Elevated Triglycerides Increase the Risk of CHD at All Levels of LDL-C Incidence of CHD Events According to Serum LDL-C and TG Concentration*

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1 Overview of LOVAZA Importance of Treating Very High Triglycerides (!5 mg/dl) in Adult Patients Pathophysiology and Clinical Importance of Very High Classification and Treatment Approaches for Very High Proposed Mechanism of Action Treatment of Adults With Very High (!5 mg/dl) Latest Clinical Data Excellent Safety and Tolerability Profile Proven, Potent, Pure Patient Profile Important Safety Information =triglyceride. Pathophysiology: Lipoprotein Formation Pathophysiology and Clinical Importance of Very High Triglycerides Apo B Glycerol B DGAT Cholesteryl B ester Free Fatty Acids Triglycerides Mitochondria B Apo B Expressed on, IDL, and Binds to -Receptor DNA Apo=apolipoprotein; DGAT = DAG acyltransferase; IDL=intermediate-density lipoprotein; =low-density lipoprotein; R= receptor; =very low-density lipoprotein. Ginsberg HN et al. Arch Med Res. 25;36: Hypertriglyceridemia: Increased Number of Apo-B Containing Lipoproteins Remain as Free Fatty Acids From Triglycerides Lipoprotein Metabolism: Balanced Secretion, Conversion, and Clearance Muscle and Adipose Tissue L LP FA FA Secretion IDL Lipase B CE Y High -C -C Low -C -C IDL=intermediate-density lipoprotein; =low-density lipoprotein; =triglyceride; =very low-density lipoprotein; LPL=lipoprotein lipase Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. 21. Krauss RM. Arterioscler Thromb Vasc Biol. 25;25: Lipase IDL Conversion Non-HDL-C R CE=cholesteryl ester; FA=fatty acid; HDL-C=high-density lipoprotein cholesterol; IDL=intermediate-density lipoprotein; =low-density lipoprotein; R= receptor; =triglyceride; =very low-density lipoprotein. Ginsberg HN. Circulation. 22;16: Clearance

2 Lipoprotein Metabolism: Hypertriglyceridemia Adversely Affects the Balance Muscle and Adipose Tissue CE R Secretion Y LARGE Conversion CE=cholesteryl ester; =low-density lipoprotein; R= receptor; =triglyceride; =very low-density lipoprotein. Olefsky JM et al. Am J Med. 1974;57: Hokanson JE. Curr Cardiol Rep. 22;4: CHD Cases / 1 in 8 Years Elevated Triglycerides Increase the Risk of CHD at All Levels of -C Incidence of CHD Events According to Serum -C and Concentration* Baseline <2 mg/dl Baseline!2 mg/dl < !19 Baseline -C (mg/dl) * Lipids from 4849 middle-aged men who were followed up for 8 years to record incidence of CHD. Study demonstrated that fasting levels of s were an independent risk factor for CHD events, irrespective of serum levels of -C. The effect of LOVAZA on cardiovascular mortality and morbidity in patients with elevated triglyceride levels has not been determined. 112 CHD=coronary heart disease; -C=low-density lipoprotein cholesterol; =triglyceride. Assmann G et al. Eur Heart J. 1998;19(suppl M):M8-M Classification and Treatment Approaches for Very High Triglycerides NCEP ATP III Definitions for Patient Types Based on Fasting Levels Patient Type (category) Very high High Borderline high Normal Fasting Level (mg/dl)! <15 NCEP ATP III=National Cholesterol Education Program Adult Treatment Panel III; =triglyceride. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report Executive Summary. 