SBIR-STTR Award

The Specific Aim of this proposal is to test the feasibility of using an orally available small molecule (FGH10019) to reduce obesity. Obesity contributes to the prevalence of many disease states and accounts for more than 25% of all health care costs in the US according to recent market reports. Prescription pharmaceuticals account for less than 1 percent of the total obesity market because of limited efficacy, poorly understood biology and significant safety issues. We have discovered a diarylthiazole compound that inhibits insulin-mediated adipogenesis by blocking SREBP-1 and 2. Administration of the compounds to obese ob/ob mice led to weight loss, marked reduction of visceral fat, increased insulin sensitivity, and lower blood glucose levels. We have since improved the drug properties of this original compound. Our current lead compound is FGH10019, which has higher potency in blocking SREBP-1 and 2, has improved oral bio-availability in mice, and other improved drug like properties. FGH10019 is effective in reducing weight and improving hyperglycemia in Ob/Ob mice. However, before moving to IND enabling studies, must evaluate this compound in a small animal model that more closely resembles human obesity. In this Phase I study, we will therefore test efficacy of our compound in a high fat diet rat model. To this end, we will carry out the following Tasks: Task 1: Evaluate maximum tolerated dose (MTD) by oral gavage of FGH-10019 to Sprague-Dawley rats. Task 2: Evaluate dose to reduce weight gain and lower triglycerides, LDL and blood glucose. Test of Feasibility: we must observe: 1) MTD at or greater than 100 mg/kg;2) significant effective dose at 1/10 or 1/5 the MTD and we must observe reduced weight by 8%, due to decrease in fat content, improved hyperglycemia and lowering LDL and TG by more than 25%, without affecting HDL. In Phase II, we will move FGH 10019 toward IND enabling studies and search for improved back-up compounds.

Public Health Relevance:
Obesity and related disorders currently account for almost 25% of the total healthcare budget and the problem is getting worse as rates of obesity continue to increase. Diet and exercise are the mainstays of weight loss programs, but in most cases they are not sufficient to address the problem. Prescription drugs are generally of limited use and they can exhibit serious side effects. This is a proposal to develop a truly effective drug tha acts through a novel mechanism for effectively treating obesity and related disorders.

The Specific Aim of this proposal is to file an IND to allow for a Phase I clinical safety study of FGH 10019 with an indication for the control of obesity. We successfully met the primary endpoints of our SBIR Phase I study (R43 HL112484). As shown by the Phase I report of this proposal, following oral gavage, significant control of weight gain and improvement in body composition was observed with a therapeutic index (TI) of at least 40 in high fat high carbohydrate (HFHC) fed rats. We are submitting this SBIR Phase II proposal to develop our compound to the IND stage. Obesity and excess fat is a major risk factor for cardiovascular disease, diabetes mellitus, and cancers, among other chronic diseases. Diet and exercise are the mainstays of weight loss programs, but in most cases they are not sufficient to address the problem. Prescription drugs are widely used to treat obesity, butthey generally have limited efficacy, seldom work without significant lifestyle modification (stric control of diet and exercise), and they can have serious side effects. Targeting individual enzymes in lipid and fat metabolism has been used to develop drugs against obesity and related complications; however, these efforts have not proven effective clinically, due to lack of efficacy or intolerable side effects. Therefore, we have taken a new mechanistic approach with the goal of finding a drug that will help control weight without dose-limiting unwanted side effects. To this end, we identified a small molecule (FGH10019) that targets master regulators of multiple pathways of lipid and fat synthesis, which are important elements in adipogenesis and developing obesity. FGH10019 is an orally available small molecule diarylthiazole. FGH10019 blocks the activity of transcription factors SREBP-1 and 2, master regulators of fat and lipid synthesis. Oral administration of FGH10019 resulted in 8% weight loss at 2.5/mg/kg and 15% loss at 10 mg/kg in an industry standard model for such testing in diet- induced (HFHC) obese rats. Furthermore, the loss was primarily due to loss of fat, while lean body mass percent remained constant in the treated animals (see Phase I report). No adverse effects of drug treatment were seen with repeated dosing of 100 mg/kg. We therefore have a therapeutic index (TI) of at least 40, using 2.5 mg/kg as the dose that elicited at least 5% weight loss (FDA requires at least 5%). We find these results to be promising and our Specific Aim of this proposal is to file an IND for testing safety of this compound in a clinical Phase I trial. To thatend, we will carry out well known IND enabling studies that we expect will results in a successful IND filing by the end of this Phase II proposal. During the course of these studies, we will be running our back-up program in parallel using internal funds. If at any point, our lead compound fails a key test, we will be able to replace it rapidly with a back-up compound. Properties of some back-up compounds were discussed in the Phase I proposal. Additional compounds are also available.

Thesaurus Terms:
Accounting;Address;Adult;Adverse Drug Effect;Adverse Effects;Affect;Animals;Back;Behavior Therapy;Body Composition;Body Weight Decreased;Budgets;Canis Familiaris;Carbohydrates;Cardiovascular Diseases;Chronic Disease;Clinical;Clinical Trials;Clinical Trials Design;Cyclic Gmp;Diabetes Mellitus;Diet;Diet And Exercise;Disease;Dose;Dose-Limiting;Drug Formulations;Drug Prescriptions;Enzymes;Fatty Acid Glycerol Esters;Feeding;Funding;Genotoxicity;Goals;Healthcare;In Vitro;Indium;Individual;Industry;Lead;Lipid Biosynthesis;Lipid Metabolism;Lipids;Malignant Neoplasms;Meetings;Modeling;Obesity;Oral;Oral Administration;Pathway Interactions;Pharmaceutical Preparations;Phase;Phase 1 Study;Phase I Clinical Trials;Preclinical Study;Programs;Property;Public Health Relevance;Rattus;Reporting;Response;Risk Factors;Running;Safety Study;Safety Testing;Small Business Innovation Research Grant;Small Molecule;Sprague-Dawley Rats;Sre-1 Binding Protein;Staging;Testing;Therapeutic Index;Toxic Effect;Transcription Factor;Weight Gain;Weight Maintenance Regimen;Weight-Loss Drugs;Work;