Healthcare Industry News: aspirin
News Release - March 31, 2008
Patients Treated with Merck's Investigational Extended-Release Niacin/Laropiprant (CORDAPTIVE(TM)) Reported Significantly Less Flushing Than Patients Treated with Niaspan(TM) in Phase III Study
CHICAGO--(HSMN NewsFeed)--Patients with dyslipidemia treated with CORDAPTIVE™ (extended release niacin/laropiprant) reported significantly less flushing and significantly fewer discontinuations due to flushing than patients treated with Niaspan™ (Abbott). Niacin is a proven lipid-modifying agent; however, a major barrier to its use is the side effect of flushing. These Phase III study results were presented today at the Scientific Session of the American College of Cardiology in Chicago.CORDAPTIVE is an investigational lipid-modifying agent in development by Merck & Co., Inc. that combines Merck-developed extended release (ER) niacin with the agent laropiprant, a novel flushing pathway inhibitor. Niacin-induced flushing is caused primarily by a prostaglandin, PGD2, a chemical that acts through the DP1 flushing pathway to cause vasodilation in the skin and flushing symptoms. Laropiprant selectively blocks the binding of PGD2 to its receptor, DP1 thereby reducing flushing associated with niacin. One tablet of CORDAPTIVE contains 1 g of Merck-developed ER niacin and 20 mg of laropiprant.
"Niacin lowers 'bad' cholesterol (LDL-C) and triglycerides, is a highly effective therapy for raising ‘good’ cholesterol (HDL-C) and is proven to reduce the risk of cardiovascular events in patients with heart disease. Yet, the severity, frequency and duration of the flushing side effect of niacin limits patients from staying on therapy and reaching the recommended dose of 2 g," said Michael J. Koren, M.D., F.A.C.C., CEO and Medical Director, Jacksonville Center for Clinical Research, and co-author of the study. "This study shows that the improved tolerability profile of CORDAPTIVE may prevent more patients from discontinuing therapy due to flushing."
About the study
The double-blind, randomized, parallel, 16-week study of 1,455 patients with dyslipidemia evaluated flushing symptoms with CORDAPTIVE (n = 726) dosed at 1 g for four weeks and then advanced to 2 g (two 1 g tablets) for 12 additional weeks versus Niaspan (n = 729) dosed at 500 mg for four weeks and titrated in 500 mg increments every four weeks (1 g after four weeks, 1.5 g after eight weeks, and 2 g after 12 weeks for the last four weeks of the study).
The primary endpoint was to compare the effect on flushing between the two treatment groups as measured by the number of days per week with moderate, severe or extreme flushing according to the validated Global Flushing Severity Score (GFSS ≥4) over the 16 week duration of the study. All patients were permitted to use aspirin or non-steroidal anti-inflammatory drugs (NSAIDS) and were advised that if taken 30 minutes prior to study medication these agents may help to mitigate niacin-induced flushing symptoms.
Significantly fewer niacin-induced flushing events with CORDAPTIVE versus Niaspan
Across the 16-week treatment period, patients on CORDAPTIVE reported significantly less flushing as measured by the number of days per week with moderate, severe or extreme flushing compared to the Niaspan group (p<0.001). More than twice as many patients on CORDAPTIVE experienced no episodes of moderate, severe or extreme flushing compared to Niaspan, 46.7 percent (337/722) and 22 percent (160/727), respectively. This difference was seen despite a study design in which patients on CORDAPTIVE were on a higher dose of niacin therapy than patients on Niaspan throughout most of the study.
At the end of the 16-week treatment period, patients in the CORDAPTIVE group experienced fewer days per week with moderate, severe or extreme flushing than patients in the Niaspan group, 0.2 versus 0.7 days/week (i.e. approximately 1 day/month versus 1 day/week) respectively. Additionally, the percentage of patients with a maximum GFSS of moderate, severe and extreme flushing at week 16 was 7.7 percent (39/505) for the CORDAPTIVE group versus 21.3 percent (108/506) for the Niaspan group.
Significantly fewer patients on CORDAPTIVE discontinued therapy due to flushing compared to patients on Niaspan, 7 percent versus 12 percent, respectively (p=0.002). The discontinuation rates due to non-flushing clinical and laboratory events were 11.2 percent and 8 percent, respectively. When adjusted for time of exposure to 2 g of niacin (week eight for CORDAPTIVE and week 16 for Niaspan), the estimated discontinuations due to non-flushing events were similar, 9.2 percent and 8.8 percent, respectively.
Twice as many patients in the Niaspan group used aspirin or NSAIDS to attempt to mitigate flushing than in the CORDAPTIVE group (22 percent versus 11 percent respectively).
"The improved flushing profile of CORDAPTIVE supports a recommended dosing regimen in which patients start at the 1 g dose and advance to a 2 g maintenance dose after four weeks, thereby increasing the therapeutic potential of niacin," said John F. Paolini, M.D., Ph.D., Clinical Research, Cardiovascular Disease, Merck Research Laboratories.
About the tolerability of CORDAPTIVE
Except for flushing which occurred more frequently in the Niaspan group, the safety profile of CORDAPTIVE was similar to that of Niaspan. Certain reported adverse events and changes to laboratory parameters that occurred more frequently in the CORDAPTIVE group appeared to be niacin dose-related, including liver enzyme elevations ≥3x ULN (1.1 percent for CORDAPTIVE and 0.1 percent for Niaspan) and adjustments to anti-diabetic medications for patients with diabetes (16.2 percent for CORDAPTIVE and 5.2 percent for Niaspan). These differences were expected due to exposure to higher doses of niacin for a longer period of time in the group treated with CORDAPTIVE. No cases of rhabdomyolysis or drug-related hepatitis were reported. No cases of creatine kinase (CK) levels ≥10x ULN were reported with CORDAPTIVE and two cases were reported with Niaspan. In the Niaspan group, there was one case of myopathy which was associated with excessive exercise.
Additional safety data from Phase II and III studies presented
Also presented at the Scientific Session at the ACC was a pooled safety analysis in 4,747 patients (of which 2,548 were treated with CORDAPTIVE, 1,268 with ER niacin or Niaspan and 931 with simvastatin or placebo) in the Phase II and III clinical program for up to one year. This analysis showed that the tolerability profile of CORDAPTIVE was similar to that of ER niacin, except for flushing-related side effects and associated discontinuations.
“The findings from this large pool of patients support the safety and tolerability profile of CORDAPTIVE,” said James M. McKenney, PharmD, president and CEO of National Clinical Research in Richmond, Virginia, professor emeritus of the Virginia Commonwealth University School of Pharmacy, and co-author of the study. "These data show that CORDAPTIVE offers comparable safety to the other niacin formulations studied and supports the use of laropiprant to reduce niacin-induced flushing."
In the pooled safety analysis, 1 percent of patients on CORDAPTIVE experienced consecutive ≥3x ULN elevations in ALT and/or AST, which were asymptomatic, reversible and not associated with clinical hepatotoxicity versus 0.5 percent for ER niacin/Niaspan.
Additionally, no significant difference was seen among treatment groups in the number of patients who met the criteria for myopathy or who experienced elevated CK levels ≥10x ULN. CORDAPTIVE and ER niacin/Niaspan produced similar, small median increases in fasting serum glucose levels (~4 mg/dL) which were consistent with the known effects of niacin. Between the CORDAPTIVE and ER niacin/Niaspan groups, the number of patients with new onset diabetes (0.5 percent versus 0.3 percent, respectively) and worsening of diabetes (19.9 percent versus 16.7 percent, respectively) was low and similar.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.
Source: Merck
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