Pfizer Investigational Antibiotic Combination Demonstrates Efficacy Against Gram-Negative Infections

Pfizer recently reported results from its phase 3 program comprising the REVISIT and ASSEMBLE trials for its novel combination antibiotic, aztreonam-avibactam (ATM-AVI), which showed a therapeutic benefit and had a favorable safety profile when treating serious bacterial infections due to Gram-negative bacteria, including metallo-β-lactamase (MBL)-producing multidrug-resistant pathogens.

ATM-AVI combines aztreonam, a monobactam β-lactam, with avibactam, a recent broad-spectrum β-lactamase inhibitor. The combination of aztreonam with avibactam restores aztreonam’s activity against bacteria that co-produce MBLs and other β-lactamases

“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, senior vice president and chief development officer, Internal Medicine, Anti-Infectives and Hospital, Pfizer, said in a statement. “We are committed to meeting this critical need and helping to address the global health threat of antimicrobial resistance.”

The REVISIT study compared ATM-AVI ± metronidazole (MTZ) with meropenem (MER) ± colistin (COL) for the treatment of cIAI, HAP, and VAP.

The topline data from the study included:

• For patients with cIAI, cure rate in the intention to treat (ITT) analysis set was 76.4% (95% confidence interval (CI) [70.3, 81.8]) for the ATM-AVI ± MTZ treatment arm vs 74.0% (95% CI [65.0, 81.7]) for the MER ± COL treatment arm, with a treatment difference of 2.4% (95% CI [-12.4, 19.1]). In the clinically evaluable (CE) analysis set, cure rate was 85.1% (95% CI [79.2, 89.9]) for ATM-AVI ± MTZ versus 79.5% (95% CI [69.9, 87.1]) for MER ± COL.
• For patients with HAP/VAP, cure rate in the ITT analysis set was 45.9% (95% CI [34.9, 57.3]) for ATM-AVI ± MTZ versus 41.7% (95% CI [26.7, 57.9]) for MER ± COL, with a treatment difference of 4.3% (95% CI [-25.6, 32.2]). In the CE analysis set, cure rate was 46.7% (95% CI [32.7, 61.1]) for ATM-AVI ± MTZ vs 54.5% (95% CI [34.3, 73.7]) for MER ± COL.
• All-cause 28-day mortality rates were 4/208 (1.9%) for ATM-AVI ± MTZ versus 3/104 (2.9%) for MER ± COL in cIAI, and 8/74 (10.8%) for ATM-AVI ± MTZ versus 7/36 (19.4%) for MER ± COL in HAP/VAP.
• ATM-AVI ± MTZ was well-tolerated, with an overall observed pattern of treatment-emergent adverse events (TEAEs) in line with that described for aztreonam alone. The incidence of serious adverse events (SAEs) was similar between treatment groups (53 [19.3%] patients in the ATM-AVI ± MTZ group and 25 [18.2%] patients in the MER ± COL group). No patient treated with ATM-AVI ± MTZ experienced a treatment-related SAE.

For the ASSEMBLE study, 5/12 (41.7%) of the ATM-AVI ± MTZ patients with infections due to confirmed MBL-producing Gram-negative bacteria were cured at TOC versus 0/3 (0%) of those on best available therapy (BAT). ATM-AVI patients experienced TEAEs that were in line with those of aztreonam alone. No patient treated with ATM-AVI experienced a treatment-related SAE.

The company is planning to provide its full results from the studies in a future scientific publication. And Pfizer is planning regulatory filings in the European Union, United Kingdom, China, and the US in the second half of 2023.