First‐in‐Human (FIH), Single‐ and Multiple‐Ascending‐Dose (SAD/MAD) studies in healthy subjects of E2511, a novel tropomyosin receptor kinase a (TrkA) positive allosteric modulator (PAM)

Abstract

AbstractBackgroundCholinergic innervation is affected in multiple neurodegenerative diseases associated with cognitive dysfunction. Loss of cholinergic neurons in Alzheimer’s disease (AD) is correlated with cognitive impairment. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons. The activation of NGF‐induced trophic signaling via TrkA could be a promising therapy for neurodegenerative diseases including AD. E2511 is a novel small molecule TrkA biased PAM that has shown reinnervative effects on cholinergic neurons in nonclinical studies (without NGF‐associated hyperalgesia). The main objectives of the E2511 FIH Phase 1 studies (SAD [completed] and MAD [ongoing]) are to evaluate the safety, tolerability and pharmacokinetics in healthy subjects.Methods: Both SAD and MAD are randomized, double‐blind and placebo‐controlled studies. The SAD evaluated 5 cohorts (n = 8/cohort) in adults and 1 cohort in elderly subjects (n = 5). Food effect was evaluated in one SAD cohort. Safety was evaluated through the review of adverse events, physical examinations, clinical laboratory tests, vital signs, electrocardiogram and electroencephalograms. Blood samples were collected for determination of plasma E2511 concentrations. Repeat dosing with E2511 (once daily for 14 days) is under evaluation in the MAD study.Results: Single doses of E2511 were safe and well‐tolerated across the investigated doses in adult and elderly subjects. There were no dose‐dependent nor severe treatment‐emergent adverse events (TEAEs). There were no clinically significant changes in the evaluated safety parameters on E2511 compared to placebo. Pharmacokinetic results show that E2511 was rapidly absorbed (tmax: 1 hour). Plasma half‐life was 3.2 hours. Plasma exposures (Cmax and AUC) increased dose proportionally over the investigated dose range. Food led to a decrease of 19% in Cmax and 15% in AUC compared to fasted conditions. Plasma exposures in elderly and younger adult subjects were comparable. Evaluation of E2511 safety, tolerability and PK/PD following multiple doses is ongoing.ConclusionE2511 presented an adequate safety and PK profile in healthy adults and elderly subjects. These results support further development of E2511 as a disease‐modifying therapy for neurodegenerative diseases.