Overview
To view our CMO present an overview of the exebacase program at the Duke-Margolis Center for Health Policy Forum on Emerging Non-Traditional Antibiotics, please click on the link below
Exebacase (CF-301) is a lysin with potent activity against Staphylococcus aureus ("Staph aureus"). Exebacase has the potential to be the first-in-class of a new treatment for patients with Staph aureus bacteremia. The addition of exebacase to either vancomycin or daptomycin increased survival significantly in animal models of disease when compared to treatment with SOC antibiotics or exebacase alone. Exebacase targets a highly conserved region of the cell wall that is vital to bacteria, thus making resistance less likely to develop. When used in combination with SOC antibiotics, the result is a novel treatment modality that has the potential to combat the high unmet clinical need of Staph aureus infections.
Exebacase is the first and only lysin to enter human clinical trials in the US and recently completed a Phase 2 superiority study evaluating the safety efficacy and tolerability of exebacase in patients with Staph aureus bacteremia, including endocarditis. In particular, the improvement in patient response rates of the pre-specified MRSA population was remarkable across the whole MRSA population (42.8% improvement; p=.010) as well as MRSA subgroups – by SOC antibiotic, source of infection or complicated bacteremia – establishes the basis on which exebacase will be studied in Phase 3.
Clinical Summary
Exebacase is the first bacteriophage-derived lysin to enter clinical development in the US. The clinical development program will investigate exebacase in addition to approved anti-staphylococcal agents for the treatment of Staph aureus bloodstream infections, including endocarditis.
We recently completed an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) regarding the advancement of exebacase. At this meeting we obtained concurrence with the FDA on key design features of the Phase 3 protocol and that positive results from this single Phase 3 study could support a Biologics License Application (BLA) for approval of exebacase under the FDA paradigm for streamlined development of antibacterial agents for patients with unmet needs. Based on this feedback, we plan to initiate a single Phase 3 clinical trial of exebacase for the treatment of patients with Staph aureus bacteremia, including right-sided endocarditis. The Phase 3 superiority design trial (the “DISRUPT” study – Direct Lysis of Staph aureus Resistant Pathogen Trial) will be a randomized, double-blind, placebo-controlled clinical study conducted in the U.S. to assess the efficacy and safety of exebacase in approximately 350 patients with Staph aureus bacteremia, including right-sided endocarditis. Patients entering the Phase 3 DISRUPT study will be randomized 2:1 to either exebacase or placebo, with all patients receiving standard-of-care antibiotics. The primary efficacy endpoint will be clinical responder rates at Day 14 in patients with MRSA bacteremia, including right-sided endocarditis. Key secondary endpoints will include clinical responder rates at Day 14 in the All Staph aureus bacteremia patient group (MRSA and methicillin-sensitive Staph aureus (MSSA)), 30-day all-cause mortality in MRSA patients, and clinical responder rates at Day 60. We plan to conduct an interim futility analysis following the enrollment of approximately 60% of the study population. More information about the Phase 3 DISRUPT trial can be found at www.clinicaltrials.gov.
A first-in-patient Phase 2 superiority study of exebacase for the treatment of Staph aureus bacteremia, including endocarditis, caused by MRSA or MSSA was completed in May 2019. We have announced positive results which showed clinically meaningful improvement in clinical responder rates among patients treated with exebacase in addition to SOC antibiotics compared to SOC antibiotics alone. In the primary efficacy analysis population of 116 patients with documented Staph aureus bloodstream infection, who received a single intravenous (IV) infusion of blinded study drug, the clinical responder rate was 70.4% for patients treated with exebacase and 60.0% for patients dosed with SOC antibiotics alone. In a pre-specified analysis of MRSA-infected patients, the clinical responder rate in patients treated with exebacase was 42.8% higher than the clinical responder rate in patients treated with SOC antibiotics alone (74.1% for patients treated with exebacase compared to 31.3% for patients treated with SOC antibiotics alone (p=0.010)). The clinical responder rate of patients with bacteremia including right-sided endocarditis was 80.0% for patients treated with exebacase compared to 59.5% for patients treated with SOC antibiotics alone, an increase of 20.5% (p=0.028). In the subgroup of patients with a final diagnosis of bacteremia, the clinical responder rate was 81.8% for patients treated with exebacase compared to 61.5% for patients treated with SOC antibiotics alone, an increase of 20.3% (p=0.035). Exebacase was well-tolerated and treatment emergent adverse events, including treatment-emergent SAEs were balanced between the treatment groups. There were no SAEs that we determined to be related to exebacase, there were no reports of hypersensitivity related to exebacase and no patients discontinued treatment with study drug in either treatment group. The study also generated positive health economic data whereby exebacase reduced length of stay and 30-day readmission rates for US patients with MRSA bacteremia including endocarditis compared to patients treated with SOC antibiotics alone. Among US MRSA patients discharged alive from the hospital, the median length of stay was reduced by 4 days. The 30-day all cause readmission rate was reduced to 16.0% from 30.8%. The study also generated a positive 30-day mortality benefit for MRSA patients treated with exebacase, compared to standard-of-care alone, of 3.7% vs 25.0%, (p=0.055). This supplements the positive efficacy and health economics data exebacase demonstrated in this study. We believe these data establish proof of concept for exebacase and for direct lytic agents as potential therapeutics. More information about this trial can be found at www.clinicaltrials.gov.
A Phase 1 trial of exebacase in healthy volunteers was concluded in December 2015. No clinical adverse safety signals were observed. This study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single escalating doses of exebacase administered intravenously to healthy volunteers.
Market Need
Staph aureus bloodstream infections occur in both hospital and community settings, causing an estimated 200,000 hospitalizations each year in the U.S. with mortality rates over 20%. Drug-resistant strains of Staph aureus such as MRSA have now been reported to exhibit resistance to SOC antibiotics (e.g. vancomycin and daptomycin). New agents are necessary to address this emerging threat, which may ultimately result in infections for which no available therapies are effective. Exebacase has the potential to address this therapeutic need as demonstrated by its in vitro and in vivo microbiologic activity against MRSA and the Phase 2 clinical data.
Annual Cases of Staph Bacteremia In the U.S.
Cases in the U.S. That Result in Death
Gram-negative lysins
We have discovered and engineered lysins which target and kill Gram-negative pathogens, including multi-drug resistant strains.
View Gram-negative lysins »
Amurins
We have discovered a new class of direct lytic agents, antimicrobial peptides, that have potent in vitro activity across a wide range of resistant Gram-negative pathogens.
View Amurins »