R-5280, A Novel Modified Superior Resistant Starch Therapy for Type 1 Diabetes

Project Summary Type 1 diabetes (T1D) is a devastating disease and there is no current curative treatment, with insulin being the only product available. T1D affects not only glycemic control but also many important aspects of a patient's life, including emotional well-being, quality of life, working ability, and social interactions29. In addition, persons with T1D present increased risk of developing other serious complications. Therefore, there is an urgent need to develop new cutting-edge strategies for T1D management. The steep rise in the incidence and prevalence of T1D cannot be explained solely by genetic factors implicating the environment, and specifically the gut microbiome, as a culprit for the disease etiopathogenesis45. The gut microbiome influences multiple host functions, including immunity, and persons with T1D present changes in gut microbiota associated with immunological deregulation and gut leakiness6. Clinical studies demonstrate that fecal microbiome therapy (FMT) and probiotics can halt the progression of new onset T1D13, corroborating the importance of the gut microbiome. A promising and safe approach for the treatment of T1D that leverages the body’s own natural microbiome- associated immune regulatory mechanisms is the use of resistant starches. High amylose starch (HAMS) is a well-tolerated source of dietary fiber that modulate the gut microbiome and the host immune response. HAMS consumption shifts the gut microbiome profile towards dietary fiber fermenters, producing the beneficial short chain fatty acids SCFAs. However, HAMS only partially ameliorates T1D in humans. A potentially better strategy is to use HAMS that has been esterified, releasing larger amounts of SCFAs in the intestinal tract and eventually the circulation. Rise Therapeutics is developing R-5280, a modified version of HAMS that has been butyrylated and acetylated. In our prior Phase 1 clinical trial enrolling adolescents with recent onset of T1D, oral administration of R-5280 increased SCFA production leading to improved overall glycemic control. In addition, R-5280 consumption resulted in significant increases in specific beneficial metabolites, and reduction of inflammatory T cells. Given the limited success of prior therapeutic strategies and potential long-term risks of immunomodulatory therapies in patients with T1D, the use of a microbiome modulating therapy like R-5280 offers a simple, safe, and inexpensive alternative approach to mitigating this devastating disease. The goal of this proposal is to perform a confirmatory double blinded placebo-controlled Phase 2 clinical trial of adolescents with early onset of T1D. The key aims of this proposal are: 1) compounding of R-5280 and placebo to prepare for patient distribution; 2) execute the Phase 2 clinical trial; and 3) expand biomarker discovery and characterization. Successful commercialization of R-5280 will provide a profound medical advancement for treating T1D.