The combination of the experimental bactericidal drug exebacase with standard-of-care antibiotics failed to improve clinical response in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and infective endocarditis, researchers reported today in Clinical Infectious Diseases.

The investigators say the results of the DISRUPT trial, a superiority-design phase 3 study, were unexpected given the outcome of a phase 2 trial, which found that clinical recovery in MRSA patients who received exebacase plus antibiotics was 42.8% percent higher compared with those who received antibiotics alone. The Food and Drug Administration granted exebacase Breakthrough Therapy designation in 2020 based on the phase 2 results.

In the phase 3 trial, 259 patients aged 12 and older with S aureus bacteremia/endocarditis were randomly assigned 2:1 to receive a single dose of intravenous exebacase—a first-in-class anti-staphylococcal lysin—or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population.

Clinical response rates at day in the MRSA patients were 50% for the exebacase-plus-antibiotics group compared with 60.6% in the patients who received antibiotics alone, and failure rates were 46.9% versus 39.4%, respectively. Overall, the incidence of treatment-emergent adverse events was similar in both groups.

Trial stopped early

The trial was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board.

The investigators say heterogeneity within the study population and relatively small sample size in both the phase 2 and 3 trials "may have increased the probability of imbalances in multiple components of the day 14 outcome," and that a larger sample size, 1:1 randomization, and using both MRSA and methicillin-susceptible S aureus patients for the primary analysis could enhance the study design.

"The failure of this trial offers important considerations for future investigators seeking to design superiority trials for regulatory approval in similar indications," they wrote.

Contrafect, the company that developed exebacase, filed for bankruptcy in December 2023.

The failure of this trial offers important considerations for future investigators seeking to design superiority trials for regulatory approval in similar indications.

Over the past few days, three states reported more highly pathogenic avian influenza outbreaks in poultry, including a commercial turkey farm in Indiana, according to the latest updates from the US Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS).

Indiana's outbreak—its first since May 2023—occurred at a facility in Daviess County that had 13,100 turkeys.

Elsewhere, Florida and Maine reported outbreaks involving backyard flocks. Florida's outbreak was in DeSoto County, and in Maine, the virus struck a location in Kennebec County.

Pace of outbreaks slows

After a steady rise in poultry outbreak that began in early October, the pace of newly reported events since early January has slowed dramatically. So far this month, outbreaks have affected 2.02 million birds, compared to 11.47 million in December.

In related developments, APHIS reported about 60 more H5N1 detections in wild birds, mostly waterfowl across a wide swath of the country, from the Southwest to the Northeast. Most were wild birds found dead, including a few raptors, a gull, and an American crow.