- A recently published study in the New England Journal of Medicine highlighted the clinical findings that led in part to approval of Achaogen's antibiotic Zemdri last year for complicated urinary tract infections caused by Enterobacteriaceae.
- Published in the same issue, but to much lower billing, was a letter to the editor detailing difficulties Achaogen encountered in another trial, one that was deemed insufficient to support an approval in treating bloodstream infections.
- The divergent outcomes reported from the studies, which also received federal funding, spurred two officials and a NEJM deputy editor to pen an accompanying editorial raising concerns about the challenges facing antibiotic clinical research, particularly for serious drug-resistant infections.
Achaogen's mixed success with Zemdri (plazomicin) serves as an illustrative example of the challenges of antibiotic drug development.
In the successful EPIC study, Zemdri proved noninferior to meropenem, a carbapenem antibiotic increasingly used to treated complicated urinary tract infections. Investigators in that study were able to achieve full enrollment and effectively demonstrate a clinical profile that convinced FDA reviewers.
Conversely, the CARE study testing Zemdri in carbapenem-resistant Enterobacteriaceae (CRE) infections ran into enrollment difficulties that ultimately led to an early halt of the trial. Of the more than 2,000 patients screened for the study, only 39 were enrolled and the findings could only be considered descriptive.
"This drug development program illustrates some of the major challenges inherent in developing a new antibacterial drug: a clinical trial involving patients with a common infection was successfully conducted, although the need for a new drug in UTIs is limited," the FDA officials and NEJM deputy editor wrote in the accompanying editorial, "whereas a clinical trial in patients who have the greatest need of a new therapeutic option had such slow enrollment that the trial was halted after enrollment of only a fraction of the planned number of patients."
The editorial goes on to suggest that enrolling patients with the right infection, but not necessarily a confirmed resistance type, is a more feasible way to generate evaluable data.
Overly restrictive study enrollment criteria and obtaining informed consent for acute illnesses were also highlighted as challenges. Clinical trial networks, which can help to develop standardized approaches, could be one solution, the editorial notes.
Patients with CRE infections have few treatment options and face high levels of mortality. Carbapenems aren't the only problem either; there are emerging infections susceptible to few — and sometimes no — available antibiotics. Pan-resistant infections are rare, but a strain of Klebsiella pneumoniae emerged in the U.S. in 2016.
Patients with serious acute bacterial infections need treatment as quickly as possible, ideally within an hour of presentation. Yet accurate identification of bacteria and enrollment into a clinical trial generally doesn't come until later — potentially skewing results of a study.
Developing alternatives is economically challenging, too. Antibiotic stewardship, for instance, means newer and broader-spectrum agents are kept aside to preserve utility, which also limits the economic return drug developers can hope to achieve.
The FDA is working to support antibiotics R&D through legislation such as the Generating Antibiotic Incentives Now (GAIN) act, as well as expedited reviews and market exclusivity.
"Those who have followed this field will recognize that scientific challenges and economic strain are not the exception but represent the typical scenario that is faced when a new antibacterial drug is developed," the editorial authors noted.