK in a second treatment period (Cohort B2), bridging safety, tolerability and PK in healthy elderly subjects (Part C) and in Japanese subjects (Part D). cGMP was measured using a novel validated LC-MS-MS assay. In Part A, single doses from 10 to 1200 mg were well tolerated and the maximum tolerated dose (MTD) was not reached. E2027 was rapidly absorbed (tmax 2–4 hrs) and underwent biphasic elimination with a terminal half life of approximately 30 h. Cmax and AUC(0-inf) increased with dose, with absorption saturating above 800 mg. Peak CSF cGMP levels increased by 293% and 410% from baseline after single doses of 100 and 400 mg, respectively. A PK/PD model was developed to investigate gender, age, ethnicity and food effects and to predict CSF cGMP elevation after chronic dosing. Single ascending doses of E2027 are well tolerated and associated with robust PD effects on CSF cGMP.