21; NIH Publication No NCEP Guidelines Recommend a Multifaceted Lifestyle Approach to Reduce Risk for CHD Therapeutic lifestyle changes (TLC) Reduced intakes of saturated fats (<7% of total calories) and cholesterol (<2 mg/day) Therapeutic options for enhancing -C lowering such as plant stanols/sterols (2 g/day) and increased viscous (soluble) fiber (1-25 g/day) Weight reduction Increased physical activity Depending on baseline -C, TLC may be the first step in therapy. If -C or other cholesterol goals are not met after 12 weeks, lipid-lowering drug therapy may need to be added Even if lipid-lowering drug therapy is started, TLC should be continued CHD=coronary heart disease; -C= cholesterol; NCEP=National Cholesterol Education Program. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report Executive Summary. 21; NIH Publication No NCEP Guidelines Identify and Non-HDL-C As Important Parameters for Lipid Management Treatment Objectives for Elevated Triglycerides Very High!5 High Primary Objective: reduction Secondary Objective: -C and non-hdl-c reduction Primary Objective: -C goal Secondary Objective: non-hdl-c reduction (-C* and -C) * -C levels are influenced by triglyceride levels. LOVAZA is indicated for the reduction of very high triglycerides (!5 mg/dl), in addition to diet, in adult patients. HDL-C=high-density lipoprotein cholesterol; -C=low density lipoprotein cholesterol; NCEP=National Cholesterol Education Program; =triglyceride; -C=very low-density lipoprotein cholesterol. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report Executive Summary. 21; NIH Publication No

3 Non-HDL-C Apo B-containing lipoproteins* 1,2 IDL HDL What Is Non-HDL-C? Very low-density lipoprotein () Made in the liver 1 -rich 1 Atherogenic 2 Intermediate-density lipoprotein (IDL) Formed from by lipolysis 1 Also known as a remnant particle 1 Atherogenic 2 Low-density lipoprotein () Formed from IDL due to further lipolysis 1 Taken up by the liver and other organs via the receptor 1 Major atherogenic particle 2 sd is a highly atherogenic form of that may occur under high levels 1 High-density lipoprotein (HDL) Carries cholesterol away from artery wall (and other peripheral tissues) for metabolism or excretion 1 Other possible antiatherogenic effects include anti-inflammatory and antioxidant actions, and improvement in endothelial function 1 *Formed in the liver and cleared by receptor. Apo=apolipoprotein; sd=small, dense low-density lipoprotein; =triglyceride. 1. Stone NJ, Blum CB. Management of Lipids in Clinical Practice. 25:24-27, 33, 34, Garg R et al. Prev Cardiol. 25;8: Cholesterol (mg/dl) Why Treat to Non-HDL-C Goals? Case 1 Case 2 HDL TC= 29 mg/dl 12 mg/dl 4 mg/dl -C 24 mg/dl 88 mg/dl -C 145 mg/dl 89 mg/dl HDL-C 4 mg/dl 32 mg/dl Non-HDL-C 169 mg/dl 177 mg/dl Non-HDL-C goal = -C goal + 3 /HDL-C ratio TC 29 mg/dl 29 mg/dl HDL HDL-C=high-density lipoprotein cholesterol; -C=low-density lipoprotein cholesterol; TC=total cholesterol; =triglyceride; =very low-density lipoprotein. Non-HDL Cholesterol = 177 mg/dl Non-HDL-C: An Important Measure of Cholesterol Cholesterol contained within potentially atherogenic apo B-containing particles Non-HDL-C = TC HDL-C NCEP target level of non-hdl-c is 3 mg/dl greater than the -C goal Treatment Options: Is There an Unmet Clinical Need for Triglyceride Reduction? LOVAZA Statins Fibrates Niacin Apo=apolipoprotein; HDL-C=high-density lipoprotein cholesterol; -C=low-density lipoprotein cholesterol; NCEP=National Cholesterol Education Program; TC=total cholesterol. Garg R et al. Prev Cardiol. 25;8: LOVAZA: Proposed Mechanism of Action Proposed Mechanism of Action: LOVAZA Reduces Hepatic Triglyceride Synthesis! Triglycerides Apo B Glycerol " DGAT Cholesteryl ester B " FFA # Beta-oxidation of FA " Lipogenesis Mitochondria DNA! with! (smaller ) Apo=apolipoprotein; DGAT=DAG acyltransferase; FA=fatty acid; FFA=free fatty acid; =triglyceride; =very low-density lipoprotein.

