UTILITY therapeutics Ltd.

An FDA advisory panel will discus Iterum’s urinary tract infection treatment sulopenem on Monday ahead of its October 25 decision date at the agency. Five months after signing off on Utility Therapeutics’ Pivya as the first new treatment for uncomplicated urinary tract infections (uUTIs) in more than two decades, the FDA is weighing the pros and cons of another oral treatment in the indication.Iterum’s sulopenem (sulopenem etzadroxil/probenecid), which was initially rejected by the US regulator in 2021, is back for another swing, with a target decision date set for October 25.On Monday, an FDA advisory committee will put sulopenem under its microscope, fleshing out concerns that “inappropriate use” of the treatment could cause antimicrobial resistance (AMR), according to an FDA briefing document (PDF).There also is concern that inappropriate use of sulopenem could increase “cross-resistance to other carbapenems,” the FDA added, referring to the class of drugs that treat severe bacterial infections, often as a last-resort measure.On the plus side, an approval for sulopenem would “potentially address an unmet need,” the FDA wrote, as it would become the first oral therapy from the penem class to reach the market as a treatment for uUTIs. Additionally, it could be provided in an outpatient visit, as opposed to the administration of intravenous therapies which can require hospitalization.  Three years ago, the FDA turned down Iterum’s application for sulopenem, asking for a new trial. Iterum’s prior phase 3 study showed the drug beat another antibiotic, ciprofloxacin, at treating infections in patients whose infections resisted that antibiotic. But it was inferior to ciprofloxacin in treating those whose pathogens were susceptible to the older antibiotic.In January of this year, Dublin-based Iterum revealed that the phase 3 REASSURE study showed that sulopenem was non-inferior to Augmentin (amoxicillin/clavulanate), producing a 62% response rate versus 55% for the comparator.The FDA, however, in its briefing documents pointed out that neither of Iterum’s phase 3 trials were “designed to evaluate the efficacy of the study drug for the treatment of uUTI caused by resistant bacterial isolates.”The FDA also noted that the trials weren’t designed to evaluate Iterum's prospect in uUTI patients who had failed first-line treatment.  Over the years, antibiotic treatments have become less effective as resistance to them has increased. More than 1 in 5 who receive treatment are now resistant, which can lead to progression of infections, including life-threatening sepsis.The void is significant as more than 30 million uUTIs are diagnosed every year in the U.S., with nearly half of all women contracting the infection at some point in their life. Outside of a hospital setting, UTIs account for more antibiotic use than any other disorder.

