The US Food and Drug Administration (FDA) may have voted to keep Avandia on the shelf, but the agency remains worried enough about the beleaguered diabetes drug to tell GlaxoSmithKline, Avandia’s manufacturer, to momentarily halt its use in a clinical trial. Today, the FDA told the pharma giant that its ongoing study, called TIDE, which compares Avandia (rosiglitazone) to its chief competitor, Takeda Pharmaceuticals’ Actos (pioglitazone), would be placed on partial clinical hold. This means that no new subjects can be recruited, but currently enrolled patients can continue treatment.
Meanwhile, two possible conflicts of interest with members of the FDA advisory panels have emerged over the past few days. The Wall Street Journal found that David Capuzzi, one of the three panelists who voted to leave Avandia on market with no new warnings, was paid $14,750 by GSK, at least $6,750 of which came after 2008. Capuzzi says he was paid to speak about lipid-lowering drug named Lovaza, but a GSK spokesman told Pharmalot that at least one talk prior to 2008 was for Avandia.
On the opposite end of the vote, Abraham Thomas, one of twelve members of the panel who recommended withdrawing Avandia from the market, was paid $2,000-$3,000 by Takeda Pharmaceuticals between 2007 and 2008. The FDA is currently investigating possible conflicts of interest for Capuzzi but not Thomas, since all payments he received from Takeda were more than a year before the advisory panel. Results from that investigation could come by the end of the week.
And last, there’s a new paper published online today in Nature that sheds some light on how, exactly, diabetes drugs like Avandia and Actos work — and how safer ones could be made. They belong to a class of drugs nicknamed “glitazones”, which were discovered in the 1980s when they were found to lower blood sugar in mice. Glitazones were thought to improve insulin sensitivity by binding to a cell nucleus receptor called peroxisome proliferator-activated receptor gamma (PPAR-gamma), but details beyond that were sketchy.
Now a team from Harvard Medical School has discovered that the mechanism of interest is actually the addition of a phosphate to PPAR-gamma by a protein kinase called Cdk5. This suggests an alternative avenue for the development of more specific diabetes drugs by focusing solely on Cdk5, possibly avoiding the cardiovascular side effects of glitazones.
Here’s a timeline to the glitazone family from tomorrow’s issue of Nature: