LB1 - (LATE-BREAKING ABSTRACT) 8- and 12-week Efficacy and Safety Data from ECOSPOR-III a Phase 3 Double-blind, Placebo-Controlled Randomized Trial of SER-109 an Investigational Microbiome Therapeutic for the Treatment of Patients with Recurrent Clostridioides difficile Infection (rCDI)
Bret A. Lashner MD, MPH, FACG1, Louis Korman, MD2, Colleen S. Kraft, MD3, Matthew Sims, MD4, E.E. Wang5, K. Brady5, C.B. Ford5, E.J. O’Brien5, M-J. Lombardo5, J.R.Wortman5, K.D. Litcofsky5, D. Li5, J. Mahoney5, C.W. McChalicher5, J.A. Winkler5, S. Garant5, Erin McMullen1, B.H. McGovern5, J.G. Aunins5, M.R. Henn5, M. Trucksis5, L.L. von Moltke5; 1Cleveland Clinic, Cleveland, OH, 2Capital Digestive Health, an affiliate of Georgetown University, Washington, DC, 3Emory Clinic, an affiliate of Emory University, Atlanta, GA, 4Beaumont Hospital, Royal Oak, MI, 5Seres Therapeutics, Cambridge, MA
Introduction: Antibiotics targeted against C. difficile bacteria are necessary, but insufficient, to achieve a durable clinical response because they have no effect on C. difficile spores that germinate within a disrupted microbiome. ECOSPOR-III evaluated SER-109, an investigational, biologically-derived microbiome therapeutic of purified Firmicute spores for treatment of rCDI. Methods: Adults >18 years with rCDI (>3 episodes in 12 months) were screened at 75 US/CAN sites. CDI was defined as >3 unformed stools/day for >48 hours with a (+) C. difficile assay. After completion of 10-21 days of vancomycin or fidaxomicin, adults with symptom resolution were randomized 1:1 to SER-109 (4 capsules x 3 days) or matching placebo and stratified by age (> or <65 years) and antibiotic received. Primary objectives were safety and efficacy at 8 weeks. Primary efficacy endpoint was rCDI (recurrent toxin+ diarrhea requiring treatment); secondary endpoints included efficacy at 12 weeks after dosing. Results: 287 subjects were screened and 182 randomized (59.9% female; mean age 65.5 years). The most common reason for screen failure was a negative C. difficile toxin assay. A significantly lower proportion of SER-109 subjects had rCDI after dosing compared to placebo at week 8 (11.1% vs 41.3%, respectively; RR 0.27; 95% CI 0.15, 0.51; p-value <0.001; Figure 1). This translates into a higher rate of sustained clinical response with SER-109 compared to placebo (88.9% vs 58.7%, respectively). Similarly, a significantly lower proportion of SER-109 subjects had rCDI compared to placebo at week 12 (16.7% vs 47.8%, respectively; RR 0.35; 95% CI 0.21, 0.58; p-value <0.001). Efficacy rates were significantly higher with SER-109 vs placebo in both stratified age groups (Figure 1). SER-109 was well-tolerated with a safety profile similar to placebo. The most common treatment-emergent adverse events (TEAEs) were gastrointestinal and were mainly mild to moderate. No serious TEAEs, infections, deaths or drug discontinuations were deemed related to study drug. Discussion: Introduction SER-109, an oral live microbiome therapeutic, achieved high rates of sustained clinical response with a favorable safety profile. By enriching for Firmicute spores, SER-109 achieves high efficacy, while mitigating risk of transmitting infectious agents, beyond donor screening alone. SER-109 represents a major paradigm shift in the clinical management of patients with recurrent CDI.