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Long-term Tolerability and Efficacy of Evolocumab (AMG 145) in Hyperlipidemic Subjects: A 52 Week Phase 3 Double-blind, Randomized, Placebo-controlled.

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Presentation on theme: "Long-term Tolerability and Efficacy of Evolocumab (AMG 145) in Hyperlipidemic Subjects: A 52 Week Phase 3 Double-blind, Randomized, Placebo-controlled."— Presentation transcript:

1 Long-term Tolerability and Efficacy of Evolocumab (AMG 145) in Hyperlipidemic Subjects: A 52 Week Phase 3 Double-blind, Randomized, Placebo-controlled Study Dirk Blom, Tomas Hala, Michael Bolognese, Michael J Lillestol, Phillip D Toth, Lesley Burgess, Richard Ceska, Eli Roth, Michael J Koren, Maria Laura Monsalvo, Kate Tsirtsonis, Jae B Kim, Scott M Wasserman, Rob Scott, Christie M Ballantyne, Evan A Stein, for the DESCARTES Investigators March 29, 2014, Featured Clinical Research Session 400 American College of Cardiology, Washington DC

2 2 Background: PCSK9 Inhibition PCSK9 is a well validated therapeutic target based on gain and loss of function human genetic abnormalities, Mendelian randomization studies, and its recently elucidated role in LDL receptor function and regulation of LDL cholesterol. Evolocumab (AMG 145), a fully human monoclonal antibody against PCSK9, reduced LDL-C by up to 65% and was well tolerated in 4 randomized, placebo-controlled, phase 2 clinical trials of 12 weeks duration in over 1300 hypercholesterolemic patients. 1-4 An open label extension study of patients from phase 2 trials with evolocumab (OSLER) recently reported 1 year safety and efficacy data. 5 1.Lancet. 2012;380: Circulation. 2012;126: JAMA. 2012;308: Lancet. 2012;380: Circulation 2014;129:

3 3 The DESCARTES Study Durable Effect of PCSK9 antibody CompARed wiTh placEbo Study (NCT ) A 52 week global, randomized, double-blind, placebo- controlled multicenter study to provide longer term data on the efficacy and safety of evolocumab Included patients with a wide range of cardiovascular risk Lipid-lowering therapy, ranging from diet alone to atorvastatin 80 mg plus ezetimibe, was optimized to reach NCEP ATP III LDL-C treatment goals

4 4 DESCARTES: Endpoints Primary: % change from baseline in LDL-C measured by ultracentrifugation (UC) at week 52 Secondary % change from baseline in UC LDL-C at week 12 Change from baseline in UC LDL-C at week 52 % of patients with UC LDL-C < 70 mg/dL at week 52 % changes from baseline for TC, HDL-C, ApoB, VLDL-C, triglycerides, and Lp(a) at week 52 % changes in total cholesterol/HDL cholesterol ratio and apolipoprotein B/apolipoprotein A1 ratio at week 52

5 5 DESCARTES: Patients Adults aged 18 to 75 years Screening LDL-C 75 mg/dL and TG 400 mg/dL Exclusion: LDL-C 99 mg/dL with CHD or risk equivalent and not receiving a statin Following lipid stabilization period At NCEP ATP III target or receiving maximal therapy (atorvastatin 80 mg plus ezetimibe 10 mg) LDL-C 75 mg/dL

6 6 DESCARTES: Screening and Lipid Stabilization Screening LDL-C 75 mg/dL Background Therapy Assigned Based on CV Risk, LDL-C, and Current Therapy: 1)Diet alone 2)Diet and atorvastatin 10 mg 3)Diet and atorvastatin 80 mg 4)Diet, atorvastatin 80 mg, and ezetimibe 10 mg 4 Week Dietary Run-in and Lipid Stabilization Screening Period 4 Weeks to 16 Weeks Yes No Initial LDL-C < 75 mg/dL = Screen Fail LDL < 75 mg/dL = Screen Fail (except on maximal background therapy – allowed one downtitration CHD/risk equivalent: LDL < 100 mg/dL OR No CHD/risk equivalent: LDL < 130 mg/dL OR On Maximal background therapy Up-titrate Background Therapy Randomization 2:1 (~900 Subjects) Evolocumab 420 mg SC QM Placebo SC QM

