Public healthOld antibiotics, new tools to combat bio agents

More than 100 antibiotic compounds have been discovered since Alexander Fleming invented penicillin in 1928, but none within the past thirty years. Now a joint venture between the Defense Threat Reduction Agency’s Joint Science and Technology Office, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Joint Program Executive Office (JPEO) and Paratek Pharmaceuticals, a U.S.-based biopharmaceutical company, is exploring a new class of tetracycline that could combat biological threats to our warfighters.

While a new antibiotic is necessary to combat drug resistant biowarfare pathogens, which are inherent challenges in antibiotic discovery, such as difficulty in establishing a broad-spectrum application while avoiding potential toxicity. In addition, in order to be suitable for warfighter use, new antibiotics must exhibit superiority or equivalence compared to the current military standard of care.

Biowarfare pathogens also require special handling and biosafety precautions, such as Biosafety Level (BSL)- 3 containment and compliance with Food and Drug Administration (FDA) requirements for development under the Animal Rule, as clinical trials in humans are unethical or unfeasible. USAMRIID provides expertise in both handling biowarfare pathogens and testing compounds against biowarfare pathogens through animal models.

The Defense Threat Reduction Agency says that the group’s Core Antibiotic Screening Project, with funding from JSTO, screens antibacterial compounds against BSL-3 select agents and identifies which compounds have activity. Within this core capability, small molecules are screened against a panel of 150 bacterium strains (30 strains per select agent of interest including B. pseudomallei (melioidosis), B. mallei (glanders), Bacillus anthracis (anthrax), Yersinia pestis (plague), and Francisella tularensis (tularemia) to establish effectiveness against select agents.

The antibacterial compounds demonstrating good in vitro efficacy are advanced to in vivo evaluation in biological warfare agent challenge models. Ultimately, the compounds will become part of the FDA’s Animal Rule studies through the Label Expansion program. This program assesses whether or not a specific drug can treat additional types of patients and diseases beyond the drug’s original intended use.

In 2015, the Label Expansion program yielded FDA approval of a supplemental New Drug Application for moxifloxacin for the oral and IV treatment and post-exposure prophylaxis of infection caused by Y. pestis. This success spurred JSTO and JPEO to provide additional funding, expanding USAMRIID’s Label Expansion program to integrate a pipeline of potential late-development candidates for repurposing against biowarfare agents. This approach allows the Department of Defense to reduce the development cycle for new medical countermeasures while increasing warfighter safety, supporting efficiency and cost-saving initiatives.

Omadacycline, a Paratek-developed antibiotic, is currently under evaluation by USAMRIID’s Label Expansion program. The well-tolerated, once-daily oral and IV antibiotic is the first in a new class of tetracyclines, known as aminomethylcyclines, with broad-spectrum activity against gram-positive, gram-negative and atypical bacteria.

In June 2016, the new antibiotic demonstrated positive results for efficacy and safety in a Phase 3 clinical study for skin structure infection and acute bacterial skin. The Phase 3 registration study for community-acquired bacterial pneumonia comparing IV-to-oral omadacycline to IV-to-oral moxifloxacin was initiated in November 2015.

Enrollment figures are on track to report top line data as early as the third quarter of 2017. The FDA granted omadacycline ‘Qualified Infectious Disease Product’ designation and ‘Fast Track’ status. The Animal Rule studies, performed in collaboration with USAMRIID, are designed to confirm humanized dosing regimens of omadacycline and establish the efficacy of omadacycline against biodefense pathogens, including Yersinia pestis and Bacillus anthracis.

DTRA says that the joint DTRA, JPEO, USAMRIID and Paratek effort represents a valuable partnership within the Chemical and Biological Defense Program. The work highlights continuing efforts to engage industry and reduce biological threats to our warfighters. The resulting capability will bolster the military’s medical defense toolbox, increasing the number of options available to combat infections in the event of a biological attack.