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Clinical Trial
. 2024 Jun 14;78(6):1473-1481.
doi: 10.1093/cid/ciae043.

Exebacase in Addition to Standard-of-Care Antibiotics for Staphylococcus aureus Bloodstream Infections and Right-Sided Infective Endocarditis: A Phase 3, Superiority-Design, Placebo-Controlled, Randomized Clinical Trial (DISRUPT)

Vance G Fowler Jr  1 , Anita F Das  2 , Joy Lipka-Diamond  3 , Jane E Ambler  3 , Raymond Schuch  3 , Roger Pomerantz  3 , Cara Cassino  4 , Luis Jáuregui-Peredo  5 , Gregory J Moran  6 , Mark E Rupp  7 , Anne M Lachiewicz  8 , Joseph L Kuti  9 , Robert A Wise  10 , Keith S Kaye  11 , Marcus J Zervos  12 , W Garrett Nichols  3
Affiliations
Clinical Trial

Exebacase in Addition to Standard-of-Care Antibiotics for Staphylococcus aureus Bloodstream Infections and Right-Sided Infective Endocarditis: A Phase 3, Superiority-Design, Placebo-Controlled, Randomized Clinical Trial (DISRUPT)

Vance G Fowler Jr et al. Clin Infect Dis. .

Abstract

Background: Novel treatments are needed for Staphylococcus aureus bacteremia, particularly for methicillin-resistant S. aureus (MRSA). Exebacase is a first-in-class antistaphylococcal lysin that is rapidly bactericidal and synergizes with antibiotics.

Methods: In Direct Lysis of Staph Aureus Resistant Pathogen Trial of Exebacase (DISRUPT), a superiority-design phase 3 study, patients with S. aureus bacteremia/endocarditis were randomly assigned to receive a single dose of intravenous exebacase or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population.

Results: A total of 259 patients were randomized before the study was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board. Clinical response rates at day 14 in the MRSA population (n = 97) were 50.0% (exebacase + antibiotics; 32/64) versus 60.6% (antibiotics alone; 20/33) (P = .392). Overall, rates of adverse events were similar across groups. No adverse events of hypersensitivity related to exebacase were reported.

Conclusions: Exebacase + antibiotics failed to improve clinical response at day 14 in patients with MRSA bacteremia/endocarditis. This result was unexpected based on phase 2 data that established proof-of-concept for exebacase + antibiotics in patients with MRSA bacteremia/endocarditis. In the antibiotics-alone group, the clinical response rate was higher than that seen in phase 2. Heterogeneity within the study population and a relatively small sample size in either the phase 2 or phase 3 studies may have increased the probability of imbalances in the multiple components of day 14 clinical outcome. This study provides lessons for future superiority studies in S. aureus bacteremia/endocarditis. Clinical Trials Registration.NCT04160468.

Keywords: S aureus bacteremia; exebacase; lysin.

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Conflict of interest statement

Potential conflicts of interest. V. G. F. reports grants to his institution and personal consulting fees from ContraFect. Grants/research support: MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Basilea. Paid Consultant: 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, Destiny. Membership: Merck Co-Chair V710 Vaccine. Educational fees: Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm. Royalties: UpToDate. Patent pending: sepsis diagnostics. ArcBio and Valanbio stock. A. F. D. reports personal consulting fees from ContraFect, Achaogen, IterumTx, Paratek, Nabriva, Wockhardt, UTILITY, Zavante, Tetraphase, Theravance, and Cempra. Membership: Scynexis. Stock options from Utility. J. L. D. reports personal consulting fees and membership for ContraFect. J. E. A. is an employee of ContraFect and has a PCT Application with publication no. W0/2022/261360 and reports grants from the Cystic Fibrosis Foundation (CONTRAFECT20XO-SC; CONTRAFECT21WO-SC). R. S. is an employee of ContraFect and has US Patent No. 9,889,181 issued and US Patent No. 9,499,594 issued, stock options and support for meetings and/or travel from ContraFect. R. P. is an employee of ContraFect. C. C. was an employee of ContraFect and reports stock options from ContraFect. L. J. P. reports grants from ContraFect. G. J. M. reports grants from ContraFect; grants and personal consulting fees from Nabriva. Consulting fees and stock options for Light AT, payment for lectures from Hippo Education. M. E. R. reports grants from ContraFect and Magnolia; personal consulting fees from Citius, Teleflex, Armata, and 3M. Payment for lectures from ACP- Dynamed, Membership: Armata Pharmaceuticals. A. M. L. reports grants/research support from ContraFect, Cidara, Veru, Shionogi, and Novartis. J. L. K. reports grants from ContraFect, bioMeriuex, Entasis, Food and Drug Administration, Merck, Pfizer, Shionogi, and Venatorx; consulting/advisory board/speaker fees from Abbvie, GSK, and Shionogi. R. A. W. reports personal consulting fees from ContraFect, Pulmonx, Roche, Merck, AbbVie, Kamada, Galderma, AstraZeneca, Savara, Bristol-Myers, Boehringer-Ingelheim, and Chiesi; grants from Shinogi, Sanofi-Aventis, AstraZeneca, Verona, and Chiesi, Pfizer, Moderna. Membership: ContraFect. K. S. K. reports personal consulting fees from ContraFect, Merck, Spero, Abbvie, Allecra, Carb-X, Shionogi, VenatoRX, MicuRx, Glaxo SmithKline, Entasis; DSMB for Entasis. Membership: Venato-Rx, Meiji, ContraFect M. J. Z. reports personal consulting fees from ContraFect; grants from Pfizer, Merck, Medimmune, and Genetech. W. G. N. reports personal consulting fees from ContraFect and Istari Oncology, stock options from ContraFect Corporation Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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