Oral Candidate Against ESBL-Producing Enterobacteriaceae Proves Promising in Phase 1 Trial

Late-stage biopharmaceutical company Achaogen, has just announced favorable top-line results yielded from a phase 1 clinical trial looking at the safety, tolerability, and clinical pharmacology of C-scape, an oral combination of ceftibuten and clavulanate for the treatment of multidrug-resistant gram-negative infections.

C-scape was reportedly “well-tolerated” across all doses studied in the trial and did not demonstrate any drug-drug interaction when dosed in combination. Achoagen’s second antibacterial candidate for problematic MDR gram-negative infections, C-scape has already been awarded Qualified Infectious Disease Product (QIDP) status by the US Food and Drug Administration to treat complicated urinary tract infections, including acute pyelonephritis. “QIDP designation provides incentives for new antibiotic treatments, including priority review and additional market exclusivity,” according to the press release.

The development of new antibiotics is especially important as more organisms are increasingly developing resistance to oral therapies that are currently available; one such organism is extended-spectrum beta-lactamases(ESBL)-producing Enterobacteriaceae. “ESBL are enzymes produced by Enterobacteriaceae that hydrolyze most beta-lactams. They are frequently encoded by plasmids that carry genes conveying resistance to other antibiotic groups, such as aminoglycosides and fluoroquinolones,” a recent study explains. Without effective oral therapy, these infections usually result in hospitalization, as intravenous therapy is the only treatment option left.

“There is a tremendous need for orally-administered antibiotics with activity against MDR pathogens, such as ESBL-producing Enterobacteriaceae,” past Peer Exchange panelist Yoav Golan, MD, MS, associate professor of medicine at Tufts University School of Medicine, stressed in the press release. “For patients suffering from complicated urinary tract infections due to ESBL-producing Enterobacteriaceae, intravenous carbapenem therapy is often their only treatment option. I would welcome a new oral beta-lactam and beta-lactamase inhibitor combination that would help limit the use of carbapenems in these patients.”

Enter C-scape.

In the double-blind, randomized, placebo-controlled, parallel group study consisting of 41 healthy subjects, investigators were able to ascertain that C-scape was well-tolerated across all dosing regimens tested when administered for the duration of 14 days. Additionally, they found the safety profile to be “consistent with expectations…when administered based on existing product labels.” The investigators report that none of the participants experienced any serious adverse events. Vascular access site bruising, headaches, diarrhea, gastroenteritis, and nausea were among the most common adverse events that were reported. Lastly, the investigators found that following the administration of C-scape, preliminary pharmacokinetics were “similar” to those following administration of ceftibuten and clavulanate alone.

“The positive top-line results from this first-in-human clinical trial for C-scape are supportive of further evaluation and we continue to plan for phase 3 in 2018. FDA has previously indicated that a single phase 3 study in cUTI, if successful, would be sufficient for licensure, and we plan to meet with the FDA in early 2018 to seek agreement on the details of our development plan,” Achaogen’s presidents of R&D Kenneth Hillan, MB, ChB, commented in the press release. “Given the need for additional oral antibiotic options for infections due to ESBL-producing Enterobacteriaceae, we plan to pursue a 505(b)(2) development pathway to take advantage of the development studies performed on ceftibuten and clavulanate, the two previously approved component drugs of C-scape.”