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, but they 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 that end, 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.
Obesity affects 72 million adults in the US and over one billion adults globally. For the most part, obesity remains an unmet clinical condition. This is a project to develop the first highly effective and safe weight loss drug that will also have positive effect on body composition.