Lipid-altering Efficacy and Safety Profile of Co-administered Extended Release Niacin/Laropiprant and Simvastatin in Patients With Dyslipidemia Gilbert.

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Presentation transcript:

Lipid-altering Efficacy and Safety Profile of Co-administered Extended Release Niacin/Laropiprant and Simvastatin in Patients With Dyslipidemia Gilbert Gleim 1, Nancy Liu 1, Sally Thompson-Bell 1, Amy Johnson- Levonas 1, Christie Ballantyne 2, Richard C Pasternak 1, Yale Mitchel 1, John F Paolini 1 1 Merck Research Laboratories, Rahway, NJ 2 Baylor College of Medicine and Methodist DeBakey Heart Center, Houston, TX

Presenter Disclosure Information Lipid-altering Efficacy and Safety Profile of Co-administered Extended Release Niacin/Laropiprant and Simvastatin in Patients With Dyslipidemia The following relationships exist related to this presentation: Gilbert Gleim, Nancy Liu, Sally Thompson-Bell, Amy Johnson-Levonas, Richard C. Pasternak, Yale Mitchel, and John F. Paolini are employees of Merck & Co., Inc. and may own stock/hold stock options in the Company. Christie Ballantyne has served as a Clinical Investigator, Consultant, Speaker, and Advisor for Merck & Co. Inc.

Residual Risk in Statin Clinical Trials Numerous statin outcomes trials have demonstrated relative risk reductions in CV endpoints of approximately 30%. ▬Despite the benefits of reducing LDL-C, upward of 60% residual risk remains. Low HDL-C exists in ~ 25% of Americans and is an independent risk factor for CHD. Niacin therapy lowers LDL-C and triglycerides and raises HDL-C. Niacin therapy has been shown to lower CV morbidity and total mortality in combination with and without statins.

ER Niacin/Laropiprant Concept Niacin-induced flushing ▬Primarily caused by a prostaglandin D 2 (PGD 2 ) acting through the prostaglandin D receptor (DP 1 ) flushing pathway. Laropiprant ▬Selectively blocks binding of PGD 2 to DP 1. ▬Experiments show blocking DP 1 reduces flushing associated with niacin. ER niacin/Laropiprant ▬Merck-developed ER Niacin with laropiprant, a selective flushing pathway inhibitor. ▬Simplified dosing paradigm: Initiate at 1g and advance to 2g dose after week 4.

ER Niacin/Laropiprant/Simvastatin Concept  Niacin has beneficial effects on LDL-C, HDL-C, TG and other lipid/lipoprotein parameters and has been shown in clinical trials to reduce CV events and atherosclerosis progression.  Simvastatin effectively lowers LDL-C and has been shown to reduce cardiovascular risk.  It is hypothesized that the combination of ER niacin/laropiprant with simvastatin will provide beneficial effects on all three major lipid parameters relative to either monotherapy, with an improved flushing profile versus ER niacin.

Objective To assess the efficacy and safety of ER niacin/ laropiprant (ERN/LRPT) coadministered with simvastatin (ERN/LRPT + SIMVA) in patients with primary hypercholesterolemia or mixed dyslipidemia.

ER Niacin/Laropiprant + Simvastatin Lipid- Altering Efficacy/Safety Study (PN022) Double-blind, parallel, factorial study Washout PBO Run-in ERN/LRPT 1g ERN/LRPT 1g + 10mg ERN/LRPT 1g + 20mg ERN/LRPT 1g + 40mg SIMVA 10mg SIMVA 20mg SIMVA 40mg ERN/LRPT 2g ERN/LRPT 2g + SIMVA 20mg ERN/LRPT 2g + SIMVA 40mg SIMVA 20mg SIMVA 40mg VISIT Prescreen WEEK Fibrate Washout Statin Washout RandomizationDose AdvancementFinal Visit Commence PBO Run-in For All Patients 2 Week Follow-up SIMVA

