By Marie Rosenthal, MS
Although the FDA asked the Antimicrobial Drugs Advisory Committee (AMDAC) to discuss sulopenem etzadroxil/probenecid (oral sulopenem, Iterum Therapeutics) as an option to treat uncomplicated urinary tract infections (uUTIs), the agency did not ask the panel to vote on a recommendation.
Still, the panel had plenty to say. While acknowledging the need for a safe, oral option to treat UTI, there was concern that oral sulopenem would be used off-label, and this would drive resistance to other carbapenems, which are used to treat serious infections.
Although oral sulopenem would be beneficial for some patients, “there's a high risk of off-label use with significant community risk for amplification of resistance, particularly CRE [carbapenem-resistant Enterobacterales]. There's individual risk to that amplification, not just community risk, and mitigation is likely to center on a timely identification of who's at highest risk,” said Lindsey R. Baden, MD, the acting chairperson of AMDAC.
The FDA shared this concern, according to Peter Kim, MD, MS, the director of the Division of Anti-Infectives, Office of Infectious Diseases, Office of New Drugs, at the Center for Drug Evaluation and Research, FDA. Although an oral penem could address an unmet need for treating uncomplicated infection caused by resistant bacteria, "its use in an ambulatory setting where treatment is most commonly empiric raises concern for inappropriate use," which raises the risk for resistance, he said.
Sulopenem is a broad-spectrum thiopenem beta-lactam antibiotic that is active against Enterobacterales species, which encode for resistance to third-generation cephalosporins, explained Michael Dunne, MD, a board member and consultant at Iterum Therapeutics. Dr. Dunne had been the medical director of the company, and he was one of the presenters for Iterum.
A new drug application (NDA) was submitted in November 2020, and in July 2021, the FDA issued a Complete Response Letter because two trials of effectiveness failed. However, trial 301 found that sulopenem was superior to ciprofloxacin in patients with uUTIs.
The FDA asked for another trial (310), and Iterum resubmitted its NDA in April 2024, to treat adult women with uUTIs caused by designated organisms susceptible to sulopenem, explained Angela Kopack, MD, the FDA clinical reviewer for the application.
Both trials 301 and 310 were phase 3, multicenter, randomized, double-blind, double placebo-controlled studies in women 18 years of age and older. The researchers compared sulopenem etzadroxil/probenecid twice daily for five days with ciprofloxacin twice a day for three days (trial 301) and amoxicillin-clavulanate twice a day for five days (trial 310).
The primary end points in both trials were overall response—both clinical and microbiological—on day 12 and test of cure in three analysis populations, Dr. Kopack explained.
Clinical efficacy was determined by resolution of baseline symptoms of UTI and no new UTI symptoms, and microbiological cure was determined by culture results of less than 103 CFU/mL of the baseline pathogen.
In trial 301, sulopenem was similar to ciprofloxacin for clinical response but did not do as well for microbiological response. In trial 310, superiority was established in participants who were susceptible to amoxicilline-clavulanate.
Dr. Kopack also discussed trial 302, which tested sulopenem in people with complicated UTI, and it was inferior to ciprofloxacin, as were the results in trial 303 for complicated intraabdominal infections. Therefore, everyone-including the company-said it was important that the product, if approved, was labeled and used only for uUTIs.
Because IV sulopenem followed by oral sulopenem was inferiror to the active comparator when it was used to treat cUTI in trial 302, the panel was concerned that oral sulopenem may be used off label for cUTI or other infections, and there was no data about the efficacy of oral sulopenem as stepdown therapy after IV treatment of cUTI with another antibiotic. There was a lot of discussion about the importance of making sure the label was specific about how the drug should be used.
Urinary tract infections are among the most common bacterial community infections, particularly in women, according to Dr. Dunne.
“The total number of prescriptions per year in adult women for uncomplicated UTI in the U.S. generated from various claims databases totals about 40 million prescriptions a year,” Dr. Dunne said, adding that nitrofurantoin, an antibiotic introduced in the 1950s, is most commonly prescribed, but so are quinolones, trimethoprim-sulfamethoxazole and other antibiotics. Many have developed resistance, he explained. As a result, the treatment of UTIs has become more challenging.
Almost 60% of all women experience at least one uUTI at some point in their lives, added Marjorie Golden, MD, the site chief of infectious diseases at the St. Rayfield campus of Yale New Haven Hospital, in Connecticut, and an associate professor of medicine.
“I have a large outpatient clinical practice where I treat many women with recurrent uncomplicated urinary tract infections. We have seen increasing rates of infection with resistant pathogens, which is associated with prolonged duration of symptoms and often requires use of intravenous antibiotics,” Dr. Golden explained.
“Recurrent rates for women with uncomplicated urinary tract infections approach 40%. Furthermore, among women who have already had more than one uncomplicated urinary tract infection, up to 50% can suffer multiple recurrences,” she said.
Dr. Golden said her patients often suffer significant discomfort that affects their quality of life. They suffer pain, and the need for frequent urination and incontinence have “major impacts on their quality of life.” As a result, she added, “studies have documented increased rates of depression in women with recurrent UTIs.”
Diagnosis is often made based on symptoms and a dipstick urinalysis that is positive for leukocyte esterase or nitrite, according to Dr. Kim.
“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 to first-line antibacterial drugs, including through production of extended-spectrum beta-lactamases,” Dr. Kim said.
The current standard of care is usually empiric antibiotic treatment, and although many patients see a clinical cure and resolution of symptoms, others do not respond, according to Dr. Golden.
The fact that most uUTIs are treated empirically is one of the problems, according to members of the panel. Since clinicians do not know the causative organism or its susceptibility, there is a chance that they will prescribe the wrong antibiotic and increase the chances for resistance. Yet, making all patients obtain a urinalysis, which might not be covered by insurance, would put an undue burden on the patient, they said.
Still, the panel felt it was important to obtain this information, perhaps through post-marketing surveillance.
“Whatever tools sort of make sense for that, which are available post-marketing surveillance, will be essential as this is a dynamic problem. So the solutions will have to keep up with the evolutionary pressures, and if there is some mechanism for regulatory review with some period of time and some new data with post-marketing studies to be able to further refine the label and the education and the optimization of its use, I think that is sort of what I heard is multiple themes from the committee,” Dr. Baden said.
“My sense is we share your enthusiasm for new treatments for our patients. We are concerned with how this will fit in so that it doesn't create new problems for us. And we appreciate the agency's hard work and really trying to think this through and get as much input as possible, including from us,” he said.
The panel’s concerns and comments will be considered by the FDA when it makes its final decision on the company’s new drug application, Dr. Kim assured them.
The Prescription Drug User Fee Act date for oral sulopenem is Oct. 25.
