Diabetes: Agonists versus Inhibitors

Dec 01, 2010

Diabetes is pharma's second-largest global market, worth close to $25 billion and growing by double digits annually, even in the developed world. Competition among drugmakers is fierce, with hundreds of new compounds entering the pipeline each year despite the fact that the disease is already well treated, from first-line metformin to last-ditch injectable insulin. The space between is where the new drug action is.



Controlling glucose is no longer the exclusive therapeutic challenge. Says Datamonitor analyst Dr. Nick Karachalias: "Diabetes is increasingly viewed as a cardiovascular disease effected by metabolism, so CV outcomes are critical." And in recent years, Merck's Januvia and Lilly's Byetta, the first-in-class GLP-1 agonist, have raised the bar even higher because both drugs cause little or no weight gain.



The two hottest classes are the GLP-1 (glucagon-like peptide-1) agonists and the SGLT2 (sodium glucose transporter 2) inhibitors. The GLP-1 stimulator class, being injectables, present the opportunity for drugmakers to increase convenience and compliance with longer-lasting models. Lilly's Bydureon—a once-weekly version of twice-daily Byetta—was delayed indefinitely after the FDA asked the firm to run additional tests of cardio and kidney risks that may result from higher-than-expected levels of the extended-release drug in the blood. Meantime, Novo Nordisk, the longtime diabetes shop par excellence, launched the GLP-1 to beat this year, once-daily Victoza. GSK's longer-acting Phase III GLP-1, Syncria, may succeed as a once-weekly injectable, but its second-rate efficacy is likely to limit its use.



The oral anti-SGLT2 molecules target an intestinal protein that ferries glucose to the kidney, where 90 percent is reabsorbed, and instead reroutes and expels it through the urine. AstraZeneca/BMS's Phase III dapagliflozin is the front-runner among anti-SGT2 contenders, with recent data showing that in conjunction with metformin it is as effective as glipizide plus metformin, but causes the loss of seven pounds compared to a three-pound gain by its opponent. AZ/BMS are shrewdly developing a fixed-dose dapagliflozin/metformin combo to maximize its convenience. J&J, which like Merck is increasing its investment in cardiovascular and metabolic R&D, is testing its own anti-SGLT2, canagliflozin, in a 10,000-patient Phase III trial.



"There is a huge number of targets and compounds, including longer-acting insulins," says Karachalias. "Many companies are taking a scattershot approach to hit every molecule and see what comes out the other side."