FDA approves oral sulopenem for uncomplicated urinary tract infection

The FDA has granted approval to oral sulopenem (sulopenem etzadroxil and probenecid; Orlynvah) for the treatment of uncomplicated urinary tract infections (uUTIs) caused by the designated microorganisms Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis in adult women who have limited or no alternative oral antibacterial treatment options, Iterum Therapeutics announced in a news release.¹

According to the company, oral sulopenem is the first oral penem approved for use in the US.

According to the company, oral sulopenem is the first oral penem approved for use in the United States.

The approval is supported by data from the phase 3 SURE 1 (NCT03366207) and REASSURE (NCT05584657) trials. In SURE 1, oral sulopenem demonstrated superiority over ciprofloxacin in the treatment of patients with fluoroquinolone-resistant infections and non-inferiority to ciprofloxacin in the treatment of patients with a quinolone-susceptible uropathogen. In REASSURE, the oral penem demonstrated non-inferiority to oral amoxicillin/clavulanate in the treatment of patients with uUTI.

“The FDA approval of Orlynvah is tremendous news for those of us who have been hoping for a new option to treat appropriate at-risk patients suffering from UTIs,” said Marjorie Golden, MD, FIDSA, Site Chief, Infectious Disease, St. Raphael Campus Yale New Haven Hospital, in the news release.¹ “Based on the totality of clinical data generated, Orlynvah has the potential to be an important treatment alternative for use in the community.”

The approval of oral sulopenem comes after a meeting of the FDA's Antimicrobial Drugs Advisory Committee to discuss the potential benefits and risks associated with approval of the New Drug Application of the oral penem. Specifically, the committee addressed concerns regarding the drug’s potential contribution to antimicrobial resistance. In the discussion, the members indicated that a more specific indication may prevent off-label use, and post-market observation of changes to the rates of antimicrobial resistance may be necessary.

Data on oral sulopenem

SURE-1

The approval is supported by data from the phase 3 SURE 1 and REASSURE trials.

In SURE 1, oral sulopenem demonstrated superiority over ciprofloxacin in the treatment of patients with uUTI with a quinolone non-susceptible uropathogen. The oral penem also demonstrated non-inferiority to ciprofloxacin in the treatment of patients with uUTI with a quinolone-susceptible uropathogen.²

Specifically, in the quinolone non-susceptible population, the overall response rate at the test of cure visit (day 12) was 62.6% among patients in the sulopenem arm vs 36.0% in the ciprofloxacin arm (difference, 26.6; 95% CI, 15.1 to 37.4; P < .001). Clinical success was achieved by 83% of patients in the sulopenem arm vs 62.6% in the ciprofloxacin arm (difference, 20.4; 95% CI, 10.2 to 30.4; P < .001). Microbiologic success was achieved by 74.1% vs 49.6% of patients in the sulopenem vs ciprofloxacin arms, respectively (difference, 24.5; 95% CI, 13.4 to 35.1; P < .001.

In the quinolone-susceptible population, the overall response rate at the test of cure visit on day 12 was 66.8% in the sulopenem arm vs 78.6% in the ciprofloxacin arm (difference, -11.8; 95% CI, -18.0 to -5.6), which met the threshold for non-inferiority. Clinical success was achieved in 81.1% of patients in the sulopenem arm and 84.1% of patients in the ciprofloxacin arm (difference, -3.0; 95% CI, -8.4 to 2.3). Microbiologic success was achieved by 77.6% and 88.9% of patients in each arm, respectively (difference, -11.3; 95% CI, -16.7 to -6.2).

In total, the trial enrolled 1671 patients with uUTI who were randomly assigned 1:1 to receive oral sulopenem (n = 835) or ciprofloxacin (n = 836). Of those, 1071 were included in the micro-MITT population. The quinolone-susceptible population (microMITT S) consisted of 370 patients in the sulopenem arm and 415 patients in the ciprofloxacin arm. The quinolone non-susceptible population (microMITT R) consisted of 147 patients in the sulopenem arm and 139 patients in the ciprofloxacin arm.

