ACD856, a Novel Positive Allosteric Modulator of Trk-receptors, Single Ascending Doses in Healthy Subjects: Safety and Pharmacokinetics

AlzeCure Pharma AB is developing novel positive allosteric modulators of Trk-receptors for treatment of Alzheimer’s disease, depression, other psychiatric conditions and other disorders where cognition is impaired. The first candidate drug ACD855 was, in a single ascending dose study, shown to have a too long elimination half-life in humans for further development. To de-risk the development of the follow-up compound ACD856, an intravenous microdose study was conducted to assess the elimination half-life in plasma prior to conducting ascending oral dose studies. Reported within this article are the results of the phase 0 study with a microdose of ACD856 (0.100 mg), conducted in six healthy male subjects, followed by a Phase I single ascending oral dose study (1–150 mg) in 56 healthy subjects. ACD856 was well tolerated with no treatment emergent, or dose related trends observed for adverse events or other safety assessments. In the microdose study, ACD856 exhibited a bi-exponential plasma decline, low distribution volume, low plasma clearance with a half-life of approximately 20 hours. Orally, ACD856 exhibited rapid absorption, approximately 100% bioavailability and a dose proportional increase in exposure. While the C max was lowered and delayed by food intake, the effect on plasma half-life and the overall bioavailability was low. No renal elimination of ACD856 was detected. The pharmacokinetics of ACD856 in humans following a microdose was used to de-risk a long elimination half-life as well as predict oral pharmacokinetics. The prediction proved accurate demonstrating the value of conducting a microdose study prior to ascending dose studies. TRN NCT05783830 March 24, 2023 (microdose study, retrospectively registered) and NCT05077631 October 14, 2021 (Single ascending dose study).