4 Muscle and Adipose Tissue Proposed Mechanism of Action: LOVAZA Decreases Secretion and Increases Conversion of to LOVAZA: Treatment of Adults With Very High Triglycerides (!5 mg/dl) Secretion CE Conversion R Y CE=cholesteryl ester; =low-density lipoprotein; R= receptor; =triglyceride; =very low-density lipoprotein. Chan CD et al. Am J Clin Nutr. 23;77:3-37. in the Treatment of Very High Triglycerides FDA approved as an adjunct to diet to reduce levels in adult patients with very high (!5 mg/dl) levels 1 Naturally derived omega-3 prescription product containing EPA 465 mg and DHA 375 mg 1 Available in the US since October 25 2 More than 1 years of European experience 2 LOVAZA is the fastest growing prescription branded triglyceride-lowering agent in the US 3 DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid; =triglyceride Data on file, GlaxoSmithKline. 3. Verispan VONA through April 28 Dramatically Reduced in Patients With s!5 mg/dl Median Values (mg/dl) =triglyceride. Baseline 1. 2.Data on file, GlaxoSmithKline. $ 45% P <.1 vs Placebo Treatment Very High s 3. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest. 2;16: Stalenhoef AFH, de Graaf JD, Wittekoek ME, et al. The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia. Atherosclerosis. 2;153: C value in patients receiving increased by 45% from a median baseline of 89 mg/dl to a median of 19 mg/dl 5. Garg R, Vasamreddy CR, Blumenthal RS. Non-high-density lipoprotein cholesterol: why lower is better. Prev Significantly Increased HDL-C in Patients with s!5 mg/dl HDL-C Median Values (mg/dl) Baseline HDL-C=high-density lipoprotein cholesterol; =triglyceride. Data on file, GlaxoSmithKline. +9% P =.3 vs Placebo End of Treatment Significantly Reduced Non-HDL-C in Patients With s!5 mg/dl Non-HDL-C Median Values (mg/dl) Baseline $ 14% P =.13 vs Placebo -C -42% -C +45% End of Treatment HDL-C=high-density lipoprotein cholesterol; -C=low-density lipoprotein cholesterol; =triglyceride; -C=very low-density lipoprotein cholesterol. Data on file, GlaxoSmithKline.

5 LOVAZA: Excellent Safety and Tolerability Profile Demonstrates an Excellent Safety and Tolerability Profile!!! * In rats, omega-3 fatty acid-containing products have been was very well tolerated in clinical studies 1 LOVAZA has more than 1 years of European experience 2 With LOVAZA, clinically significant drug drug interactions due to cytochrome P45 inhibition are not expected* 1 shown to increase hepatic concentrations of cytochrome P45 and activities of certain enzymes. The potential of LOVAZA to induce P45 activities in humans has not been studied. 1 =triglyceride Data on file. GlaxoSmithKline. LOVAZA: Very Well Tolerated in Clinical Studies Skin In 8 Randomized, Placebo-controlled, Double-blind Studies Body System Subjects with at least 1 adverse event Body as a whole Cardiovascular Digestive Special senses * Placebo was corn oil for all studies. Pain Adverse Event (!1% of patients) Back pain Flu syndrome Infection Angina pectoris Dyspepsia Eructation Rash Taste perversion (n=226) Laboratory studies should be performed periodically to measure the patient s triglyceride, low-density lipoprotein cholesterol (-C), and alanine aminotransferase (ALT) levels during therapy with LOVAZA. n 8 % Placebo* (n=228) n % LOVAZA: Drug Interactions Clinically significant drug-drug interactions due to cytochrome P45 metabolism mediated by LOVAZA are not expected in humans Since the free forms of the EPA and DHA are undetectable in the circulation (<1 µm), clinically significant drug-drug interactions due to inhibition of CYP45-mediated metabolism EPA/DHA combinations are not expected in humans In rats, omega-3-fatty acid-containing products have been shown to increase hepatic concentrations of CYP45 and activities of certain P45 enzymes. The potential of LOVAZA to induce CYP45 activities in humans has not been studied ALT levels should be monitored periodically during therapy with LOVAZA Some omega-3 