P1‐268: Clinical trials of EHT 0202, a neuroprotective and procognitive alpha‐secretase stimulator for Alzheimer's disease

Abstract

EHT 0202 is a GABAA receptor modulator and a PDE4 inhibitor developed for the treatment of Alzheimer's disease (AD). EHT 0202 is novel because it stimulates α-secretases, increasing the production of procognitive and neurotrophic sAPPα fragment of APP. Preclinical studies have shown that EHT 0202 1°) protects cortical neurons against Aβ42 and associated stresses and neuroprotection is associated with sAPPα induction, 2°) demonstrates procognitive properties in various preclinical models: age-related memory impairment and scopolamine-induced amnesia and 3°) chronic oral administrations of EHT 0202 reduce Aβ42 levels in brain and CSF in rat and guinea pigs. These data suggest that EHT 0202 is able to reduce Aβ burden by redirecting APP processing towards the α-secretase pathway and have favorable effects on neuron viability and cognition. Phase I studies demonstrated good tolerability of EHT 0202 in healthy young volunteers. No sedative effects or emesis were observed clinically and no alteration of attention and cognition on test battery were detected. Further, repeated doses in aged volunteers (60-75 years old) indicated that overall tolerability of EHT 0202 was good after a 10-day repeated administration up to 160 mg BID. Based on phase I results, a phase 2, parallel group, placebo-controlled, study of EHT 0202 (40 and 80 mg bid) was initiated. This randomized, double-blind, multicentre study was designed to explore the clinical safety/tolerability and exploratory efficacy of EHT 0202 as adjunctive therapy to acetylcholinesterase inhibitor in ambulatory patients suffering from mild to moderate AD. 135 patients are randomized to receive either 40 or 80 mg EHT 0202 bid or placebo bid. Patients are being followed over a 3-month period to determine the safety of EHT 0202 as well as its efficacy as measured by cognitive measures (ADAS-Cog, NTB, MMSE), global patient's assessment (CDR-SB, CGI-C), behavior (NPI), activities of daily living (ADCS-ADL) and caregiver's burden (Zarit's scale). In addition, EHT 0202's efficiency will be monitored using ExonHit's recently developed companion diagnostic that allows quantitation of sAPPα in blood and patients' transcriptomic profile will be determined using ExonHit's SpliceArray™ platform. Trial status and information concerning EHT 0202 development program will be presented.