7 7 DESCARTES: Study Overview Day 1 Week 8 End of Study Week 52*Week 4 Visits: Placebo SC QM n = 303 Evolocumab 420 mg SC QM n = 602 Randomization 2:1 QM: Study Drug (Evolocumab or Placebo) Screening - Assign background Rx based on CV risk, LDL, and +/- prior statin : 1.No drug 2.Low dose: 10 mg atorvastatin 3.High dose: 80 mg atorvastatin 4.Maximal: 80 mg atorvastatin + 10 mg ezetimibe Subcutaneous injection of 6 mL Placebo Period = Max. 16 weeks / Min: 4 weeks Lipid Stabilization Period Fasting LDL-C 5–10 days before randomization * Last dose administered at week 48

8 8 DESCARTES: Patient Disposition Screened: entered lipid stabilization period 905 randomized to evolocumab or placebo 635 screen failures 580 lipid stabilization period failures

9 9 DESCARTES: Patient Disposition II 112 Diet alone (38 P: 74 Evo) 385 Atorvastatin 10 (129 P: 256 Evo) 219 Atorvastatin 80 (73 P: 146 Evo) 189 Atorvastatin 80 + Ezetimibe 10 (63 P: 126 Evo ) 905 Randomized 2:1 allocation to evolocumab or placebo 800 completed 52 weeks of Study Drug E = Ezetimibe, Evo = Evolocumab, P = Placebo * Study Drug 4 never received SD* 73 discontinued evolocumab 28 discontinued placebo

10 10 DESCARTES: Baseline Characteristics Characteristic Diet Alone A 10 mg/dA 80 mg/d A 80 mg/d +E10 mg/d All n Age, y, mean (SD) 51.7 (12.1) 57.1 (10.4) 58.0 (9.2) 54.8 (10.7) 56.2 (10.6) Male, % BMI, kg/m 2, mean (SD) 30.5 (7.6) 29.8 (6.2) 30.8 (5.7) 29.8 (4.8) 30.1 (6.0) Race/White, % A = Atorvastatin E = Ezetimibe Full Analysis Set (FAS) data presented: Patients who received at least one dose of study drug

11 11 DESCARTES: Baseline Patient Characteristics II Characteristic Diet Alone A 10 mg/dA 80 mg/d A 80 mg/d +E10 mg/d All Coronary artery disease,% Type 2 diabetes,% Current smoker, % Hypertension, % Family history of premature CAD, % or more CV risk factors, % A = Atorvastatin E = Ezetimibe

12 12 DESCARTES: Baseline Lipids PlaceboEvolocumab n *UC LDL-C, mg/dL, mean (SD)104 (22) ApoB, mg/dL, mean (SD)88 (16)87 (16) Lipoprotein(a), nmol/L, median (Q1, Q3) 40 (12,145)38 (14,137) HDL-C mg/dL mean, (SD)54 (16)53 (16) ApoA1, mg/dL mean, (SD)155 (28)152 (27) Triglycerides, mg/dL, median, (Q1, Q3) 110 (85,155) 105 (80,140) *UC = ultracentrifugation

13 13 DESCARTES: Baseline LDL-C on Background Therapy Prior to First Dose of Study Drug Treatment Diet Alone A 10 mg/dA 80 mg/d A 80 mg/d + E 10 mg/d All GroupPEVOP P P P n UC LDL-C Baseline mg/dL mean (SD) 112 (16) 112 (15) 98 (15) 101 (15) 96 (13) 95 (13) 120 (32) 117 (35) 104 (22) A = Atorvastatin E = Ezetimibe EVO = Evolocumab P = Placebo

14 14 DESCARTES: % Change in UC LDL-C From Baseline - FAS UC LDL-C Percent Change from Baseline, Mean (± SE) BaselineWeek 12Week Number of patients: Study Week Placebo QM (N = 302)Evolocumab 420 mg QM (N = 599) FAS = Full analysis set, UC = ultracentrifugation -51.5% 6.0% Treatment difference 57%

15 15 DESCARTES: % Change in UC LDL-C from Baseline at Week 52 Error bars represent standard error for treatment difference Treatment difference are least squares mean derived from a repeated measures model EvolocumabPlaceboTreatment Difference Overall Diet Alone Atorvastatin 10 mg Atorvastatin 80 mg Atorvastatin 80 mg + Ezetimibe 10 mg

