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.
Alzheimer Dis Assoc Disord
; 36(3): 200-207, 2022.
Article
en En
| MEDLINE
| ID: mdl-35700341
ABSTRACT
BACKGROUND:
E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies.METHODS:
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.RESULTS:
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.CONCLUSIONS:
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidores de Fosfodiesterasa
/
Enfermedad por Cuerpos de Lewy
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Aged
/
Humans
Idioma:
En
Revista:
Alzheimer Dis Assoc Disord
Asunto de la revista:
NEUROLOGIA
/
PSIQUIATRIA
Año:
2022
Tipo del documento:
Article