SBIR-STTR Award

In this Phase 1 proposal, Forkhead BioTherapeutics Inc. (Forkhead Bio) aims to demonstrate target validation that selective Foxo1 inhibitors reprogram gut cells into glucose-responsive insulin-producing (?-like) cells in vitro and in vivo, use a recently established robust assay platform to drive compound optimization, and identify one or more lead molecules with attractive profiles suitable for additional proof-of-concept studies. Our preliminary data strongly suggest that we’re well positioned to complete the proposed work within the funding period and provide key feasibility data to show that chemical inhibitors of Foxo1 can leverage the body’s potential for conversion of gut cells into ?-like cells to cure type 1 and treat type 2 diabetes. Over 12 million patients with type 1 diabetes or late stage type 2 diabetes in the US and EU require life- long insulin injections. Under current treatment paradigm, over 50% of patients with diabetes fail to meet clinical goals of blood glucose management. This is largely due to the narrow therapeutic window and life- threatening potential of hypoglycemia of all insulins in clinical use. Therefore, developing therapies that restore or mimic endogenous pancreatic ? cell function, namely, releasing insulin in a glucose-regulated manner, remains the holy grail for diabetes research. Forkhead Bio’s co-founder Dr. Domenico Accili and colleagues made the groundbreaking discovery that ablation of Forkhead box protein O1 (Foxo1), a transcription factor, in the gastrointestinal tract leads to reprogramming of a subpopulation of enteroendocrine cells into insulin- positive cells in mice and in cultured human gut organoids. The reprogrammed gut cells release insulin only when ambient glucose is high and can restore normal glucose metabolism in a mouse model of insulin- deficient diabetes. These findings raise the possibility of an innovative approach by which specific enteroendocrine cells can be converted into ?-like cells by inhibiting Foxo1, so that the gut takes over insulin production from the failing pancreatic ? cells in diabetes. Work by Accili et al. also uncovered several series of small-molecule chemicals that specifically inhibit Foxo1, providing evidence that developing an oral therapy for this target is possible. These data collectively suggest that this approach has the potential to produce a transformative oral therapy that would radically reduce or even eliminate the need for insulin injections and the burden of frequent blood glucose monitoring through finger pricks, thereby significantly improving clinical outcomes and quality of life for patients with diabetes, while substantially reducing medical costs. Forkhead Bio, recently co-founded by Dr. Accili (Director, Chair of Scientific Advisory Board), Charles Queenan (Director, CEO), and Dr. Hua Lin (CSO), has established strategic collaborations with investigators at the Naomi Berrie Diabetes Center and the Organic Chemistry Collaborative Center at Columbia University. If awarded, work under this SBIR will complement and boost these efforts and substantially accelerate the translation of this promising innovation into an efficacious and patient-friendly therapy.

Public Health Relevance Statement:
Over 12 million patients in the US and EU with type 1 diabetes or late-stage type 2 diabetes require life-long insulin therapy, which carries a tremendous personal health burden and staggering economic costs. Forkhead BioTherapeutics seeks to develop a transformative oral therapy that coverts endogenous gut endocrine cells into glucose-responsive ?-like cells via selective inhibition of FoxO1. Our innovative technology harnesses the potential of native gut cells to produce insulin, thereby replacing chronic insulin injections and achieving normal blood glucose control without the risk of hypoglycemia, effectively curing insulin-dependent diabetes.