studies demonstrated prolongation of bleeding time and increased bruising. Patients receiving LOVAZA and anticoagulants should be monitored periodically ALT=alanine aminotransferase; DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid. Laboratory studies should be performed periodically to measure the patient s triglyceride, low-density lipoprotein cholesterol (-C), and alanine aminotransferase (ALT) levels during therapy with LOVAZA. Addition of LOVAZA in Patients Taking Simvastatin: FDA Approvable Action Letter LOVAZA: Latest Clinical Data The COMBination of Prescription Omega-3s With Simvastatin (COMBOS) Trial was designed to provide additional data to demonstrate that coadministration of with a 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) will not attenuate the clinical effectiveness of the statin The Prescribing Information for LOVAZA was updated on June 12, 27, to reflect the additional data, showing results when LOVAZA 4g/day was added on to simvastatin therapy for high s* LOVAZA is not indicated for use in combination with a statin or in patients with s mg/dl * The COMBOS Trial is not mentioned by name in the labeling.

6 Addition of in Patients Taking Simvastatin with High Triglycerides (2-499 mg/dl): Study Flow Pre-study* Visit 1 Wk $8 Simvastatin 4 mg n=254 Visit 2 Wk $2 Visit 3 Wk $1 Open-Label Diet/Statin Lead In Visit 4 Wk Davidson MH, Stein EA, Bays HE, et al. Clin Ther. 27;29: Simvastatin 4 mg/day + Placebo Visit 5 Wk 4 n=132 Simvastatin 4 mg/day + n=122 Visit 6 Wk 6 Double-Blind Treatment * Adult patients were taking a statin and discontinued all non-study-related lipidlowering agents. Triglyceride reductions achieved with the pre-study statin were not measured in this study. Visit 7 Wk 8 Addition of in Patients Taking Simvastatin with High Triglycerides (2-499 mg/dl): Results Parameter Non-HDL-C TC -C Apo B HDL-C -C BL Simvastatin + (n=122) EOT Median % Chg* BL Simvastatin + Placebo (n=132) EOT Median % Chg* Difference *Response to the addition of after reductions achieved with 8 weeks of simvastatin 4 mg therapy during the lead-in phase. Apo=apolipoprotein; BL=baseline; EOT=end of treatment; HDL-C=high-density lipoprotein cholesterol; -C=low-density lipoprotein cholesterol; TC=total cholesterol; =triglyceride; -C=very low-density lipoprotein cholesterol P value <.1 <.1 <.5 <.5 <.5 <.5 =.5 LOVAZA: Dosage and Administration The daily dose of LOVAZA is 4 g per day Flexible dosing: Four 1-gram capsules once daily OR Two 1-gram capsules twice daily LOVAZA: Proven, Potent, Pure Patients should be placed on an appropriate lipid-lowering diet before receiving LOVAZA, and should continue this diet during treatment with LOVAZA. In clinical trials, LOVAZA was administered with meals. Therapy with LOVAZA should be withdrawn in patients who do not have an adequate response after 2 months of treatment. LOVAZA Is Highly Purified and Concentrated in a 5-Step Refinement Process LOVAZA Lowers Very High Triglycerides with Prescription-Proven Potency 3% Omega-3 Crude fish oil 3% EE 5% EE 7% EE 84% EPA/DHA EE (9% omega-3) LOVAZA Late purification steps: reduction of saturated fatty acids; oxidized fatty acids; other byproducts Ethyl esterification: facilitates further purification and concentration of omega-3 Early purification steps: reduction of environmental toxins (mercury, PCBs, dioxins), cholesterol and proteins, and short-chain fatty acids 1-gram capsule Docosahexaenoic acid (DHA) Eicosapentaenoic acid (EPA) Ethyl Esters EPA 465 mg DHA 375 mg Other omega-3s 8 mg Omega-6 %3 mg Other, including antioxidants %5 mg DHA=docosahexaenoic acid; EE=ethyl ester; EPA=eicosapentaenoic acid; PCB=polychlorinated biphenyl. Data on file, GlaxoSmithKline. United States Patent and Trademark Office. United States Patent Nos. 5,945,318; 6,518,49; 5,719,32; 6,24,41; and 6,63,188. Available at: g EPA/DHA in only 4 capsules DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid. Data on file, GlaxoSmithKline.