Nearly half of women will get a urinary tract infection in their lifetime. For the first time in more than 20 years the FDA has approved an antibiotic to treat the condition. For the first time in more than 20 years, the FDA has approved a treatment for uncomplicated urinary tract infections (uUTI). And the nod has come for an oral antibiotic that has been available in Europe for more than 40 years. It’s an odd set of circumstances and a dose of foresight by Utility Therapeutics that bring Pivya (pivmecillinam) to the market in the United States in the therapy’s golden years. The London-based company was formed specifically to develop and commercialize pivmecillinam in the U.S. where antimicrobial resistance is growing to standard of care antibiotics. The decreased “utility” of first-line antibiotics and the void the company is attempting to fill in the U.S. were the inspiration of the name of the company. And the void is significant as more than 30 million uUTIs are diagnosed every year in the U.S., with nearly half of all women contracting the infection at some point in their life. Outside of hospital setting, UTIs account for more antibiotic use than any other disorder. In 2018, Utility inked a licensing agreement with LEO Pharma, acquiring the U.S. rights to pivmecillinam and its subcutaneous formulation mecillinam, which the company has submitted for approval as a first-line therapy for complicated urinary tract infections (cUTI) in the hospital setting. The difference between cUTIs and uUTIs is that the former has reached the kidneys while the latter is limited to the bladder. “The FDA is committed to fostering new antibiotic availability when they prove to be safe and effective and Pivya will provide an additional treatment option for uncomplicated UTIs,” Peter Kim, M.D., the director of the Division of Anti-Infectives at the FDA’s Center for Drug Evaluation and Research, said in a release. The year that Utility acquired the rights to pivmecillinam and mecillinam, the FDA signed off on each as a Qualified Infectious Disease Product (QIDP). The status is extended to antibacterial and antifungal drug candidates intended to treat serious or life-threatening infections. When a QIDP treatment is approved, it gains an additional five years of market exclusivity. On the same day in January, when Utility revealed that the FDA had accepted the company’s new drug applications for pivmecillinam and mecillinam, it also announced it had received private funding from the AMR Action Fund. The global initiative—which was established by several prominent drugmakers including Amgen, Bayer, Eli Lilly, GSK, Novo Nordisk and Roche—invests in the development of new antimicrobial therapeutics. In addition to being a prodrug, which means that it is not pharmacologically active until it is digested and absorbed into the system, Pivya has a unique mechanism of action, targeting penicillin binding protein-2 in the cell wall of gram-negative bacteria. Pivya’s efficacy was assessed in separate trials versus placebo, an oral antibacterial and ibuprofen. The primary measure of efficacy in the studies was the composite response rate, which included clinical cure (resolution of the symptoms of the uUTI that were present in patients at trial entry and no new symptoms) and microbiological response (demonstration that the bacteria cultured from patients’ urine at trial entry was reduced). In the placebo trial, 62% of the participants who received Pivya achieved composite response compared to 10% of those on placebo. In the oral antibacterial trial, 72% of the subjects who received Pivya achieved composite response versus 76% of those on the comparator. In the third trial, 66% of the subjects who received Pivya achieved composite response compared to 22% of those on ibuprofen.  Commonly prescribed drugs for uUTIs in the U.S. are bactrim (sulphamethoxazole/trimethoprim), nitrofuranatoin and fluoroquinolones. But more than 1 in 5 who receive these are resistant, which can lead to progression of the disease, including life-threatening sepsis. Last month, Germany’s Allecra Therapeutics scored FDA approval for its antibiotic Exblifep, which is a combination of cephalosporin antibacterial cefepime and the beta-lactamase inhibitor enmetazobactam, to treat cUTI. The approval came days after the U.S. regulator rejected another combo therapy in the same indication from Venatorx Pharmaceuticals and Melinta Therapeutics.

Pivya is intended for treating UTIs. Credit: ANN PATCHANAN via Shutterstock. The US Food and Drug Administration (FDA) has approved Utility Therapeutics’ Pivya tablets, a new treatment for female adults with uncomplicated urinary tract infections (UTIs). This decision is based on the efficacy of Pivya in treating UTIs caused by susceptible Escherichia coli isolates , Staphylococcus saprophyticus and Proteus mirabilis. The approval was supported by three controlled clinical trials. These trials assessed the efficacy of Pivya in treating females aged 18 years or older with uncomplicated UTIs, comparing various dosing regimens of the drug to placebo, another oral antibacterial drug, and to anti-inflammatory drug ibuprofen. The trials’ primary efficacy measure was the composite response rate, which included both clinical cure and microbiological response. In the study comparing Pivya to placebo, 62% of the 137 participants receiving the therapy achieved the composite response, significantly higher than the 10% response rate in the placebo group. See Also: Mundipharma to acquire rezafungin assets from Cidara Therapeutics Novartis bags paediatric FDA label expansion for Lutathera When compared to another oral antibacterial drug, Pivya’s composite response rate was 72%, closely matching the comparator drug’s 76%. Against ibuprofen, Pivya showed a 66% response rate, compared to 22% for those who received the anti-inflammatory drug. Nausea and diarrhoea were the common side effects reported during the trials for Pivya. The FDA advises against the use of Pivya in patients with a history of severe hypersensitivity to beta-lactam antibacterial drugs, those with carnitine deficiency disorders, and individuals suffering from porphyria. Pivya carries warnings for potential hypersensitivity reactions, carnitine depletion, severe cutaneous adverse reactions, Clostridioides difficile-associated diarrhoea, and possible interference with newborn screening tests for metabolic disorder isovaleric acidemia. The FDA granted Pivya priority review and qualified infectious disease product designations. FDA Center for Drug Evaluation and Research Anti-Infectives division director Peter Kim said: “Uncomplicated UTIs are a very common condition impacting women and one of the most frequent reasons for antibiotic use. “The FDA is committed to fostering new antibiotic availability when they prove to be safe and effective, and Pivya will provide an additional treatment option for uncomplicated UTIs.”