The U.S. Food and Drug Administration (FDA) has granted approval to Orlynvah (sulopenem etzadroxil and probenecid), a novel oral penem antibiotic, for the treatment of uncomplicated urinary tract infections (uUTIs) in adult women who have limited or no alternative treatment options. Developed by Iterum Therapeutics, Orlynvah is indicated for uUTIs caused by susceptible strains of Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis.
The FDA's decision was influenced by data from two Phase 3 randomized controlled trials. The REASSURE trial, involving 2,241 adult women with uUTIs, demonstrated that Orlynvah achieved a 62% composite response rate (combined microbiologic and clinical response) in patients with amoxicillin/clavulanate-susceptible pathogens, compared to a 55% response rate in those treated with amoxicillin/clavulanate, establishing non-inferiority.
In the SURE-1 trial, conducted with 1,660 adult women suffering from uUTIs caused by ciprofloxacin-resistant pathogens, Orlynvah exhibited superiority over ciprofloxacin, yielding a 48% composite response rate versus 33% in the ciprofloxacin group.
Clinical Efficacy and Safety Profile
The most commonly reported side effects of Orlynvah in clinical trial participants included diarrhea, nausea, vaginal yeast infection, headache, and vomiting. These adverse events were considered manageable and did not significantly impact the overall safety profile of the drug.
Corey Fishman, CEO of Iterum, stated, "Orlynvah offers new hope for patients suffering from difficult-to-treat uUTIs. As the first oral penem approved in the US, Orlynvah offers an excellent alternative treatment option for appropriate patients in the underserved uUTI market."
Concerns Regarding Antimicrobial Resistance
Despite its approval, the FDA and its Antimicrobial Drugs Advisory Committee have expressed concerns regarding the potential for inappropriate use of Orlynvah, which could contribute to antimicrobial resistance. The agency emphasized the need for careful antimicrobial stewardship and consideration by guidelines committees to ensure appropriate positioning of sulopenem etzadroxil/probenecid in the hierarchy of treatment options for uUTI.
The FDA highlighted that the use of an oral penem in an ambulatory setting, where treatment is often empiric, raises concerns about inappropriate use and the potential amplification of resistance to carbapenems, a closely related class of antibiotics crucial for treating serious, multidrug-resistant infections.
Unmet Needs in uUTI Treatment
uUTIs are a prevalent condition among women, accounting for approximately 40 million antibiotic prescriptions annually in the United States. It is estimated that 50% of all women will experience at least one uUTI in their lifetime. Current oral antibiotic treatments for uUTIs have resistance rates near or above 20% and have additional safety concerns. Approximately 5% of patients in the SURE-1 trial had pathogens resistant to all available oral antibiotics.
The FDA's full prescribing information advises that Orlynvah should be reserved for treating uUTIs proven or strongly suspected to be caused by susceptible bacteria. It is not approved as a primary or step-down treatment for complicated UTIs or complicated intra-abdominal infections.
