The US Food and Drug Administration's (FDA's) Antimicrobial Drug Advisory Committee recommended omadacycline (Paratek) for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) on August 8.
The committee voted 17 to 1 in favor of recommending omadacycline for BSSSI and 14 to 4 in favor of recommending omadacycline for CABP.
Omadacycline is a modernized tetracycline with broad-spectrum activity that "is designed to overcome tetracycline resistance," the FDA explains in a briefing document.
The panel's vote follows consideration of data from three phase 3 trials that included 2150 patients who received the study drugs. The FDA had initially said that one "successful and well-controlled trial" for each indication would be acceptable for both indications. The company submitted a second phase 3 trial with oral-only dosing in March 2016.
Acute Bacterial Skin and Skin Structure Infections
Study ABSI-1108 was a global noninferiority (NI) study that evaluated initial intravenous (IV) treatment followed by oral treatment in patients (mean age, 47 years) with ABSSSI severe enough to need 3 or more days of IV treatment. The study included 316 patients in the omadacycline group and 311 patients treated with linezolid.
Study ABSI-16301 was an NI study conducted in the United States and included patients (mean age, 43 years) taking only the oral formulation or linezolid; there were 360 patients in each group. None of the patients in this study required hospitalization.
The primary endpoint in both trials was reduction in lesion size of 20% or more 48 to 72 hours after initiation of treatment in the modified intent-to-treat (mITT) population. Patients appeared to experience a sustained treatment effect at later evaluations.
Both studies demonstrated noninferiority.
"I voted 'no' for concerns of safety. I do firmly believe that the sponsor has demonstrated noninferiority to linezolid, has shown effectiveness over a range of skin flora including MRSA, including relatively large areas of skin involvement, and patients with abscess…however, the length of treatment was relatively short — 7 to 10 days. It was a relatively young population that was generally Caucasian. … I think it's possible that with use in older patients and patients with comorbidities…we might have a safety signal emerge, and we lack data in a wide range of racial and ethnic groups," said voting committee member Joanna M. Schaenman, MD, PhD, associate clinical professor of medicine, division of infectious diseases, David Geffen School of Medicine at UCLA, Los Angeles, California.
"Were this drug to go to market, I think the labeling should indicate that this may not be ideal therapy for patients with bacteremia given the limited data and again that it's not tested in older patients or patients with immunocompromise," Schaenman added.
Community-Acquired Bacterial Pneumonia
Study CABP-1200 was a global noninferiority trial in adults with CABP. The trial included 382 patients in the omadacycline group and 388 patients treated with moxifloxacin. All patients were sick enough to require 3 or more days of IV treatment. Patients received at least 3 days of IV treatment followed by oral treatment.
The primary efficacy endpoint was early clinical response evaluated at 72 to 120 hours after receipt of the first dose of the study drug in the ITT population. The study demonstrated noninferiority to moxifloxacin.
Overall, 2150 patients received study drugs. Three patients died in study ABSI-1108 (one in the omadacycline group and two in the linezolid group). In study ABSI-16301, one patient in the linezolid group died 94 days after treatment ended.
In Study CABP-1200, eight patients in the omadacycline group and four patients in the moxifloxacin group died. One patient in the moxifloxacin group died on day 71 from pancreatic cancer. Six of the eight patients who died in the omadacycline group and one patient who died in the moxifloxacin group, had chronic lung disease at baseline.
The most common adverse reactions experienced by more patients in the omadacycline groups in the ABSSSI studies were nausea and vomiting, and these were more frequent in the oral-only trial. The majority of adverse reactions were mildly to moderately severe. The most common adverse reaction experienced by more patients in the omadacycline group in Study ABSI-1108 was infusion-site reaction.
The most common adverse reactions that caused patients to discontinue the study drug were infections and infestations, most of which were a worsening of the index infection being studied. "These patients were recorded as treatment failures in the efficacy analyses," the FDA writes in a briefing document.
"It's comforting to me that this drug is safe and effective within the parameters we look at normally for infectious disease products, especially given the size of the trial that was done. Postmarketing surveillance is always prudent and will occur whether mandated or not. ... Additional studies in those with cardiac conditions, COPD and diabetes would be helpful, though," Peter Joseph Weina, PhD, MD, colonel, Medical Corps, USA, and chief, Department of Research Programs, Walter Reed National Military Medical Center, Division of Education, Training and Research, Bethesda, Maryland, said of his "yes" vote.
Medscape Medical News © 2018
Cite this: Omadacycline Recommended by FDA Panel for ABSSSI and CABP - Medscape - Aug 10, 2018.