Oral sulopenem (ORLYNVAH; Iterum Therapeutics), a novel penem antibiotic, demonstrated non-inferiority to amoxicillin/clavulanate for treating uncomplicated urinary tract infections (uUTIs) in adult women, according to results from the phase 3 REASSURE trial published in NEJM Evidence. The findings support the drug's potential role in addressing growing antibiotic resistance challenges in urinary tract infection management.
Trial Design and Patient Population
The REASSURE study, conducted under a special protocol agreement with the FDA, enrolled 2,222 adult women with uUTIs. Participants were randomized to receive either sulopenem etzadroxil combined with probenecid or amoxicillin/clavulanate, both administered orally twice daily for five days. The trial's primary endpoint was overall success, defined as the combination of clinical cure and microbiologic eradication at the test-of-cure visit on Day 12.
Efficacy Results
In the microbiologically modified intent-to-treat (mMITT) population, which included participants with baseline urine cultures showing ≥10⁵ CFU/mL of Enterobacterales uropathogens such as Escherichia coli or Klebsiella species, overall success was achieved in 60.9% of patients treated with sulopenem compared to 55.6% of those receiving amoxicillin/clavulanate. The between-group difference of 5.4 percentage points (95% CI, −0.8 to 11.5) met the predefined criteria for noninferiority.
Subgroup Analysis by Susceptibility
Among patients with baseline uropathogens susceptible to amoxicillin/clavulanate, sulopenem demonstrated statistical superiority with a success rate of 61.7% compared to 55.0% for amoxicillin/clavulanate (difference, 6.7 percentage points; 95% CI, 0.3 to 13.0).
However, in the small subgroup of patients with baseline uropathogens not susceptible to amoxicillin/clavulanate (n=67), sulopenem showed a success rate of 52.4% compared to 68.0% for amoxicillin/clavulanate, though this comparison resulted in a wide confidence interval (−15.6 percentage points; 95% CI, −37.5 to 9.1).
Safety Profile
Adverse events occurred more frequently in the sulopenem group, with diarrhea being the most common (8.1% vs 4.1%), followed by nausea (4.3% vs 2.9%) and headache (2.2% vs 1.5%). These adverse events were predominantly mild in severity.
Addressing Antibiotic Resistance
The trial highlighted significant resistance challenges in the patient population, with 9.2% of patients having baseline pathogens resistant to three or more classes of antibiotics. Oral sulopenem demonstrated potent activity against extended-spectrum beta-lactamase (ESBL) and AmpC-producing organisms, which confer resistance to multiple commonly used antibiotics.
"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.
Regulatory Approval and Market Impact
The FDA approved oral sulopenem on October 25, 2024, for treating 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.
As the first oral penem approved in the United States, sulopenem addresses a significant clinical need in the underserved uUTI market. UTIs account for approximately 15 million emergency room and office visits annually, with over 40 million total prescriptions for uUTIs in the US, according to market research cited by Iterum Therapeutics.
"We expect ORLYNVAH to be available to treat women with hard-to-treat infections in the next quarter," Fishman added, emphasizing the drug's potential impact on patients facing limited treatment options due to antibiotic resistance.
