Satiogen Pharmaceuticals Inc
Satiogen Pharmaceuticals has discovered a mechanism of action that is a novel target for treating type 2 diabetes and obesity without intervention by systemically absorbed drugs. This “Bile Acid Brake” is a metabolic regulatory mechanism which potently suppresses food intake and postprandial glucose when excessive amounts of bile acids arrive in the colon and rectum. There, bile acids are ligands for intraluminal G-protein coupled receptors on colorectal L-cells which secrete multiple metabolic hormones that regulate satiety and glucose homeostasis.
Preclinical experiments tested two concepts for activating the Bile Acid Brake, and the results demonstrated metabolic effects comparable to marketed drugs. Clinical studies have confirmed these findings in humans. In both cases the active molecules are not absorbed into systemic circulation, an important pharmacological advantage that mitigates the safety concerns typically associated with chronic therapy of metabolic disorders.
Satiogen is now seeking commercial partners for commercializing its intellectual property covering these two product ideas: a substitute for metformin in gliptin formulations which would offer advantages over the currently marketed products, and an over-the-counter nutraceutical that would reduce body weight and postprandial glucose and would enhance the efficacy of gliptin therapy.
The Bile Acid Brake is a physiological regulator of body weight and glucose homeostasis intrinsic to the gastrointestinal system:
- L-cells are important metabolic regulators: This population of cells, ubiquitous throughout the body, secretes three metabolic hormones that are known to have satiogenic and incretin effects: GLP-1, PYY, and oxyntomodulin.
- Bile acids are stimulators of L-cell activity: Bile acids are ligands for TGR5 cell-surface and nuclear receptors which activate L-cell secretion. This discovery dating from 2003 expanded the role of bile acids: instead of being viewed as merely digestive surfactants, they are now known to be hormonal signaling mechanisms for regulating blood glucose and body weight.
- Luminal L-cells are most prevalent in the colon-rectum: Gastrointestinal L-cells receive bile acid signaling from within the lumen of the gut, and the tissue concentration of these L-cells increases 100-fold from the duodenum to the rectum.
- Elevations in colorectal bile acids activate satiogenic and incretin hormones: The arrival of bile acids in the colon-rectum exerts a strong secretory effect on luminal L-cells, and this activation raises blood concentrations of the satiogenic and incretin hormones which slow down nutrient transit and amplify insulin response.
The Bile Acid Brake is an important feedback mechanism which activates changes in eating behavior, hepatic glucose production, and insulin secretion. A teleological rationale is that the Bile Acid Brake acts to protect the endogenous bile acid pool from depletion when bile acids are not sufficiently reabsorbed into systemic circulation before entering the large intestine. Satiogen believes that this intraluminal L-cell activation is metformin’s principal mechanism of action: metformin increases colorectal bile acid, which stimulates L-cell secretion and elevates plasma GLP-1; metformin has no glucose lowering effects when administered intravenously.
Satiogen has tested activating the Bile Acid Brake in preclinical animal models by using rectal administration of exogenous bile acid, and by blocking endogenous bile acid transport/reuptake from the ileum. These experiments confirm that postprandial glucose and food intake can be reduced with agents that are not absorbed into systemic circulation.
Clinical studies have provided proof of concept in humans:
- Colorectal delivery of bile acid: In a study of obese patients with type 2 diabetes, rectal instillation of taurocholic acid stimulated release of GLP-1 and PYY in sufficient amounts to reduce food intake, and the release of GLP-1 was sufficient to stimulate insulin secretion and reduce postprandial glucose. These effects were comparable to those of approved diabetes agents which must be absorbed systemically to be effective.
- Blocking of bile acid reuptake in the ileum: In a different study of obese T2D patients, a non-absorbed inhibitor of bile acid reuptake in the ileum (ASBT inhibitor) caused an increase in fecal bile acids, which reduced food intake and postprandial glucose. These effects were comparable to those of metformin, which is a weak ASBT inhibitor, except that they were achieved without metformin’s systemic absorption.
These experiments support the idea of medicines for treating diabetes and obesity with a novel competitive advantage: because they would not be absorbed into systemic circulation, they would avoid the long-term safety concerns that have been the Achilles heel of most new drug concepts in this class.
Satiogen believes that there are two clinical development opportunities for products that would treat diabetes and obesity by stimulating the Bile Acid Brake:
- Non-absorbed replacement for metformin in combination with DPP4 inhibitors (gliptins): By increasing the potency of ASBT inhibition and eliminating systemic absorption, an ASBT inhibitor would offer dosing advantages and safety improvements over metformin. In the 1990s several ASBT inhibitors were tested through Phase 2 for cholesterol reduction, and at least one compound is now off-patent.
- An over-the-counter nutraceutical for glucose control and weight loss: Medicinal uses of bile acids are Generally Regarded as Safe (GRAS) from a regulatory standpoint, and bile acid tablets are sold OTC. Enteric, delayed release tablet coatings are available for nutritional supplements. A bile acid tablet designed for delayed release in the colon could be an inexpensive OTC nutraceutical for treating diabetes and obesity, and its potency would be amplified when used with a DPP4 inhibitor.
Satiogen has focused its efforts on two activities: sponsoring research – clinical and preclinical – aimed at demonstrating proof of concept, and crafting patent applications based on its discoveries. Several of Satiogen’s patent claims have been approved by the USPTO and various foreign patent authorities, and the company is seeking licensees and collaborators to pursue commercial development of these drug concepts.
Since starting in 2007 Satiogen has operated as a virtual company focused on demonstrating therapeutic proof-of-concept and on crafting a patent estate. In 2010 Satiogen out-licensed its ASBT inhibitor technology to Lumena Pharmaceuticals, which was purchased by Shire PLC in 2014; because Shire is focused on the orphan drug indications being developed by Lumena, Shire returned to Satiogen patent claims directed to diabetes and obesity in 2017.