Cardiovascular safety determines the direction of PPAR agonist R&D

The two peroxisome proliferator-activated receptor (PPAR) gamma agonists pioglitazone and rosiglitazone approved for treatment of type 2 diabetes achieved combined 2004 global sales of US$ 3.96 bln shared between Takeda & Eli Lilly (52 %) and GlaxoSmithKline (48 %). Companies with next generation dual PPAR gamma and alpha agonists lead by BMS with muraglitazar are prevented from entering this market by FDA’s request for extensive preclinical and clinical characterization due to cardiovascular safety concerns on the PPAR agonist’s fenofibrate-like alpha component. As a consequence, the four companies with improved PPAR gamma modulators will have a competitive advantage. The field of novel PPAR delta and of triple (or pan-) PPAR agonists is lead by GSK. These results were found in a search conducted by La Merie Business Intelligence. The results were published in the November 28 issue of R&D Pipeline News, edited by La Merie Business Intelligence.

The use of insulin sensitizing, first generation PPAR gamma agonists is associated with an increased incidence of edema and weight gain. Clinical data with improved modulators of PPAR gamma from Metabolex indicate that this side effect can be avoided. While two other PPAR gamma agonist developers are active in diabetes, Daiichi Sankyo decided to begin clinical development of its PPAR gamma agonist CS-7017 in oncology although previous experience with a PPAR gamma ligand in metastatic breast cancer was negative.

At least 10 companies are engaged in R&D of dual PPAR alpha and gamma agonists for the treatment of type 2 diabetics with dyslipidemia. The companies most affected by FDA’s requests are BMS & Merck, AstraZeneca and Eli Lilly. Impact of FDA’s decision on the pipeline of PPAR alpha agonists with fenofibrate-like actions on triglycerides and HDL cholesterol is not yet evident as these projects are in earlier clinical development.

GlaxoSmithKline leads the field of companies with interest in PPAR delta agonism which affects cholesterol transport. Apart from its PPAR delta agonist GW 501516, GSK has a triple PPAR alpha, gamma and delta agonst in phase II studies ahead of three other companies with pan PPAR agonists. The use of pharmacogenomics for patient stratification might be one strategy to select responders and avoid side effects as is intended by Perlegen in its MC-555 program. Other research strategies are to omit the PPAR alpha component and search for dual PPAR gamma and delta agonists or to work with completely new classes of chemical structures.

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