Converting gut endocrine cells to glucose-responsive insulin-producing cells by selective FOXO1 inhibition to cure insulin-dependent diabetes

点击翻译按钮获取中文摘要

PROJECT SUMMARY Forkhead BioTherapeutics aims to develop a novel oral therapy for diabetes that will make all insulin therapies obsolete. Over 50 million patients with type 1 diabetes (T1D) or late stage type 2 diabetes (T2D) worldwide require life-long insulin injections. By current standards of care, >50% of the patients fail to meet glucose control goals, leading to vascular complications and premature death. This is largely due to the narrow therapeutic window of insulin and its potential to cause life-threatening hypoglycemia. Novel therapies that replace native pancreatic b cell function, namely, releasing insulin in a glucose-regulated manner, remain a tremendous unmet need. Forkhead Bio’s co-founder Dr. Domenico Accili discovered that genetic ablation of the transcription factor Forkhead box protein O1 (FOXO1) in gut endocrine cells reprograms them into “b-like” cells that secrete insulin in response to glucose. Accili et al. also uncovered several series of small-molecule FOXO1 inhibitors. This body of work delineates a path towards developing an oral FOXO1 inhibitor therapy that converts specific gut cells to replace b cell function. The product of this SBIR will be an oral pill that normalizes glucose control and eliminates the burden of insulin injections and frequent blood glucose checks, thus improving patients’ quality of life, reducing medical costs, and making “insulin-dependent” diabetes a disease of the past. In Phase I, we validated the target pharmacologically, showing that small-molecule FOXO1 inhibitors induce gut b-like cells in mice. In addition, we synthesized >350 novel molecules, established structure-activity relationships, and identified compounds suitable for oral dosing. We also created ex vivo assays critical for assessing clinical translatability, showed evidence for non-human primate (NHP) as an appropriate large animal efficacy model and identified collaborators at the Oregon National Primate Research Center with strong expertise in this area. The significant Phase I results proved the feasibility of our SBIR goal to develop an oral agent that converts b- like cells in the gut to normalize glucose control in both T1D and T2D. In Phase II, we aim to (1) complete lead optimization to identify Lead Candidate molecules with sufficient activity, selectivity, drug-like properties, and tolerability; (2) demonstrate the Lead Candidates’ efficacy in diabetic mouse models; and (3) select one Lead Candidate to demonstrate in vivo gut b-like cell conversion in NHPs. If awarded, this Phase II will accelerate chemistry optimization and enable the demonstration of large-animal translatability for a novel target. Following Phase II, we will perform additional IND-enabling studies and submit an application to the FDA to initiate Phase 1 clinical trials. We have secured intellectual properties including composition of matter claims. Our lead product, likely to be licensed or acquired in preclinical or early clinical stage by a major pharmaceutical company, will be an oral pill that normalizes glucose control and improves quality of life for over 50 million patients with diabetes, with the potential to displace >$30 billion annual sales of insulins.