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 Pseudomonas aeruginosa, Acinetobacter baumanii, carbapenem-resistant Enterobacteriaceae, and Neisseria gonorrhoeae.
ETX2514 is a broad-spectrum and potent inhibitor of class A, C, and D beta-lactamases. Sulbactam is a beta-lactam antimicrobial with activity against A. baumannii, but beta-lactamase-mediated resistance to sulbactam is now widespread. In preclinical studies, ETX2514 restores sulbactam’s antimicrobial activity. Entasis is developing the combination of sulbactam and ETX2514 for the treatment of drug-resistant A. baumannii infections.
Acinetobacter baumannii is a Gram-negative bacterium that causes severe infections which are associated with high mortality. A. baumannii infections are frequently multi-drug resistant, with rates in excess of 50% in the US. There are very few effective treatment options currently and they have poor efficacy and tolerability, resulting in mortality rates approaching 50% for pneumonia and bacteremia. For this reason, the Infectious Diseases Society of America has included A. baumannii among the six most-threatening antimicrobial-resistant pathogens and the WHO has placed it at the top of its “Critical” priority pathogen list for R&D of new antibiotics.
A Phase 1 trial of ETX2514SUL has been recently completed with positive results for pharmacokinetics and drug toleration. The Company is conducting additional preclinical and clinical work, including a Phase 2 clinical trial, and plans to move ETX2514SUL to Phase 3 in early 2019. ETX2514SUL has been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Food and Drug Administration and awarded Fast Track status.
Entasis’ publications and presentations on ETX2514 can be seen here.
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 multi-drug 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.
Entasis’ publications and presentations on ETX0282 can be seen here.
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.
Entasis’ publications and presentations on zoliflodacin can be seen here.
The NBP program and our targeted design platform
Multi-Drug 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 could lead to a safe, pre-clinical candidate 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.
NBP 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.