Darrell Pardi, MD, MS, FACG1, Bikash Sahay, PhD2, Sathya Janardhanan, 3, Chuck Bourne, 3, Janet Stephens, PhD3, Kaitlyn Skeie, 3, Hudson Lowe, 3, Gary Fanger, PhD3, Christian Furlan Freguia, PhD3 1Mayo Clinic, Rochester, MN; 2University of Florida, Gainesville, FL; 3Rise Therapeutics, Rockville, MD Introduction: R-3750 is an oral synthetic biology-based immunotherapy for ulcerative colitis (UC), delivering the immunoregulatory protein Surface Layer Protein A (SlpA) via engineered Lactococcus lactis. SlpA modulates gut immune responses and restores homeostasis through microbiome-derived signaling. Methods: A first-in-human trial evaluated safety, tolerability, and pharmacodynamics of R-3750 in mild-to-moderate UC. Participants received daily R-3750 for 28 days with 3 months of follow-up. Clinical response was measured via SCCAI, partial Mayo score (pMS), and IBDQ. Blood and stool samples were collected longitudinally for immunophenotyping, transcriptomics, and microbiome analysis. Results: R-3750 was safe and well tolerated, with no drug-related adverse events. qPCR showed no systemic SlpA, confirming gut-restricted activity. Clinically, treatment with R-3750 led to meaningful and sustained improvements in disease activity and quality of life. The mean SCCAI score decreased by 1.6 points on Day 35 (end of treatment) and by 2.6 points on Day 125 (end of study). Similarly, pMS decreased by 1.0 point on Day 35 and 1.4 points on Day 125. Quality of life, as measured by the IBDQ, improved by 12.9 points on Day 35 and by 34.1 points on Day 125. Bristol stool scores showed a decline from a score of 7.0 at baseline (indicative of watery stools/diarrhea) to 5.4 by Day 35, and further to 3.3 by Day 125, indicating a normalization of stool consistency indicative of improved gut barrier integrity. Transcriptomic analysis of whole blood revealed activation of pathways associated with mucosal protection, epithelial barrier restoration, and resolution-phase inflammation. Immunophenotyping showed an increase in regulatory T cells on Day 35, which aligned with the mechanism of action of R-3750. Lastly, microbiome profiling revealed a shift from pro-inflammatory to health-associated taxa, supporting a link between microbial remodeling and therapeutic response. Discussion: R-3750 demonstrates a favorable safety and efficacy profile with supportive mechanistic data. By engaging the mucosal immune axis and remodeling the microbiome, R-3750 reduces inflammation, supports barrier repair, and promotes long-term gut homeostasis. These findings support continued clinical development of R-3750 as an oral, early-intervention UC therapy.
