FDA AdCom supports Entasis’ antibiotic for resistant infections

On 17 April, a US Food and Drug Administration (FDA) Advisory Committee (AdCom) has unanimously voted in favour of the potential approval of Entasis Therapeutics’ sulbactam-durlobactam for the treatment of adults with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible strains of Acinetobacter baumannii-calcoaceticus complex.

Members of the FDA’s Antimicrobial Drugs AdCom voted 12-0 for the drug’s potential approval based on a positive benefit-risk assessment. The agency accepted the drug’s new drug application (NDA) for priority review in November 2022.

The application’s PDUFA date was set to 29 May 2023. Entasis is a subsidiary of Innoviva.

Also known as SUL-DUR, sulbactam-durlobactam is a targeted antibiotic that combines the β-lactamase inhibitors sulbactam and durlobactam.

Acinetobacter is a major cause of hospital-acquired infections, said Dr. David Paterson, professor at National University of Singapore’s Saw Swee Hock School of Public Health, who presented at the meeting. There is no clear standard of care for these infections, said Paterson.

The World Health Organization (WHO) designated carbapenem-resistant Acinetobacter baumannii as a priority pathogen for new antibiotic development in 2017. Carbapenems are a class of antibiotics.

New treatment needed but postmarket surveillance is important

There is a clear clinical need for an effective treatment against an extremely drug-resistant organism, said Dr. Michael Green, professor of paediatrics, surgery, and clinical and translational science at the University of Pittsburgh’s School of Medicine.

Specifically, the committee voted on whether the overall benefit-risk assessment was favourable for the use of the drug in the patients prespecified in the NDA.

The NDA submission features data from the Phase III ATTACK trial, which studied the treatment’s safety and efficacy in comparison to the antibiotic colistin, based on a November 2022 press release. Also called polymyxin E, colistin is used as a “last-resort” treatment for bacterial infections caused by susceptible Gram-negative bacteria.

According to the trial’s results, sulbactam-durlobactam was reported to be statistically non-inferior against colistin in the primary endpoint of the 28-day all-cause mortality. The drug had a favourable safety profile, including a statistically significant reduction in nephrotoxicity, based on the press release.

However, there are some concerns with the relatively small size of the studied population, which impacts the understanding of the drug’s safety profile, said Green.

While the number of patients is small, this disease process is difficult to study, said panel member Dr. Richard Murphy, chief of infectious diseases at the Veterans Affairs White River Junction Medical Center. It is also unlikely that the efficacy would be lower than the antibiotic colistin, which is less safe, he added.

Overall, sulbactam-durlobactam appears “friendlier” to the patient’s kidneys than colistin, noted Dr. George Siberry, medical officer at the Adult Clinical Branch of the Office of HIV/AIDS at the United States Agency for International Development’s Bureau of Global Health.  

According to Siberry, the high risk of death that comes with these infections was the reason for his positive vote. He adds that due to limited available data, there should be enhanced surveillance when it comes to the safety profile.