First-in-Human Study to Assess Safety, Tolerability and Pharmacokinetics of APX001 Administered by Intravenous Infusion to Healthy Subjects

Abstract

APX001 is a first-in-class, intravenous (IV) and oral (PO) broad-spectrum antifungal agent in clinical development for the treatment of invasive fungal infections (IFIs) due to Candida, Aspergillus and rare molds. The active moiety APX001A inhibits Gwt1, an early step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Excellent in vivo efficacy has been demonstrated in murine models of IFIs with APX001A AUC0–24 target exposures ranging from 2 to 80 µg hours/mL.There were six single ascending dose (SAD) and four multiple ascending dose (MAD) cohorts, eight subjects/cohort. Subjects were randomized in a 6:2 ratio to receive 3-hour IV infusions of APX001 or placebo. SAD Cohorts 1–6 received single doses of 10, 30, 100, 200, 275, and 350 mg, respectively. MAD Cohorts 7–10 received doses of 50, 150, 300, and 600 mg, respectively, once daily for 14 days. Pharmacokinetic (PK) parameters for APX001A in plasma were calculated using non-compartmental analysis. Safety monitoring and intense PK sampling occurred throughout the trial. A safety committee reviewed the PK and safety data to determine dose escalation steps.Plasma exposure to APX001A was linear, dose proportional, with low intersubject variability and a half-life of ~2.5 days. As expected from the half-life and dosing frequency, accumulation of APX001A was observed in the MAD cohorts. A single APX001 dose of 350 mg maintained drug levels above the minimum inhibitory concentration (MIC) of Candida and Aspergillus for one week. The 600 mg/day AUC0–24on Day 14 was 245 μg.hours/mL. APX001 was well tolerated across all doses with no clinically significant adverse events observed. One subject discontinued due to the adverse event (AE) of flu. There were no dose limiting toxicities. Most of the AEs were mild, transient and required no treatment. The most common AE was headache.Target exposures of APX001A for efficacy against Candida and Aspergillus as well as the high MIC rare mold pathogens were exceeded at doses that are safe and well tolerated.M. R. Hodges, Amplyx Pharmaceuticals: Employee, Salary; E. Ople, Amplyx Pharmaceuticals Inc.: Employee, Salary. K. J. Shaw, Amplyx Pharmaceuticals Inc.: Employee, Salary; R. Mansbach, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee; S. J. Van Marle, PRA Health Sciences: Employee, Salary. E. J. Van Hoogdalem, PRA Health Sciences: Employee, Salary. P. Wedel, Amplyx Pharmaceuticals Inc.: Employee, Salary. W. Kramer, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee.