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'Unprecedented': Cholesterol drug called dramatic success
 
 
  'Jaw-dropping' data on Merck & Co's anacetrapib
 
pharmatimes.com World News | November 18, 2010
 
www.suntimes.com
 
Kevin Grogan
 
Merck & Co has presented eagerly-anticpated data on its experimental drug anacetrapib which shows that it more than doubles the level of good cholesterol and cuts the bad type nearly in half, without increasing blood pressure.
 
When taken with statins, anacetrapib raised HDL levels 138 percent and cut LDL 40 percent, compared with a placebo, the study found.
 
Patients treated with the drug also didn't experience the dangerous side-effects that doomed an earlier drug in the same class, torcetrapib.
 
The new drug -- called anacetrapib -- still has to be tested in a larger trial to determine whether it reduces heart attacks, stroke and other cardiovascular events.
 
But the results from the long-awaited DEFINE trial, presented Wednesday at an American Heart Association conference at McCormick Place, were "unprecedented," according to the lead researcher, Dr. Christopher P. Cannon of Brigham and Women's Hospital in Boston.
 
"There are very few drugs available to treat low levels of good cholesterol, and this new drug, anacetrapib, is 4 to 10 times more effective in raising good cholesterol compared to current therapies," Cannon said.
 
Cholesterol-lowering statin drugs effectively reduce levels of "bad" cholesterol, also known as LDL. But "a lot of people die [of heart disease] even though we have all these statins available," Cannon said.
 
Results of the Phase III, 1,623-patient, 18-month DEFINE study have been presented at the American Heart Association meeting in Chicago. The data show that anacetrapib, a cholesterylester transfer protein (CETP) inhibitor reduced low-density lipoprotein (LDL), or 'bad' cholesterol by 40% from 81mg/dL to 49 mg/dL.
 
It also more than doubled the level of high-density lipoprotein cholesterol (HDL) which helps clear lipids from the bloodstream - from 40 mg/dL to 101 mg/dL. This was done without raising blood pressure, which has particularly impressed researchers as the latter led in part to the termination of lat-stage trials of another CETP inhibitor, Pfizer's much-touted torcetrapib at the end of 2006.
 
Christopher Cannon of the Brigham and Women's Hospital in Boston, and lead investigator on DEFINE, said "Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL". He added that these changes are striking because virtually all the patients in the study were already taking cholesterol-lowering drugs and achieved previously unattainable levels of good and bad cholesterol".
 
Although the study was not powered to assess the effects of anacetrapib on cardiovascular events, fewer of the latter occurred in the anacetrapib group than in the statin-only group. Prof Cannon said "this agent provides us a very strong add-on treatment to statins", adding that "if the cardiovascular effects are borne out by future research, it would be a very promising approach to reducing cardiovascular events in patients with or prone to atherosclerosis". Michael Mendelsohn, head of the cardiovascular franchise at Merck Research Laboratories, said that these results are promising "and serve as the basis for our decision to further develop anacetrapib," which will be studied further in a large cardiovascular clinical outcomes trial.
 
A much larger, four-year study of anacetrapib announced Wednesday should answer many of the lingering safety and efficacy questions.
 
A four-year, 30,000-patient study will begin next year and observers believe that anacetrapib has the potential to be an enormous seller. Merck thinks so too and last month, Daniel Bloomfield, head of clinical and translational medicine, cardiovascular, told PharmaTimes World News he believes the drug may "change the landscape of heart disease".
 
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In Phase III Study Merck's Investigational CETP Inhibitor Anacetrapib Met Safety and Efficacy Endpoints in Patients with CHD
 
WHITEHOUSE STATION, N.J., Nov. 17, 2010 - Researchers today presented results from the Phase III DEFINE (Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib) study with Merck's investigational CETP inhibitor, anacetrapib. In the trial of 1,623 patients with coronary heart disease (CHD) or CHD risk equivalents, anacetrapib showed no significant differences from placebo in the primary safety measures studied. There were no significant differences in mean changes in blood pressure between the anacetrapib and placebo treatment groups, nor were there any significant differences in serum electrolytes or aldosterone levels. During the 76-week treatment phase, the pre-specified adjudicated cardiovascular endpoint (defined as cardiovascular death, myocardial infarction, unstable angina or stroke) occurred in 16 anacetrapib-treated patients (2.0 percent) compared with 21 placebo-treated patients (2.6 percent) (p=0.40). At 24 weeks, anacetrapib decreased LDL-C by 40 percent (from 81 to 45 mg/dl vs. 82 to 77 mg/dl for placebo, p<0.001) and increased HDL-C by 138 percent (from 40 to 101 mg/dl vs. 40 to 46 mg/dl for placebo, p<0.001) in patients already treated with a statin and at guideline-recommended LDL-C goal. The DEFINE data were presented today at the American Heart Association Scientific Sessions and published concurrently online in the New England Journal of Medicine.
 
"These results are promising and serve as the basis for our decision to further develop anacetrapib," said Michael Mendelsohn, M.D., senior vice president and franchise head, Cardiovascular, Merck Research Laboratories. "We look forward to continuing to study anacetrapib in a large cardiovascular clinical outcomes trial."
 
Safety and Efficacy of Anacetrapib The DEFINE trial was an 18-month study in more than 1,600 patients with or at high risk for CHD who were already receiving statins and were at guideline-established LDL-C goal. The study was designed to assess the lipid-modifying efficacy, safety and tolerability of anacetrapib 100 mg daily added to ongoing statin therapy with or without other lipid-modifying agents.
 
