dm+d

Unassigned

New Medicines

Uncomplicated urinary tract infection, especially fluoroquinolone resistant - oral formulation

Information

New molecular entity
Iterum Therapeutics
Iterum Therapeutics

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Not approved
Jul 21US FDA reject new drug application for oral sulopenem as a potential treatment for uUTI in pts with a quinolone non-susceptible pathogen. Whilst the FDA agreed that the sulopenem etzadroxil/probenecid demonstrated a statistical significance in the the PIII SURE-1 study, the overall response rate compared to ciprofloxacin in the ciprofloxacin-resistant population. The FDA called for an additional study that uses a different drug for comparison and a non-clinical study to determine optimal dosing. Iterum say they remain confident in the value of, and unmet medical need for, oral sulopenem to treat multi-drug resistant infections, including fast-growing quinolone non-susceptible pathogens. [11]
Mar 21Iterum is considering the timing of filing to the EMA. It intends to use a third party to commercialise oral sulopenem in the US. In H1 2021, it plans to request a meeting with the FDA to discuss the potential path to regulatory approval for oral sulopenem and the IV formulation in cUTI; depending on the outcome of that discussion, it may need to perform additional clinical development. It may also pursue development of the sulopenem program in additional indications in adults and children, including community acquired bacterial pneumonia, bacterial prostatitis, diabetic foot infection and bone and joint infection, as well as new formulations to support these indications. If oral sulopenem is approved for treatment of uUTI in patients with a quinolone non-susceptible pathogen, Iterum plans to request a meeting with the FDA to discuss the required clinical development work for potential expansion of the label for uUTI to include all patients [10].
Jan 21Sulopenem etzadroxil-probenicid has been granted priority review in the US and a decision is expected from the FDA by 25th July [9].
Sep 20Iterum Therapeutics announce positive pre-NDA meeting with FDA for oral sulopenem etzadroxil-probenicid for treatment of uncomplicated UTI. The company now plans to proceed with a regulatory submission [8].
Jun 20After announcing negative results from the PIII SURE 2 trial, Iterum is evaluating its corporate, strategic and financial alternatives. These could include licensing, sale or divestiture of company assets or proprietary technologies, a sale of the company, a merger or other business combination, restructuring, dissolving and liquidating assets or seeking protection under bankruptcy laws. Presume there are no plans for further development in cUTI [7].
Mar 20Company presentation indicates potential EU filing Q2 2020.[6]
Jan 19Company pipeline indicates sulopenem is in PIII trials with data expected later in 2019.[2]
Jun 17The US FDA granted the QIDP designation to sulopenem for the treatment of uUTI, cUTI and cIAI.[3]

Category

Carbapenem antibiotic formulated as an oral bilayer tablet with probenecid
UTIs are among the most common bacterial infections encountered in the community. Up to 10% of women have a urinary tract infection in a given year and 50% of all women experience at least one UTI at some point in their lives [1].
Uncomplicated urinary tract infection, especially fluoroquinolone resistant - oral formulation
Oral

Trial or other data

Mar 21Results have been announced in all three trials. In December 2019, Iterum announced that sulopenem did not meet the primary endpoint of statistical non-inferiority compared to the control therapy for the cIAI SURE 3 trial. In Q2 2020, Iterum announced that in the cUTI SURE 2 trial, sulopenem did not meet the primary endpoint of statistical non-inferiority vs. control therapies with the difference in response rates driven almost entirely by higher rates of asymptomatic bacteriuria (ASB) on the sulopenem IV to oral sulopenem arm relative to the ertapenem IV to oral ciprofloxacin arm, only evident at the test of cure visit. The rates of patients receiving additional antibiotics or with residual cUTI symptoms were similar between therapies. Similarly, in the uUTI SURE 1 trial, sulopenem did not meet the primary endpoint of statistical non-inferiority compared to ciprofloxacin, in the population of patients with baseline pathogens susceptible to ciprofloxacin driven to a large degree by a greater amount of ASB in the sulopenem treated patients at the test of cure visit relative to those receiving ciprofloxacin. However, in the uUTI SURE 1 trial, in the population of patients with baseline pathogens resistant to quinolones, sulopenem achieved the related primary endpoint by demonstrating superiority to ciprofloxacin, providing evidence of a treatment effect in patients with uUTI [10].
Mar 21Oral sulopenem etzadroxil-probenicid (SE-P) is being studied in a PIII uncomplicated urinary tract infection (uUTI) trial (SURE 1), a PII complicated UTI (cUTI) trial (SURE 2) comparing IV sulopenem followed by oral SE-P to IV ertapenem followed by oral, and a PIII complicated intra-abdominal infection (cIAI) trial (SURE 3) comparing IV sulopenem followed by oral SE-P to IV ertapenem followed by a combination of oral ciprofloxacin and oral metronidazole in adults with cIAI. The company designed one PIII trial in each indication based on our end of Phase 2 meeting with the U.S. FDA and feedback from the EMA [10].
Jun 20Sulopenem fails to meet primary endpoint in PIII SURE 2 trial (n=1395). Clinical response was achieved in 67.8% of patients with complicated UTI treated with sulopenem vs 73.9 % treated with ertapenem [7].
Dec 19Iterum Therapeutics announces topline results from PIII SURE-3 trial. The primary endpoint of clinical response on day 28 was achieved in 85.5% of patients treated with sulopenem vs. 90.2% treated with ertapenem (difference 4.7%, 95% CI[-10.3% to 1.0%]). Non-inferiority required that the lower limit of the difference in the outcome rates be >-10% for FDA [5].
Sep 18PIII SURE-2 randomised, multi-center, double-blind, trial (NCT03357614) is recruiting ~1056 pts and has an estimated primary completion date of Oct 19. This will compare the efficacy, tolerability & safety of sulopenem followed by sulopenem-etzadroxil/probenecid vs. ertapenem followed by ciprofloxacin for the treatment of cUTI in adults. Overall response (combined clinical and microbiologic response) at 21 +/- 1 days.[3,4]
Aug 18PIII trial NCT03354598 (SURE 1), is a multi-center randomised study to measure efficacy, tolerability, and safety of oral sulopenem (bd for 5 days) vs. oral ciprofloxacin (bd for 3 days) for the treatment of uUTI in approximately 1,364 adult women. Results expected in the second half of 2019 [1].