Merck cholesterol drug extremely effective in study

http://www.reuters.com/article/idUSN1719543320101117

Wed, Nov 17 2010
* Raises good HDL cholesterol 138 pct
* Cuts bad LDL cholesterol 40 pct in patients on statins
* No safety or torcetrapib-like problems observed
* 30,000-patient outcomes study to begin in 2011 Q2
By Bill Berkrot and Ransdell Pierson
NEW YORK/CHICAGO, Nov 17 (Reuters) - An experimental Merck & Co (MRK.N: Quote, Profile, Research, Stock Buzz) heart drug, from a class of medicine with a troubled past, appeared to be safe and had a "jaw dropping" effect on both good and bad cholesterol levels, according to data from a clinical trial.
Merck's anacetrapib increased good HDL levels by a stunning 138 percent after 24 weeks of treatment, and lowered levels of bad LDL cholesterol by 40 percent in patients already taking LDL-lowering statins, researchers said.
"The lipid effects are jaw dropping in both directions," said Dr. Christopher Cannon, the study's lead investigator from Brigham and Women's Hospital in Boston. He presented the data at the American Heart Association scientific meeting in Chicago on Wednesday.
Researchers found no anacetrapib safety issues during the 18-month study, and patients receiving the drug had fewer serious heart problems than those given a placebo.
Even if development of the medicine continues without a hitch, it will likely be at least five years before Merck can begin selling the drug.
Anacetrapib belongs to a class of drugs called CETP inhibitors that produced one of the most spectacular clinical failures in pharmaceutical history. A pivotal study of Pfizer Inc's (PFE.N: Quote, Profile, Research, Stock Buzz) highly touted torcetrapib was stopped in late 2006 after higher death rates were found among those taking the drug, pulling the plug on an $800 million Phase III program.
Based on the data from the anacetrapib trial, called Define, "we are 94 percent confident that anacetrapib doesn't have the clinical (side) effects of torcetrapib," Cannon said.
The HDL increase seen with anacetrapib "is double what torcetrapib does; it's four times what niacin can do if you can push niacin to its full 2 gram dose; and 10 times the effect seen with statins," Cannon said, comparing anacetrapib with other therapies.
It is believed that HDL has a heart protective effect, possibly by carrying LDL away from the arteries.
Anacetrapib also cut by 36 percent levels of LP(a), which is believed to be an independent cardiovascular risk factor.
The 1,623-patient, 18-month Define trial was designed to show anacetrapib does not have the unintended effects on blood chemistry and blood pressure found in detailed analyses of what went wrong with the Pfizer drug.
"It's been found that torcetrapib unfortunately as a molecule somehow lands itself in the adrenal gland and then pumps out aldosterone, other hormones, and has all these effects," Cannon explained.
Compared with the placebo group, patients receiving anacetrapib in the study showed no difference in electrolytes, aldosterone or blood pressure, and no other safety concerns were seen with the drug, he said.
"This trial was set up so that we would have some more reassurance that the drug was safe before doing a gigantic trial. And that's what we found, that it looks safe so far," Cannon said.
In the wake of torcetrapib, Merck has long known that to gain approval for anacetrapib, it will have to conduct a large so-called outcomes trial to prove its drug cuts heart attacks and death rather than just impacts cholesterol levels.
Plans for such a study were announced on Wednesday. It will include some 30,000 patients at high risk of heart attack or other serious heart problems, and take about four years to complete. Enrollment is expected to begin in the second quarter of 2011, researchers said.
Patients in the 18-month Define study all had coronary disease or were at high risk for heart disease, and were already taking a statin, such as Lipitor, to lower their LDL levels. They received either 100 milligrams of anacetrapib or a placebo once a day on top of their statin.
At the start of the study, patients on average had a baseline HDL of 40 and LDL of 81. Those on anacetrapib on average saw HDL leap to 101 and LDL drop to 45. HDL levels of placebo patients rose only to 46, while LDL fell to 77.
Patients whose LDL dropped below 25 were taken off the drug as a precaution, which was part of the study's design. "We didn't see any problems, but this gets the LDL down as low as its ever been in any study," Cannon said.
Researchers observed a trend toward lower rates of cardiovascular death, heart attack, stroke and hospitalization for unstable angina. The need for angioplasty or bypass surgery over 18 months was significantly lower on anacetrapib -- eight patients versus 28 on placebo.
While the dramatic impact on HDL is clear, it remains to be determined if raising it through the CETP inhibitor mechanism can save lives and hospitalizations.
Roche (ROG.VX: Quote, Profile, Research, Stock Buzz) and Japan Tobacco (2914.T: Quote, Profile, Research, Stock Buzz) are also forging ahead with development of a CETP inhibitor, called dalcetrapib.
"There is very real uncertainty as to what anacetrapib will do on clinical outcomes," said Rory Collins, co-director of the clinical trial service unit at the University of Oxford, who will lead the outcomes study program.
"It is incredibly exciting. It could be really the next big thing in cardiovascular disease," Collins said. (Reporting by Bill Berkrot and Randell Pierson; editing by John Wallace)