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Ahead of an meeting on Monday, FDA reviewers voiced ongoing concerns about the benefits versus risks of a novel oral antibiotic for the treatment of uncomplicated urinary tract infections (uUTIs), including its potential for inappropriate use.

The drug in question -- sulopenem etzadroxil/probenecid (sulopenem) -- is a penem antibiotic with in vitro activity against gram-positive, gram-negative, and anaerobic organisms including Enterobacterales species that encode extended-spectrum β-lactamases (ESBLs) and AmpC-type β-lactamases.

Based on mixed data from phase III trial outcomes, the FDA rejected the antibiotic in 2021 and recommended that Iterum Therapeutics conduct an additional trial.

After completing another phase III trial, Iterum of this year. Iterum is seeking approval for sulopenem etzadroxil/probenecid as treatment for uUTI in adult women caused by susceptible organisms.

New antibiotics are needed for the treatment of uUTIs. Currently, oral first-line treatment of uUTIs include nitrofurantoin, trimethoprim-sulfamethoxazole, fosfomycin, and pivmecillinam (Pivya). Alternate drugs include amoxicillin or oral cephalosporins. However, drug-resistant uUTI may require treatment with IV antibiotics, the FDA pointed out.

"While there are multiple FDA-approved oral antibacterial drugs for the treatment of uUTI, treatment options can be limited by adverse reactions and increasing antimicrobial resistance (AMR) to first-line antibacterial drugs, including through production of extended-spectrum β-lactamases," the agency wrote.

The phase III trial from the previous NDA application (Trial 301, ) showed sulopenem etzadroxil/probenecid was superior to ciprofloxacin for the overall response rate in the microbiological modified intent to treat-resistant (micro-MITTR) population with ciprofloxacin-resistant pathogens. However, it was inferior to ciprofloxacin in the microbiological modified intent to treat susceptible (micro-MITTS) population with ciprofloxacin-susceptible baseline pathogens.

Moreover, two previously conducted phase III trials -- one for complicated UTI (Trial 302, ) and another for complicated intra-abdominal infections (Trial 303, SURE-3) -- failed to meet their primary endpoints for noninferiority to a comparator and clinical response, respectively.

Findings from these trials "created uncertainty regarding the efficacy of sulopenem and the treatment of bacterial infections caused by pathogens relevant to uUTI," FDA staff wrote. As a result, the FDA advised Iterum to conduct another trial using another comparator.

According to details in an agency , the new trial data (Trial 310, REASSURE) demonstrated that sulopenem etzadroxil/probenecid was non-inferior to amoxicillin/clavulanate in overall clinical and microbiologic response and superior to its comparator in the micro-MITTS population.

However, the sample size of patients with amoxicillin/clavulanate-resistant organisms (n=67) in the trial was too small to allow for conclusions regarding efficacy of sulopenem etzadroxil/probenecid in that population, FDA staff pointed out.

Also, Trials 301 and 310 were not designed to evaluate the efficacy of sulopenem etzadroxil/probenecid in the treatment of antimicrobial resistant uUTI or in women who had failed first-line treatment, the agency said.

Regulators warned that "inappropriate use of the drug may contribute to AMR or increase cross-resistance to other carbapenems," such as during empiric use in the outpatient setting. They also voiced concerns that oral sulopenem etzadroxil/probenecid may be used off-label for the treatment of complicated UTI or other infections, as step-down treatment after IV therapy.

"Careful antimicrobial stewardship and consideration by guideline committees are needed to ensure appropriate positioning of sulopenem etzadroxil/probenecid in the hierarchy of treatment options for uUTI," the FDA said.

Nearly 5,000 patients have been exposed to sulopenem IV and/or sulopenem etzadroxil/probenecid across its development, the FDA wrote. No serious or unexpected safety signals have emerged, but some hypersensitivity reactions and mild elevations of liver enzymes have occurred. Gastrointestinal disturbance and vulvovaginal yeast infections are the most common adverse events associated with sulopenem.

Currently, carbapenem drugs are the mainstay for treatment of infections caused by ESBL-producers, but they all require IV administration and are not recommended for empirical treatment.

On Monday, the FDA advisory committee will discuss sulopenem etzadroxil/probenecid's risks and benefits and what medical providers should know to ensure appropriate use.

The agency does not plan to vote on the drug's approval until October 25. If approved, sulopenem would be the first oral penem antibiotic marketed in the U.S.

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