WASHINGTON – Hot on the heels of July's FDA approval of Recarbrio (imipenem, cilastatin and relebactam) in complicated urinary tract infections (cUTIs), Merck & Co. Inc. rolled out pivotal phase III data at the Infectious Disease Society of America's IDWeek 2019 that could support expanding its label to another high-need group, people with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). Shionogi & Co. Ltd., which is advancing its investigational antibiotic, cefiderocol, in the same indications, also shared new phase III data supporting its use in the high-risk population.
Top-line data from Merck's study, RESTORE-IMI 2, found Recarbrio just as effective as piperacillin/tazobactam in treating HABP/VABP, setting the stage for it to join another Merck product, Zerbaxa (ceftolozane/tazobactam), which won label language in the U.S. and Europe indicating its use in treating HABP/VABP in June. (See BioWorld, June 5, 2019.)
Zerbaxa and Recarbrio each have "a slightly different spectrum of activity," Joan Butterton, vice president of infectious disease clinical research at Kenilworth, N.J.-based Merck, told BioWorld. "What we're trying to do is to make sure we can provide many choices to prescribers so they can pick the best drug for their particular patient and for their local ecology," she said.
The randomized global trial established both statistical noninferiority vs. piperacillin/tazobactam in day 28 all-cause mortality – the FDA's approval endpoint in the indication – and clinical response at early follow-up in the trial's modified intent-to-treat population – the EMA's approval endpoint – with comparable safety in both the Recarbrio and the pip/tazo arms.
Often working without the luxury of a culture to be able to know exactly what bacteria are causing a problem for their patients, doctors must work fast, sometimes making empiric choices based on what they know about their local ecologies, Butterton said. "Any delay in treatment leads to increases in morbidity and mortality, particularly in these patients with pneumonia," she said. "We see doing these studies and expanding indications into hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia as really being key for physicians to understand how to use these drugs," she said.
Recarbrio has been in development since the late 1990s and is just the latest of 31 antimicrobials Merck has developed since the 1930s, starting with sulfa drugs and spanning antibacterials, antifungals, antivirals and antiparasitics. Recently though, many of its efforts, like those of its peers, have focused on highly resistant gram-negative bacteria.
A new mechanism to beat resistance
Addressing gram-negative infections is a top priority among health care providers globally, due to the threat of the bugs' increasing resistance to most available antibiotics. That has put it front and center at Osaka, Japan-based Shionogi, which has made cefiderocol the leading asset in its infectious disease pipeline and the subject of an NDA for complicated urinary tract infections currently filed with the FDA. The PDUFA date is Nov. 14.
A siderophore cephalosporin with a new mechanism for penetrating the outer cell membrane of gram-negative pathogens, cefiderocol has already been extensively tested against cUTIs. But with the double-blinded APEKS-NP trial, the company has now generated evidence for cefiderocol effectiveness in nosocomial pneumonia (another name for HABP/VABP), testing it against high-dose extended infusion time meropenem, the standard of care for gram-negative infections. "We wanted to establish equivalence with a really potent competitor," Shionogi's medical director, Simon Portsmouth, told BioWorld.
Results from the study, to be presented Thursday at IDWeek, showed that cefiderocol was noninferior compared to high-dose meropenem in all-cause mortality at 14 days after initiation of study drug, meeting the primary endpoint of the trial. Demonstrating further comparability, at day 14, all-cause mortality in the modified intent-to-treat population was 12.4% for cefiderocol vs. 11.6% for high-dose meropenem (difference: 0.8, 95% CI: –6.6; 8.2).
Cefiderocol also met key secondary endpoints of clinical and microbiological outcomes at test of cure. No unexpected safety signals were observed, and the incidence of treatment-emergent adverse events was similar between treatment arms.
Those data could ultimately help cefiderocol find a place in the limited armamentarium available to fight carbapenem-resistant gram-negative pneumonias, which today have very limited options and often there is a need to resort to the nephrotoxic antibiotic colistin, Portsmouth said. Though such cases are few in number, there is even emerging resistance to colistin in some cases, "so there's desperate unmet need," he said.
IDWeek continues through Sunday, Oct. 6.