Sulopenem Narrowly Misses Primary End Point in Phase 3 cIAI Study

The difference in outcomes was 4.7% with a 95% confidence interval on that difference of -10.3% to 1.0%. This fell short of non-inferiority which required that the lower limit of the difference in the outcome rates be >-10%.

Interim Therapeutics has announced topline results from a phase 3 trial evaluating sulopenem for the treatment of complicated intra-abdominal infections (cIAIs). According to the new results, the agent “narrowly missed” the primary end point.

Sulopenem is a novel penem anti-infective that has both oral and intravenous formulations. The novel agent has demonstrated in vitro activity against gram-negative, gram-positive and anaerobic bacteria resistant to other antibiotics. The agent was evaluated in the phase 3 Sulopenem for Resistant Enterobacteriaceae (SURE) clinical trial.

The multicenter, double-blind study randomized patients to receive either intravenous sulopenem once daily for at least 5 days followed by oral sulopenem/probenecid twice daily to complete 7-10 total days of treatment, or intravenous ertapenem once daily for at least 5 days followed by oral ciprofloxacin twice daily along with oral metronidazole 4 times daily or, for those patients with ciprofloxacin-resistant organism at baseline, amoxicillin-clavulanate twice daily.

The primary US Food and Drug Administration (FDA) end point was clinical response on day 28 in the micro-modified intent-to-treat population. According to the statement used by Iterum Therapeutics, the difference in outcomes was 4.7% (sulopenem 85.5%, ertapenem 90.2%) with a 95% confidence interval (CI) on that difference of -10.3% to 1.0%. This fell short of non-inferiority which required that the lower limit of the difference in the outcome rates be >-10%.

However, in an analysis designed to address any imbalances in patients with “indeterminate” outcomes at test of cure, the difference in outcomes was 4.7% (95% CI: -9.9% to 0.5%).

Of the 668 patients in safety population, 6.0% and 5.1% of individuals in the sulopenem and ertapenem reported treatment-related adverse events, respectively. The most common adverse events were diarrhea at 4.5% and 2.4%, respectively. Serious adverse events that were not related to treatment were seen in 7.5% of patients on sulopenem and 3.6% of patients on ertapenem.

The investigators note that discontinuations were uncommon but occurred in 1.5% of patients on sulopenem and 2.1% of patients on ertapenem.

“While the difference in the primary outcome is one patient shy of the target of -10%, imputing an outcome for the patients with missing data and the secondary supporting analyses, both at the end of treatment as well as the test of cure, provide support for the potential of sulopenem in the treatment of multi-drug resistant infections,” Michael Dunne, MD, chief scientific officer at Iterum Therapeutics said in the company’s statement.

Dunne also noted that over 10% of patients in this study had a gram-negative pathogen that was resistant to quinolones and β-lactams which are most commonly used asstep down therapy for cIAI.

“We believe that these topline results, while narrowly missing the primary endpoint, provide data that emphasize the potential for sulopenem to help address the growing challenge of antibiotic resistance,” Corey Fishman, chief executive officer of Iterum Therapeutics said in a the statement.

Sulopenem is being evaluated in phase 3 clinical trials for uncomplicated urinary tract infections, complicated urinary tract infections and complicated intra-abdominal infections.

The FDA has granted Special Protocol Agreements and Qualified Infectious Disease Product designations for sulopenem. This was accomplished in accordance with the Generating Antibiotics Incentives Now (GAIN) Act, which provides 5 years of additional regulatory exclusivity and expedited fast track FDA review.