Manufacturer: Amgen Inc FDA Approval Date: August 27, 2015 Repatha™ - Evolocumab Manufacturer: Amgen Inc FDA Approval Date: August 27, 2015

Repatha™ - Evolocumab Objectives At the end of this presentation participants will be able to: Appropriately recommend Repatha™ - (Evolocumab) Effectively educate patients on the purpose, proper use and potential adverse effects of Repatha ™ - (Evolocumab)

Repatha™ - Evolocumab Clinical Application Indications: Adjunct to diet in adults on maximally tolerated statin therapy with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease that need additional lowering of LDLc Adjunct to diet in adults on other LDL therapies with homozygous hypercholesterolemia who need additional lowering of LDLc Repatha [package insert].

Repatha™ - Evolocumab Clinical Application Contraindications: Serious hypersensitivity to evolocumab or any component of the formulation Repatha [package insert].

Repatha™ - Evolocumab Clinical Application Warnings and Precautions Allergic reactions like rash and urticaria Discontinue treatment if serious allergic reaction Repatha [package insert].

Repatha™ - Evolocumab Clinical Application Pregnancy: Animal studies show it crosses the placenta during 2nd and 3rd trimester Lactation: IgG is present in human milk; data shows it doesn’t enter neonatal and infant circulation in substatial amounts Repatha [package insert].

Repatha™ - Evolocumab Drug Facts Pharmacology: Human monoclonal IgG2 antibody, binds to proprotein convertase substilsin/kexin 9 (PCSK9) and inhibits it from binding to LDL receptor preventing PCSK9 mediated degradation and increasing number of LDLRs available to clear LDL from blood Repatha [package insert].

Repatha™ - Evolocumab Drug Facts Pharmacokinetics: A Absolute bioavailability 72% D Mean ss volume of distribution 3.3 L M Proteolytic degradation E Estimated half life 11 – 17 days Repatha [package insert].

Repatha™ - Evolocumab Drug Interactions Drug Interactions – Precipitant Drugs: In patient on a high intensity statin there was a 20% decrease in the Cmax and AUC of evolocumab Repatha [package insert].

Repatha™ - Evolocumab Adverse Effects Common Adverse Effects: Evolocumab Placebo Nasopharyngitis 10.5 9.6 Upper respiratory tract infection 9.3 6.3 Influenza 7.5 Injection site reactions 5.7 5.0 Cough 4.5 3.6 Repatha [package insert].

Repatha™ - Evolocumab Monitoring Parameters Efficacy Monitoring: HoFH: measure LDL-C 4-8 weeks after initiation of evolocumab Toxicity Monitoring: Signs and symptoms of hypersensitivity or adverse reaction Repatha [package insert].

Repatha™ - Evolocumab Prescription Information Dosing: HeFH or primary hyperlipidemia with CVD: 140 mg SQ every 2 weeks or 420 mg SQ once monthly HoFH: 420 mg SQ once monthly Cost: $14,000 per year Medscape –accessed 1/11/2016 Repatha [package insert].

Repatha™ - Evolocumab Literature Review DESCARTES 52 week trial Purpose: To evaluate safety and efficacy of a 52 week treatment with evolocumab Design: randomized, double blind phase 3 88 centers in 9 countries Blom DJ et. al. N Engl J Med: 370 (19); 1809-1819

Repatha™ - Evolocumab Literature Review Inclusion Criteria Exclusion Criteria 18-75 yo LDL-C ≥ 75 mg/dL Fasting TG ≤ 400 mg/dL Heart Failure Recent MI Recent or planned revascularization procedure Uncontrolled HTN Hyper/hypothyroidism Moderate to severe renal dysfunction Active liver disease or hepatic dysfunction Blom DJ et. al. N Engl J Med: 370 (19); 1809-1819

Repatha™ - Evolocumab Literature Review Intervention: 420 mg evolocumab or placebo monthly Primary endpoint: Percent change from baseline of LDL-C at week 52 Secondary endpoint: Absolute change in LDL-C at week 52 % change in LDL-C at week 12 % of pts with LDL-C < 70 mg/dL at week 52 Blom DJ et. al. N Engl J Med: 370 (19); 1809-1819 .

Repatha™ - Evolocumab Literature Review Baseline Characteristics: Placebo (N = 302) Evolocumab (N = 599) Age Male White 56.7 46.4% 82.1% 55.9 48.4% 79.5% CV risk factors BMI DM2 Smoker HTN 30.5 13.9% 15.9% 49.3% 29.9 10.4% 14.5% 48.2% LDL-C 104.0 +/-21.6 104.2+/-22. Blom DJ et. al. N Engl J Med: 370 (19); 1809-1819 .

Repatha™ - Evolocumab Literature Review Results Placebo Evolocumab Mean LDL-C at baseline 104 +/- 21.6 104.2 +/- 22.1 No of pts at week 52 264 542 Mean % LDL change at week 52 6.8 +/- 1.8 -50.1 +/- 1.2 Mean Chol vs placebo 107.9 +/- 1.9 50.9 +/- 1.4 Pts with LDL-C < 70 6.4% 82.3% Blom DJ et. al. N Engl J Med: 370 (19); 1809-1819 .

Repatha™ - Evolocumab Literature Review Safety endpoints Adverse Event Placebo Evolocumab Any Serious Death 74.2% 4.3% 74.8% 5.5% 0.3% (2) Common adverse events Nasopharyngitis Upper resp. tract infection Influenza Cough Injection Site Erythema 9.6% 6.3% 3.6% 2.0% 10.5% 9.3% 7.5% 4.5% 2.7% Blom DJ et. al. N Engl J Med: 370 (19); 1809-1819 .

Repatha™ - Evolocumab Literature Review Trial conclusion: Evolocumab reduced LDL-C levels by 57% as compared with placebo at 52 weeks in patients at risk for coronary diseases receiving lipid lowering therapy Blom DJ et. al. N Engl J Med: 370 (19); 1809-1819 .

Repatha ™ - Evolocumab Summary Repatha™ ,evolocumab, is a PCSK9 inhibitor that reduces LDL-C by increasing the number of available LDL-Rs Evolocumab is indicated as adjunct treatment with HeFH, HoFH or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C Suggested subcutaneous dosing is 140 mg every 2 weeks or 420 mg every month Common adverse drug reactions include respiratory and injection-site reactions Suggested monitoring: LDL-C 4 to 8 weeks after starting therapy in patients with HoFH

Repatha™ - Evolocumab References www.repatha.com Repatha [evolocumab] package insert. Amgen Inc. (Thousand Oaks, CA): Aug. 2015; http://dailymed.nlm.nih.gov/dailymed/drugInfo.cf m?setid=709338ae-ab8f-44a9-b7d5-abaabec3493a Blom DJ et. al. A 52 week placebo controlled trial of Evolocumab in hyperlipidemia. N Engl J Med. 2014: 370 (19); 1809-1819