A Phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis

Henn, Matthew R.; O’Brien, Edward J.; Diao, Liyang; Feagan, Brian G.; Sandborn, William J.; Huttenhower, Curtis; Wortman, Jennifer R.; McGovern, Barbara H.; Wang-Weigand, Sherry; Lichter, David I.; Chafee, Meghan; Ford, Chris B.; Bernardo, Patricia; Zhao, Peng; Simmons, Sheri; Tomlinson, Amelia; Cook, David; Pomerantz, Roger; Misra, Bharat K.; Auninš, John G.; Trucksis, Michele

Abstract Background & Aims Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon. Methods We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4–10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly or SER-287 once daily. Clinical endpoints included safety and clinical remission (modified Mayo score ≤ 2; endoscopic subscores 0 or 1). Microbiome endpoints included SER-287 engraftment (dose species detected in stool after, but not before, SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo. Results Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P=.024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P<.05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points, through 4 weeks post-dosing, compared with the placebo group (P<.05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P<.05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups. Conclusions In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 following vancomycin was significantly more effective than placebo for induction of remission in patients with active mild-to-moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287.