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

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

Aug 31, 2022 220 likes •411 views

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

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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

ORION-1 Trial RNAi therapeutic targeting PCSK9: Pre-specified analysis of atherogenic lipoproteins

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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 investigators Ulf Landmesser, MD, Lawrence A Leiter, MD, R Scott Wright, MD Members David Kallend, MB BS, Peter Wijngaard, PhD PhD candidate Robert Stoekenbroek, MD

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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

ORION-1: Atherogenic lipoproteins

Disclosures

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Therapeutic means to reduce LDL-C via the LDL receptor

Three principal approaches

Nordestgaard B, Nicholls SJ, Langsted A, Ray KK and Tybjӕg-Hansen A. Nature Reviews Cardiology 2018;15:261-272

1 3 2

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Monoclonal antibodies to PCSK9 modify atherogenic lipoproteins1 Reducing intracellular PCSK9 might have important effects on apo B containing lipoproteins by altering production

ORION-1: Atherogenic lipoproteins

Background and rationale

  • 1. Blom DJ et al. N Engl J Med 2014; 370:1809-1819

LDL-C

 59%

Lp(a)

 28%

non-HDL-C

 50%

TG

 12%

apo B

 44%

HDL-C

 5%

VLDL-C

 29%

apo A1

 3%

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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%

ORION-1: Summary of previously published data

Optimal starting dose selected: 300 mg given twice

Ray KK et al. N Engl J Med 2017; 376:1430-1440

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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)

ORION-1: Atherogenic lipoproteins

Pre-specified secondary endpoints:

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Completed (n=483) Screening (Day -14 to Day -1) Randomization (Day 1, n=501) Treated (n=497)

Day 1 Study drug given Day 14 1st follow-up visit Monthly follow-up visits Day 30 Day 90 Day 180 Day 210 End of study visit Primary evaluation Day 360 Extended follow-up

One dose starting regimen 200 mg

N=60

Placebo

N=65

500 mg

N=65

300 mg

N=61

ORION-1: Methods

Trial design

Day 1 Study drug given Day 14 1st follow-up visit Monthly follow-up visits Day 30 Day 90 Day 180 Day 210 End of study visit Primary evaluation Day 360 Extended follow-up

Two dose starting regimen 100 mg

N=61

Placebo

N=62

300 mg

N=61

200 mg

N=62

Study drug given

Randomized (n=501)

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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

Mean years

62 63 63 64 Statin Rx

%

70.8 75.0 77.4 69.9 LDL-C

Mean mg/dL

126.9 126.0 125.0 131.5 Non-HDL-C

Mean mg/dL

155.1 154.3 154.6 162.5 Apo-B

Mean mg/dL

102.1 102.7 103.3 106.5 VLDL-C

Median mg/dL

25.0 24.0 26.5 24.7 Lipoprotein(a)

Median nmol/L

25.5 35.0 43.8 39.8 Triglycerides Median mg/dL 126.5 123.3 131.3 126.3 HDL-C

Mean mg/dL

50.1 50.4 52.0 48.1 Apo A1

Mean mg/dL

149.7 151.6 155.0 146.9

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ORION-1: Secondary efficacy endpoints

Non-HDL cholesterol

  • 60
  • 50
  • 40
  • 30
  • 20
  • 10

10 20 30 60 90 120 150 180 210

Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo

Visit Day

  • 25.1%
  • 35.2%
  • 36.9%

1.5% P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo)

  • 31.7%
  • 38.9%
  • 46.0%

1.3% P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo)

  • 60
  • 50
  • 40
  • 30
  • 20
  • 10

10 20 30 60 90 120 150 180 210

Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo

Visit Day

Mean percent change ± 95% CI

Non-HDL cholesterol MITT population, one starting dose Non-HDL cholesterol MITT population, two starting doses

Mean percent change ± 95% CI

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ORION-1: Secondary efficacy endpoints

Apolipoprotein B

  • 22.9%
  • 30.8%
  • 33.1%

1.7% P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo)

  • 27.8%
  • 35.0%
  • 40.9%

0.9% P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo)

  • 60
  • 50
  • 40
  • 30
  • 20
  • 10

10 20 30 60 90 120 150 180 210

Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo

Visit Day

  • 60
  • 50
  • 40
  • 30
  • 20
  • 10

10 20 30 60 90 120 150 180 210

Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo

Visit Day

Mean percent change ± 95% CI

Apolipoprotein B MITT population, one starting dose Apolipoprotein B MITT population, two starting doses

Mean percent change ± 95% CI

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ORION-1: Secondary efficacy endpoints

VLDL cholesterol

  • 11.6%
  • 23.8%
  • 14.6%

2.4% P = NS P<0.001 P<0.05 Percent change from baseline to day 180 (P-values versus placebo)

  • 16.4%
  • 21.2%
  • 16.0%

2.7% P<0.01 P<0.05 P<0.05 Percent change from baseline to day 180 (P-values versus placebo) Median percent change ± 95% CI

VLDL cholesterol MITT population, one starting dose VLDL cholesterol MITT population, two starting doses

  • 60
  • 40
  • 20

20 40 60 30 60 90 120 150 180 210

Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo

Visit Day

  • 60
  • 40
  • 20

20 40 60 30 60 90 120 150 180 210

Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo

Visit Day

Median percent change ± 95% CI

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ORION-1: Secondary efficacy endpoints

Lipoprotein (a)

  • 14.3%
  • 14.3%
  • 18.2%

0.5% P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo)

  • 14.9%
  • 17.3%
  • 25.6%

0% P<0.001 P<0.001 P<0.001 Percent change from baseline to day 180 (P-values versus placebo) Median percent change ± 95% CI

Lipoprotein (a) MITT population, one starting dose Lipoprotein (a) MITT population, two starting doses

  • 40
  • 30
  • 20
  • 10

10 30 60 90 120 150 180 210

Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg Placebo

Visit Day Visit Day

  • 40
  • 30
  • 20
  • 10

10 30 60 90 120 150 180 210

Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Placebo

Visit Day Visit Day

Median percent change ± 95% CI

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ORION-1: Secondary efficacy endpoints

Other atherogenic lipoproteins

MITT population, one starting dose Change from baseline MITT population, two starting doses 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

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Results vs. guideline-recommended goals for high and very high risk patients

ORION-1: Secondary efficacy endpoints

ApoB and non HDL-C

MITT population, one starting dose Percent of patients achieving goal MITT population, two starting doses Percent of patients achieving goal Parameter Goal mg/dL Placebo N=64 Inclisiran 300 mg N=60 Placebo N=61 Inclisiran 300 mg N=59 ApoB <80 19% 73% 25% 78% <100 58%

¶83%

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

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ORION-1: Secondary endpoints

Individual patients: % change from baseline – 180d

  • 100
  • 50

50 100 150 200 250

Apolipoprotein B Non-HDL cholesterol VLDL cholesterol Lipoprotein (a) Triglycerides

Placebo x2 (N=61) 100 mg inclisiran x2 (N=59) 200 mg inclisiran x2 (N=60) 300 mg inclisiran x2 (N=59)

Two starting doses

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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

ORION-1: Atherogenic lipoproteins

Conclusions and next steps

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10.1161/CIRCULATIONAHA.118.034710

ORION-1: Atherogenic lipoproteins

Full paper available this week