Merck/Kyorin Phase III Dual PPAR Agonist On First-In-Class Path For Diabetes

Merck/Kyorin's dual peroxisome proliferator-activated receptor agonist MK-0767, a new antidiabetic in Phase III, appears to be winning the development race for first market entrant in its class.

While traditional PPAR insulin sensitizers - such as Lilly's Actos (pioglitazone) and GSK's Avandia (rosiglitazone) - target PPAR gamma receptors only, dual PPARs target both the gamma and alpha receptors.

The dual PPAR class is expected to contribute almost $1 bil. in annual sales to the diabetes market by 2005 and approximately $4.3 bil. (more than one-third of the market) by 2010, according to projections cited by Bristol-Myers Squibb in a 2002 presentation. Bristol is also developing a dual PPAR.

Dual PPARs are aimed at controlling both the hyperglycemia and dyslipidemia associated with type 2 diabetes.

PPAR gamma stimulation influences fatty acid uptake and glucose metabolism, resulting in increased insulin sensitization and reduced glucose levels. PPAR alpha stimulation influences lipid homeostasis, producing increases in HDL cholesterol and reductions in LDL cholesterol, free fatty acids and triglycerides.

Merck licensed exclusive co-development and co-marketing rights (outside Asia) for MK-0767 from Kyorin.

The Phase III program for the drug was initiated at the end of 2002, with Merck targeting a 40% decrease in triglyceride levels and a 20% increase in HDL cholesterol. In a December analyst presentation, Merck said the agent was "generally safe and well-tolerated."

MK-0767's positive safety profile could be its major advantage, as other dual PPARs have encountered toxicity problems such as edema, liver enzyme elevations and bladder tumors. Merck maintains it has not seen such effects in its trials.

Development of Dr. Reddy's/Novo Nordisk's dual PPAR agonist ragaglitazar was discontinued in February due to findings of bladder tumors in rodents. The drug had entered Phase III at the end of 2001 and was touted by its sponsors as leading the first-in-class race. Novartis had briefly signed on to commercialize ragaglitazar in North America in 2001 but bowed out on the eve of Phase III trials.

Novartis has been finicky in the dual PPAR arena: the company also recently returned rights for the preclinical dual PPAR DRF-4158 to Dr. Reddy's. Novartis will instead license a similar "backup" compound from Dr. Reddy's pursuant to the companies' 2001 agreement.

Development also has been discontinued for Pharmacia/Japan Tobacco's dual PPAR reglitazar. The agent was dropped in October 2002 following completion of Phase II trials, with safety concerns apparently a factor.

According to F-D-C Reports' NDA Pipeline, there are as many as nine dual PPAR agonists still in clinical development, with only Merck's MK-0767 in Phase III; three agents are in Phase II and five are in Phase I.

[Editor's Note: NDA Pipeline is a drug development and clinical trials database compiled by the publisher of "The Pink Sheet." For more information, contact Betsy Goodfellow at [phone].]

Close behind MK-0767 is Bristol's BMS-298585, which is in Phase IIb. The other Phase II agent in the class is AstraZeneca's Galida (tesaglitazar). AstraZeneca anticipates an NDA filing as early as 2005.

Three of the agents come from a "PPAR modulators" development partnership between Lilly and Ligand. LY-818 entered Phase II in March. LY-929 entered Phase I in June 2002, and LY-674 began Phase I at the end of last year.

Although Lilly and Ligand are not disclosing the exact combination of receptors targeted by each drug, the agents' indications (which include dyslipidemia for 929 and 674, and metabolic diseases for 818) strongly suggest dual PPAR activity.

GlaxoSmithKline is developing the three Phase I agents, including GW-501516, also a collaboration with Ligand. Similar to the Lilly/Ligand products, 516's dyslipidemia indication suggests it is a dual PPAR. GSK's other Phase I agents are GW-590735, indicated for dyslipidemia, and GW-677954, which carries a type 2 diabetes indication and thus may target only the PPAR gamma receptor.