Microbiome data support clinical efficacy of UC drug candidate

Seres Therapeutics revealed microbiome data from its phase 1b study of SER-287, which showed bacteria derived from the study drug engrafted into the colonic microbiome of patients with mild-to-moderate ulcerative colitis for whom current treatments failed. Engraftment occurred in a dose-dependent and durable manner that correlated with clinical remission, according to a press release.

The company said it now plans to discuss a development plan with the FDA, and expects to begin the next clinical trial in mid-2018.

SER-287 is an oral formulation of live bacterial spores sourced from healthy individuals, which is in development for UC and other inflammatory bowel diseases. Researchers believe the drug works by altering a dysbiotic microbiome to reduce inflammation without immunosuppression effects.

“A healthy microbiome has been shown to maintain the integrity of the colonic barrier, reduce the signaling by pro-inflammatory molecules produced by certain bacteria, and induce regulatory T cells in the colon to modulate immune responses,” according to the press release.

As Healio Gastroenterology and Liver Disease previously reported, the FDA issued the candidate orphan drug designation for pediatric UC in December 2017.

These newly revealed microbiome analyses were a co-primary endpoint of the phase 1b trial, the initial clinical results of which Seres reported in October 2017.

This was a randomized, double-blind, placebo-controlled induction study in which 58 patients with UC received one of three SER-287 regimens with and without vancomycin pretreatment or placebo for 8 weeks. As we previously reported, the study drug improved clinical remission rates and endoscopic findings in a dose-dependent manner, and showed a favorable safety and tolerability profile.

According to the current press release, there was a high clinical response placebo rate similar to the study drug arms. “Clinical response is a subjective endpoint and is prone to high variability, as previously observed in several other UC trials of various drug types,” the release noted. “In the most recent FDA regulatory guidance, clinical remission, and not clinical response, is recommended as the primary endpoint in UC registrational studies.”

For the microbiome analyses, investigators used metagenomic sequencing to analyze patient stool samples and characterize species-level changes in their gut microbiota.

The company reported that these data showed dose-dependent engraftment of bacteria derived from the study drug into the colonic microbiome of patients, and those who received the regimen with vancomycin pre-treatment followed by daily dosing of SER-287 showed the highest levels of engraftment, which reached statistical significance. Notably, the same group of patients showed the most significant clinical benefits.

Vancomycin vs. placebo pre-treatment “led to an immediate reduction of microbiome diversity followed by rapid and robust engraftment of SER-287-derived bacterial species,” per the press release. “These data suggest that vancomycin pre-treatment opens ecological niches for SER-287 engraftment in the human microbiome of patients with UC.”

Further, investigators found that changes in microbiota composition after treatment were correlated with clinical remission, and engraftment persisted through dosing period and 4 weeks after the final dose.

“These microbiome data provide Seres with important proprietary insights into the mechanisms of action of SER-287 in ulcerative colitis and inform the study design of our next SER-287 clinical trial,” Roger J. Pomerantz, MD, president, CEO and chairman of Seres, said in the press release. “The SER-287 bacterial signatures identified in humans also provide indispensable clinical insights towards optimizing the composition of SER-301, a rationally designed microbiome therapeutic candidate for UC and other forms of inflammatory bowel disease. We look forward to discussing the SER-287 clinical and microbiome data with the FDA as we move this program forward in clinical development.”

The company said it plans to share additional study data via webcast at the 2018 JP Morgan Healthcare Conference on Jan. 11. – by Adam Leitenberger

Disclosures: Pomerantz is employed by Seres.