Pfizer today announced positive findings from two phase 3 trials evaluating an investigational antibiotic combination in treating multidrug-resistant bacterial infections.
The results from the two trials indicate that aztreonam-avibactam (ATM-AVI), which combines an old beta-lactam antibiotic (aztreonam) with a newer beta-lactamase inhibitor (avibactam), is safe and effective in treating serious infections caused by multidrug-resistant, gram-negative pathogens. Company officials say the results will form the basis for regulatory filings later this year in the United States, European Union, United Kingdom, and China.
"We believe these data demonstrate that ATM-AVI, if approved, could be an important treatment option for patients with life-threatening bacterial infections that are resistant to almost all currently available antibiotics," James Rusnak, MD, PhD, Pfizer's senior vice president and chief development officer for internal medicine, anti-infectives, and hospital, said in a company news release.
Patients with complicated infections, pneumonia
The combination of aztreonam with avibactam aims to restore aztreonam's activity against gram-negative bacteria that carry two defense mechanisms that can negate beta-lactam antibiotics—beta-lactamase enzymes and metallo-beta-lactamase (MBL) enzymes. The increasing global prevalence of gram-negative pathogens that carry these enzymes is leading to a rise in severe infections that have limited treatment options.
While aztreonam is able to evade degradation by MBLs, it is susceptible to other beta-lactamase enzymes, which limits its clinical usefulness. The addition of avibactam protects aztreonam from those beta-lactamases.
In the phase 3 REVISIT trial, the safety, efficacy, and tolerability of ATM-AVI with or without metronidazole was compared against meropenem with or without colistin in 422 patients in 20 countries who were hospitalized with complicated intra-abdominal infections (cIAI) or hospital-acquired and ventilator-associated pneumonia (HAP/VAP). The patients were in regions where carbapenem resistance was emerging or endemic and where MBL-producing pathogens were suspected.
We believe these data demonstrate that ATM-AVI, if approved, could be an important treatment option for patients with life-threatening bacterial infections that are resistant to almost all currently available antibiotics.
For patients with cIAI, the cure rate in the intention-to-treat (ITT) analysis was 76.4% for patients in the ATM-AVI treatment arm and 74.0% for patients in the meropenem arm, with a treatment difference of 2.4%. In the clinically evaluable (CE) analysis, the cure rate was 85.1% vs 79.5%. For HAP/VAP patients, the ITT cure rate was 45.9% for ATM-AVI and 41.7% meropenem (treatment difference, 4.3%) and the CE cure rate 46.7% vs 54.5%.
All-cause 28-day mortality rates for cIAI patients were 1.9% in the ATM-AVI group and 2.9% for meropenem, and 10.8% for ATM-AVI versus 19.4% for meropenem in HAP/VAP patients. ATM-AVI was well-tolerated, with a similar incidence of serious adverse events (19.3%) as in the meropenem treatment arm (18.2%)
In the ASSEMBLE trial, ATM-AVI was compared with the best available therapy (BAT) in 15 patients in nine countries who had infections due to confirmed MBL-producing gram-negative bacteria.
The results showed that 41.7% of patients in the ATM-AVI arm were cured at test-of-cure, compared with none of the patients in the BAT arm. None of the patients treated with ATM-AVI experienced a treatment-related serious adverse event.
Promising data for critically ill patients
"These data are particularly promising given the complexities of managing cIAI and HAP/VAP infections in these hospitalized, critically ill patients, and the challenges of real-world patient recruitment within this population," Yehuda Carmeli, MD, MPH, head of the National Institute for Antibiotic Resistance and Infection Control at Tel Aviv Medical Center in Israel, said in the news release.
Pfizer is jointly developing AVM-ATI with AbbVie. The trials were sponsored by Pfizer, with additional support from the US Department of Health and Human Services, the Administration for Strategic Preparedness and Response, and the Biomedical Advanced Research and Development Authority.