The FDA has raised concerns about potential “inappropriate use” of Iterum’s oral candidate for uncomplicated urinary tract infections (uUTIs) ahead of a Monday advisory committee meeting.
If approved, Iterum’s oral sulopenem (sulopenem etzadroxil/probenecid) would be the first oral antibacterial of the “penem” class on the US market. The drug was rejected by the FDA in 2021 due to a “lack of substantial evidence of effectiveness,” according to the FDA. Now Iterum is back with new data, and the company is arguing that an approval would make available a “safe, and well-tolerated” oral option that can be administered in the outpatient setting.
There are multiple antibacterials already on the market for uUTIs, but unwanted side effects and growing antimicrobial resistance limit some patients’ options. Carbapenem drugs are the “mainstay” of treatment for patients who produce enzymes called extended-spectrum β-lactamases — a group that tends to be resistant to first-line antibacterials, according to the FDA. But those drugs are administered intravenously and sometimes require hospitalization.
An oral option would solve an unmet need, regulators said in briefing documents published Thursday. It would also raise concerns about how the treatment is used.
“Inappropriate use of the drug may contribute to AMR or increase cross-resistance to other carbapenems,” the agency said. Experts suggest that by 2050, AMR or antimicrobial resistance could lead to 10 million deaths annually.
Regulators also raised concerns that the drug may be used off-label as a step-down treatment following the IV treatment of complicated UTI with other drugs.
“There are no data on the effectiveness of oral sulopenem etzadroxil/probenecid as stepdown therapy following IV treatment of cUTI with another β-lactam or carbapenem drug,” regulators said, suggesting that “antimicrobial stewardship and consideration by guidelines committees” may help determine whether sulopenem is an appropriate treatment option.
Sulopenem’s first FDA submission was based on data from the Phase 3 trial known as 301, which showed the drug was superior to an oral comparator called ciprofloxacin in patients who had ciprofloxacin-resistant baseline pathogens, but inferior in patients with ciprofloxacin-susceptible baseline pathogens. Regulators asked for an additional trial.
Upon refiling earlier this year, Iterum also included data from a Phase 3 trial known as 310, which showed that sulopenum was superior to an oral amoxicillin/clavulanate regimen on overall clinical and microbiological response. But regulators noted in briefing documents that the two Phase 3 trials “were not designed to evaluate the efficacy of the study drug for the treatment of uUTI caused by resistant bacterial isolates,” or for uUTI patients who failed first-line treatment.
The FDA is expected to decide on the drug’s approval by Oct. 25.
The agency’s Antimicrobial Drugs Advisory Committee will not vote on the drug, according to the draft agenda, but the agency is asking the committee to discuss the benefits and risks of sulopenem in adults with uUTI caused by designated susceptible microogranisms, and “considerations that would be important for medical providers to know” to ensure appropriate use.