Phase 3 data of oral sulopenem for uUTIs published in NEJM Evidence

Data from the phase 3 REASSURE trial (NCT05584657) have been published in NEJM Evidence, demonstrating the non-inferiority of oral sulopenem (sulopenem etzadroxil combined with probenecid in a bilayer tablet; Orlynvah) to oral amoxicillin/clavulanate (Augmentin) in adult women with uncomplicated urinary tract infections (uUTIs).^1,2

Data from REASSURE showed that oral sulopenem was non-inferior to oral amoxicillin/clavulanate.

Oral sulopenem was approved by the FDA in October 2024 based in part on results from the REASSURE trial.³ Specifically, the antibiotic is indicated for the treatment of uUTI caused by the designated microorganisms Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis in adult women who have limited or no alternative oral antibacterial treatment options.

“We are very pleased that NEJM Evidence have published the results from the REASSURE trial,” said Corey Fishman, Iterum’s CEO, in a news release.² “This article highlights the need for new antibiotics, like Orlynvah, for the treatment of uUTI given the increasing rates of multidrug resistance to the currently available antibiotics. We expect Orlynvah to be available to treat women with hard-to-treat infections in the next quarter.”

REASSURE Data

Overall, data from REASSURE showed that oral sulopenem was non-inferior to oral amoxicillin/clavulanate regarding the trial’s primary end point of overall response rate (combined clinical cure plus microbiologic eradication) in patients with uUTI.

Specifically, in the microbiologic-modified intent-to-treat (m-MITTS) population, overall success was achieved in 60.9% of patients in the oral sulopenem arm vs 55.6% of patients in the amoxicillin/clavulanate arm. The between-group difference of 5.4 percentage points (95% CI, -0.8 to 11.5) met the criteria for non-inferiority.

Further, in the primary population of patients with a baseline uropathogen susceptible to amoxicillin/clavulanate, overall success was achieved in 61.7% of patients who received oral sulopenem vs 55% of patients who received amoxicillin/clavulanate (treatment difference, 6.7; 95% CI, 0.3 to 13.0), indicating statistically significant superiority of oral sulopenem in this arm.

In the primary population of patients with a baseline uropathogen that was not susceptible to amoxicillin/clavulanate, overall success occurred in 52.4% of patients in the oral sulopenem arm vs 68% of patients in the amoxicillin/clavulanate arm (difference, -15.6 percentage points; 95% CI, -37.5 to 9.1).

Regarding safety, more patients in the oral sulopenem arm experienced a treatment-emergent adverse event compared with patients in the amoxicillin/clavulanate arm. Specifically, diarrhea was reported in 8.1% vs 4.1% of patients, nausea was reported in 4.3% vs 2.9% of patients, and headache was reported in 2.2% vs 1.5% of patients, respectively.

The REASSURE trial, which was conducted under a special protocol agreement with the FDA, included a total of 2222 adult women with uUTIs. Patients were enrolled across clinical trial sites in the US.⁴ The median age of participants was 51 years IQR, 35 to 62).

Notably, 9.2% of patients in the m-MITTS population had a baseline pathogen that was resistant to 3 or more classes of antibiotics.

For the study, patients were randomly assigned 1:1 to receive 5 days of either oral sulopenem twice daily or amoxicillin/clavulanate twice daily. The primary end point for the study was overall success, defined as the combined clinical cure plus microbiological eradication at the test-of-cure visit (day 12 +/- 1 day).

REFERENCES

1. Puttagunta S, Aronin SI, Gupta J, et al. Sulopenem versus amoxicillin/clavulanate for the treatment of uncomplicated urinary tract infection. NEJM Evid. 2025;4(7):EVIDoa2400414. doi:10.1056/EVIDoa2400414

2. Iterum Therapeutics announces publication of REASSURE trial in NEJM Evidence. News release. Iterum Therapeutics PLC. Published online and accessed June 25, 2025. https://ir.iterumtx.com/press-releases/detail/150/iterum-therapeutics-announces-publication-of-reassure-trial

3. Iterum Therapeutics receives U.S. FDA approval of ORLYNVAH (oral sulopenem) for the treatment of uncomplicated urinary tract infections. News release. Iterum Therapeutics. October 25, 2024. Accessed June 25, 2025. https://www.iterumtx.com/news/press-releases/detail/136/iterum-therapeutics-receives-u-s-fda-approval-of

4. Oral sulopenem versus amoxicillin/​clavulanate for uncomplicated urinary tract infection in adult women (REASSURE). ClinicalTrials.gov. Last updated November 20, 2024. Accessed June 25, 2025. https://clinicaltrials.gov/study/NCT05584657