REASSURE

The phase 3 REASSURE trial was then conducted to compare oral sulopenem to oral amoxicillin/clavulanate (Augmentin) in patients with uUTI. Overall, data showed that oral sulopenem was non-inferior to oral amoxicillin/clavulanate in regard to the trial’s primary end point of overall response rate (combined clinical cure plus microbiologic eradication) in the treatment of patients with uUTI.³

Specifically, data from the trial showed that overall response was achieved in 61.7% of patients who received oral sulopenem vs 55% of patients who received amoxicillin/clavulanate (treatment difference, 6.7; 95% CI, 0.3 to 13.0).

Further, clinical success (defined as symptom resolution and no new uUTI symptoms) was achieved in 77.3% of patients in the oral sulopenem arm, compared with 76.7% of patients in the amoxicillin/clavulanate arm (treatment difference, 0.6; 95% CI, -4.8 to 6.1). Microbiological success (defined at eradication of qualifying uropathogen to less than 103 CFU/mL at the test-of-cure visit) was achieved in 75.2% of patients in the oral sulopenem cohort vs 66.7% of patients in the amoxicillin/clavulanate cohort (treatment difference, 8.5; 95% CI, 2.6 to 14.3).

Regarding safety, treatment was generally well-tolerated in both study groups. Less than 1% of patients on both regimens discontinued treatment due to adverse events. No serious adverse events (SAEs) were observed among patients in the oral sulopenem arm, compared with 5 SAEs experienced by patients in the amoxicillin/clavulanate arm. The investigators believe that no SAEs were related to study treatment.

Further, no new safety signals with oral sulopenem were observed. The overall safety profile for the therapy was consistent with that of previous phase 3 studies.

In total, the REASSURE trial included 2222 adult women who were randomly assigned 1:1 to receive oral sulopenem twice daily for 5 days or amoxicillin/clavulanate twice daily for 5 days. The primary end point for the study was overall response at the test-of-cure visit (day 12) among patients in the microbiological-modified-intent-to-treat susceptible population.

Additional information on oral sulopenem

Iterum Therapeutics initially submitted their new drug application (NDA) for oral sulopenem in January 2021.⁴ The FDA issued a complete response letter in July 2021, requesting additional data in order to support approval on oral sulopenem for the treatment of adult women with uUTI.⁵

Following their guidance, Iterum entered into a special protocol assessment agreement with the FDA to conduct a phase 3 trial that would adequately address the objectives necessary to support resubmission of their NDA.⁶ Thus, the phase 3 REASSURE (REnewed ASsessment of Sulopenem in uUTI caused by Resistant Enterobacterales) trial was conducted to compare oral sulopenem with oral amoxicillin/clavulanate in the treatment of women with uUTI.

Iterum Therapeutics reported topline data from the phase 3 REASSURE trial (NCT05584657) in January 2024, after which they resubmitted the NDA for the drug in April 2024. The FDA accepted the filing in May 2024, issuing a PDUFA action date for Q4 of 2024.⁷

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. Published online and accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/136/iterum-therapeutics-receives-u-s-fda-approval-of

2. 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

3. 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. January 30, 2024. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/116/iterum-therapeutics-announces-positive-topline-results-from

4. Iterum Therapeutics announces U.S. FDA filing acceptance of New Drug Application for oral sulopenem. News release. Iterum Therapeutics. January 25, 2021. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/58/iterum-therapeutics-announces-u-s-fda-filing-acceptance-of

5. Iterum Therapeutics receives Complete Response Letter from U.S. Food and Drug Administration for oral sulopenem. News release. Iterum Therapeutics. July 26, 2021. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/73/iterum-therapeutics-receives-complete-response-letter-from

6. Iterum Therapeutics Announces Special Protocol Assessment (SPA) Agreement With the FDA. News release. Iterum Therapeutics. July 11, 2022. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/92/iterum-therapeutics-announces-special-protocol-assessment

7. Iterum Therapeutics receives FDA acceptance of resubmission of NDA for oral sulopenem for the treatment of uncomplicated urinary tract infections. News release. Iterum Therapeutics. May 31, 2024. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/124/iterum-therapeutics-receives-fda-acceptance-of-resubmission