An FDA advisory committee raised concerns Monday about whether Iterum’s application for a new oral antibacterial to treat urinary tract infections is restrictive enough to balance the risk of increased antimicrobial resistance.
The agency’s Antimicrobial Drugs Advisory Committee was asked to weigh in on the benefits and risks of approving Iterum’s oral sulopenem in adults with uncomplicated urinary tract infections (uUTIs) caused by designated susceptible microorganisms. While the committee was not asked to vote on the matter, some members suggested the indication should be more restrictive.
“An acceptable positive benefit-risk ratio would require wording that restricts the use to a population at substantially higher risk of treatment failure with currently available first-line oral agents,” said Roger Lewis, an advisory committee member and UCLA professor-in-residence.
In briefing documents published ahead of the meeting, the FDA cautioned that inappropriate use of sulopenem may contribute to antimicrobial resistance, which the World Health Organization has called one of the top global public health threats. But advisory committee members also stressed that misuse could pose risks to individual patients, by increasing cross-resistance to other drugs in the “penem” class.
If approved, Iterum’s sulopenem would be the first oral antibacterial “penem” drug on the US market.
“How would we feel as providers if we gave somebody courses of a penem antibiotic for a non-life threatening uncomplicated urinary tract infection, and then a month later, or two months later, or three months later, that patient gets admitted with sepsis due to a penem-resistant organism and dies from that infection?” asked Arjun Srinivasan of the CDC’s Division of Healthcare Quality Promotion.
Srinivasan said sulopenem could be a “really desirable option” for a patient with a resistant infection, or someone who’s failed a prior treatment. But he added that “almost all antibiotic use is off-label. There’s nothing that would stop this from going down that exact same road.”
Labeling considerations
While there are multiple antibacterials already on the market for uncomplicated UTIs, unwanted side effects and growing antimicrobial resistance limit some patients’ options. Iterum has argued that sulopenem would fill an unmet need, making the case that a substantial number of infected women will have “severely limited” options. The company said in briefing documents that the wrong choice of therapy for these women is risky, in part because of additional side effects from another antibiotic course.
The FDA said it has a number of labeling strategies that could be useful in a situation like this, including contraindications, limitations of use or warnings. Regulators also mentioned the FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) pathway, which requires specific labeling and pre-review of promotional materials to convey that the drug should only be used in a limited population.
However, they specified that they haven’t determined whether sulopenem would fit into that category, and Iterum would need to voluntarily seek approval via the pathway.
The FDA rejected sulopenem in 2021 due to a “lack of substantial evidence of effectiveness.” Iterum submitted new data this time showing that sulopenem was superior to an oral amoxicillin/clavulanate regimen on overall clinical and microbiological response in patients susceptible to the comparator.
The FDA is expected to decide on the drug’s approval by Oct. 25.