S30 A Phase 2b Study to Evaluate the Efficacy and Safety of Investigational Microbiome Therapeutic SER-287 in Mildly-to-Moderately Active UC

Abstract

Background: Ulcerative colitis (UC) drug development has mainly targeted moderate-to-severe disease while few agents have been approved for mild disease. When first-line drugs fail in patients with mild disease, therapeutic options often include steroids and immunosuppressives with modest efficacy and increased risk of infections and malignancy. Microbiome disruption characterized by depletion of Firmicutes bacteria has been postulated to play a role in the pathogenesis of UC. SER-287 is an investigational oral formulation of purified Firmicutes spores designed to produce metabolites associated with maintenance of the intestinal barrier integrity and improved mucosal immunity. A previous Phase 1b study of patients with mildly-to-moderately active UC demonstrated that SER-287 following vancomycin pre-conditioning was well-tolerated and provided clinical benefit. Methods: This double-blind, placebo-controlled Phase 2b study screened 494 adults and randomized 203 (51.7% male; mean age 45.6 years; 83.7% White) 1:1:1 to SER-287 Induction Dose, SER-287 Step-Down Induction Dose, or placebo, and stratified subjects by baseline endoscopic score (ES 1-2 vs 3) and by concomitant use of UC medications at baseline (5-ASA alone vs immunomodulators +/- 5-ASA vs none). Subjects were required to have mildly-to-moderately active UC at screening: ≥ 15 cm of disease from the anal verge, and a Three-Component Modified Mayo Score of 3-7, composed of ES ≥ 1, determined by local and central reader scores, with adjudication by a second central reader, if necessary, stool frequency (SF) subscore ≥1, and rectal bleeding (RB) subscore (no eligibility requirement). Subjects were required to have inadequate or loss of response to, or intolerance of, ≥ 1 conventional UC therapy, and were permitted to remain on stable oral 5-ASAs and/or immunomodulators. SER-287 or placebo was administered as 2 oral capsules once-daily for 10 weeks following 6 days of pre-conditioning with oral vancomycin or placebo, respectively. Subjects who achieved clinical remission were randomized to a placebo-controlled maintenance treatment period, while non-remitters were eligible for open-label SER-287 Induction Dose. The primary endpoint was clinical remission with the SER-287 Induction Dose compared to placebo, defined as ES = 0/1 with ≥ 1 point decrease from baseline, RB = 0, SF = 0/1 with ≥ 1 point decrease from baseline, and no UC flares during the treatment period. Results: The study did not meet its primary endpoint of clinical remission (10.3% for the SER-287 Induction Dose vs 11.6% for placebo [adjusted difference of −1.3; P = 0.802; 95% confidence interval: −11.7, 9.0]). No meaningful differences were observed across the 3 groups for endoscopic improvement, endoscopic remission, or symptomatic remission. During induction, 76/133 (57.1%) subjects who received SER-287, vs 35/69 (50.7%) in placebo, experienced treatment-emergent adverse events (TEAEs). Most TEAEs were mild or moderate and dose-dependent. The most common TEAEs were worsening of UC, diarrhea, and nausea. Conclusion(s): SER-287 was not better than placebo for induction of clinical remission in mildly-to-moderately active UC. The therapy was generally well-tolerated. Future efforts will evaluate the impact of SER-287 on the microbiome and the role of biomarkers to identify patients with microbiome disruption who may benefit from microbiome-based therapies.