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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 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 Lancet. 2012;380: JAMA. 2012;308: Circulation. 2012;126: Lancet. 2012;380: Circulation 2014;129:

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

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

8 DESCARTES: Patient Disposition
Screened: 2120 635 screen failures 1485 entered lipid stabilization period 580 lipid stabilization period failures 905 randomized to evolocumab or placebo

9 DESCARTES: Patient Disposition II
905 Randomized 2:1 allocation to evolocumab or placebo 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) 73 discontinued evolocumab 28 discontinued placebo 4 never received SD* 800 completed 52 weeks of Study Drug E = Ezetimibe, Evo = Evolocumab, P = Placebo * Study Drug

10 DESCARTES: Baseline Characteristics
Diet Alone A 10 mg/d A 80 mg/d A 80 mg/d +E10 mg/d All n 111 383 218 189 901 Age, y, mean (SD) 51.7 (12.1) (10.4) (9.2) 54.8 (10.7) 56.2 (10.6) Male, % 45.0 43.9 50.0 54.5 47.7 BMI, kg/m2, mean (SD) 30.5 (7.6) (6.2) (5.7) (4.8) 30.1 (6.0) Race/White, % 67.6 85.9 86.2 69.8 80.4 A = Atorvastatin E = Ezetimibe Full Analysis Set (FAS) data presented: Patients who received at least one dose of study drug

11 DESCARTES: Baseline Patient Characteristics II
Diet Alone A 10 mg/d A 80 mg/d A 80 mg/d +E10 mg/d All Coronary artery disease,% 1.8 2.6 15.6 47.6 15.1 Type 2 diabetes,% 2.7 7.0 21.7 11.5 Current smoker, % 17.1 11.7 14.2 21.2 15.0 Hypertension, % 42.3 41.8 57.3 56.1 48.6 Family history of premature CAD, % 13.5 14.6 22.0 47.1 23.1 2 or more CV risk factors, % 29.7 26.6 46.3 61.4 39.1 A = Atorvastatin E = Ezetimibe

12 DESCARTES: Baseline Lipids
Placebo Evolocumab n 302 599 *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 UC LDL-C Baseline mg/dL mean (SD)
DESCARTES: Baseline LDL-C on Background Therapy Prior to First Dose of Study Drug Treatment Diet Alone A 10 mg/d A 80 mg/d A 80 mg/d + E 10 mg/d All  Group P EVO n 37 74 129 254 73 145 63 126 302 599 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 DESCARTES: % Change in UC LDL-C From Baseline - FAS
20 6.0% 10 -10 Treatment difference 57% -20 UC LDL-C Percent Change from Baseline, Mean (± SE) -30 -40 -50 -51.5% -60 -70 Number of patients: -80 302 294 264 599 582 542 Baseline Week 12 Week 52 Study Week Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599) FAS = Full analysis set, UC = ultracentrifugation

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

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

17 Changes in Mean Levels of Unbound PCSK9
Placebo Evolocumab 700 Diet Only Atorvastatin 80 mg Atorvastatin 10 mg Atorvastatin 80 mg + Ezetimibe 10 mg 600 500 400 Mean ± SE PCSK9 Level, ng/mL 300 200 100 Baseline Week 12 Week 13 Week 52 4 weeks post-dose 1 week post-dose 4 weeks post dose

18 DESCARTES: Other Lipids at Week 52
-50 -40 -30 -20 -10 10 2% 6% ApoB HDL-C 6 4 Percent Change from Baseline, Mean (%) Percent Change from Baseline, Mean (%) 2 -42% -2 Lp(a) ApoA1 2% -5 3 -6% (-21 to 1) -10 2 Percent Change from Baseline, Median (%) -15 1 -20 Percent Change from Baseline, Mean (%) -25 -30 -28% (-49 to -6) -1 -2 -1% 3% (-17 to 25) Triglycerides 6 4 2 Placebo QM Percent Change from Baseline, Median (%) -2 -4 Evolocumab 420 mg QM -6 -8 Error bars represent standard error Data in parentheses represent Q1 to Q3 -10 -9% (-26 to 13)

19 DESCARTES: Safety and Tolerability

20 DESCARTES: Treatment Emergent Adverse Events
Placebo N=302 Evolocumab N=599 Any Treatment Emergent Adverse Event 224 (74.2) 448 (74.8) Serious 13 (4.3) 33 (5.5) Death 0 (0.0) 2 (0.3) Adjudicated events 2 (0.7) 6 (1.0) Leading to discontinuation of study drug 3 (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 DESCARTES: Treatment Emergent Adverse Events II
Placebo N=302 Evolocumab N=599 Most Common Treatment Emergent AEs Nasopharyngitis 29 (9.6) 63 (10.5) Upper respiratory tract infection 19 (6.3) 56 (9.3) Influenza 45 (7.5) Back pain 17 (5.6) 37 (6.2) Neurocognitive AEs 2 (0.7) 1 (0.2) Amnesia - Short-term memory loss 0 (0.0) Dementia With Lewy Bodies 1 (0.3) Encephalopathy Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study

22 DESCARTES: Hepatic and Muscle Safety
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 Myalgia 9 (3.0) 24 (4.0) CK > 5 × ULN* 7 (1.2) CK > 10 × ULN* * At any visit post baseline, TEAE = treatment emergent adverse event

23 DESCARTES: Glycemic Parameters
Changes from baseline at week 52  Placebo Evolocumab Diet alone A 10 mg/d A 80 mg/d A 80 mg/d + E10 mg/d n 273 63 225 131 114 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) 64 227 129 115 HbA1C, (%); mean (SE) 0.00 (0.03) (0.04) 0.04 (0.02) (0.03) 0.09 (0.04) A = Atorvastatin E = Ezetimibe

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 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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