All Thumbs Up From FDA Panel for Bacterial Pneumonia Therapy

An FDA advisory panel voted unanimously in favor of recommending that the FDA approve sulbactam-durlobactam for the treatment of adults with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by Acinetobacter baumannii‐calcoaceticus complex (ABC) infections.

By a vote of 12-0, the Antimicrobial Drugs Advisory Committee agreed that the benefit-risk assessment for sulbactam-durlobactam was favorable despite limited data, given the tremendous unmet need for treatment of Acinetobacter spp. infections, including carbapenem‐resistant ABC (CRABC) organisms. Still, the advisory committee's unanimous vote came amidst several concerns, with a strong recommendation to monitor the drug closely.

"I voted yes, and this decision was really driven by the clear clinical need for an effective treatment for an organism that is often really drug-resistant if not pan-resistant," said Michael Green, MD, MPH, of Children's Hospital of Pittsburgh, following the vote. There was "no doubt" that 28-day mortality outcomes were improved compared with patients given colistin, he noted, but "clearly there are concerns with the limited size of this study population."

Advisory committee members proposed that the drug developer, Entasis Therapeutics, continue collecting data. "I hope that the company would be mandated to continue to capture safety data going forward, even if it gets approval for this indication," Green added. "There's a great need to enforce surveillance for the development of resistance and even when it occurs, to try to understand it, and also how easily it might spread."

Sulbactam-durlobactam was found to be non-inferior compared with colistin, a last-resort antibiotic for CRABC, for the 28-day mortality primary endpoint (19% vs 32.3%).

The vote occurred in the context of the combo drug having been designated as a qualified infectious disease product, a designation intended to spur development of new antibiotics for difficult-to-treat infections. It now has priority review status, with the FDA to announce a decision on approval at the end of May.

A. baumannii infections are increasingly becoming resistant to colistin, a factor that makes new options necessary, and made it difficult to recruit for the current trial, as patients with colistin-resistant infections were excluded from participating.

Committee members had suggestions for labeling, particularly since both treatment and control participants received background therapy with imipenem‐cilastatin, an antibiotic that targets bacterial infections.

"Since it [sulbactam-durlobactam] was proven efficacious only as combination therapy, it should not be used as monotherapy as we really have no idea how it would perform as monotherapy and the FDA should consider this in the labeling," Richard Murphy, MD, MPH, of the VA White River Junction Medical Center in Vermont, told the committee.

Sally Hunsberger, PhD, of the National Institute of Allergy and Infectious Diseases, suggested that another logistic regression analysis be done to better understand the treatment benefit while controlling for other covariates, which the current trial was not powered to study. "That could help with potentially using this treatment for younger children," she said.

Committee chair Lindsey Baden, MD, of Brigham and Women's Hospital in Boston, added that it will be important to understand how the agent is used in combination with other antimicrobial therapy agents, particularly those that contain β-lactamase, which is inhibited by durlobactam.

Further, "practical issues need to be weighed, such as how it's delivered and if it's delivered 3 out of 4 hours in certain patients," Baden added.

From a clinical perspective, continuous use might be better, some members suggested. The FDA acknowledged this would be reviewed.

ATTACK trial data

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

The data supporting Entasis Therapeutics' application presented at the committee meeting came mainly from a phase III assessor‐blinded, active‐controlled trial (ATTACK) involving 177 patients, most with HABP (43%) and VABP (53%) infections caused by CRABC; 2% had bacteremia, and 2% had ventilator pneumonia.

Among 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% in those who received colistin, a difference also within the non-inferiority margin.

Clinical cure favored sulbactam-durlobactam versus colistin at multiple time points, including at the end of treatment (74.6% vs 45.2%), at the test-of-cure visit (61.9% vs 40.3%), and at a late follow-up visit 14 days after the end of treatment (42.9% vs 30.6%).

In a safety assessment, nephrotoxicity was found to be significantly lower with sulbactam-durlobactam than colistin (13.2% vs 37.6%, P=0.0002).

Compared with the colistin group, the sulbactam‐durlobactam group experienced fewer serious adverse events (48.8% vs 39.6%) and treatment-emergent adverse events (30.2% vs 12.1%). One patient taking sulbactam-durlobactam had a drug‐related serious adverse event (anaphylactic reaction), also a concern discussed among committee members, given the small group of participants.

A decision on approval is expected by next month, with a PDUFA target action date of May 29, according to a press release from Entasis.

The FDA is not obligated to follow the recommendations of its advisory panels, but often does.

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