167. A Phase 1b, Randomized, Double-blind, Placebo-controlled, Multiple-ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S in Patients with staphylococcus Aureus Bacteremia Receiving Standard-of-care Antibiotics

Abstract

Background: New treatment approaches for complicated Staphylococcus aureus bacteremia (SAB) are needed. DSTA4637S is a THIOMABTM antibody-antibiotic conjugate consisting of an engineered human IgG1 monoclonal antibody that binds to wall teichoic acid at the surface of S. aureus, a protease-cleavable linker, and a novel rifamycin class antibiotic, dmDNA31. This Phase 1b study assessed the safety, tolerability, and pharmacokinetics of DSTA4637S in patients with complicated SAB. Method(s): Multicenter, double-blind, placebo controlled, multiple-ascending dose clinical trial. Patients 18-79 years old with complicated SAB requiring at least 4 weeks of IV anti-staphylococcal standard-of-care (SOC) antibiotics were randomized to receive 4-6 doses of 15, 45, and 100 mg/kg IV DSTA4637S or placebo (6 active:2 placebo) every 7 days in combination with SOC antibiotics. Patients needed >= 1 blood culture positive for S. aureus collected within 120 hours prior to randomization. Patients were followed for 120 days after the end of treatment. Result(s): Twenty-five patients with complicated SAB (bone & joint, n=14; endocarditis, n=5; other endovascular, n=5; pneumonia, n=1) were randomized and received 1-6 doses of study drug (19 active:6 placebo). Nine patients (36%) had MRSA. Ten patients completed >=4 doses of DSTA4637S. The most common treatment-related adverse events were infusion-related reactions (IRRs) (5/19), and abnormal serum color (5/19)/skin discoloration (3/19 (due to dmDNA31). IRRs were not dose-dependent and were reversible with supportive care. Ten of 19 patients (40%) discontinued study drug (9 DSTA4637S,1 placebo); 4/19 (21%) due to IRR. DSTA4637S recipients showed no dose-related changes in laboratory values or vital signs vs. placebo. Observed exposures (Cmax and AUC) were lower in patients immediately after dosing compared to a prior study in healthy volunteers; minimal accumulation occurred. No obvious trends in exploratory bacterial and inflammatory biomarkers were observed between treatment groups. Conclusion(s): DSTA4637S in patients with complicated SAB demonstrated increased IRRs and decreased exposure compared to healthy volunteers, highlighting the importance of Phase I studies of novel treatments in infected SAB patients and not simply healthy controls.