Epanova ® - Omega-3- carboxylic acids Manufacturer: AstraZeneca FDA Approval Date: 05/2014

Epanova ® - Omega-3-carboxylic acids Clinical Application Indications: Treatment of severe hypertriglyceridemia (≥ 500 mg/dL) as an adjunct to diet Place in therapy: Used after diet changes have failed to lower TG levels adequately

Epanova ® - Omega-3-carboxylic acids Clinical Application Contraindications: Known hypersensitivity to Epanova or any of its components

Epanova ® - Omega-3-carboxylic acids Clinical Application Warnings and Precautions: LDL-C should be monitored during treatment with Epanova as LDL has increased in some patients ALT/AST should be monitored periodically in patients with hepatic impairment Epanova should be used with caution in patients who have fish allergies

Epanova ® - Omega-3-carboxylic acids Clinical Application Pregnancy: C Lactation: Studies with fish oil have shown that excretion into breast milk occurs at higher concentration than that in plasma and the effect of Epanova on infants is not known

Epanova ® - Omega-3-carboxylic acids Drug Facts Pharmacology: The mechanism of action is not completely understood. Potential mechanisms of action include: Acyl-CoA:1,2-diacylglycerol acetyltransferase inhibition Increased mitochondrial and peroxismal β-oxidation in the liver

Epanova ® - Omega-3-carboxylic acids Drug Facts Pharmacology: The mechanism of action is not completely understood. Potential mechanisms of action include: Decreased lipogenesis in the liver Increased plasma lipoprotein lipase activity EPA and DHA are poor substrates for the enzyme responsible for triglyceride synthesis

Epanova ® - Omega-3-carboxylic acids Drug Facts Pharmacokinetics: A Directly absorbed in the small intestine. Cmax 5-9 hours. Steady state concentrations of EPA and DHA are achieved after 2 weeks of repeat daily dosing. D The majority of EPA and DHA is incorporated in phospholipids, triglycerides and cholesteryl esters. Free unesterified fatty acids represent 0.8% of the EPA and 1.1% of the DHA. M EPA and DHA are mainly oxidized in the liver. E Epanova does not undergo renal excretion. EPA half-life is 37 hours, DHA half-life is 46.

Epanova ® - Omega-3-carboxylic acids Drug Interactions Drug Interactions – Object Drugs: None

Epanova ® - Omega-3-carboxylic acids Drug Interactions Drug Interactions – Precipitant Drugs: None

Epanova ® - Omega-3-carboxylic acids Drug Interactions Drug Interactions – Pharmacodynamic interactions: Anticoagulants – may increase bleeding time

Epanova ® - Omega-3-carboxylic acids Adverse Effects Common Adverse Effects: PlaceboEpanova 2gEpanova 4g Diarrhea2%7%15% Nausea1%4%6% Abdominal pain or discomfort 2%3%5% Eructation<1%3%

Epanova ® - Omega-3-carboxylic acids Monitoring Parameters Efficacy Monitoring: Monitor triglycerides Toxicity Monitoring: Monitor for changes in INR as studies with fish oil have shown an increased bleeding time

Epanova ® - Omega-3-carboxylic acids Prescription Information Dosing: 2 or 4 g once daily Dosing is individualized according to response and tolerability. Cost: – Epanova has not reached the market yet and a price has not been set by AstraZeneca

Epanova ® - Omega-3-carboxylic acids Literature Review Purpose: To evaluate the efficacy and safety of Epanova (OM3-FFA)…in subjects with severe hypertriglyceridemia (TGs ≥ 500 but < 2000) Design: Double-blind, randomized, parallel, 4-arm study Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)

Epanova ® - Omega-3-carboxylic acids Literature Review Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8) Inclusion criteria Exclusion criteria ≥ 18 years oldKnown lipoprotein lipase impairment Not pregnant or lactatingHx of pancreatitis, symptomatic gallstone disease BMI ≥ 20Uncontrolled diabetes (A1c ≥ 9%) Be willing to: maintain customary activity level, follow TLC diet, restrict consumption of fish Cancer in the past 2 years Untreated or on already-established dosing of other lipid-lowering drugs Cardiovascular event in the past 6 months Poorly controlled HTN (≥160/≥100) Abnormal ALT/AST, GFR, BG, platelets or Hgb

