Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis

Abstract

BACKGROUNDNovel 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.METHODSIn 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.RESULTSClinical 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.CONCLUSIONThis 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 REGISTRATIONClinicaltrials.gov NCT03163446.FUNDINGContraFect Corporation.

Keywords: Bacterial infections; Clinical Trials; Infectious disease.

Conflict of interest statement

Conflict of interest: VGF reports grants to his institution and personal consultancy fees from Contrafect. In addition, VGF reports grant/research support from MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, and Basilea, as well as paid consultancies from Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, and Destiny, and royalties from UpToDate. VGF was a cochair with Merck for the V710 Vaccine; has received educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm; and has a patent pending for sepsis diagnostics. AFD reports personal consulting fees from ContraFect, Achaogen, IterumTx, Paratek, Nabriva, Wockhardt, UTILITY, Zavante, Tetraphase, Theravance, and Cempra. JLD reports personal consulting fees from ContraFect. RS is an employee of ContraFect and has US Patent No. 9.889,181 issued and US Patent No. 9,499,594 issued. RP is an employee of ContraFect. LJP reports grants from ContraFect. AB reports grants from ContraFect and personal consulting fees from Theravance, Biopharma, and Allergan. DE reports grants from ContraFect and Merck, as well as grants and personal consulting fees from Tetraphase and AtoxBio. GJM reports grants from Contrafect, as well as grants and personal consulting fees from Nabriva. MER reports grants from ContraFect and Magnolia, and personal consulting fees from Citius and 3M. RW reports personal consulting fees from Contrafect, Pulmonx, Roche, Spiration, Sunovion, Merck, Circassia, Pneuma, Verona, Mylan/Theravance, Propeller Health, AbbVie, Novartis, and Kiniksa; grants from Pearl Therapeutics and Sanofi-Aventis; and grants and personal consulting fees from AstraZeneca/Medimmune/Pearl, Boehringer Ingelheim, and GSK. GRC reports personal consulting fees from Contrafect, Arsanis, Medtronic, Melinta, Motif, Paratek, Regeneron, SCPharma, Shionogi, Tetraphase, and the Medicines Company. MZ reports personal consulting fees from ContraFect and grants from Pfizer, Merck, Medimmune, and Genetech. PSD reports grants from ContraFect. CC is an employee of ContraFect.

Figures

Figure 1. Patient disposition.

1The reasons prescreened patients were deemed to be ineligible are summarized in Supplemental Table 4. 2The local laboratory identified Gram-positive cocci in clusters on Gram stain plus positive direct-tube coagulase test and the patients were enrolled; however, the central laboratory subsequently determined that the isolates were Staphylococcusepidermidis.

Figure 2. Forest plot of clinical responders by diagnosis.

BSI, bloodstream infection; cBSI, complicated bloodstream infection; CI, confidence interval; LIE, left-sided endocarditis; RIE, right-sided endocarditis; NA, not available as there was no observation in the antibiotic-alone group.