16 16 Diet Alone Diet + Atorvastatin 10 mg Diet + Atorvastatin 80 mg Diet + Atorvastatin 80 mg + Ezetimibe 10 mg DESCARTES: UC LDL-C Goal Achievement LDL-C < 70 mg/dL at Week 52 Total

17 17 Changes in Mean Levels of Unbound PCSK BaselineWeek 12Week 13Week 52 Mean ± SE PCSK9 Level, ng/mL Placebo Diet Only Atorvastatin 10 mg Atorvastatin 80 mg Atorvastatin 80 mg + Ezetimibe 10 mg 4 weeks post-dose 1 week post-dose 4 weeks post dose Evolocumab

18 18 DESCARTES: Other Lipids at Week % % (-17 to 25) -9% (-26 to 13) 2% ApoB Lp(a) HDL-C ApoA1 Triglycerides -42% % 2% % (-21 to 1) -28% (-49 to -6) Placebo QM Evolocumab 420 mg QM Percent Change from Baseline, Mean (%) Percent Change from Baseline, Median (%) Percent Change from Baseline, Median (%) Percent Change from Baseline, Mean (%) Percent Change from Baseline, Mean (%) Error bars represent standard error Data in parentheses represent Q1 to Q3

19 DESCARTES: Safety and Tolerability

20 20 DESCARTES: Treatment Emergent Adverse Events n (%) Placebo N=302 Evolocumab N=599 Any Treatment Emergent Adverse Event224 (74.2)448 (74.8) Serious13 (4.3)33 (5.5) Death0 (0.0)2 (0.3) Adjudicated events2 (0.7)6 (1.0) Leading to discontinuation of study drug3 (1.0)13 (2.2) Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study

21 21 DESCARTES: Treatment Emergent Adverse Events II n (%) Placebo N=302 Evolocumab N=599 Most Common Treatment Emergent AEs Nasopharyngitis29 (9.6)63 (10.5) Upper respiratory tract infection19 (6.3)56 (9.3) Influenza19 (6.3)45 (7.5) Back pain17 (5.6)37 (6.2) Neurocognitive AEs 2 (0.7)1 (0.2) Amnesia - Short-term memory loss 0 (0.0)1 (0.2) Dementia With Lewy Bodies 1 (0.3) 0 (0.0) Encephalopathy 1 (0.3)0 (0.0) Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study

22 22 DESCARTES: Hepatic and Muscle Safety n (%) Placebo N=302 Evolocumab N=599 Liver function tests ALT or AST > 3 × ULN*3 (1.0)5 (0.8) ALT or AST > 5 × ULN*1 (0.3)3 (0.5) Muscle TEAEs and Laboratory Results Myalgia9 (3.0)24 (4.0) CK > 5 × ULN*1 (0.3)7 (1.2) CK > 10 × ULN*1 (0.3)3 (0.5) * At any visit post baseline, TEAE = treatment emergent adverse event

23 23 DESCARTES: Glycemic Parameters Changes from baseline at week 52 PlaceboEvolocumab Diet alone A 10 mg/d A 80 mg/d A 80 mg/d + E10 mg/d n Glucose, (mg/dL); mean (SE) 0.4 (0.9)-0.5 (1.5)1.7 (1.2)0.3 (1.0)2.6 (1.9) n HbA1C, (%); mean (SE) 0.00 (0.03) (0.04) 0.04 (0.02) (0.03) 0.09 (0.04) A = Atorvastatin E = Ezetimibe

24 24 DESCARTES: Injection Sites and Antibodies Potential injection site reactions Evolocumab 34 (5.7%) Placebo 15 (5.0%) Antibodies to evolocumab 2 patients (allocated to evolocumab) had binding antibodies prior to evolocumab exposure One patient on evolocumab developed transient binding antibodies during therapy No neutralizing antibodies detected throughout study

25 25 DESCARTES: Conclusions Largest and longest double-blind, randomized placebo controlled trial reported to date, of a monoclonal antibody to PCSK9 Evolocumab 420 mg QM reduced placebo adjusted UC LDL-C 57% from baseline in patients with a wide range of cardiovascular risk receiving background lipid lowering therapies ranging from diet alone to the combination of atorvastatin 80 mg/d and ezetimibe 10 mg/d Durable effect with consistent LDL-C reductions at weeks 12 and 52 Similar AE profile in placebo and active treatment groups No adverse laboratory signals observed Cardiovascular outcome trial is ongoing


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