AMDINOCILLIN PIVOXIL

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.

Pictured: FDA signage at its office in Washington, DC/iStock, JHVEPhoto The FDA on Wednesday approved the use of UTILITY therapeutics’ oral antibiotic pivmecillinam, which will now carry the brand name Pivya, for the treatment of adult women with uncomplicated urinary tract infections. In its approval announcement, the FDA noted that uncomplicated urinary tract infections (UTIs) are bacterial infections of the bladder in females with no structural abnormalities of their urinary tract. The regulator added that approximately one-half of all women experience at least one UTI in their lifetime. Pivya is indicated for patients whose UTIs are caused by susceptible strains of Escherichia coli, Proteus mirabilis and Staphylococcus saprophyticus. UTILITY is working to make Pivya available in the U.S. in 2025, according to reporting from The New York Times. The antibiotic’s approval “will provide an additional treatment option for uncomplicated UTIs,” Peter Kim, director of the Division of Anti-Infectives at the FDA’s Center for Drugs Evaluation and Research, said in a statement. “Uncomplicated UTIs are a very common condition … and one of the most frequent reasons for antibiotic use.” The FDA’s approval on Wednesday was supported by data from three clinical trials, which compared Pivya to placebo, another oral antibacterial agent as well as to the anti-inflammatory drug ibuprofen. All three studies primarily evaluated Pivya’s composite response rate, which included clinical cure and microbiological response. In the placebo study, Pivya treatment elicited a 62% composite response rate at eight to 14 days after enrollment. Only 10% of placebo counterparts achieved the composite response endpoint. When compared with another antibacterial agent, Pivya elicited a 72% composite response rate versus 76% in those who received the other drug. In the third trial, 66% of patients treated with Pivya achieved composite response compared to only 22% of those who were given ibuprofen. In terms of safety, Pivya was overall well-tolerated and its most common side effects were nausea and diarrheas. The antibiotic carries warnings for hypersensitivity reactions, carnitine depletion, Clostridioides difficile-associated diarrhea and severe cutaneous adverse reactions. It should not be taken by patients with known histories of severe hypersensitivities against beta-lactam drugs. Pivya can also interfere with a newborn screening test for the rare metabolic disorder isovaleric acidemia. Pivya’s active ingredient pivmecillinam is an aminopenicillin, which is a specific subclass of beta-lactams that work by disrupting the synthesis of the bacterial cell wall. According to UTILITY’s website, pivmecillinam has already been commercially approved for more than 40 years outside the U.S. and has long been used to successfully treat UTIs. Pivmecillinam has also been recommended as the frontline treatment option in many countries. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.