1503. Engraftment of Investigational Microbiome Drug, SER-262, in Subjects Receiving Vancomycin Is Associated with Reduced Rates of Recurrence after Primary Clostridium Difficile Infection (CDI)

Abstract

BackgroundCDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance.MethodsSERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks.ResultsSER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3).ConclusionIn this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI. Disclosures All authors: No reported disclosures.

Synthetic biology in the clinic: engineering vaccines, diagnostics, and therapeutics

“…SER-262 is able to compete with C. difficile for up to 90% of its carbon sources, and 10 of 12 strains included in the synthetic community convert primary to secondary bile acids to inhibit the growth and reduce the toxicity of C. difficile. SER-262 was safe and well tolerated in patients in a phase I clinical trial (NCT02830542), but it did not meet its primary endpoint of reducing overall rates of CDI in patients following antibiotic treatment (Ford et al, 2019), although efficacy may differ depending on the specific antibiotic used.…”

“…Seres SER-262 is a rationally designed synthetic microbial community designed to include highly prevalent bacterial species isolated from healthy donors from the Human Microbiome Project (Turnbaugh et al, 2007) and successful iterations of SER-109 (J.R. Wortman et al, 2016, conference). SER-262 contains a proprietary blend of spores from 12 bacterial strains including several Firmicutes species from the Lachnospiraceae, Erysipelatrichaceae, Peptostreptococcaceae, and Clostridiaceae families (Ford et al, 2019). SER-262 is able to compete with C. difficile for up to 90% of its carbon sources, and 10 of 12 strains included in the synthetic community convert primary to secondary bile acids to inhibit the growth and reduce the toxicity of C. difficile.…”

Microbiota-Based Live Biotherapeutic Products for Clostridioides Difficile Infection- The Devil is in the Details

“… ● Delivered as doubly encapsulated V-caps ® stored at 2 to 8°C until dispensing. Phase 2 trial complete, halted further development CP-101 94 , 119 Finch Therapeutics ● Oral Full-Spectrum MicrobiotaTM (broad consortium) ● Lyophilized capsule of, full-spectrum microbiota containing diverse microorganisms Further development halted Designed oral capsules VE-303; 103 , 104 Vendanta Biosciences ● A defined consortium of 8 commensal strains of clonally derived and distinct Clostridium species (5 strains from Clostridia cluster XIVa, 2 from cluster IV, and 1 from cluster XVII) ● Enteric capsules each containing 1×10 8 CFU of lyophilized bacteria from each species for a total 8×10 8 CFU of bacteria in 400mg combined with sucrose, histidine, yeast extract, cysteine, and other excipients Phase 2 trial complete NTCD-M3 (VP20621 ); 105 , 120 Shire pharmaceuticals ● Enteric capsules containing a non-toxigenic C. difficile strain M3 Phase 2 trial complete MET-2; 93 Microbial Ecosystem Therapeutics ● A proprietary consortium of 40 commensal bacterial species from strains which are then purified and combined as a lyophilized product into capsules for oral delivery Phase 1 trial complete ART24 (ADS024) 9 Adiso Therapeutics ● A single-strain of Bacillus velezensis lyophilized and administered via capsule Phase 1 DSM33864 DifProtec(TM) 117 Novozymes A/S ● A single strain probiotic dietary supplement capsule containing Bacillus velezensis Phase = N/A SER-262 121 Seres Therapeutics ● Cultivated Eubacterial Spore Suspension, Encapsulated Ecobiotic ® ● A rationally designed, multi-strain microbiome therapeutic produced synthetically by in vitro anaerobic fermentation to produce commensal bacteria in spore form Phase 1 complete Abbreviation : CFU, colony-forming unit...…”

The role of faecal microbiota transplantation: looking beyond Clostridioides difficile infection

“…Understandably creation of a 'synthetic' FMT is a desired goal in terms of reproducibility, safety, regulation and scalability, as well as commercial opportunity. Results of 'manufactured' FMT to date have shown promise, 134,135 and further trials are ongoing [ClinicalTrials.gov identifiers: NCT03244644, NCT03788434 and NCT04208958 to list a few], but there remains a way to go before we are likely to see these entering widespread practice.…”