FDA notes Paratek antibiotic’s noninferiority as it heads to AdComm vote

Paratek Pharmaceuticals’ first drug, and the first in a new class of broad-spectrum antibiotics called aminomethylcyclines, has shown to be noninferior to current regimens for bacterial pneumonia and skin infections, FDA reviewers wrote ahead of an Aug. 8 advisory committee meeting.

Aminomethylcyclines are structurally related to the commonly used class of tetracycline-based therapies, with omadacycline designed to overcome certain forms of antibiotic resistance found in community-acquired infections, the company said.

In vitro and in vivo studies have shown activity against bacterial infections resistant to penicillin, vancomycin and other combinations of drugs, as well as MRSA, Paratek said. Omadacycline, being studied orally and intravenously, binds to a subunit of the bacterial ribosome to prevent protein synthesis.

Although the drug demonstrated noninferiority compared to moxifloxacin and linezolid—with omadacycline and its controls both reaching similar clinical success rates between 80% and 90%, across three phase 3 trials enrolling a total of more than 3,300 patients—FDA reviewers pointed to the number of deaths in the study in community-acquired bacterial pneumonia, or CABP.

"An important safety concern is the imbalance in 30-day all-cause mortality observed in the CABP trial, with eight deaths in the omadacycline arm compared to three deaths in the control arm," the reviewers wrote (PDF) in their briefing documents for the agency’s Antimicrobial Drugs Advisory Committee.

Four of the eight deaths were related to cardiovascular outcomes, though the FDA said omadacycline does not appear to carry risks of causing an arrhythmia, and the reviewers said they could not determine the cause from the available data.

"Although the rate of mortality in the omadacycline group appears to be similar to the 30-day mortality observed in recently conducted CABP trials, this mortality imbalance in a randomized controlled trial is noteworthy," they added.

"No significant differences in adverse events, [serious adverse events] or adverse events leading to treatment discontinuations were seen between treatment groups in the CABP trial," they added. In addition, based on pharmacokinetics analyses, no dose adjustment is needed based on race, body weight or liver or kidney impairment, including in patients on dialysis.

Paratek, at the same time, was unable to identify "a biologically plausible or clinically associated causal relationship" explaining the deaths, the company wrote in its own briefing (PDF) for the committee, which described the deaths as "consistent with identified causes of mortality in patients hospitalized with CABP."

According to the FDA, overall mortality rates for CABP are around 1% to 2%, with about 80% treated as outpatients. However, 30-day mortality rates for hospitalized patients have reached as high as 23%, the agency said.

The FDA’s advisory panel is set to vote on whether omadacycline has shown evidence of safety and efficacy against CABP and acute bacterial skin and skin structure infections, as well as recommendations for labeling and whether any additional studies are needed.

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