Epanova ® - Omega-3-carboxylic acids Literature Review Baseline characteristics: Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8) Placebo (OO)Epanova 2 gEpanova 3 gEpanova 4 g Number Men77 (78%)80 (80%)79 (78%)71 (72%) Mean age 51 ± ± ± 9 53 ± 11 White race95 (96%)93 (93%)92 (91%)88 (89%) Diabetes30 (30%)39 (39%)45 (45%)36 (36%) HTN64 (65%)69 (69%)69 (68%)67 (68%) Statin/CAI users 34 (34%)35 (35%) 34 (34%)

Epanova ® - Omega-3-carboxylic acids Literature Review Treatment arms: Olive oil (OO) 4 g/day x 12 weeks Epanova 2 g/day + OO 2 g/day x 12 weeks Epanova 3 g/day + OO 1 g/day x 12 weeks Epanova 4 g/day x 12 weeks Efficacy monitoring: Lipid panel Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)

Epanova ® - Omega-3-carboxylic acids Literature Review Statistical analysis: 332 patients needed for 80% power to detect at least 20% difference in TG levels Intention-to-treat analysis, included participants with 1+ doses and 1+ efficacy assessments Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)

Epanova ® - Omega-3-carboxylic acids Literature Review Primary endpoint: TG percentage change Secondary endpoint: non-HDL-C and HDL-C percentage change Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)

Epanova ® - Omega-3-carboxylic acids Literature Review Results: (% Δ from baseline, 95% CI) Significantly different from placebo: † p<0.05, ‡ p<0.01, * p<0.001 Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8) Placebo (OO)Epanova 2 gEpanova 3 gEpanova 4 g TG-4.3% (-13.1 to 5.4) -25.9% (-32.8 to -18.3) ‡ -25.5% (-32.4 to -17.8) ‡ -30.9% (-37.3 to -23.7)* Non- HDL-C 2.5% (-2.3 to 7.6) -7.6% (-12.0 to -3.0) † -6.9% (-11.4 to -2.2) † -9.6% (-14.0 to -5.1) ‡ HDL-C1.9% (-2.0 to 6.0) 7.4% (3.2 to 11.7) 3.8% (-0.3 to 8.0) 5.8% (1.7 to 10.1) Total-C3.2% (-1.0 to 7.5) -5.4% (-9.3 to -1.4) † -4.9% (-8.7 to -0.8) -7.5% (-11.2 to -3.5) ‡ LDL-C3.0% (-2.9 to 9.3) 19.2% ( 12.3 to 26.6) ‡ 14.3% (7.6 to 21.4) 19.4% (12.4 to 26.8)*

Epanova ® - Omega-3-carboxylic acids Literature Review Adverse events: Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8) Placebo (OO)Epanova 2 gEpanova 3 gEpanova 4 g Diarrhea2.0%10.0%5.9%10.1% Nausea1.0%6.0%8.9%5.1% Abdominal pain/discomfort 1.0%4.0%1.0% Eructation1.0%3.0%4.0% Infections (all)11.1%14.0%6.9%12.1%

Epanova ® - Omega-3-carboxylic acids Literature Review Discussion: Total N = 364 No significant difference between treatment groups for those who discontinued Discontinuation due to GI upset was 5- 7% for Epanova and 0% for placebo Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)

Epanova ® - Omega-3-carboxylic acids Literature Review Discussion: Epanova reduced TG levels by at least 25% The degree of TG lowering was less with 3 g/day than the 2 or 4 g/day Non-HDL-C was also significantly lowered in each Epanova group LDL was significantly increased in Epanova groups Kastelein, J., et al. Journal of Clinical Lipidology. 2014(8)

Epanova ® - Omega-3-carboxylic acids Summary Epanova is indicated for the treatment of severe hypertriglyceridemia (≥ 500 mg/dL) as an adjunct to diet. Epanova should be used after diet changes have failed to lower triglycerides. Epanova ® has no pharmacokinetic interactions but a pharmacodynamic interaction occurs between Epanova ® and anticoagulants - increased bleeding time Epanova is commonly dosed between 2 and 4 grams daily but dosing is individualized

Epanova ® - Omega-3-carboxylic acids References / Epanova package insert. AstraZeneca. May Kastelein, J.J.P., Maki, K.C., et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: The EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. Journal of Clinical Lipidology (2014)8;