After positive results of ezetimibe’s CV outcomes trial IMPROVE-IT had been presented in November 2015, Merck hoped to obtain a label expansion for its cholesterol lowering drugs Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin) for the reduction of CV events in patients with coronary heart disease (CHD). However, Merck’s hopes took a blow after receiving a complete response letter (CRL) in February from the U.S. FDA stating they would not approve the supplemental new drug application (sNDA) in its current form. The company announced they will review the letter and determine next steps. The main question they have to think about could be is it even worth pursuing label expansion at this late state of ezetimibe’s shelf life?
The FDA’s decision against Zetia’s sNDA does not come as a surprise. In December 2015, the Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. FDA voted against a recommendation of the additional use of ezetimibe in the secondary prevention setting in patients with CHD. The authorities may feel that as ezetimibe only showed an additional risk reduction of 2 percent points compared to treatment with simvastatin alone (although statistically significant), it is not clinically meaningful enough to warrant an updated label. Also, a subgroup analysis showed that the majority of the benefits were seen in patients with diabetes, and no effect was seen among non-diabetic patients aged under 75. Merck might think about filing for a label for secondary-prevention in CHD patients with diabetes, where the IMPROVE-IT study almost exclusively showed the greatest benefit.
But to be honest, in light of the looming patent expiry that might be wasted effort. With respect to the pending expiry of ezetimibe’s patent the United States in April 2017, one might argue Merck should not spend too much time and effort to act on the FDA’s CRL. Once generic versions enter the market sales for Zetia and Vytorin will decline rapidly.