Phase 1 Study to Assess Safety, Tolerability and Pharmacokinetics of Single and Multiple Oral Doses of APX001 and to Investigate the Effect of Food on APX001 Bioavailability

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 ~ 80 µg.hours/mL. Eight subjects in Cohort 1a were randomized in a 6:2 ratio to receive APX001 or placebo. Single doses of IV 200 mg were infused over 3 hours followed by single (tablet) doses of 100, 300, and 500 mg, each separated by a 14-day washout period. Ten subjects in Cohort 1b were randomized in a 8:2 ratio to receive either APX001 or placebo. A single PO (tablet) dose of 400 mg was administered under fed and fasted conditions, each separated by a 14-day washout period. MAD Cohorts 2 and 3 were comprised of eight subjects randomized in a 6:2 ratio to receive APX001 or placebo. Subjects received PO (tablet) doses of 500 and 1000 mg 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. Accumulation of APX001A was observed in the MAD cohorts. After 14 days of dosing at 500 and 1000 mg AUC0-24 were 192 and 325 µg.hours/mL, respectively. The oral bioavailability was >90%. Administration of APX001 with a high fat, high calorie meal had no effect on the rate or extent of absorption. APX001 was well tolerated across all doses with no clinically significant adverse events observed. All subjects completed dosing. There were no dose limiting toxicities. Most of the adverse events (AEs) were mild, transient and required no treatment. The most common AE was headache. APX001 given orally is highly bioavailable, has no food effect and can exceed target exposures of APX001A for efficacy against Candida and Aspergillus 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. P. Van Marle, PRA Health Sciences: Employee, Salary; E. J. Van Hoogdalem, PRA Health Sciences: Employee, Salary; W. Kramer, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee; P. Wedel, Amplyx Pharmaceuticals Inc.: Employee, Salary