FPI-1465 Increases Activity of Certain Antibiotics against Drug-Resistant Bacteria
Findings Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
EDMONTON, Alberta – September 12, 2013 – Fedora Pharmaceuticals, Inc. and its collaborators presented results of preclinical studies demonstrating that FPI-1465 increases the activity of beta-lactam antibiotics against bacteria that have developed resistance through the production of beta-lactamase enzymes. Beta-lactamases destroy the molecular structure of beta-lactam antibiotics, eliminating their antimicrobial activity. FPI-1465 is a beta-lactamase inhibitor (BLI) being investigated as an adjunct to antibiotics for the treatment of patients with difficult-to-treat bacterial infections.
In a pair of in vitro studies, three beta-lactam antibiotics (ceftazidime, aztreonam and meropenem) were tested alone and in combination with FPI-1465 against cultures of bacteria that produce two of the most prevalent beta lactamases: the extended-spectrum beta-lactamases (ESBLs) and carbapenemases. In each case, the FPI- 1465+antibiotic combination eliminated resistant bacteria at a much lower concentration than did the antibiotics alone. In the case of the parenteral carbapenem, meropenem, which displayed moderate activity against the bacterial cultures tested, the addition of FPI-1465 often increased its potency four-fold against bacteria producing ESBLs and as much as 128-fold against bacteria producing carbapenemases. In contrast, ceftazidime and aztreonam, which showed little antibacterial activity when tested alone, demonstrated up to a respective 256-fold and 1,024-fold greater potency in combination with FPI-1465 against bacteria producing ESBLs; and up to 256-fold and 4,096-fold greater potency against bacteria producing carbapenemases.
“The synergy observed in these studies suggests that FPI-1465 has the potential to negate the mechanism of resistance employed by beta-lactamase-producing bacteria and rescue the antimicrobial activity of the entire class of beta-lactam antibiotics,” stated Dr. Rodrigo E. Mendes, associate director, molecular and microbiology at JMI Laboratories, and lead author of these two in vitro studies. “The fact that FPI-1465 can accomplish this for bacteria producing several combinations of beta-lactamase enzymes, including metallo-beta-lactamases, is of tremendous importance, as these organisms now represent a worldwide therapeutic crisis. If these findings are supported by future clinical studies, we believe that the combination of BLIs such as FPI-1465 with beta-lactam antibiotics could represent a promising strategy for treating infections caused by multidrug-resistant bacterial infections.”
The above results were confirmed in an in vivo study in which mice were infected with strains of either Klebsiella pneumoniae or Enterobacter cloacae that produce VIM-1, KPC-2 and KPC-3, beta-lactamase enzymes that represent significant clinical challenges in the U.S. and Europe. Mice were then treated with ceftazidime alone or in combination with FPI-1465, and efficacy was assessed by number of colony forming units (CFUs) six hours after K. pneumoniae infection or 24 hours after E. cloacae infection. The FPI-1465+ceftazidime (256mg/kg / 1,024mg/kg) combination administered as a single dose resulted in a 3-log reduction in CFUs in mice infected with K. pneumonia. In mice infected with E. cloacae, FPI-1465+ceftazidime (75mg/kg / 150mg/kg) resulted in a 3.82-log reduction.
“In these highly resistant strains, the degree of bacterial clearance generated by the combination of FPI- 1465+ceftazidime is truly impressive,” stated Christopher G. Micetich, founder and chief executive officer of Fedora Pharmaceuticals. “These results taken in combination with the data generated by our collaborators at JMI Laboratories as well as others, give us great optimism about the broad antimicrobial activity of FPI-1465 and its flexibility to pair with any number of beta-lactam antibiotics. The BLI class containing FPI-1465 has the potential to be an important adjunct to antibiotic therapy for patients with resistant infections. We look forward to completing preclinical studies and initiating clinical trials with one or more BLI candidates in late 2014.”
Fedora also presented results of a pharmacokinetic study of FPI-1465, demonstrating that FPI-1465 has a similar profile to other BLIs in clinical development and suggesting that it may be compatible with several possible betalactam antibiotics. In a safety study, FPI-1465 was shown to be well tolerated in mice and may have a low risk for major drug interactions. A further presentation reports on possible mechanisms of action of FPI-1465. FPI-1465 appears to exert multiple mechanisms of action beyond acting only as an inhibitor of the beta-lactamase enzymes. These properties combine to offer potential advantages by attacking microbes at multiple points.
The Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) is the annual infectious diseases meeting of the American Society for Microbiology. This year’s ICAAC meeting is being held in Denver, CO September 10-13, 2013. For more information on ICAAC, please visit www.icaac.org.
About Fedora Pharmaceuticals
Fedora Pharmaceuticals is developing a family of beta-lactamase inhibitors designed to have activity against pathogens containing all four classes of beta-lactamases. Beta-lactamases are enzymes produced by bacteria that destroy the ring structure common to beta-lactam antibiotics. This class of antibiotics, which includes penicillin derivatives, cephalosporins, monobactams and carbapenems, is estimated to comprise 65% of the antibiotics market worldwide. The beta-lactamase inhibitors under development at Fedora will be used in combination with various beta-lactam antibiotics to treat those antibiotic infections currently resistant to therapy. Fedora Pharmaceuticals is in the lead optimization stage of preclinical development with its first beta-lactamase inhibitor candidates, and anticipates entering the final stages of preclinical investigation in 2013, leading to an Investigational New Drug (IND) application and initiation of clinical studies in 2014. Fedora was founded in 2012 and is headquartered in Edmonton, Alberta, Canada. For more information on the company, please visit www.fedorapharma.com.