FDA Approves Oral Sulopenem (Orlynvah) for Uncomplicated Urinary Tract Infections

The FDA has approved oral sulopenem (sulopenem etzadroxil/probenecid), marketed as Orlynvah from Iterum Therapeutics, based on data from a pair of phase 3 trials, SURE 1 (NCT03354598) and REASSURE (NCT05584657), demonstrating its effectiveness against infections caused by Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.

In the SURE 1 trial, oral sulopenem showed superiority over ciprofloxacin for fluoroquinolone-resistant infections, while the REASSURE trial indicated a better response rate compared with amoxicillin/clavulanate. Experts view this approval as a significant advancement in UTI treatment alternatives, especially amid growing concerns about antimicrobial resistance. The FDA’s Antimicrobial Drugs Advisory Committee highlighted the need for careful post-market monitoring to prevent off-label use.

Corey Fishman, CEO of Iterum Therapeutics, highlighted the importance of Orlynvah in providing new options for patients and addressing antimicrobial resistance in a statment, saying, “We are so pleased to have achieved this historic milestone and would like to thank all the patients, investigators, Iterum colleagues and Iterum consultants and vendors who participated in the development of Orlynvah Orlynvah offers new hope for patients suffering from difficult-to-treat uUTIs. The introduction of novel products, like Orlynvah, is an important way to combat antimicrobial resistance to other approved oral agents and offers a potential solution to patients and physicians. As the first oral penem approved in the US, Orlynvah offers an excellent alternative treatment option for appropriate patients in the underserved uUTI market. With FDA approval and a clear label, we will renew our efforts to achieve a strategic transaction involving Orlynvah with the goal of maximizing value for our stakeholders.”¹

Approximately 40 million uUTI prescriptions are generated annually in the US, with about 1% because of pathogens resistant to standard oral antibiotics. Orlynvah is contraindicated in patients with a history of hypersensitivity to its components and may cause adverse reactions such as diarrhea and nausea.

Earlier this year, in September, the FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) met to discuss the drug’s new drug application,^2,3 focusing on the overall benefits and risks and key considerations for medical providers. The agency did not ask the AMDAC to vote on any matter in the meeting. Fishman noted at the time that the company was “encouraged by the AMDAC’s discussion” and pleased that the AMDAC considered it an important option for certain patients and agreed on its appropriate use.

Key Information From The SURE-1 and REASSURE Trials

SURE 1 trial (NCT03354598)

Oral sulopenem was evaluated against ciprofloxacin in patients with uUTIs, focusing on quinolone-susceptible and nonsusceptible uropathogens. The study enrolled 1671 patients, randomly assigning them to receive either oral sulopenem or ciprofloxacin. In the quinolone nonsusceptible population, sulopenem demonstrated a significantly higher overall response rate of 62.6% compared with 36% for ciprofloxacin.

Clinical success was achieved in 83% of the sulopenem group versus 62.6% in the ciprofloxacin group, while microbiological success was noted in 74.1% of patients treated with sulopenem compared with 49.6% for ciprofloxacin, both with statistically significant differences. In the quinolone-susceptible group, sulopenem met the noninferiority threshold, with an overall response rate of 66.8% compared with 78.6% for ciprofloxacin.⁴

REASSURE trial (NCT05584657)

Further assessed oral sulopenem against amoxicillin/clavulanate (Augmentin) in a cohort of 2222 adult women with uUTIs. Participants were randomly assigned to receive either treatment for five days. The trial’s primary endpoint was the overall response rate at the test-of-cure visit. Sulopenem achieved a response rate of 61.7%, while amoxicillin/clavulanate showed a rate of 55%, with a treatment difference of 6.7%.

Clinical success rates were comparable, with sulopenem at 77.3% and amoxicillin/clavulanate at 76.7%. Microbiological success favored sulopenem at 75.2% compared with 66.7% for amoxicillin/clavulanate, indicating a significant advantage. Both treatments were well-tolerated, with less than 1% of patients discontinuing due to adverse events, and no serious adverse events were reported for sulopenem.⁵ Together, these trials underscore the efficacy and safety of oral sulopenem as a promising treatment option for uUTIs, particularly in populations facing antibiotic resistance.

References

1. Iterum Therapeutics receives U.S. FDA approval of ORLYNVAH (oral sulopenem) for the treatment of uncomplicated urinary tract infections. News release. Iterum Therapeutics. October 25, 2024. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/136/iterum-therapeutics-receives-u-s-fda-approval-of

2. September 9, 2024: Meeting of the Antimicrobial Drugs Advisory Committee Meeting Announcement. Updated September 19, 2024. Accessed October 25, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-9-2024-meeting-antimicrobial-drugs-advisory-committee-meeting-announcement-09092024

3. Iterum Therapeutics Provides Update on FDA Advisory Committee Discussion of Oral Sulopenem for the Treatment of uUTI in Adult Women. News release. Iterum Therapeutics. September 10, 2024. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/133/iterum-therapeutics-provides-update-on-fda-advisory

4. Dunne MW, Das A, Akinapelli K, Zelasky MT, Boucher HW, Aronin AI. Efficacy and safety of oral sulopenem etzadroxil/probenecid versus oral ciprofloxacin in the treatment of uncomplicated urinary tract infections (uUTI) in adult women: Results from the SURE-1 trial. Presented at: ID Week 2020. October 21, 2020. https://d1io3yog0oux5.cloudfront.net/_c686b74a40042109ff06b21eccc8f678/iterumtx/db/395/2729/pdf/SURE+1+Slide+Presentation+IDweek+2020+19OCT_final.pdf

5. Iterum Therapeutics announces positive topline results from its phase 3 REASSURE clinical trial of oral sulopenem in uncomplicated urinary tract infections. News release. Iterum Therapeutics plc. January 30, 2024. Accessed October 25, 2024. https://www.prnewswire.com/news-releases/iterum-therapeutics-announces-positive-topline-results-from-its-phase-3-reassure-clinical-trial-of-oral-sulopenem-in-uncomplicated-urinary-tract-infections-302047483.html