12:00 AM
Dec 08, 2008
 |  BioCentury  |  Strategy

Money, mechanism and time

How CV Therapeutics Inc. turned Ranexa ranolazine from a second-line drug for chronic angina with safety questions hanging over it into a first-line treatment with multiple efficacy claims - some in exactly the areas where there had been safety worries - is a story of big bets, the intertwining of mechanism of action and clinical work, and a lesson in how to run a large clinical trial so that, even if it misses the primary endpoint, there are valuable data to be gleaned.

"The key strategic decision was to do the MERLIN study," said CVT spokesperson John Bluth. "Ranexa went from a drug that looked like it would wither on the vine to a first-line drug with claims for reduction of ventricular arrhythmias, HbA1c, new onset atrial fibrillation, and bradycardia."

MERLIN-TIMI (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) cost close to $100 million, according to Chairman and CEO Louis Lange. But CVT was able to take the chance because it had raised a lot of money during the genomics bubble. In the two years from the beginning of 2000 to the end of 2001, the company raised $506.2 million. Since then CVT has raised $897.1 million, and it ended Sept. 30 with $301.9 million in cash.

Understanding the mechanism

To understand why it made sense to run MERLIN, it is necessary to look at Ranexa's mechanism of action, which is broader than CVT thought when it in-licensed the drug from the Syntex unit of Roche in 1996.

Back then, ranolazine was believed to be a partial inhibitor of fatty acid oxidation (pFOX) that altered cardiac metabolism instead of lowering heart rate and blood pressure as other angina drugs do.

But in 2002, the company discovered that ranolazine functions by binding to a specific sodium channel, late SCN5A (also called the 1.5 v sodium channel), and selectively inhibits the late sodium current. When defective, the channel doesn't close properly, and sodium builds up in the cells. Excess sodium turns on an exchange mechanism: sodium exits and calcium enters. The resulting overload of...

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