Precision antibiotics are on the horizon
Our robust pipeline consists of clinical and pre-clinical pathogen-targeted small-molecule antibacterials for the treatment of multidrug-resistant Gram-negative bacteria.
The pipeline includes programs for differentiated medicines to treat serious multidrug-resistant Gram-negative infections, such as Acinetobacter baumannii, Neisseria gonorrhoeae, carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa.
Indication: Multidrug resistant Acinetobacter infectionsPartner
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Durlobactam (DUR; previously designated ETX2514) is our novel, broad-spectrum and potent inhibitor of Class A, C, and D β-lactamases. Sulbactam (SUL) is a β-lactam antibiotic with activity against Acinetobacter baumannii; however, β-lactamase-mediated resistance to sulbactam is now widespread rendering it generally ineffective. In preclinical studies, durlobactam inhibits the β-lactamases commonly found in A. baumannii thus restoring sulbactam’s activity. We are developing SUL-DUR (previously designated ETX2514SUL), a combination of β-lactam antibiotic and a β-lactamase inhibitor for the treatment of serious infections cuased by Acinetobacter, including multidrug-resistant (MDR) strains.
A. baumannii is a Gram-negative bacterium that causes severe infections which are associated with high mortality. A. baumannii is commonly multidrug-resistant, with rates between 50% and 60% in the United States and greater than 80% in parts of Europe and Asia. The expression of Class D β-lactamases, often in combination with Class A and/or Class C β-lactamases drives A. baumannii resistance to β-lactam antibiotics like sulbactam. Prior to β-lactamase-mediated resistance, sulbactam was one of the few antibiotics of choice for the treatment of A. baumannii infections. Currently, the very few treatment options still effective against A. baumannii infections have poor efficacy and tolerability, resulting in mortality rates approaching 50% for A. baumannii pneumonia and blood stream infections. We believe that durlobactam’s expanded coverage against Classes A, C and D β-lactamases gives it the potential to restore the efficacy of sulbactam against multidrug- and carbapenem-resistant A. baumannii, once again providing physicians with a safe and effective treatment option for their patients.
In October 2021 we announced positive topline results for sulbactam-durlobactam (SUL-DUR) from Phase 3 ATTACK trial. SUL-DUR met the primary endpoint of 28-day all-cause mortality in patients with carbapenem-resistant ABC infections (CRABC m-MITT* population in Part A of the study), demonstrating statistical non-inferiority versus colistin. Mortality analyses favored SUL-DUR versus colistin in CRABC m-MITT and all study populations included in the topline results. At Test of Cure, there was a statistically significant difference in clinical cure favoring SUL-DUR over colistin. SUL-DUR met the primary safety objective of the study achieving statistically significant reduction in nephrotoxicity. NDA submission is planned for mid-2022. SUL-DUR has been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Food and Drug Administration and awarded Fast Track status.
*Carbapenem-resistant Acinetobacter baumannii-calcoaceticus Complex Microbiologically Modified Intent-to-Treat Population”
Indication: Uncomplicated gonorrheaPartners
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Zoliflodacin (ETX0914) is a novel oral antibiotic for the treatment of uncomplicated gonorrhea and the first of a novel class of molecules to be developed for this indication. Uncomplicated gonorrhea infections carry high morbidity, enhance transmission of other sexually transmitted diseases and are highly stigmatized. Gonorrhea is the second most commonly reported sexually transmitted disease and in the United States alone, an estimated 820,000 cases of the disease are contracted each year, of which 30% are resistant to existing antibiotics leaving only one injectable cephalosporin, ceftriaxone, as a recommended first-line therapy. The U.S. Centers for Disease Control and Prevention has recently designated N. gonorrhoeae as the top urgent public health threat that requires aggressive action.
A randomized, open-label Phase 2 study of oral zoliflodacin was successfully completed in December 2015 in individuals with uncomplicated gonorrhea. In July 2017, Entasis partnered with the Global Antibiotic Research and Development Partnership (GARDP) to co-develop zoliflodacin through Phase 3. In the partnership, Entasis retains all commercial rights to zoliflodacin in high-income territories while GARDP receives commercial rights in low- and some middle-income countries. Zoliflodacin has been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Food and Drug Administration and awarded a Fast Track status.
Indication: Complicated UTIs (Enterobacteriaceae including ESBL-producing and CRE)Partner
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ETX0282 is an orally bioavailable, broad spectrum inhibitor of Class A and C beta-lactamases. Entasis is developing ETX0282 in combination with cefpodoxime, an orally available cephalosporin approved for treating a variety of bacterial infections but lacking in efficacy due to beta-lactamase mediated resistance. In preclinical studies, ETX0282 restores cefpodoxime’s antimicrobial activity against a variety of pathogens including Enterobacteriaceae resistant to fluoroquinolones, cephalosporins and carbapenems.
Urinary tract infections (UTI) are one of the most common bacterial infections in the U.S. There are no effective oral treatments available for multidrug-resistant complicated UTIs. Approximately, 85% of UTIs are caused by Enterobacteriaceae and about 75% by E. coli, many of which are resistant to fluoroquinolones, current standard of care. As a result, many patients need hospitalization for treatment with IV antibiotics.
Entasis is initially developing ETX0282CPDP, the combination of ETX0282 and cefpodoxime, for the treatment of UTI caused by drug-resistant Enterobacteriaceae. ETX0282CPDP is partly funded by CARB-X (Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator), the world’s largest public-private partnership devoted to early stage antibacterial R&D, through a grant from this organization.
View Entasis’ presentations on ETX0282.
Indication: Gram-negative infections (initially multidrug-resistant Pseudomonas)Partner
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ETX0462 and our targeted design NBP platform
Multidrug-Resistant (MDR) Gram-negative bacterial pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae are on both the CDC and WHO lists of most serious public health threats which are in dire need of new therapeutic agents. Of the different classes of antibiotics used to treat these serious infections, beta-lactams have been the agents of choice given their safety and impressive efficacy. However, bacteria have evolved to produce beta-lactamase enzymes which inactivate beta-lactams. Our novel, covalent non-beta-lactam PBP inhibitors (NBP) have activity against several MDR Gram-negative strains and are not degraded by any of the beta-lactamases we’ve tested. Lead optimization has lead to a pre-clinical candidate, ETX0462, which if successful in development, will be the first new antibiotic class approved for use against these MDR Gram-negative pathogens in over 25 years. The NBP program is partly funded by CARB-X (Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator), the world’s largest public-private partnership devoted to early stage antibacterial R&D, through a grant from this organization.
ETX0462 is the latest program to be developed from our targeted design platform. Historically, many antibiotics have been discovered by screening high volumes of natural and synthetic compounds for activity against bacterial pathogens, and advancing these molecules toward clinical development with limited visibility into their efficacy, safety or clinical differentiation. In contrast, our platform utilizes bacterial genomics and state-of-the-art molecular and dynamic models to design active new compounds that target validated mechanisms of resistance. Throughout the design process, we aim to maximize compound penetration into target cells and incorporate predictive safety tools and pharmacodynamic modeling with the goal of optimizing efficacy and safety in the clinic. Finally, we focus our clinical development on pathogens with high unmet medical need to leverage the streamlined development and regulatory pathways available for first-in-class or best-in-class antibiotics.