FDA Reviewers Voice Concerns Over Novel UTI Treatment

Ahead of an Antimicrobial Drugs Advisory Committee assembly on Monday, FDA reviewers voiced ongoing considerations about the advantages versus dangers of a novel oral antibiotic for the remedy of uncomplicated urinary tract infections (uUTIs), together with its potential for inappropriate use.

The drug in query — sulopenem etzadroxil/probenecid (sulopenem) — is a penem antibiotic with in vitro exercise in opposition to gram-positive, gram-negative, and anaerobic organisms together with Enterobacterales species that encode extended-spectrum β-lactamases (ESBLs) and AmpC-type β-lactamases.

Based on blended information from part III trial outcomes, the FDA rejected the antibiotic in 2021 and really useful that Iterum Therapeutics conduct a further trial.

After finishing one other part III trial, Iterum resubmitted a new drug application (NDA) in April of this yr. Iterum is looking for approval for sulopenem etzadroxil/probenecid as remedy for uUTI in grownup ladies attributable to prone organisms.

New antibiotics are wanted for the remedy of uUTIs. Currently, oral first-line remedy of uUTIs embrace nitrofurantoin, trimethoprim-sulfamethoxazole, fosfomycin, and pivmecillinam (Pivya). Alternate medicine embrace amoxicillin or oral cephalosporins. However, drug-resistant uUTI might require remedy with IV antibiotics, the FDA identified.

“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 company wrote.

The part III trial from the earlier NDA software (Trial 301, SURE-1) confirmed sulopenem etzadroxil/probenecid was superior to ciprofloxacin for the general response charge within the microbiological modified intent to treat-resistant (micro-MITTR) inhabitants with ciprofloxacin-resistant pathogens. However, it was inferior to ciprofloxacin within the microbiological modified intent to deal with prone (micro-MITTS) inhabitants with ciprofloxacin-susceptible baseline pathogens.

Moreover, two beforehand carried out part III trials — one for classy UTI (Trial 302, SURE-2) and one other for classy intra-abdominal infections (Trial 303, SURE-3) — failed to fulfill their main endpoints for noninferiority to a comparator and medical 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 workers wrote. As a end result, the FDA suggested Iterum to conduct one other trial utilizing one other comparator.

According to particulars in an company briefing document, the brand new trial information (Trial 310, REASSURE) demonstrated that sulopenem etzadroxil/probenecid was non-inferior to amoxicillin/clavulanate in general medical and microbiologic response and superior to its comparator within the micro-MITTS inhabitants.

However, the pattern dimension of sufferers with amoxicillin/clavulanate-resistant organisms (n=67) within the trial was too small to permit for conclusions relating to efficacy of sulopenem etzadroxil/probenecid in that inhabitants, FDA workers identified.

Also, Trials 301 and 310 weren’t designed to judge the efficacy of sulopenem etzadroxil/probenecid within the remedy of antimicrobial resistant uUTI or in ladies who had failed first-line remedy, the company stated.

Regulators warned that “inappropriate use of the drug may contribute to AMR or increase cross-resistance to other carbapenems,” comparable to throughout empiric use within the outpatient setting. They additionally voiced considerations that oral sulopenem etzadroxil/probenecid could also be used off-label for the remedy of sophisticated UTI or different infections, as step-down remedy after IV remedy.

“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 stated.

Nearly 5,000 sufferers have been uncovered to sulopenem IV and/or sulopenem etzadroxil/probenecid throughout its growth, the FDA wrote. No severe or surprising security indicators have emerged, however some hypersensitivity reactions and delicate elevations of liver enzymes have occurred. Gastrointestinal disturbance and vulvovaginal yeast infections are the commonest hostile occasions related to sulopenem.

Currently, carbapenem medicine are the mainstay for remedy of infections attributable to ESBL-producers, however all of them require IV administration and are usually not really useful for empirical remedy.

On Monday, the FDA advisory committee will focus on sulopenem etzadroxil/probenecid’s dangers and advantages and what medical suppliers ought to know to make sure acceptable use.

The company doesn’t plan to vote on the drug’s approval till October 25. If authorised, sulopenem can be the primary oral penem antibiotic marketed within the U.S.