Clavulanic Acid

The FDA has cleared Iterum’s oral antibiotic for certain patients with uncomplicated urinary tract infections (uUTIs) who have limited or no alternative oral options. Orlynvah, also known as oral sulopenem, will join a host of antibacterials already on the market for uUTIs. But because of growing antimicrobial resistance and unwanted side effects with some drugs, the company sees a chance to fill an unmet medical need. The drug will also be the first oral drug in a class of antibiotics known as “penems.” Iterum is now looking for a partner with “enough resources to be able to support an appropriate launch,” CEO Corey Fishman said in an interview with Endpoints News . If it can find a partner, Orlynvah could hit the market by the middle of next year. If not, Fishman said “we would consider doing it on our own.” “But we, of course, would have to raise substantial capital to do it,” he said. While the company had applied for broad use in adults with uUTIs, Fishman said the FDA’s label restrictions are “very consistent with how we’ve been thinking the whole time.” The drug is approved specifically for women with uUTIs caused by three microorganisms — Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis — who have limited options. Uncomplicated UTIs are one of the most frequently diagnosed bacterial infections in the US, generating millions of office visits per year, according to research from UCSF’s Department of Clinical Pharmacy. But last month, an FDA advisory committee that reviewed the company’s drug raised concerns about the risks of increasing antimicrobial resistance by opening the door to potential misuse. “We’re not for the otherwise healthy, younger adult woman who has a UTI,” Fishman told Endpoints News on Friday. “What we’ve always said is we are for that at-risk patient, that higher-risk patient, and I think the label supports that.” That jibes with the FDA’s concerns, which in briefing documents for the advisory committee said that an oral penem could result in “inappropriate and/or extensive use,” potentially leading to cross-resistance with carbapenems, a class of antibiotics commonly used for severe infections or in patients resistant to other antibiotics. “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, a deputy director in the CDC’s Division of Healthcare Quality Promotion, during the committee discussion in September. The FDA rejected the drug in 2021, citing a “lack of substantial evidence of effectiveness.” This time around, Iterum submitted new data showing it was superior to an oral amoxicillin/clavulanate regimen on overall clinical and microbiological response in patients susceptible to the comparator.

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.” 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.