Cefepime-taniborbactam is Venatorx’s beta-lactam / beta-lactamase inhibitor (BL/BLI) combination antibiotic that is being developed for the treatment of complicated urinary tract infections (cUTIs) and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).
Cefepime, a fourth-generation cephalosporin, is a widely used beta-lactam (BL) antibiotic with more than two decades of proven safety and clinical utility against susceptible gram-negative and gram-positive bacteria. Taniborbactam is a beta-lactamase inhibitor (BLI) that, in combination with cefepime, may offer a potential treatment option for patients with serious bacterial infections caused by difficult-to-treat drug resistant gram-negative bacteria, most notably carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA). Many of these organisms are also multidrug-resistant (MDR), further limiting treatment options.
CERTAIN-1 (Cefepime Rescue with Taniborbactam in cUTI) (ClinicalTrials.gov – NCT03840148) was a global, randomized, double-blind, active-controlled non-inferiority Phase 3 study evaluating the efficacy, safety, and tolerability of cefepime-taniborbactam compared to meropenem in adults with cUTI, including acute pyelonephritis. The trial enrolled 661 adult patients who were randomized 2:1 to receive cefepime-taniborbactam 2.5g q8h or meropenem 1g q8h for 7 days (up to 14 days for patients with bacteremia). The primary efficacy endpoint evaluated the composite clinical and microbiologic response (i.e., bacterial eradication) at the Test of Cure (TOC) visit (Day 19-23) in the microbiological intent-to-treat (microITT) population as specified by FDA and European Medicines Agency guidance.
Cefepime-taniborbactam met the primary efficacy endpoint of statistical noninferiority (NI) to meropenem in the microITT population at TOC with composite microbiologic and clinical success occurring in 70.0% of cefepime-taniborbactam treated patients and 58.0% of meropenem treated patients (treatment difference 11.9; 95% confidence interval (CI), 2.4, 21.6). A prespecified superiority test following confirmation of NI demonstrated the statistical superiority of cefepime-taniborbactam for the composite endpoint at TOC. The superiority of cefepime-taniborbactam was sustained for the composite microbiologic and clinical response at the Late-Follow-Up (Day 28-35) visit.
Rates of treatment-emergent adverse events (TEAEs) were 35.5% for cefepime-taniborbactam and 29.0% for meropenem. Serious TEAEs occurred in 2.0% and 1.8% of cefepime-taniborbactam and meropenem treated patients, respectively. Treatment discontinuations due to TEAEs occurred in 3.0% of cefepime-taniborbactam patients and 0.9% of meropenem treated patients. There was one death in the cefepime-taniborbactam treatment group, which was unrelated to study treatment as assessed by the investigator.
Complete CERTAIN-1 study results will be presented at an upcoming scientific meeting.
In addition to cUTI, Venatorx is pursuing HABP/VABP indication for cefepime-taniborbactam and is targeting study start in 2022. The Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services, announced an extension of the contract with Venatorx in August 2021 to support the development and studies needed for marketing authorization of cefepime-taniborbactam to treat HABP/VABP. Venatorx and BARDA will share the costs of the HABP/VABP clinical trial including site activation, patient enrollment, and completion.
The U.S. Food and Drug Administration (FDA) granted cefepime-taniborbactam Qualified Infectious Disease Product (QIDP) and Fast Track designations for the treatment of cUTI and HABP/VABP. Fast Track designation is designed to facilitate the development, and to expedite the review of drugs to treat serious conditions that do not have sufficient treatment options. QIDP designation provides certain incentives for the development of new antibiotics, including priority review, as well as a five-year regulatory exclusivity extension. QIDP was authorized under the Generating Antibiotic Incentives Now (GAIN) Act of 2012, as part of the FDA Safety and Innovation Act, to underscore the urgency in development of new antibiotics.
The FDA and the EMA approved Venatorx’s initial Pediatric Study Plan (iPSP) and Pediatric Investigation Plan (PIP), respectively, for cefepime-taniborbactam. The PIP approvals enable Venatorx and its partner, the Global Antibiotic Research and Development Partnership (GARDP), to initiate clinical trials for cefepime-taniborbactam in pediatric patients, including newborns. In support of the PIP and iPSP, juvenile toxicology dose ranging finding studies for cefepime-taniborbactam are ongoing.
Development of cefepime-taniborbactam began with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number HHSN272201300019C, and Wellcome Trust under Award No. 360G-Wellcome-101999/Z/13/Z, and continues with federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract number HHSO100201900007C.
In September 2018, Venatorx entered into an exclusive license agreement with Everest Medicines to support the development, registration and commercialization of cefepime-taniborbactam in Greater China, South Korea, and select countries in Southeast Asia. Everest will be solely responsible for the commercialization of cefepime-taniborbactam in its territory and Venatorx will be eligible to receive royalties on net sales.
In April 2020, Venatorx and GARDP announced a collaboration to accelerate the development of, and access to, cefepime-taniborbactam for adult and pediatric populations. Venatorx has granted GARDP exclusive rights to distribute and sub-distribute cefepime-taniborbactam, once it is approved for clinical use, in low- and lower-middle-income countries.
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