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 Pseudomonas aeruginosa, Acinetobacter baumanii, carbapenem-resistant Enterobacteriaceae, and Neisseria gonorrhoeae.
Indication: Multidrug resistant Acinetobacter infections
ETX2514 is our novel, broad-spectrum and potent inhibitor of Class A, C, and D β-lactamases. Sulbactam (SUL) is a generic β-lactam antimicrobial with activity against Acinetobacter baumannii infections, but β-lactamase-mediated resistance to sulbactam is now widespread rendering it generally ineffective. In preclinical studies, ETX2514 inhibits the β-lactamases commonly found in Acinetobacter thus restoring sulbactam’s antimicrobial activity. We are developing ETX2514SUL, a fixed-dose combination of ETX2514 with sulbactam, as a novel IV antibiotic for the treatment of infections caused by carbapenem-resistant Acinetobacter.
Acinetobacter is a Gram-negative bacterium that causes severe infections which are associated with high mortality. Acinetobacter 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 Acinetobacter 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 Acinetobacter infections. Currently, the very few treatment options still effective against Acinetobacter infections have poor efficacy and tolerability, resulting in mortality rates approaching 50% for Acinetobacter pneumonia and bacteremia infections. We believe that ETX2514’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 Acinetobacter, once again providing physicians with a safe and effective treatment option for their patients.
A Phase 1 trial of ETX2514SUL has recently been completed with positive results for pharmacokinetics and drug toleration. We are conducting additional preclinical and clinical work, including an ongoing Phase 2 clinical trial, and plan 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.
Indication: Carbapenem-resistant infections (Pseudomonas, CRE and others)More InfoLess Info
Class A, C and D β-lactamases have spread not only to Acinetobacter but also to other Gram-negative pathogens, such as E. coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, allowing these pathogens to develop multidrug-resistance to a variety of commonly used antibiotic classes. To target these other key pathogens, we measured their susceptibility to ETX2514 combined with imipenem, the broad-spectrum carbapenem component of the branded antibiotic, PrimaxinTM. In our preclinical studies, ETX2514 improved the overall potency of imipenem across hundreds of strains of E. coli, Klebsiella and Pseudomonas. Based on this preclinical data, we believe that ETX2514SUL in combination with Primaxin has the potential to be a novel and potent broad-spectrum agent for treating infections caused by Acinetobacter, E. coli, Klebsiella and Pseudomonas. For this reason, and because patients with Acinetobacter infections may be co-infected with such other resistant pathogens, we plan to administer ETX2514SUL in combination with Primaxin in our Phase 2 and Phase 3 clinical trials to further explore ETX2514’s ability to restore Primaxin’s activity against such multidrug-resistant pathogens.
Indication: Complicated UTIs (Enterobacteriaceae including ESBL-producing and CRE)
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: Uncomplicated gonorrhea
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 Drugs for Neglected Diseases initiative (DNDi) to co-develop zoliflodacin through Phase 3. In the partnership, Entasis retains all commercial rights to zoliflodacin in high-income territories while DNDi 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: Gram-negative infections (initially multidrug resistant Pseudomonas)
The NBP program and our targeted design 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 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.