It missed the primary endpoint by a narrow margin—so narrow, in fact, it comes to about a single patient.
Iterum Therapeutics reported topline results from its SURE 3 Phase III clinical trial of an oral and intravenous penem antibiotic for infections caused by multi-drug resistant pathogens in the community and hospital settings. It missed the primary endpoint by a narrow margin—so narrow, in fact, it comes to about a single patient.
The primary endpoint agreed upon with the U.S. Food and Drug Administration (FDA) was clinical response on Day 28 in the micro-MITT population. In that population, the difference in outcomes was 4.7% with a 95% confidence interval on the difference of -10.3% to 1.0%. In order to be defined as non-inferior, the lower limit in the difference rates needed to be greater than -10%.
Using a prespecified multiple imputation analysis required by the agency, the difference in outcomes was 4.7% with a 95% confidence interval on that difference of -9.9% to 0.5%.
“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,” said Michael Dunne, Iterum’s chief scientific officer.
He added, “Over 10% of the patients in this study had a gram-negative pathogen that was resistant to both quinolones and beta-lactams, the two classes of oral agents that are most commonly used for step down therapy for this indication. In this era of rapidly emerging multi-drug resistance, we believe the availability of sulopenem in its oral and IV formulations would provide the healthcare system with a much-needed option for step-down therapy from hospital to home.”
Sulopenem is a novel penem anti-infective with both oral and IV formulations. It has shown activity against a wide variety of gram-negative, gram-positive and anaerobic bacteria resistant to other antibiotics.
Investors were clearly worried about the results, with shares dropping 48% after hours.
Patients in the trial were dosed with either IV sulopenem once a day for a minimum of five days followed by oral sulopenem/probenecid twice a day for a total of 7 to 10 days of treatment or IV ertapenem once a day for a minimum of five days followed by oral ciprofloxacin twice a day with oral metronidazole four times a day. Or, for patients whose baseline results indicated ciprofloxacin resistance, they received amoxicillin-clavulanate twice a day.
Ami Fadia, an analyst with SVB Leerink, agreed that the trial narrowly missed the mark, but was nonetheless less optimistic that the company’s two remaining late-stage trials would be successful. She wrote, “We agree that the statistical treatment of indeterminate patients is usually controversial, but we still believe that the chance of approval is low for the cIAI indication, as we have no knowledge of precedents in antibiotics that received approval despite missing the primary endpoint.”
Those Phase III studies in complicated and uncomplicated urinary tract infections are expected to report out in the first quarter of 2020. The company indicates that if those trials hit their endpoints, the safety and efficacy data from the cIAI trial would support a regulatory filing.
One factor—a big one—is the overwhelming need for antibiotics to treat drug-resistant infections. The U.S. Centers for Disease Control and Prevention (CDC) issued a new report in November describing the threats of antibiotic resistance. In it, the agency found that more than 2.8 million antibiotic-resistant infections occurred in the U.S. each year, killing more than 35,000 people.
The report wasn’t completely negative, noting that in 2017, drug-resistant infections killed approximately 36,000 people in the U.S., but it was down 18% from the estimated 2013 figure of 44,000. This decline was attributed to significant efforts on the part of hospitals and health systems to prevent and control these types of infections.
“We are pushing back in a battle we were losing,” Michael Kirsch, a pharmacist with AdventHealth Tampa, in Florida, told the Los Angeles Times in response to the report. “I would not by any means declare success.”
