Seres Therapeutics presents Phase 3 results of SER-109 for rCDI

Seres Therapeutics announced the presentation of data from its Phase 3 ECOSPOR III study that suggest investigational microbiome-based therapeutic SER-109 prevents recurrent C. difficile infections by rapidly establishing a long-lasting colony of beneficial gut microbes, which can produce fatty acids that disrupt the C. difficile lifecycle. These data were shared in oral and poster presentations at the 2022 Digestive Disease Week Annual Meeting. Seres expects to finalize a Biologics License Application submission for SER-109 with the U.S. Food and Drug Administration in mid-2022, positioning SER-109 up to potentially become the first ever FDA-approved microbiome-based therapeutic for treating recurrent C. difficile infections with a potential product launch in the first half of 2023. The ECOSPOR III Phase 3 study, a multicenter, randomized, placebo-controlled clinical trial that enrolled 182 adults with rCDI, previously demonstrated that SER-109 prevented rCDI in 88% of recipients at the eight-week primary endpoint, whereas only 60% in the placebo arm remained recurrence-free over the same time period. The safety profile was similar across both groups. A pre-planned exploratory analysis from the ECOSPOR III trial shows that approximately two-thirds of CDI recurrences occurred within the first two weeks following antibiotic treatment for CDI - the window of vulnerability - when the microbiome is further decimated and C. difficile spores, untouched by antibiotics, are free to germinate into toxin-producing vegetative bacteria. SER-109 introduces a diverse consortium of bacterial species into the gut in the form of spores, which rapidly germinate and incorporate themselves into the microbiome, showing up in the stool as vegetative bacteria. This process is called engraftment. Within a week of SER-109 treatment, the number of new bacterial species in stool increased and remained significantly higher than the placebo group for the entire 24-week study period. Bacterial diversity rebounded more slowly and to a lesser degree in the placebo group. The pattern of results was the same regardless of which antibiotic participants received, vancomycin or fidaxomicin. To better understand how SER-109 prevents rCDI on the molecular level in a post-hoc analysis, stool samples collected from ECOSPOR III participants were analyzed for changes in their microbial makeup and fatty acid concentrations across the eight weeks following SER-109 treatment. Fatty acids with long and medium carbon chain lengths, such as butyrate, valerate and hexanoate, have been shown to inhibit the growth of C. difficile. For participants who received SER-109, butyrate, valerate and hexanoate levels rapidly increased, starting within the two-week window of vulnerability, and remained significantly higher than the placebo group for the eight-week data analysis period. Among members of the placebo group who experienced a CDI recurrence, valerate levels tended to be lower compared to members of the placebo group who did not experience a recurrence, further suggesting that valerate plays a protective role against rCDI. These data and data published previously in the New England Journal of Medicine suggest that a two-pronged approach for the treatment of rCDI, with standard-of-care antibiotics to kill vegetative C. difficile bacteria followed by investigational agent SER-109 to repair the disrupted microbiome through engraftment of Firmicutes bacteria and the modulation of multiple metabolic pathways in the gut, may be effective.