Ciprofloxacin

An FDA advisory panel will discus Iterum’s urinary tract infection treatment sulopenem on Monday ahead of its October 25 decision date at the agency. Five months after signing off on Utility Therapeutics’ Pivya as the first new treatment for uncomplicated urinary tract infections (uUTIs) in more than two decades, the FDA is weighing the pros and cons of another oral treatment in the indication.Iterum’s sulopenem (sulopenem etzadroxil/probenecid), which was initially rejected by the US regulator in 2021, is back for another swing, with a target decision date set for October 25.On Monday, an FDA advisory committee will put sulopenem under its microscope, fleshing out concerns that “inappropriate use” of the treatment could cause antimicrobial resistance (AMR), according to an FDA briefing document (PDF).There also is concern that inappropriate use of sulopenem could increase “cross-resistance to other carbapenems,” the FDA added, referring to the class of drugs that treat severe bacterial infections, often as a last-resort measure.On the plus side, an approval for sulopenem would “potentially address an unmet need,” the FDA wrote, as it would become the first oral therapy from the penem class to reach the market as a treatment for uUTIs. Additionally, it could be provided in an outpatient visit, as opposed to the administration of intravenous therapies which can require hospitalization.  Three years ago, the FDA turned down Iterum’s application for sulopenem, asking for a new trial. Iterum’s prior phase 3 study showed the drug beat another antibiotic, ciprofloxacin, at treating infections in patients whose infections resisted that antibiotic. But it was inferior to ciprofloxacin in treating those whose pathogens were susceptible to the older antibiotic.In January of this year, Dublin-based Iterum revealed that the phase 3 REASSURE study showed that sulopenem was non-inferior to Augmentin (amoxicillin/clavulanate), producing a 62% response rate versus 55% for the comparator.The FDA, however, in its briefing documents pointed out that neither of Iterum’s phase 3 trials were “designed to evaluate the efficacy of the study drug for the treatment of uUTI caused by resistant bacterial isolates.”The FDA also noted that the trials weren’t designed to evaluate Iterum's prospect in uUTI patients who had failed first-line treatment.  Over the years, antibiotic treatments have become less effective as resistance to them has increased. More than 1 in 5 who receive treatment are now resistant, which can lead to progression of infections, including life-threatening sepsis.The void is significant as more than 30 million uUTIs are diagnosed every year in the U.S., with nearly half of all women contracting the infection at some point in their life. Outside of a hospital setting, UTIs account for more antibiotic use than any other disorder.

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.