Exebacase Combined With Antibiotics Fails to Improve MRSA Bacteremia Outcomes

In a DISTRUPT clinical trial investigating new treatments for MRSA infections, a phase 3 study revealed that the antistaphylococcal lysin exebacase, when combined with standard antibiotics, did not improve clinical outcomes in patients with MRSA bacteremia/endocarditis. This outcome was unexpected, especially considering the promising results from the phase 2 study, which showed the potential effectiveness of the exebacase and antibiotic combination.

The study was terminated early for futility on the recommendation of the unblinded data safety monitoring board, after randomizing 259 patients. In the MRSA group (n=97), Day 14 clinical response rates were 50.0% for exebacase plus antibiotics (32/64) and 60.6% for antibiotics alone (20/33) (P=0.392). Adverse event rates were similar across both groups, and no exebacase-related hypersensitivity events were reported.

“The clinical response rate was unexpected based on the phase 2 study, in which the clinical response rate in the MRSA subgroup at day 14 was 42.8% higher in the exebacase+ antibiotics group compared with the antibiotics alone group (71.1% (20/27) vs. 31.3% (5/16), ad hoc P= 0.0101),” investigators wrote. “The clinical response rate in the antibiotics alone group in the MRSA population (60.6%) was higher than that encountered in the phase 2 execabase study (31.3%) and in most but not all clinical trials in MRSA bacteremia. The sample size calculation for this phase 3 study estimated a 40% clinical response rate in the antibiotics alone group based on the phase 2 study.”

3 Key Takeaways

  1. The phase 3 clinical trial exploring the efficacy of exebacase combined with standard antibiotics for treating MRSA infections ended unexpectedly, as it did not demonstrate improved clinical outcomes in patients with MRSA bacteremia/endocarditis.
  2. The trial was prematurely concluded on the advice of the unblinded Data Safety Monitoring Board after enrolling 259 patients, due to futility.
  3. The discrepancies between the phase 2 and phase 3 trial results, particularly in the clinical response rates within the MRSA population, underscore the need for careful consideration of study design, including the selection of endpoints and the composition of the study population.

In the group receiving only antibiotics, the clinical response rate exceeded what was observed in phase 2. Variability in the study population and the limited sample size of phase 2 and phase 3 studies could have heightened the chance of discrepancies in the diverse elements of the Day 14 clinical outcome.

“Clinical response was a composite endpoint including symptom improvement and no metastatic foci/septic emboli, change in antibiotics due to non-response, or death,” investigators wrote. “This composite endpoint was designed to specifically address regulatory requirements as to how the patient feels, functions, and survives by including a 2-step improvement in a 4-step ordinal scale of attributable symptoms of infection.”

The study’s design was particularly notable; it was structured as a phase 3 superiority trial comparing exebacase plus antibiotics to antibiotics alone, diverging from the conventional noninferiority framework of comparing a new antibiotic against a standard one. Additionally, it focused on a primary efficacy assessment at day 14, rather than utilizing a test-of-cure evaluation.

All in all, this study offers insights for upcoming superiority trials targeting S. aureus bacteremia/endocarditis. Future studies should consider whether improvement or resolution of pain, fatigue, and other symptoms should be a part of clinical response criteria at early time points. The results of the DISTRUPT study were unexpected but it offers important considerations for future investigators seeking to design superiority trials for regulatory approval in similar indications.


Fowler V, Das A, Lipka-Diamond J, Ambler J, Schuch R, et. al. Exebacase in addition to standard-of-care antibiotics for staphylococcus aureus bloodstream infections and right-sided infective endocarditis: a phase 3, superiority-design, placebo-controlled, randomized clinical trial (DISRUPT). Clinical Infectious Diseases. Published January 31, 2024. Accessed February 1, 2024. https://doi.org/10.1093/cid/ciae043

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