Oral sulopenem demonstrates non-inferiority to amoxicillin/clavulanate in phase 3 uUTI trial

Oral sulopenem demonstrates non-inferiority to amoxicillin/clavulanate in phase 3 uUTI trial | Image Credit: © valiantsin - stock.adobe.com.

Oral sulopenem (ORLYNVAH; Iterum Therapeutics), a new penem antibiotic, was found to be non-inferior to amoxicillin/clavulanate (Augmentin) for the treatment of uncomplicated urinary tract infections (uUTIs) in adult women, according to findings from the phase 3 REASSURE trial (NCT05584657) recently published in NEJM Evidence.^1,2

Conducted under a special protocol agreement with the US Food and Drug Administration (FDA), the REASSURE study enrolled 2,222 adult women with uUTIs. The trial was designed to compare the safety and efficacy of sulopenem etzadroxil combined with probenecid, administered orally twice daily for five days, with oral amoxicillin/clavulanate at the same frequency and duration. The primary endpoint was overall success, defined as the combination of clinical cure and microbiologic eradication at the test-of-cure visit (Day 12 ± 1 day).

In the microbiologically modified intent-to-treat (mMITT) population, comprising participants with baseline urine cultures showing ≥105 CFU/mL of an Enterobacterales uropathogen such as Escherichia coli or Klebsiella species, overall success was achieved in 60.9% of patients treated with sulopenem and in 55.6% of those treated with amoxicillin/clavulanate. The between-group difference of 5.4 percentage points (95% CI, –0.8 to 11.5) met the criteria for noninferiority.

Among patients with a baseline uropathogen susceptible to amoxicillin/clavulanate, success was observed in 61.7% of sulopenem recipients compared with 55.0% for amoxicillin/clavulanate (difference, 6.7 percentage points; 95% CI, 0.3 to 13.0), indicating statistical superiority for sulopenem in this subgroup.

However, in patients with baseline uropathogens not susceptible to amoxicillin/clavulanate, sulopenem showed a success rate of 52.4%, compared to 68.0% for amoxicillin/clavulanate, though this comparison included a small sample size (n=67) and resulted in a wide confidence interval (–15.6 percentage points; 95% CI, –37.5 to 9.1).

Adverse events were more frequently reported in the sulopenem group, with diarrhea (8.1% vs 4.1%), nausea (4.3% vs 2.9%), and headache (2.2% vs 1.5%) being the most common. These were predominantly mild in severity.

Iterum Therapeutics emphasized the relevance of these findings in the context of growing antibiotic resistance. “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,” said Corey Fishman, CEO of Iterum Therapeutics.

Notably, 9.2% of patients in the primary population had a baseline pathogen resistant to three or more classes of antibiotics, underscoring the clinical need for effective oral agents against multidrug-resistant Enterobacterales. Oral sulopenum demonstrated potent activity against extended-spectrum beta-lactamase (ESBL)– and AmpC-producing organisms, which are known to confer resistance to multiple commonly used antibiotics.

RELATED COVERAGE: FDA approves oral sulopenem for treatment of uncomplicated UTIs

On October 25, 2024, the FDA approved oral sulopenum for the treatment of uUTIs caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis in adult women with limited or no alternative oral antibacterial options. The approval was supported by data from two pivotal phase 3 trials, including REASSURE.³

“We expect ORLYNVAH to be available to treat women with hard-to-treat infections in the next quarter,” Fishman added.

The REASSURE trial supports sulopenem as a viable alternative for women with uUTIs, particularly those facing resistance to existing first-line therapies. The findings may help inform treatment decisions for patients with limited oral antibiotic options due to resistance profiles.

References:

1. Puttagunta S, Aronin SI, Gupta J, Das AF, Gupta K, Dunne MW. Sulopenem versus Amoxicillin/Clavulanate for the Treatment of Uncomplicated Urinary Tract Infection. NEJM Evidence. 2025;4(7). doi:https://doi.org/10.1056/evidoa2400414
2. Iterum Therapeutics. Iterum Therapeutics Announces Publication of REASSURE Trial in NEJM Evidence. Global Newswire. June 25, 2025. Accessed June 25, 2025. https://www.globenewswire.com/news-release/2025/06/25/3104937/0/en/Iterum-Therapeutics-Announces-Publication-of-REASSURE-Trial-in-NEJM-Evidence.html
3. Iterum Therapeutics Receives U.S. FDA Approval of ORLYNVAH™ (Oral Sulopenem) for the Treatment of Uncomplicated Urinary Tract Infections. 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

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