Phase 1 Single Ascending and Multiple Ascending Dose Studies of Phosphodiesterase-9 Inhibitor E2027: Confirmation of Target Engagement and Selection of Phase 2 Dose in Dementia With Lewy Bodies Trial

• Published in: Alzheimer disease and associated disorders Vol. 36; no. 3; p. 200
• Main Authors: Landry, Ishani S, Aluri, Jagadeesh, Schuck, Edgar, Ino, Mitsuhiro, Horie, Kanta, Boyd, Peter, Reyderman, Larisa, Lai, Robert
• Format: Journal Article
• Language: English
• Published: United States 01.07.2022
• Subjects: Aged; Area Under Curve; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Guanosine Monophosphate; Healthy Volunteers; Humans; Lewy Body Disease - drug therapy; Phosphodiesterase Inhibitors - therapeutic use; Phosphoric Diester Hydrolases
• ISSN: 1546-4156
• DOI: 10.1097/WAD.0000000000000515

E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies. Phase 1, randomized, double-blind, single ascending dose (SAD, n=96) and multiple ascending dose (MAD, n=68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The impact of age, race (Japanese/non-Japanese), and food on pharmacokinetics (PK)/pharmacodynamics were evaluated. Serial cerebrospinal fluid (CSF) samples were collected to assess the target engagement. E2027 PK profiles were biphasic (elimination half-life: ~30 hours. Approximately 3-fold accumulation was observed following multiple once-daily dosing. E2027 single doses of 50 to 400 mg resulted in mean maximum increases in CSF cyclic guanosine monophosphate ranging from 293% to 461% within 5.37 to 12.9 hours after dose administration to assess target engagement. Dose-response modelling of steady-state predose CSF cyclic guanosine monophosphate concentrations showed ≥200% increase from baseline is maintained with doses of ≥50 mg QD. The most common adverse events with E2027 were post-LP syndrome and back pain. PK profiles were similar between Japanese and non-Japanese. Higher exposure observed in fed versus fasted state was not considered clinically significant. PK exposure was higher in elderly subjects. S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial.