ORION-1 Trial RNAi therapeutic targeting PCSK9: Pre ... 1 LBCT EAS FI… · ORION-1: Patients High-risk CV patients, balanced by randomization One dose starting regimen Two dose starting

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Kausik K Ray, MB ChB, FRCP (Lon), FRCP (Ed), MD, MphilProfessor of Public Health at the School of Public HealthImperial 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


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

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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


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)


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 givenDay 14 1st follow-up visit

Monthly follow-up visitsDay 30

Day 90

Day 180

Day 210 End of study visit

Primary evaluation

Day 360 Extended follow-up

One dose starting regimen

200 mgN=60

PlaceboN=65

500 mgN=65

300 mgN=61

ORION-1: Methods

Trial design

Day 1 Study drug givenDay 14 1st follow-up visit

Monthly follow-up visitsDay 30

Day 90

Day 180

Day 210 End of study visit

Primary evaluation

Day 360 Extended follow-up

Two dose starting regimen

100 mgN=61

PlaceboN=62

300 mgN=61

200 mgN=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 InclisiranN=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

0

10

20

0 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


-60

-50

-40

-30

-20

-10

0

10

20

0 30 60 90 120 150 180 210


Visit Day

Mean p

erc

en

t change ±

95%

CI

Non-HDL cholesterol

MITT population, one starting dose

Non-HDL cholesterol

MITT population, two starting doses

Mean p

erc

en

t change ±

95%

CI

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Apolipoprotein B

-22.9% -30.8% -33.1% 1.7%

P<0.001 P<0.001 P<0.001


-27.8% -35.0% -40.9% 0.9%

P<0.001 P<0.001 P<0.001


-60

-50

-40

-30

-20

-10

0

10

20

0 30 60 90 120 150 180 210


Visit Day

-60

-50

-40

-30

-20

-10

0

10

20

0 30 60 90 120 150 180 210


Visit Day

Mean p

erc

en

t change ±

95%

CI

Apolipoprotein B


Apolipoprotein B


Mean p

erc

en

t change ±

95%

CI

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VLDL cholesterol

-11.6% -23.8% -14.6% 2.4%

P = NS P<0.001 P<0.05


-16.4% -21.2% -16.0% 2.7%

P<0.01 P<0.05 P<0.05


Media

n p

erc

ent c

hange ±

95%

CI

VLDL cholesterol


VLDL cholesterol


-60

-40

-20

0

20

40

60

0 30 60 90 120 150 180 210


Visit Day

-60

-40

-20

0

20

40

60

0 30 60 90 120 150 180 210


Visit Day

Media

n p

erc

ent c

hange ±

95%

CI

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Lipoprotein (a)

-14.3% -14.3% -18.2% 0.5%

P<0.001 P<0.001 P<0.001


-14.9% -17.3% -25.6% 0%

P<0.001 P<0.001 P<0.001


Media

n p

erc

ent c

hange ±

95%

CI

Lipoprotein (a)


Lipoprotein (a)


-40

-30

-20

-10

0

10

0 30 60 90 120 150 180 210


Visit DayVisit Day

-40

-30

-20

-10

0

10

0 30 60 90 120 150 180 210


Visit DayVisit Day

Media

n p

erc

ent c

hange ±

95%

CI

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Other atherogenic lipoproteins


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

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


ApoB and non HDL-C


Percent of patients achieving goal


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

0

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)



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


Conclusions and next steps

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10.1161/CIRCULATIONAHA.118.034710


Full paper available this week

Documents

ORION-1 Trial RNAi therapeutic targeting PCSK9: Pre ... 1 LBCT EAS FI… · ORION-1: Patients High-risk CV patients, balanced by randomization One dose starting regimen Two dose starting