An experimental lipid-lowering combination developed by Merck hit a snag in the form of an FDA rejection, the firm said yesterday, but according to one analyst the compound’s real test is yet to come.


The FDA issued a complete response letter for the tablet, which combines ezetimibe—the active ingredient in Merck cholesterol fighter Zetia—with atorvastatin, the potent statin underpinning Lipitor. Merck is looking to revive sales within its cardiovascular franchise, flagging since Zetia’s cousin Vytorin, a combination of ezetimibe and simvastatin, encountered concerns about efficacy.


The rejection of the investigational drug, codenamed MK-0653C, poses a setback but not necessarily a permanent one. The agency told Merck that additional data are needed, according to a statement from the company, and Merck plans to discuss its next steps with the agency, including new data expected to be available later this year that may address the FDA’s comments.

What new data? The company referred media to three trials listed on two evaluating different dosage strengths of the ingredients, and one assessing patients not adequately controlled with Lipitor who switch to the ezetimibe-atorvastatin combo, vs. doubling the dose of Lipitor or switching to AstraZeneca’s Crestor (rosuvastatin).

There is another important trial, not mentioned in Merck’s statement, that has implications for ‘0653C: the IMPROVE-IT study of Vytorin vs. simvastatin alone (the active ingredient in Merck’s off-patent statin Zocor). That trial could help answer whether ezetimibe offers value above a statin (simvastatin or atorvastatin) alone.

The result the company is hoping for is one that proves that ezetimibe in combination with simvastatin has a mortality benefit above statin alone. Pfizer and Merck may need to work out some patent issues with regard to marketing a combination of their two cholesterol-lowering drugs, “but suffice it to say atorvastatin plus ezetimibe is only important if IMPROVE-IT works,” Barclays analyst Tony Butler, PhD, told MM&M. “If IMPROVE-IT failed, I’m not sure of the utility of ezetimibe. If it works, an even more potent compound might be atorvastatin plus ezetimibe.”

The trial is designed to answer a bigger question—whether aggressive lowering of LDL, or “bad” cholesterol, can reduce death and heart attack by more than 30%, the current standard. Merck has said publicly that a second interim analysis of IMPROVE-IT is planned for when approximately 75% of the pre-specified clinical endpoints have occurred. Timing for this is by the end of this month.

If new data help Merck satisfy FDA concerns, MK-0653C may yet prove to be a CV sleeper. If not, there’s more to the company’s cardiovascular pipeline: Tredaptive, which combines extended-release niacin with a flush inhibitor and is in Phase III to boost HDL, so-called “good” cholesterol; and anacetrapib, the CETP inhibitor that conveys both an HDL boost and LDL reduction, also in Phase III.