Pre-specified analysis of atherogenic lipoproteins Kausik K Ray, MB - PowerPoint PPT Presentation

ORION-1 Trial RNAi therapeutic targeting PCSK9: Pre-specified analysis of atherogenic lipoproteins Kausik K Ray, MB ChB, FRCP (Lon), FRCP (Ed), MD, Mphil Professor of Public Health at the School of Public Health Imperial College of London 1

ORION-1: Atherogenic lipoproteins Presented on behalf of the Steering Committee Principal investigator Kausik K Ray, MD, MPhil Chairman John JP Kastelein, MD, PhD Members and national Ulf Landmesser, MD, Lawrence A Leiter, MD, investigators R Scott Wright, MD Members David Kallend, MB BS, Peter Wijngaard, PhD PhD candidate Robert Stoekenbroek, MD 2

ORION-1: Atherogenic lipoproteins Disclosures Research grants • Amgen, Sanofi, Regeneron, MSD, Pfizer Consultancy • Amgen, Sanofi, Regeneron, MSD, Pfizer, Astra Zeneca, Lilly, The Medicines Company, Kowa, IONIS, Takeda, Novo Nordisk, Boehringer Ingelheim, Esperion, Cipla, Algorithm, Abbvie, Resverlogix, Cerenis 3

Therapeutic means to reduce LDL-C via the LDL receptor Three principal approaches 2 1 3 Nordestgaard B, Nicholls SJ, Langsted A, Ray KK and Tybj ӕ g-Hansen A. Nature Reviews Cardiology 2018;15:261-272 4

ORION-1: Atherogenic lipoproteins Background and rationale Monoclonal antibodies to PCSK9 modify atherogenic lipoproteins 1  59%  28% LDL-C Lp(a)  50%  12% non-HDL-C TG  44%  5% apo B HDL-C  29%  3% VLDL-C apo A1 Reducing intracellular PCSK9 might have important effects on apo B containing lipoproteins by altering production 1. Blom DJ et al. N Engl J Med 2014; 370:1809-1819 5

ORION-1: Summary of previously published data Optimal starting dose selected: 300 mg given twice Safety data • No concerns Efficacy data • All patients responded with significant LDL-C lowering • Mean LDL-C  at 6 months: 53% (absolute reduction 64 mg/dL) • Maximum LDL-C  at 6 months: 81% Ray KK et al. N Engl J Med 2017; 376:1430-1440 6

ORION-1: Atherogenic lipoproteins Pre-specified secondary endpoints : Through day-180 • Change in non-HDL-C, apo B 100, VLDL-C, Lp(a), TC, TG, HDL-C and apo AI • The time course of these changes • Proportion of individuals who reach non-HDL-C and apo B goals • Individual variation (displayed as waterfall plots) 7

ORION-1: Methods Trial design Screening (Day -14 to Day -1) Randomization (Day 1, n=501) One dose starting regimen Randomized (n=501) Two dose starting regimen Placebo 200 mg 300 mg 500 mg Placebo 100 mg 200 mg 300 mg Treated (n=497) N=65 N=60 N=61 N=65 N=62 N=61 N=62 N=61 Day 1 Study drug given Day 1 Study drug given 1 st follow-up visit 1 st follow-up visit Day 14 Day 14 Day 30 Monthly follow-up visits Day 30 Monthly follow-up visits Day 90 Day 90 Study drug given Day 180 Primary evaluation Day 180 Primary evaluation Completed (n=483) Day 210 End of study visit Day 210 End of study visit Day 360 Extended follow-up Day 360 Extended follow-up 8

ORION-1: Patients High-risk CV patients, balanced by randomization One dose starting regimen Two dose starting regimen Placebo Inclisiran Placebo Inclisiran N=65 N=188 N=62 N=186 Age 62 63 63 64 Mean years Statin Rx 70.8 75.0 77.4 69.9 % LDL-C 126.9 126.0 125.0 131.5 Mean mg/dL Non-HDL-C 155.1 154.3 154.6 162.5 Mean mg/dL Apo-B 102.1 102.7 103.3 106.5 Mean mg/dL VLDL-C 25.0 24.0 26.5 24.7 Median mg/dL Lipoprotein(a) 25.5 35.0 43.8 39.8 Median nmol/L Triglycerides Median mg/dL 126.5 123.3 131.3 126.3 HDL-C 50.1 50.4 52.0 48.1 Mean mg/dL Apo A1 149.7 151.6 155.0 146.9 Mean mg/dL 9

ORION-1: Secondary efficacy endpoints Non-HDL cholesterol Non-HDL cholesterol Non-HDL cholesterol MITT population, one starting dose MITT population, two starting doses Mean percent change ± 95% CI Mean percent change ± 95% CI 20 20 10 10 0 0 -10 -10 -20 -20 -30 -30 -40 -40 -50 -50 -60 -60 0 30 60 90 120 150 180 210 0 30 60 90 120 150 180 210 Visit Day Visit Day Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo -25.1% -35.2% -36.9% 1.5% -31.7% -38.9% -46.0% 1.3% P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo) Percent change from baseline to day 180 (P-values versus placebo) 10

