 | Diabetes R and D Pipeline: PPAR Agonists
PPAR (peroxisome proliferator-activated receptor) agonists are insulin sensitizers and lipid metabolism modifying compounds.PPARs are a nuclear receptor superfamily with four subtypes designated as PPARa (alpha), PPAR?1 (gamma1), PPAR?2 (gamma2), and PPARd (delta). Among them, especially PPAR gamma receptors, and their agonists, have a major role in adipogenesis, insulin sensitivity and glucose and lipid metabolism.PPAR gamma receptors play a key role in adipocyte differentiation and insulin sensitivity. Their synthetic ligands, such as thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of type 2 diabetes.PPAR alpha agonists, such as fibrates, are lipid-modifying compounds. Their action results in decrease of plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations.Dual PPAR agonists usually combine lipid benefit of PPAR alpha agonists with glycemic advantages of PPAR gamma agonists.Safety IssuesIn December 2008, the US Food and Drug Administration (FDA) issued the New Recommendations on Evaluating Cardiovascular Risk of New Products Intended to Treat Type 2 Diabetes, recommending that manufacturers developing new pharmaceutical and biologic products for the treatment of type 2 diabetes provide evidence that therapeutic products will not increase the risk of such cardiovascular events as heart attack. This recommendation is part of a new guidance for industry that applies to all diabetes therapeutic products currently under development. The recommendation, which was effective immediately, defines more robust and adequate design and data collection for Phase II and Phase III clinical trials than were previously required. Specifically, the guidance recommends that Phase II and Phase III clinical trials should demonstrate that new anti-diabetic therapies do not increase cardiovascular risk in comparison with existing therapies, especially in patients of advanced age or with advanced diabetes or renal impairment. The FDA also recommended that manufacturers have any cardiovascular events in their clinical trials analyzed by committees of outside cardiologists who are unaware of which patients received the tested products and which were on placebo. Based on these evaluations, the FDA can better ensure that product labeling includes comprehensive information on its safety and effectiveness.Regardless of high popularity of PPAR agonists in the treatment of patients with type 2 diabetes, there are some serious safety issues that caused halted development of number of investigational products (muraglitazar <Actinic:Variable Name = 'Pargluva'/>, tesaglitazar, naveglitazar [LY-818]) or market withdrawal of already approved products (rosiglitazone [Avanida®], troglitazone [Rezulin®]). Recently published meta-analysis of pioglitazone (Actos®), a thiazolidinedione compound similar to Avandia®, indicated edema and cardiac failure as its adverse effects.These safety concerns include potential carcinogenicity, cardiomyopathy, cardiac failure and myocardial infarction, rhabdomyolysis, bone fractions, increase in plasma creatinine and homocysteine, liver toxicity, weight gain, fluid retention, peripheral edema, and potential unknown gene effects.Pipeline of Novel R & D PPAR Agonists for the Treatment of Diabetes (BioPolaris)The newly published Pipeline of Novel R & D PPAR Agonists for the Treatment of Diabetes (BioPolaris) lists total of 25 investigational products of which1 is in Phase II/III, 11 are in Phase II clinical trial, 6 are in Phase I clinical trial, 1 has Investigational New Drug Application (IND) filed with the US Food and Drug Administration (FDA) and 6 are in preclinical stage of development.Total of 20 R & D PPAR agonists are potential co-development or in-licensing products.Analysis of targets shows 6 gamma, 7 dual, 4 pan, 2 gamma partial agonists/antagonists, 1 alpha, 1 delta PPAR agonists and 4 products with undisclosed PPAR targets.Total of 26 companies are developing new PPAR agonists for diabetes, of which 11 are from Asia. Out of all the major pharmaceutical companies only Daiichi Sankyo Co., Ltd. (Japan), GlaxoSmithKline plc (UK), Johnson & Johnson (USA), Roche Holding AG (Switzerland) and Sanofi-Aventis SA (France) are developing new R & D PPAR agonist for the treatment of diabetes. At least 11 of listed companies are potential in-licensing candidates.BioPolaris' report features detailed profile of each listed R & D product, showing product's indications, state and stage of development, designation status, delivery mode, characteristics, mechanism of action, monotherapy or combination therapy, efficacy and safety data (if available), origin, development company and co-development and in-licensing data.Published: August 2009Pages: 27
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