7 Is a Prescription Product Approved by the FDA for Treating Very High Triglycerides LOVAZA: Patient Profile Prescription drugs 1 Demonstrated Efficacy and Safety! FDA Approved! Regulated Claims! Intended to Treat Disease! Dietary supplements are not FDA approved to treat, prevent, or cure any disease Food and Drug Administration. Drugs at FDA Glossary of Terms. Available at: Accessed February 13, Food and Drug Administration. Overview of Dietary Supplements. Available at: Accessed February 13, 27. Patient Case: Valerie Gender: Female Age: 5 Medical history: Obese since adolescence Hyperlipidemia Hypertension Positive family history of heart disease Current medications: Enalapril 1 mg/day Physical examination: Height 5 4 (64 inches) Weight: 186 pounds (84.5 kg) BP: 127/8 Heart rate: 72 BMI: 32 Waist circumference: 39 inches Laboratory results: TC 29 mg/dl 599 mg/dl HDL-C 32 mg/dl Non-HDL-C 177 mg/dl (NCEP ATP III goal: No higher than 16 mg/dl) Direct -C 89 mg/dl Glucose 98 mg/dl Diagnosis: Very high triglycerides with elevated non-hdl-c and low HDL-C What Is Your Recommended Plan of Action? Further testing? Repeat lipid profile Further CVD risk work-up " CRP, Hcy " Advanced lipid panel " Carotid ultrasound Treatment of secondary factors? TLC diet/exercise Review other possible causes of severe H and/or low HDL-C " Excess alcohol " Systemic glucocorticoids, beta blockers/thiazide diuretics, and other therapies " Hypothyroidism How would you treat Valerie? LOVAZA: Important Safety Information LOVAZA is contraindicated in patients who exhibit hypersensitivity to any component of this medication. LOVAZA should be used with caution in patients with known sensitivity or allergy to fish, -C and ALT levels should be monitored periodically during therapy with LOVAZA. In some patients, LOVAZA increased -C and ALT levels (without a concurrent increase in AST) Therapy with LOVAZA should be withdrawn in patients who do not have an adequate response after 2 months of treatment Please see complete Prescribing Information. LOVAZA: Important Safety Information (continued) Some studies with omega-3-acids demonstrated prolongation of bleeding time, which did not exceed normal limits and did not produce clinically significant bleeding episodes. Patients receiving treatment with both LOVAZA and anticoagulants should be monitored periodically The most common adverse events reported were eructation, infection, flu syndrome, and dyspepsia. Discontinuation of treatment due to adverse events was similar to placebo: 3.5% of patients treated with LOVAZA and 2.6% of patients treated with placebo Please see complete Prescribing Information.

8 : Summary is indicated as an adjunct to diet to reduce levels in adult patients with very high (!5 mg/dl) levels LOVAZA 4g/day dramatically lowered triglycerides by 45% Treatment resulted in a median increase of 45% in -C; treatment with LOVAZA resulted in an overall reduction of atherogenic cholesterol, as reflected by a 14% reduction in non HDL-C LOVAZA 4g/day demonstrates an excellent safety and tolerability profile The most common adverse events reported were: eructation, infection, flu syndrome and dyspepsia LOVAZA is the fastest growing prescription-branded triglyceridelowering agent in the US