LB7. A Randomized, Blinded, Placebo- and Vancomycin-Controlled, First-In-Human (FIH) Study of the Safety, Pharmacokinetics (PK), and Fecal Microbiome Effects of ACX-362E, a Novel Anti-Clostridial DNA Polymerase IIIC (polIIIC) Inhibitor

BACKGROUND: ACX-362E, a novel DNA polIIIC inhibitor, is a narrow-spectrum antibacterial selectively active against certain Gram-positive bacteria, including Clostridioides difficile (MIC(90) = 4 µg/mL). The objectives of this phase I study was to assess the safety, pharmacokinetics, and fecal microbiome effects of ACX-362E METHODS: This three-part FIH phase 1, double-blind, randomized healthy volunteer trial determined the safety profile, food effect, and systemic/stool pharmacokinetics of escalating single (150, 300, 600, and 900 mg) and multiple (300 and 450 mg) doses of oral ACX-362E vs. placebo (PBO). Fecal microbiome effects (metagenomic sequencing and qPCR) of multiple-dose ACX-362E were compared with 6 subjects receiving concomitant open-label vancomycin 125 mg four times daily. Dose escalation to each new cohort occurred following review of safety and PK data by a safety oversight committee. RESULTS: Forty-four subjects received ACX-362E (single dose = 24, multiple doses = 12, food effect = 8) and 12 PBO. Overall, ACX-362E was well tolerated at all dose levels. Adverse events were generally mild and transitory, and no moderate, severe, cumulative, or dose-limiting drug-related adverse events leading to discontinuation were observed. Mean plasma half-life was approximately 2 hours and no accumulation occurred with repeated dosing (Figure 1). Systemic exposure was less than 1 μg/mL and decreased with food. Fecal concentrations during multiple dosing exceeded the C. difficile MIC by multiples of up to ~2,500. ACX-362E had minimal effect on Bacteroidetes phylum and caused significantly less dysbiosis than vancomycin (Figure 2). CONCLUSION: This FIH clinical trial with ACX-362E demonstrated a favorable safety profile, low systemic and high fecal concentrations, and favorable gut microbiome changes compared with vancomycin. These results shows promise for further clinical development to treat C. difficile infections. [Image: see text] [Image: see text] DISCLOSURES: Kevin W. Garey, MS, PharmD, Acurx (Grant/Research Support), Martin Kankam, MD, PhD, MPH, Acurx Pharmaceuticals, LLC (Research Grant or Support), Julie Mercier, BS, Acurx Pharmaceuticals, LLC (Research Grant or Support), Corinne Seng Yue, BPharm, MSc, PhD, Acurx Pharmaceuticals, LLC (Grant/Research Support), Murray Ducharme, PharmD, Acurx Pharmaceuticals, LLC (Grant/Research Support), Anne J. Gonzales-Luna, PharmD, no financial relationships or conflicts of interest, M Jahangir Alam, PhD, No financial relationships or conflicts of interest, Khurshida Begum, PhD, No financial relationships or conflicts of interest, Michael Silverman, MD, Acurx Pharmaceuticals, LLC (Consultant, Employee, Shareholder).