The FDA has granted approval to Iterum Therapeutics' new drug application for ORLYNVAH (sulopenem etzadroxil and probenecid), an oral formulation indicated for the treatment of uncomplicated urinary tract infections (uUTIs) in adult women. This approval is specifically for uUTIs caused by susceptible microorganisms, including Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, and is intended for use when other oral antibacterial treatment options are limited or unavailable.
The FDA's decision marks a significant milestone as it is the first approved indication for ORLYNVAH and the first FDA-approved product for Iterum Therapeutics. According to Corey Fishman, CEO of Iterum Therapeutics, ORLYNVAH offers a potential solution to combat antimicrobial resistance to other approved oral agents.
REASSURE Trial Results
The approval was primarily based on data from the Phase 3 REASSURE trial, a randomized, double-blind, double-dummy, multicenter study. The trial compared the efficacy and safety of oral sulopenem to Augmentin in adult patients (aged 18 and older) with symptomatic uUTIs. Eligible patients presented with at least two uUTI symptoms, such as urgency, frequency, suprapubic pain, or dysuria, for a duration of 24 to 96 hours.
Exclusion criteria included symptoms of acute pyelonephritis, recent antibacterial treatment, use of concurrent non-study medications, urinary tract abnormalities, neurogenic bladder, long-term care residency, recent urinary instrumentation, or the presence of foreign materials in the urinary tract. Participants were randomized to receive either oral sulopenem or Augmentin twice daily for five days. The primary endpoint was the overall response rate on day 12, based on both clinical and microbiologic outcomes. The trial's primary criteria for non-inferiority was that the lower limit of the 95% confidence interval for effectiveness was above -10%.
Results from the REASSURE trial demonstrated that sulopenem was non-inferior to Augmentin in treating uUTIs. Sulopenem achieved an overall response rate of 61.7%, a clinical success rate of 77.3%, and a microbiologic success rate of 75.2%, compared to 55%, 76.7%, and 66.7%, respectively, for Augmentin. The overall treatment difference in response rates was 6.7%, with a 0.6% difference in clinical success and an 8.5% difference in microbiologic success.
Safety and Tolerability
Both treatments exhibited similar tolerability profiles, with adverse-event-related discontinuations occurring in less than 1% of patients in each group. Notably, no serious adverse events (SAEs) were reported among patients treated with sulopenem, while five SAEs were observed in the Augmentin group, none of which were considered drug-related. The safety profile of sulopenem was consistent with previous trials, with no new safety concerns identified beyond those typically associated with β-lactam antibiotics.
Clinical Implications
Marjorie Golden, MD, FIDSA, site chief, infectious disease at St. Raphael Campus Yale New Haven Hospital, stated that ORLYNVAH has the potential to be an important treatment alternative for use in the community. The introduction of novel products like ORLYNVAH is crucial in combating antimicrobial resistance to other approved oral agents and offers a potential solution for patients and physicians in the underserved uUTI market. As the first oral penem approved in the United States, ORLYNVAH offers an excellent alternative treatment option for appropriate patients.