PN022: Patient Population  N=1398; years of age  44% male, 56% female  Primary hypercholesterolemia (74.8%) or mixed hyperlipidemia (25.2%)  NCEP ATP III risk categories: Category I - (0-1 risk factors) 69% Category II - (without CHD and with > 2 risk factors) 29.7% Category III - (with CHD or equivalent) 1.2% Baseline Lipid Values (mg/dL)  Mean LDL-C:  Mean HDL-C: 52.8  Median TG: 134.5

Percent Change in LDL-C from Baseline to Week 12 ERN/LRPT 2g + SIMVA 10 → 20mg SIMVA 10 → 20mg ERN/LRPT 2g + SIMVA 20 → 40mg SIMVA 20 → 40mg ERN/LRPT 2g + SIMVA 40 → 40mg SIMVA 40 → 40mg ERN/LRPT 2g Pooled LS Mean % Change (+SE) -17.0% -37.0% -47.9%

Percent Change in HDL-C from Baseline to Week 12 Pooled LS Mean % Change (+SE) 23.4% 6.0% 27.5% ERN/LRPT 2g + SIMVA 10 → 20mg SIMVA 10 → 20mg ERN/LRPT 2g + SIMVA 20 → 40mg SIMVA 20 → 40mg ERN/LRPT 2g + SIMVA 40 → 40mg SIMVA 40 → 40mg ERN/LRPT 2g

Percent Change in TG from Baseline to Week 12 Pooled Median % Change (+SE) -21.6% -14.7% -33.3% ERN/LRPT 2g + SIMVA 10 → 20mg SIMVA 10 → 20mg ERN/LRPT 2g + SIMVA 20 → 40mg SIMVA 20 → 40mg ERN/LRPT 2g + SIMVA 40 → 40mg SIMVA 40 → 40mg ERN/LRPT 2g

ER Niacin/Laropiprant + Simvastatin Lipid Efficacy Total-C-9%-25%-30% Non-HDL-C-18%-33%-46% Apo B-17%-29%-41% Apo A-I8%2%9% LDL-C:HDL-C-31%-40%-57% TC:HDL-C-25%-28%-43% Lp(a)*-25%0%-20% *Median Parameter ERN/LRPT 2g Pooled SIMVA Pooled ERN/LRPT 2g + SIMVA Percent Change from Baseline

Subset Analyses for ERN/LRPT and ERN/LRPT + SIMVA Percent changes in LDL-C, HDL-C and TG were comparable by ▬gender ▬age ( 65) ▬race ▬region (U.S., ex-U.S.) ▬type of hyperlipidemia ▬baseline LDL-C ▬baseline HDL-C ▬baseline triglyceride levels

ER Niacin/Laropiprant + Simvastatin Safety The safety profile of ERN/LRPT + simvastatin was similar to that of ERN/LRPT and simvastatin alone. * consecutive or presumed consecutive † 95% CI for comparison to ERN/LRPT -4.0 (-9.0, -0.2) Liver Effects Drug-related hepatitis0 0 0 >3x ULN elevation* in ALT/AST0.5%1.0%0.3% Muscle Effects Myopathy or rhabdomyolysis000 >10x ULN elevation in CK0.5%0.3%0 Glucose Effects Median increase in FBG4.0 mg/dl1.0 mg/dl4.0 mg/dl Parameter ERN/LRPT 2g N=192 Pooled SIMVA N=585 Pooled ERN/LRPT 2g + SIMVA N=590 Flushing Discontinuations due to flushing8.7%0.3%4.8% †

ER Niacin/Laropiprant + Simvastatin Lipid Efficacy The coadministration of ERN/LRPT 2g + SIMVA was superior to the individual components for each of the three lipid parameters. Efficacy was consistent across subgroups, including baseline lipid levels.

ER Niacin/Laropiprant + Simvastatin Safety The AE profile of ERN/LRPT + SIMVA was similar to that of ERN/LRPT alone. The incidence of serious clinical AEs was low and comparable among treatment groups. There is no potentiation of statin effects on the liver or in muscle.

Conclusions ERN/LRPT + SIMVA significantly improved all three lipid parameters. ERN/LRPT + SIMVA was generally well tolerated. These data demonstrate the benefit of combining ERN/LRPT + SIMVA in the treatment of primary hypercholesterolemia or mixed dyslipidemia.