ORION-1: Secondary efficacy endpoints Apolipoprotein B Apolipoprotein B Apolipoprotein B MITT population, one starting dose MITT population, two starting doses Mean percent change ± 95% CI Mean percent change ± 95% CI 20 20 10 10 0 0 -10 -10 -20 -20 -30 -30 -40 -40 -50 -50 -60 -60 0 30 60 90 120 150 180 210 0 30 60 90 120 150 180 210 Visit Day Visit Day Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo -22.9% -30.8% -33.1% 1.7% -27.8% -35.0% -40.9% 0.9% P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo) Percent change from baseline to day 180 (P-values versus placebo) 11

ORION-1: Secondary efficacy endpoints VLDL cholesterol VLDL cholesterol VLDL cholesterol MITT population, one starting dose MITT population, two starting doses 60 60 Median percent change ± 95% CI Median percent change ± 95% CI 40 40 20 20 0 0 -20 -20 -40 -40 -60 -60 0 30 60 90 120 150 180 210 0 30 60 90 120 150 180 210 Visit Day Visit Day Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo -11.6% -23.8% -14.6% 2.4% -16.4% -21.2% -16.0% 2.7% P = NS P<0.001 P<0.05 P<0.01 P<0.05 P<0.05 Percent change from baseline to day 180 (P-values versus placebo) Percent change from baseline to day 180 (P-values versus placebo) 12

ORION-1: Secondary efficacy endpoints Lipoprotein (a) Lipoprotein (a) Lipoprotein (a) MITT population, one starting dose MITT population, two starting doses 10 10 Median percent change ± 95% CI Median percent change ± 95% CI 0 0 -10 -10 -20 -20 -30 -30 -40 -40 0 30 60 90 120 150 180 210 0 30 60 90 120 150 180 210 Visit Day Visit Day Visit Day Visit Day Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo -14.3% -14.3% -18.2% 0.5% -14.9% -17.3% -25.6% 0% P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo) Percent change from baseline to day 180 (P-values versus placebo) 13

ORION-1: Secondary efficacy endpoints Other atherogenic lipoproteins MITT population, one starting dose MITT population, two starting doses Change from baseline Change from baseline Placebo 200 mg 300 mg 500 mg Placebo 100 mg 200 mg 300 mg Triglycerides 6.4% 1.1% **-12.8% *-12.2% -3.0% -6.3% 0.7% *-14.2% HDL-C 3.8% 4.4% *8.8% 6.9% 0.5% *7.6% ***10.3% **8.6% ApoA1 3.6% 2.9% 3.8% 4.1% 0.8% 5.5% **8.6% *6.2% *P<0.05 **P<0.01 ***P<0.001 14

ORION-1: Secondary efficacy endpoints ApoB and non HDL-C Results vs. guideline-recommended goals for high and very high risk patients MITT population, one starting dose MITT population, two starting doses Percent of patients achieving goal Percent of patients achieving goal Parameter Goal Placebo Inclisiran 300 mg Placebo Inclisiran 300 mg mg/dL N=64 N=60 N=61 N=59 ApoB <80 19% 73% 25% 78% ¶ 83% <100 58% 49% 90% Non-HDL-C <100 6% 62% 12% 68% <130 33% 78% 38% 83% All P-values <0.0001 versus placebo except ¶ P = 0.0019 15

ORION-1: Secondary endpoints Individual patients: % change from baseline – 180d Apolipoprotein B Non-HDL cholesterol Triglycerides 250 200 150 100 50 0 -50 -100 VLDL cholesterol Lipoprotein (a) Two starting doses Placebo x2 (N=61) 100 mg inclisiran x2 (N=59) 200 mg inclisiran x2 (N=60) 300 mg inclisiran x2 (N=59) 16

ORION-1: Atherogenic lipoproteins Conclusions and next steps Inclisiran produced significant, prolonged reductions in atherogenic lipoproteins • The inclisiran dosage selected for Phase III trials (300 mg - two starting doses) lowered non-HDL-C, apo B, VLDL-C and Lp(a) with reductions of similar magnitude to mAbs • With this inclisiran dosage, each individual patient achieved reduction in non-HDL-C and apo B – and the majority reached goal • Individual patient changes in Lp(a), VLDL-C, TG were more variable • Phase-III lipid lowering trials of inclisiran have fully recruited 3660 patients, include atherogenic lipoprotein measurement – and are expected to report data in 2H 2019 17

ORION-1: Atherogenic lipoproteins Full paper available this week 10.1161/CIRCULATIONAHA.118.034710 18