Project Terms:
Ablation; Address; analog; Artificial Pancreas; Autoimmune Process; Autoimmunity; Award; base; Biological Assay; Biological Response Modifier Therapy; Blood; Blood Glucose; blood glucose regulation; Blood Vessels; Cell physiology; Cell secretion; Cells; Chemicals; Chronic; Clinical; clinical development; Collaborations; Complement; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease; Disease model; Dominant-Negative Mutation; Dose; druggable target; economic cost; Endocrine; Enteroendocrine Cell; Failure; Fingers; Formulation; FOXO1A gene; Funding; Gastrointestinal tract structure; Gene Expression; gene therapy; Genetic; Glucose; glucose metabolism; glucose monitor; glucose production; Goals; gut endocrine cell; Health; Hepatocyte; Human; Hypoglycemia; Immune; Immunosuppression; improved; In Vitro; in vivo; Inbred NOD Mice; induced pluripotent stem cell; inhibitor/antagonist; Injections; innovation; innovative technologies; Insulin; Insulin deficiency; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; intestinal epithelium; knock-down; Knock-out; Lead; Life; lipid biosynthesis; Literature; Measures; Mediating; Medical; Medical Care Costs; mouse model; Mus; Natural regeneration; new technology; Non-Insulin-Dependent Diabetes Mellitus; novel; novel therapeutics; Operative Surgical Procedures; Oral; Organic Chemistry; Organoids; Outcome; overexpression; Pancreas; Patients; Pharmaceutical Preparations; Phase; Physiological; pill; Pilot Projects; Positioning Attribute; pre-clinical; Production; Property; Proteins; Public Health; Publishing; Quality of life; Recurrence; Reporter; Research; Research Personnel; Risk; Series; side effect; Small Business Innovation Research Grant; small hairpin RNA; small molecule; small molecule inhibitor; Source; stem; Stem cells; Streptozocin; Structure; targeted treatment; Technology; Therapeutic; therapy development; Time; Tissues; transcription factor; Translations; type I and type II diabetes; Universities; Validation; Work

Forkhead BioTherapeutics aims to develop a novel oral therapy for diabetes that will make all insulin therapiesobsolete. Over 50 million patients with type 1 diabetes (T1D) or late stage type 2 diabetes (T2D) worldwiderequire life-long insulin injections. By current standards of care, >50% of the patients fail to meet glucose controlgoals, leading to vascular complications and premature death. This is largely due to the narrow therapeuticwindow of insulin and its potential to cause life-threatening hypoglycemia. Novel therapies that replace nativepancreatic b cell function, namely, releasing insulin in a glucose-regulated manner, remain a tremendous unmetneed. Forkhead Bio's co-founder Dr. Domenico Accili discovered that genetic ablation of the transcription factorForkhead box protein O1 (FOXO1) in gut endocrine cells reprograms them into "b-like" cells that secrete insulinin response to glucose. Accili et al. also uncovered several series of small-molecule FOXO1 inhibitors. This bodyof work delineates a path towards developing an oral FOXO1 inhibitor therapy that converts specific gut cells toreplace b cell function. The product of this SBIR will be an oral pill that normalizes glucose control and eliminatesthe 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 gutb-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 clinicaltranslatability, showed evidence for non-human primate (NHP) as an appropriate large animal efficacy modeland 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 mousemodels; 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 translatabilityfor a novel target. Following Phase II, we will perform additional IND-enabling studies and submit an applicationto the FDA to initiate Phase 1 clinical trials. We have secured intellectual properties including composition ofmatter claims. Our lead product, likely to be licensed or acquired in preclinical or early clinical stage by a majorpharmaceutical company, will be an oral pill that normalizes glucose control and improves quality of life for over50 million patients with diabetes, with the potential to displace >$30 billion annual sales of insulins.

Public Health Relevance Statement:
PROJECT NARRATIVE Over 50 million patients worldwide with type 1 diabetes or late-stage type 2 diabetes require life-long insulin therapy, which carries a tremendous personal health burden and staggering economic costs. In this SBIR project, Forkhead BioTherapeutics seeks to develop an oral small-molecule FOXO1 inhibitor therapy that coverts endogenous gut endocrine cells into b-like cells that respond to glucose and secrete insulin. Our innovative technology harnesses the potential of native gut cells to produce insulin, thereby eliminating the burden of chronic insulin injections and frequent blood glucose checks, achieving normal glucose control without the risk of hypoglycemia, and making "insulin-dependent" diabetes a disease of the past.

Project Terms:
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