title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects.
abstract: E2212, a novel γ-secretase modulator, is under development for the treatment of Alzheimer's disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10-250 mg, double-blind, placebo-controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C-SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5-19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aβ(x-42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0-24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Eisai Inc., Andover, MA, USA.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Neuroscience, Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Logovinsky
authors.affiliation: Drug Metabolism and Pharmacokinetics, Eisai Inc., Andover, MA, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Schuck
authors.affiliation: Department of Biostatistics, Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: June
authors.initials: J
authors.lastname: Kaplow
authors.affiliation: Department of Biostatistics, Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Min-Kun
authors.initials: MK
authors.lastname: Chang
authors.affiliation: Open Innovation, NGM-PCU, Eisai Co., Ltd, Tsukuba, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Miyagawa
authors.affiliation: Drug Metabolism and Pharmacokinetics, Eisai Inc., Andover, MA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Wong
authors.affiliation: Department of Clinical Pharmacology, Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Ferry
mesh_terms: D000293:Adolescent; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; E2212; modeling and simulation; pharmacodynamics; pharmacokinetics; safety; γ‐secretase modulator