Entasis Therapeutics Holdings Inc. announced that top-line data from the company's pivotal Phase 3 ATTACK trial was presented at the 32nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) annual conference, held April 23-26, 2022 in Lisbon, Portugal. In Entasis's first oral presentation, Dr. Alita Miller, PhD, Vice President, Microbiology discussed the Characterization of Acinetobacter baumannii-calcoaceticus complex (ABC) pathogens isolated at baseline from patients enrolled in the ATTACK Phase 3 trial. Dr. Miller reviewed the in vitro susceptibilities of the ABC isolates from the 183 m-MITT patients (those in the ITT population who received any study drug and had an ABC organism isolated at baseline) enrolled in the ATTACK study.

Results showed that this collection was 96% carbapenem- and multidrug-resistant, 84% extensively drug-resistant, and 15% pan-drug resistant. Colistin was the only comparator antibiotic tested with over 60% in vitro susceptibility. In contrast, only 4.6% of isolates had sulbactam-durlobactam (SUL-DUR) MICs >4 mg/L (above the preliminary breakpoint).

Susceptibility to SUL-DUR and comparators was consistent across geographic regions and infection types, except for colistin, whose non-susceptibility ranged from 0% in Latin America and China to 30% in Europe and was higher in isolates from bacteremic patients. In Entasis's second oral presentation, Dr. David Altarac, MD, Chief Medical Officer, highlighted details from the Efficacy and safety of sulbactam-durlobactam (SUL-DUR) versus colistin therapy in patients with Acinetobacter baumannii-calcoaceticus complex (ABC) infections: a global, randomized, active-controlled Phase 3 trial (ATTACK). The ATTACK trial was conducted to evaluate the efficacy and safety of SUL-DUR versus colistin, both in combination with imipenem/cilastatin, for patients with ABC infections, including carbapenem-resistant and multidrug-resistant strains.

The trial consisted of two parts: Part A was a randomized, blinded noninferiority study (SUL-DUR versus colistin; non-inferiority margin 20%) in ABC hospital-acquired pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bacteremia; Part B was an open label study (SUL-DUR only) that enrolled patients with ABC infections who did not tolerate colistin/polymyxin B or whose pathogens were resistant to colistin/polymyxin B. Dr. Altarac presented the following results from Part A of the ATTACK study: The primary efficacy endpoint, 28-day all-cause mortality (ACM) in the carbapenem resistant Acinetobacter baumannii-calcoaceticus (CRABC) m-MITT cohort (n=125) was 19.0% (12/63) and 32.3% (20/62) for SUL-DUR versus colistin, respectively (difference -13.2% [95% CI: -30.0, 3.5]). Clinical cure rates at test-of-cure (TOC) were 61.9% (39/63) and 40.3% (25/62) for SUL-DUR versus colistin (difference 21.6 [95% CI: 2.9, 40.3]). Treatment-related Adverse Events were 12.1% (11/91) and 30.2% (26/86) in the SUL-DUR and colistin groups, respectively.

A statistically significant reduction in nephrotoxicity was observed with SUL-DUR compared to colistin: 13.2% (12/91) versus 37.6% (32/85) (difference -24.4% [p=0.0002]). In addition to the oral presentations, five poster presentations highlighted additional SUL-DUR and ATTACK details and results. Characterization of Co-Infecting Gram-negative pathogens isolated in addition to Acinetobacter baumannii-calcoaceticus complex (ABC) at baseline from patients enrolled in the ATTACK Phase 3 trial examined the susceptibilities of co-infecting Gram-negative pathogens from the ATTACK trial to SUL-DUR plus imipenem.

33% of m-MITT ATTACK patients were co-infected with at least one other Gram-negative pathogen. Notably, only 45% of these isolates were susceptible to imipenem alone while 73% were imipenem-susceptible in the presence of SUL-DUR. Klebsiella and Pseudomonas species were the most common co-infecting pathogens.

Sulbactam-durlobactam (SUL-DUR) in vitro dose response studies with and without imipenem or meropenem against carbapenemase-producing Acinetobacter baumannii utilizing the hollow-fiber infection model showed that, at clinically relevant exposures, SUL-DUR alone (without the presence of a carbapenem) exhibited robust killing activity against a carbapenem resistant Acinetobacter (CRAB) isolate with a SUL-DUR MIC below the preliminary breakpoint (= 4 mg/L). Against isolates with SUL-DUR MICs of 8 mg/L, SUL-DUR activity was enhanced by imipenem or meropenem.