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)
نویسندگان
چکیده
Background Cholinergic innervation is affected in multiple neurodegenerative diseases associated with cognitive dysfunction. Loss of cholinergic neurons Alzheimer’s disease (AD) correlated impairment. Nerve growth factor (NGF) plays a major role the maintenance and function neurons. The activation NGF-induced trophic signaling via TrkA could be promising therapy for including AD. E2511 novel small molecule biased PAM that has shown reinnervative effects on nonclinical studies (without NGF-associated hyperalgesia). main objectives FIH Phase 1 (SAD [completed] MAD [ongoing]) are to evaluate safety, tolerability pharmacokinetics healthy subjects. Methods : Both SAD randomized, double-blind placebo-controlled studies. evaluated 5 cohorts (n = 8/cohort) adults cohort elderly subjects 5). Food effect was one cohort. Safety through review adverse events, physical examinations, clinical laboratory tests, vital signs, electrocardiogram electroencephalograms. Blood samples were collected determination plasma concentrations. Repeat dosing (once daily 14 days) under evaluation study. Results Single doses safe well-tolerated across investigated adult There no dose-dependent nor severe treatment-emergent events (TEAEs). clinically significant changes safety parameters compared placebo. Pharmacokinetic results show rapidly absorbed (tmax: hour). Plasma half-life 3.2 hours. exposures (Cmax AUC) increased dose proportionally over range. led decrease 19% Cmax 15% AUC fasted conditions. younger comparable. Evaluation PK/PD following ongoing. Conclusion presented an adequate PK profile These support further development as disease-modifying diseases.
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Characterization of a Novel M 1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator ( PAM ) Radioligand , [ 3 H ] PT - 1284
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ژورنال
عنوان ژورنال: Alzheimers & Dementia
سال: 2023
ISSN: ['1552-5260', '1552-5279']
DOI: https://doi.org/10.1002/alz.066208