There were no significant differences between the anacetrapib and placebo-treated patients in mean change from baseline in systolic (0.2 mmHg, p=0.83) or diastolic blood pressure (0.0 mmHg, p=0.96), nor in the percentage of patients reported to have increased blood pressure. The number of patients with clinically important changes in serum electrolytes (sodium, potassium, chloride and bicarbonate) was not significantly different between those who received anacetrapib and those given placebo during the 76-week treatment period (p value range 0.25 to 0.99), nor was there any difference in mean change from baseline in aldosterone levels between the two groups over 76 weeks (20.4 pg/mL vs. 18.4 pg/mL, respectively). In addition, there were no cases of rhabdomyolysis (severe muscle injury infrequently associated with lipid-lowering drugs) in either the anacetrapib or the placebo treatment groups. There was one case of elevated liver enzymes (two consecutive values greater than or equal to three times the upper limit of normal) in the anacetrapib-treated patients compared to eight cases in patients given placebo.
 
An early member of the CETP inhibitor class, torcetrapib, was found to cause an excess of deaths and cardiovascular events. In the DEFINE study, all cardiovascular serious adverse events and deaths from any cause were adjudicated by a blinded, external, independent adjudication committee. Reports of revascularization and heart failure were collected and adjudicated, but were not part of the pre-specified cardiovascular composite endpoint. In DEFINE, pre-specified adjudicated cardiovascular events occurred in 16 patients given anacetrapib (2.0 percent) compared with 21 patients who received placebo (2.6 percent) (p=0.40), coronary revascularization was carried out in significantly fewer people given anacetrapib compared with those taking placebo (8 vs. 28, respectively, p<0.001), and death from any cause occurred in 11 patients taking anacetrapib and in eight patients given placebo (p=0.5). Based on these results, there is confidence in moving forward to study anacetrapib in a large cardiovascular clinical outcomes trial.
 
Rates of drug-related adverse experiences (AEs), serious AEs, and drug-related serious AEs were similar between the anacetrapib and placebo groups (11.4 percent vs. 10.7 percent, 15.2 percent vs. 14.8 percent, and 0.2 percent vs. 0.5 percent, respectively). Clinical and drug-related AEs leading to discontinuation were also similar in patients taking anacetrapib and those given placebo (5.4 percent vs. 5.7 percent and 2.7 percent vs. 2.2 percent, respectively).
 
At 24 weeks, treatment with anacetrapib resulted in a placebo-subtracted 40 percent reduction in mean LDL-C (from 81 to 45 mg/dl vs. 82 to 77 mg/dl for placebo, p<0.001) and a 138 percent increase in mean HDL-C (from 40 to 101 mg/dl vs. 40 to 46 mg/dl for placebo, p<0.001). Compared to placebo, anacetrapib also raised mean apolipoprotein (apo) A-1 (a major protein component of HDL particles) by 45 percent, lowered mean apo B (a major protein component of atherogenic lipoprotein particles, including LDL) by 21 percent and reduced mean non-HDL-C by 32 percent (p<0.001 for all measures). Anacetrapib reduced median Lp(a) (an LDL-like particle) by 36 percent compared to placebo. All changes in lipids were sustained throughout the 76-week treatment period. There were no significant differences between the treatment groups in C-reactive protein (CRP). There was a pre-specified discontinuation rule for patients whose LDL-C fell below 25 mg/dL, which occurred in 18 percent of patients treated with anacetrapib and in one patient in the placebo group.
 
"These additional data add to our enthusiasm for continued study of anacetrapib in a large clinical outcomes trial, an important next step," said Yale Mitchel, M.D., vice president, Cardiovascular Disease, Global Clinical Development and Regulatory Affairs, Merck Research Laboratories.
 
More than 1,600 patients participated in 18-month study in 20 different countries
 
DEFINE was a randomized, double-blind, placebo-controlled trial designed to assess the lipid-modifying efficacy, safety and tolerability of anacetrapib 100 mg daily added to ongoing statin therapy (with or without other lipid-modifying medications) in patients with CHD or CHD risk equivalents. A total of 2,757 participants were screened at 153 centers in 20 different countries, and 1,623 patients were randomized to either anacetrapib or placebo. Patients had baseline LDL-C levels of 50 to 100 mg/dL while on statin and possibly other LDL-C-lowering therapy, HDL-C levels less than 60 mg/dL, and triglycerides levels of 400 mg/dL or lower.
 
The primary efficacy endpoint was the percent change from baseline in LDL-C after 24 weeks of treatment along with the safety and tolerability assessments (i.e., adverse experiences, safety laboratory tests including electrolytes and aldosterone and vital signs including BP, ECG, and physical exam) assessed over the 76-week treatment period. Secondary efficacy endpoints included change from baseline in LDL-C at week 76, as well as HDL-C, non-HDL-C, apo B and apo A-1 after 24 and 76 weeks of treatment.
 
The pre-specified cardiovascular composite endpoint used for evaluation of safety was comprised of cardiovascular death, nonfatal myocardial infarction, stroke and hospitalization for unstable angina. All cardiovascular serious adverse events and death from any cause were adjudicated by a blinded, external, independent adjudication committee. Reports of revascularization and heart failure were collected and adjudicated, but were not part of the pre-specified cardiovascular composite endpoint. An external, independent safety monitoring committee reviewed unblinded safety data on a regular basis throughout the study to assure patient safety. All statistical analyses were conducted by the independent statistical data analysis center.
 
 
 
 
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