Cardiac Safety and Phase I Clinical Data for ATI-7505, a Selective 5-HT4 Receptor Agonist

Abstract

Purpose: The clinical utility of 5-HT4 receptor agonists with gastrointestinal (GI) prokinetic activity has been limited due to cardiac effects. A GI prokinetic agent of this class that lacks these liabilities may have important application in several therapeutic areas. ATI-7505, a potent and selective 5-HT4 receptor agonist, is being developed for GERD and diabetic gastroparesis. Results from pre-clinical cardiac safety pharmacology studies, and Phase I single- and multi-dose ATI-7505 studies in healthy volunteers are reported. Methods: Preclinical studies: Standard electrophysiological (EP) techniques were used to assess the cardiac effects of ATI-7505 on: a) Single cell: HEK-293 cells expressing hERG -IKr; single guinea pig (GP) ventricular myocytes expressing native non-IKr currents (INaearly, late, ICa, L, IKs, IK1), b) Tissue/Organ: isolated GP hearts-conduction times and ventricular repolarization; rabbit Purkinje fibers-amplitude, dV/dt, APD, RMP; and c) anesthetized animals: rabbit methoxamine model and in vivo EP (surface ECG) studies in dog and guinea pig. Clinical studies: Six single doses of ATI-7505 ranging from 0.3 to 60 mg were tested in a double-blind, randomized, placebo-controlled Phase I study. Six doses of ATI-7505 ranging from 3 to 50 mg were given QID in a double-blind, randomized, placebo-controlled multi-dose Phase I study. Results: Cardiac findings: (1) low activity at human IKr channel (IC50= 24,500 nM), particularly compared to its binding affinity to the 5-HT4 receptor (Ki = 1.4 nM); (2) negligible activity at non-IKr cardiac currents (NOEL >1000 nM), (3) negligible effect in GP hearts (NOEL = 1000 nM) and rabbit Purkinje fibers (NOEL>1000 nM), (3) safe in vivo cardiac profile: in the rabbit methoxamine model (NOEL>3 mg/kg IV; no QT effect or torsades), in anesthetized dogs (no EP effects at cumulative dose = 3.4 mg/kg IV) and GPs (NOEL = 1 mg/kg IV). No serious adverse events and no clinically significant adverse events were seen in Phase I studies, but mild GI and non-GI events were reported. No ECG changes were seen. PK parameters for both ATI-7505 and its primary metabolite are reported. Conclusions: ATI-7505 was safe and well tolerated in Phase I human clinical trials. No serious adverse events occurred and intensive cardiac monitoring using ambulatory Holter recordings has demonstrated no significant cardiac effects. ATI-7505 is being further investigated in pharmacodynamic and Phase II efficacy studies for treatment of various GI disorders.