BACKGROUND. Novel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSIs), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics. METHODS. In this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) on day 14. RESULTS. Clinical responder rates on day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics-alone groups, respectively (difference = 10.4, 90% CI [-6.3, 27.2], P = 0.31), and were 42.8 percentage points higher in the prespecified exploratory MRSA subgroup (74.1% vs. 31.3%, difference = 42.8, 90% CI [14.3, 71.4], ad hoc P = 0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics-alone groups, respectively, with a notable difference in MRSA patients (3.7% vs. 25.0%, difference =-21.3, 90% CI [-45.1, 2.5], ad hoc P = 0.06). Among MRSA patients in the United States, median length of stay was 4 days shorter and 30-day hospital readmission rates were 48% lower in the exebacase-treated group compared with antibiotics alone. CONCLUSION. This study establishes proof of concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSIs. TRIAL REGISTRATION. Clinicaltrials.gov NCT03163446. FUNDING. ContraFect Corporation.

BackgroundExebacase, a lysin (cell wall hydrolase), is the first direct lytic agent to report Phase 2 study results in Staphylococcus aureus bacteremia including endocarditis. Among MRSA patients enrolled in this randomized, double-blind, placebo, controlled study, EXE used in addition to standard of care antibiotics (SoC), had 42.8% higher clinical responder rates (CRRs) compared SoC alone. We sought to determine whether these differences in CRRs translated into reductions in health resource utilization (HRU) in this population of critically ill, hospitalized patients.MethodsThe microbiological intent-to-treat population included 116 patients (71 EXE, 45 SoC) with documented S. aureus who received a single 2-hour infusion of blinded study drug dosed based on target attainment. The primary efficacy endpoint was CRR at Day 14. Diagnoses and clinical outcomes were determined by a blinded Adjudication Committee. HRU including length of stay (LOS), and 30-day hospital readmission rates (HRR) for all causes (AC) and for S. aureus (SA) were evaluated in MRSA patients who were alive at the time of discharge.ResultsThe average patient was white, male and ~56 years old (67.8%). Twenty-seven EXe patients (38.0%) and 16 SoC patients (35.6%) had MRSA. All but 2 MRSA patients (1 EXE, 1 SoC) were enrolled in the United States. The Day 14 CRR were 70.4% for EXE and 60.0% for SoC groups (p=0.314) overall. In a prespecified analysis of MRSA patients, the CRR with EXE was 74.1% vs. 31.3% with SoC (P = 0.010). Among MRSA patients who received study drug, incidence of treatment emergent adverse events (TEAEs) was balanced between groups (24 (88.9%) in EXE and 15 (98.3%) in SoC) as were serious TEAEs (17(63.0%) in EXE, 12 (75%) in SoC). 1 EXE and 2 SoC US MRSA patients died in hospital. Among US MRSA patients discharged alive from the hospital, the median LOS after study drug was 6 vs. 10 days for EXE and SoC, respectively. Thirty-day AC HRR were 16% vs. 30.8%, for EXE vs. SoC, respectively, and 30-day SA HRR were 8% vs. 15.4%, respectively.ConclusionsExebacase used in addition to SoC was associated with a reduction in length of hospital stay and 30-day readmission rates for all causes and for S. aureus compared with SoC alone in patients being treated for MRSA bacteremia/endocarditis.DisclosuresCara Cassino, MD, ContraFect Corporation (Employee), Hemal Shah, PharmD, Boehringer Ingelheim (Consultant), ContraFect Corp (Consultant), DBV Technologies (Consultant), Mylan specialty (Consultant), Nabriva (Consultant), Joy Lipka-Diamond, MS, ContraFect Corporation (Consultant), Anita F. Das, PhD, Achaogen (Consultant), AntiobioTx (Consultant), Boston Pharmaceuticals (Consultant), Cempra (Consultant), ContraFect Corporation (Consultant), Iterum Therapeutics (Consultant), Nabriva (Consultant), Paratek (Consultant), Tetraphase (Consultant), UTILITY (Consultant), Wockhardt (Consultant).