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Resistance is futile: DTRA working on therapies to defeat antimicrobial resistance, reduce threat

Story by Richard Johnson

WASHINGTON – The rising tide of antimicrobial resistance (AMR) and the ability of bacteria to overcome antibiotics is a growing threat to both public health and the warfighter.

Outbreaks of AMR pathogens are an increasingly serious threat to both the military’s combat readiness and to global public health. While the natural prevalence of AMR in traditional biowarfare agents remains relatively low, the potential for acquisition or deliberate genetic manipulation make the possibility of a resistant threat a reality too dangerous to ignore.

The Defense Threat Reduction Agency, which also serves as the Department of Defense’s Joint Science and Technology Office is addressing the need for more effective broad-spectrum antibacterial therapies that can overcome resistance. Their efforts include the development of novel antibiotics against validated clinical targets. One such drug candidate, gepotidacin, targets the topoisomerase/gyrase protein complex in a manner similar, but distinct from Food and Drug Administration-approved quinolones, a family of synthetic broad-spectrum antibacterial drugs.

In 2007, JSTO began funding the development, through GlaxoSmithKline, of gepotidacin, formerly named GSK-944. Gepotidacin is a broad-spectrum, novel antibiotic for the treatment of resistant biowarfare bacteria such as plague, tularemia and anthrax.

The U.S. FDA, in conjunction with JSTO, agreed that the efficacy and safety data presented during preliminary trials supported a pre-emergency use authorization filing for gepotidacin as a treatment for plague.

These events, as well as progress in the sister program funded by the Biomedical Advanced Research and Development Authority, spurred the GSK team to commit to medicine development in October 2015. This milestone allows progression of gepotidacin towards a Phase 3 development program and serves as a corporate endorsement for continued development. This endorsement is significant for an atrophying antibacterial pipeline due to the poor potential for return on investment in the commercial market.

In recent studies, the team demonstrated gepotidacin is efficacious in treating mice with Y. pestis, (the bacteria response for plague infections) induced infection by aerosol exposure. Gepotidacin was also tested twice in a pivotal Good Laboratory Practice (a system of management controls for research laboratories and organizations) to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of chemical non-clinical safety tests) African Green primate aerosol plague model. All doses of gepotidacin in these studies provided a survival benefit and eradicated bacteria from the blood and organs of surviving animals. In order to provide efficacy data to support a lower clinical dose (and to provide the FDA with additional efficacy data to support the dosage regime evaluated in the first two pivotal studies, a third and final African Green primate study is currently being conducted.

Gepotidacin has also demonstrated efficacy against other potential biowarfare agents. A proof-of-concept anthrax treatment study using New Zealand White Rabbits demonstrated 88 to 100 percent survival at both dosing regimens tested. Gepotidacin exposures in the study were similar to human 1000 mg doses. Bacterial clearance in the lung for gepotidacin-treated rabbits was comparable to levofloxacin treated control rabbits with a small number of bacteria isolated reflecting residual spores. Additionally, proof of concept studies are ongoing in rats infected with F. tularensis with the first cohort showing promising survival and bacterial clearance data. Dose selection for pivotal studies will be guided by the results of these studies and human clinical doses.

This program, in conjunction with its sister program for the treatment of clinical infections, represents an outstanding effort to develop a novel antibiotic that will overcome resistant infections. This capability will bolster supplies to combat infections in the context of a biological attack, providing a new treatment against which no resistance has arisen. Furthermore, this drug will have significant utility for the treatment of clinical infections of urgent concern to our armed forces.

POC: Dr. Amanda Horstman Smith, amanda.l.horstmansmith.civ@mail.mil

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