FDA Panel to Weigh Limited Data on Combo for Healthcare-Acquired Pneumonia

Data from small trials will determine whether an FDA advisory panel recommends the agency approve sulbactam‐durlobactam for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by Acinetobacter baumannii‐calcoaceticus complex (ABC) infections.

On Monday, the Antimicrobial Drugs Advisory Committee will weigh in on whether the benefit-risk assessment of sulbactam‐durlobactam is favorable based on evidence submitted by developer Entasis Therapeutics, which is specifically seeking an indication for the combination as a treatment for HABP/VABP cases involving susceptible strains of Acinetobacter spp., including carbapenem‐resistant ABC (CRABC) organisms.

"CRABC infections represent an urgent threat in the United States due to the emergence and rapid spread of Acinetobacter resistance and limited treatment options," FDA staff wrote in a briefing document released ahead of the advisory committee meeting.

Data supporting Entasis Therapeutics' application include a phase III trial (ATTACK) involving 177 patients, most with HABP/VABP infections; a phase II study, mostly involving complicated urinary tract infections; and six phase I studies totaling about 200 patients.

Sulbactam‐durlobactam is an investigational intravenous drug consisting of a combination of sulbactam, a β-lactam antibiotic, and durlobactam, a β-lactamase inhibitor, in development for the treatment of ABC infections, including multi-drug and CRABC strains.

Overall, FDA staff noted that sulbactam‐durlobactam "demonstrated non-inferiority" in the randomized, assessor‐blinded, active‐controlled study in hospitalized adults, primarily with HABP (43%) and VABP (53%) caused by CRABC; 2% had bacteremia, and 2% had ventilator pneumonia.

With 28-day mortality as the primary endpoint, results among the 125 patients showed that sulbactam‐durlobactam was non-inferior to colistin, a last-resort antibiotic for CRABC (19% vs 32.3%).

As for secondary endpoints, 14-day all-cause mortality for the CRABC microbiologically modified intent-to-treat group was 6.3% in those who received sulbactam‐durlobactam versus 19% of those who received colistin, a difference also within the non-inferiority margin.

However, "it is important to note the limited size of the current safety database" for sulbactam‐durlobactam, FDA staff wrote.

Compared with the colistin group, the sulbactam‐durlobactam group experienced fewer serious adverse events (48.8% vs 39.6%) and treatment-emergent adverse events (TEAEs; 30.2% vs 12.1%). One patient in the study drug group had a drug‐related serious adverse event (anaphylactic reaction). In both groups, patients experienced a greater proportion of severe TEAEs than mild or moderate TEAEs; moderate and severe TEAEs were less frequent in the sulbactam‐durlobactam group versus the colistin group.

While some subgroup demographics were imbalanced at baseline, results did not suggest these imbalances had affected the study results, FDA staff said.

Sulbactam‐durlobactam is designated by the FDA as a qualified infectious disease product, a designation designed to spur development of new antibiotics for difficult-to-treat infections. The drug is the first in the streamlined program to develop a targeted therapy for CRABC infections.

Limited Options for CRABC

Currently, treatments for infection to drug‐resistant A. baumannii are lacking. Since the bacteria can live for long periods of time on surfaces and shared equipment, and can "colonize" in a patient without causing symptoms or infection, it can be easily spread.

The CDC has designated CRABC as an urgent public health threat, reporting that it caused 8,500 hospitalizations and 700 deaths in 2017. Patients on ventilators, using catheters, those with open wounds from surgery, and those hospitalized or in intensive care are at highest risk for infection, the CDC said.

At this time, treatments include cefiderocol (Fetroja), polymyxins, tetracyclines, and aminoglycosides, but these treatments are limited by both toxicity and lower efficacy. In addition, "treatment‐emergent resistance of CRABC to cefiderocol has been reported," FDA staff wrote.

Resistance to sulbactam in Acinetobacter spp. has also been reported, although it is "primarily due to production of β‐lactamases," they noted. "[Durlobactam] inactivates several β‐lactamases expressed by Acinetobacter including those of Ambler Classes A, C, and D, which degrade [sulbactam]."

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