A novel immunological-directed live biotherapy product for treating crohn's disease

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Rise Therapeutics LLC $1,042,478 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to evaluate the safety and clinical efficacy of R-3750, an engineered live biotherapeutic product designed to modulate intestinal immune responses and restore gut homeostasis in patients with Crohn's disease.

R-3750 is an oral Lactococcus lactis probiotic engineered to express specific immunomodulatory proteins that reduce gut inflammation, reinforce mucosal barrier function, and improve microbiome composition. The product builds on a promising Phase 1 safety profile in an ongoing ulcerative colitis trial (IND 28994, NCT05666960), which demonstrated no serious adverse events or drug-related adverse events. Preclinical studies showed that R-3750 addresses overlapping immunological pathways between Crohn's disease and ulcerative colitis, offering potential to fill therapeutic gaps where current treatments often produce significant side effects and patients develop refractoriness.

Work will be performed in Rockville, Maryland, with a period of performance from September 1, 2026, through August 31, 2028. Rise Therapeutics is a small biotechnology company focused on developing microbiome-based and synthetic biology therapeutics that leverage probiotic technologies to address autoimmune and inflammatory diseases. The assistance type is a Project Grant.

Abstract

The goal of this project is to evaluate the safety and clinical efficacy of R-3750, an engineered live biotherapeutic product (LBP) designed to modulate intestinal immune responses and restore GUT homeostasis, in patients with crohn's disease (CD). This proposal is based on the promising safety profile and initial clinical activity observed in the ongoing phase 1 trial for ulcerative colitis (UC). Given the overlapping immunological pathways between CD and UC, R-3750 represents a novel therapeutic approach with the potential to address critical gaps in CD treatment. An estimated 800,000 to 1 million adults in the U.S. Suffer from CD, a chronic inflammatory disorder of the gastrointestinal tract. CD is typically diagnosed in young adulthood but can develop at any age, is life-long, and has no cure. Current treatments can have significant side effects, and many patients become refractory to available therapies. There is an urgent need for novel, targeted interventions that restore the integrity of the intestinal barrier, regulate immune responses, and modulate the GUT microbiome. Intestinal immune regulation is essential for maintaining GUT homeostasis, and its disruption is central to CD pathogenesis. The human microbiome plays a crucial role in this regulation, with commensal bacteria supporting epithelial barrier function and immune balance. Initial preclinical studies have demonstrated that oral delivery of R-3750, a slpa-expressing lactococcus lactis significantly reduced GUT inflammation, reinforced mucosal barrier function, and improved microbiome composition, propelling the clinical testing of this recombinant probiotic. R-3750 is being evaluated in an ongoing open label phase 1 clinical trial for mild-to-moderate UC (IND 28994, NCT05666960). The study demonstrated excellent safety, with no serious adverse events (SAES) or drug-related adverse events (AES). Initial clinical readout showed a significant improvement of the disease symptoms accompanied by relevant biomarkers changes such as upregulation of treg. Given the overlapping immunological mechanisms between UC and CD, these findings provide a strong rationale for expanding clinical evaluation into CD. This phase II sbir proposal seeks to carry out a proof-of-concept clinical trial of R-3750 in patients with CD. Given the strong preclinical rationale, clinical safety and pharmacodynamic data, and the urgent need for novel CD therapies, this project has the potential to introduce a safe, effective, and microbiome-targeted therapy for patients suffering from this devastating disease.