麻豆传媒

SILVER SPRING, Md. -- An FDA advisory committee voted 17-1 Wednesday to recommend approval of omadacycline, a next-generation tetracycline-class antibiotic, for treatment of acute bacterial skin and skin structure infections (ABSSSI).

The Antimicrobial Drugs Advisory Committee also voted 14-4 in favor of approving the drug, made by Boston-based Paratek Pharmaceuticals, for the treatment of community-acquired bacterial pneumonia (CABP). Both votes were responding to questions of whether the company had shown that the drug was safe and effective in the particular indication.

"Studies showed clear evidence of meeting non-inferiority [criteria], and this is an area where we are glad to have new treatments," said panel member Barbara Gripshover, MD, an associate professor of medicine at Case Western Reserve University. However, she said there didn't appear to be enough evidence to use the drug to treat patients with bacteremia, since they usually need at least 2 weeks of treatment and the drug's clinical trials didn't last that long.

Evan Tzanis, chief development officer of Paratek Pharmaceuticals, referred to omadacycline as a semisynthetic derivative tetracycline antibiotic. Known as an aminomethylcycline, it works like other tetracyclines to bind to the 30S subunit of the bacterial ribosome and blocks protein synthesis by inhibiting the binding of aminoacyl-tRNA.

"Omadacycline is the first in its class, what we describe as a new-generation tetracycline," Tzanis told 麻豆传媒 in a phone interview. "However, the modifications that we've made to the structure of the classic tetracycline are such that omadacycline has overcome the most common resistant pathways that have developed in tetracycline."

Clinical Trial Results

Omadacycline was tested in more than two dozen clinical studies. In three phase III trials, 2,150 patients were included, including 1,073 treated with omadacycline.

In two randomized, noninferiority trials, OASIS-1 and OASIS-2, omadacycline was compared to linezolid in the treatment of adults with ABSSSI. Patients treated with omadacycline in OASIS-1 reported 84.8% clinical success, or at least a 20% reduction in their lesion, compared with an 85.5% clinical success rate for those administered linezolid. In OASIS-2, omadacycline resulted in 87.5% clinical success, compared to 82.5% in the linezolid group. OASIS-1 patients were administered omadacycline intravenously, while OASIS-2 patients were administered the drug orally.

In another phase III trial comparing omadacycline with moxifloxacin in adult patients with CABP, patients demonstrated clinical success if they survived and improved in at least two CABP symptoms including cough, sputum production, pleuritic chest pain, and dyspnea. Patients treated with omadacycline exhibited 81.1% clinical success and 12.7% clinical failure, compared to an 82.7% success rate and 12.1% rate of failure when treated with moxifloxacin.

In addition, the FDA reviewers also found small "numerical differences" in clinical failure among various subgroups, each favoring the moxifloxacin group, including:

• PORT Risk Class IV
• CURB-65 score of 2
• Patients with bacteremia
• Subgroups of patients with either microbiologically documented H. influenzae or S. pneumoniae

The FDA also identified additional risk factors associated with mortality, including age >65; underlying chronic obstructive pulmonary disease, asthma, or emphysema; and diabetes mellitus.

Four of the eight patients who died also had bacterial pathogens identified at baseline, and three had more than one baseline organism identified.

Joanna Schaenman, MD, PhD, associate clinical professor of Medicine at the University of California Los Angeles, voted against the use of omadacycline to treat ABSSSI, despite believing the sponsor showed evidence of non-inferiority, she said.

"The length of treatment was relatively short -- 7 to 10 days -- and it was a relatively young population that was mostly Caucasian... [So] if used for its intended use, it's possible that with use in older patients and patients with comorbidities, you might have a safety signal emerge," she said. "If the drug does go to market, the label should include warnings that it might not be safe to use in patients with bacteremia and in older patients."

Need for Diversity

Committee members said that if the drug was approved, the company should conduct follow-up studies that examine more diverse populations, including a higher proportion of black and Hispanic patients, younger patients, and patients with comorbidities to confirm the generalizability of omadacycline for the treatment of ABSSSI.

FDA reviewers cited one "noteworthy" finding in the CABP trial was the "imbalance" in 30-day all-cause mortality, with eight deaths in the omadacycline group versus three in the control group. While they added that "an etiology for the imbalance could not be determined from the available current data," they noted there were no significant differences in adverse events between treatment groups in this trial and that six of eight deaths in the omadacycline group occurred in current smokers.

"Although four of eight deaths were related to cardiovascular disease outcomes, omadacycline does not appear to have a pro-arrhythmic risk potential to explain the finding," FDA staff indicated.

James Floyd, MD, MS, assistant professor of medicine and epidemiology at the University of Washington, in Seattle, expressed concern about the mortality imbalance between the intervention and comparator patients and recommended this information should be noted in future labeling.

"There is a safety signal here and we're wondering how to get more information," he said, referring to the eight deaths. "This is not robust evidence of efficacy from a superiority trial -- if it were, I would interpret the safety signal differently; it's from a non-inferiority trial.... The data are sparse; these trials are not powered to look at mortality.... To my mind, post-approval studies are not the way [to study it] and it could require a second study."

Pneumonia Deaths a Fluke?

William Calhoun, MD, professor of pulmonary critical care and sleep medicine at the University of Texas Medical Branch at Galveston, said he is concerned about the patient deaths, but noted that deaths within the CABP population are not uncommon.

"It's not impossible that it's a statistical variance; the data don't exclude the possibility that it's a fluke -- something that just happened," he said. "I would encourage the agency to work with the sponsor to sort out the appropriate post-marketing follow-up, whether a randomized trial or [something else]."

The Society of Infectious Diseases Pharmacists recommended the drug in a letter submitted before the meeting, referencing the need for new antibiotics that treat organisms the CDC has identified as "urgent" or "serious" threats such as carbapenem-resistant or extended spectrum beta lactamase-producing Enterobacteriaceae, drug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus.

"We see patients in acute care and post-acute care settings that are dying from multi-drug resistant infections because limited treatment options exist," they wrote. "There is an urgent and imperative need for new antibiotics that are safe, well-tolerated, and have unique mechanisms of action compared to commercially available antibiotics."

The FDA doesn't have to take the advice of its advisory committees, but it usually does.

Comment