ORION-1 Impact of a 1- or 2-dose starting regimen of inclisiran, a - - PowerPoint PPT Presentation

Kausik K Ray, Ulf Landmesser, Lawrence A Leiter, David Kallend, Peter Wijngaard, R Scott Wright, and John JP Kastelein On behalf of the ORION-1 investigators

ORION-1

Impact of a 1- or 2-dose starting regimen of inclisiran, a novel siRNA inhibitor to PCSK9 on time averaged LDL-C reductions over 1 year

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Research grants:

• Amgen, Sanofi, Regeneron, MSD, Pfizer

Consultancy:

• Amgen, Sanofi, Regeneron, MSD, Pfizer, Astra Zeneca, Lilly, Medicines

Company, Kowa, IONIS, Takeda, Novo Nordisk, Boehringer Ingelheim, Esperion, Cipla, Algorithm, Abbvie, Resverlogix, Cerenis

Disclosures

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Background

LDL-C variability common, associated with worse outcomes

1. Ray KK et al. N Engl J Med 2017; 376:1430-1440 2. Bangalore S et al. JACC 2015; 65: 1539-1548

• 60
• 40
• 20

20 40 60

Six month percent change in LDL-C among statin users from starting level1 Increase in death, CV outcomes with each 1 standard deviation of LDL-C variability2

23% 17% 16% 11% 10% Death Stroke Any coronary event Any CV event MI

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PCSK9 monoclonal antibody treatment requires 12-26 injections per year1 Adherence unlikely to show substantial improvement over statins2 Limitations are most relevant in high risk patients needing lifelong therapy In the future can we do better?

Background

PCSK9 inhibition reduces LDL-C and ASCVD1

1. Sabatine MS et al. N Engl J Med 2017; 376:1713-1722 2. Hines D et al. ACC 2017 abstract #1203-313

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Background

RNAi is an intrinsic process for inhibiting mRNA

dsRNA dicer Cleavage

Natural process of RNA interference Synthetic siRNA

mRNA

mRNA degradation

Strand separation Complementary pairing Cleavage

Targeted gene silencing

RISC

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Asialoglycoprotein receptor (ASGPR)

• Highly expressed in hepatocytes only
• High rate of uptake

Inclisiran

• siRNA conjugated to N-acetylgalactosamine
• Subcutaneous administration
• Targeted delivery to hepatocytes

Background

GalNAc-siRNA conjugates facilitate rapid hepatic uptake

GalNAc3 ASGPR (pH>5)

GalNAc-siRNA inclisiran conjugate

Clathrin-coated pit Recycling ASGPR

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Methods

ORION 1 trial design

Completed (483) Screened (696) Treated (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 start 200 mg

N=60

Placebo

N=65

500 mg

N=65*

300 mg

N=61*

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 start 100 mg

N=61*

Placebo

N=62

300 mg

N=61

200 mg

N=62*

Study drug given

Stratified by country and Rx

Randomized (501)

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Patients

High-risk CV patients, balanced by randomization

One dose starting regimen Two dose starting regimen

Placebo Inclisiran Placebo Inclisiran

N=65 N=186 N=62 N=184

Age

Mean years

62 63 63 64 Male sex

%

64.6 67.7 53.2 66.3 Prior ASCVD

%

69.2 67.9 74.2 68.3 Statin Rx

%

70.3 74.4 77.0 70.2 LDL-C

Mean mg/dL

128.5 125.9 125.2 133.0 Non-HDL-C

Mean mg/dL

157.8 156.5 157.1 165.6 Apo-B

Mean mg/dL

102.4 103.2 104.6 107.7 Lipoprotein(a) Median nmol/L 27.0 34.0 50.5 40.0 PCSK9

Mean ng/mL

404.7 428.7 431.3 416.2

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Similar overall adverse event profile and incidence for inclisiran and placebo No LFT elevations considered related to investigational drug

• Similar incidence of transient transaminase increases in randomized groups

No difference in incidence of myalgias or CPK enzyme elevation

• One clinically relevant case of myonecrosis on placebo

No deaths related to drug administration

• Two previously reported deaths1 >100 days, related to underlying disease

Safety

No safety concerns in study with follow up to Day 360

1: Patient A: History of CHD, MI and PCI died of a fatal MI on Day 104 of the study. (500mg x1 dose) Patient B: Developed complications of aortic aneurysm surgery including an aorto-esophageal fistula requiring esophagectomy, leading to infection of the prosthesis, sepsis, and stroke, culminating in death on Day 198 of the study. Patient also had AF, chronic renal failure, emphysema, HT and obesity. (200mg x2 doses)

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Efficacy: One dose starting regimen

Robust, sustained LDL-C reductions – 300 mg optimal

P-value for all comparisons to placebo <0.0001

Days from first injection Mean percent change (±95% CI)

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• 50
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• 30
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10 30 60 90 120 150 180 210 240 270 300 330 360

Placebo 200mg 300 mg 500 mg 300mg 50.9% reduction 300 mg 38.6% reduction 300 mg 19.0% reduction

12 P-value for all comparisons to placebo <0.0001

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• 50
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10 30 60 90 120 150 180 210 240 270 300 330 360

Placebo 100 mg 200 mg 300 mg

Efficacy: Two dose starting regimen

Robust, sustained LDL-C reductions – optimal start regimen

300 mg x2 55.5% 52.5% Days from first injection Mean percent change (±95% CI) 300 mg x2 31.4%

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Sustained LDL-C lowering effects over time

Time-averaged reduction from Day 1 to Day 360

• 30%
• 37%
• 39%
• 30%
• 40%
• 46%

Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg

Time adjusted percent change in LDL-C to Day 360 One dose starting regimen Two dose starting regimen

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Inclisiran dose 300mg sc Day 1, 90, 270 and 6-monthly

Sustained >50% reduction in LDL-C for 6-months

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Q1 Q3 Mean Median

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Q1 Q3 Mean Median

Day 90 % Change in LDL-C from Baseline Time adjusted LDL-C for 6 months = 41% Day 270 Day 90 Day 270 One dose starting regimen (300 mg) Two dose starting regimen (300 mg) Time adjusted LDL-C for 6 months = 51%

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Efficacy: Day 360 LDL-C reduction in mg/dL

Individual patient responses

• 200
• 160
• 120
• 80
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40

100 mg N = 41 200 mg N = 48 300 mg N = 53

• 200
• 160
• 120
• 80
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40

200 mg N = 30 300mg N = 38 500 mg N = 44

One dose starting regimen (N = 112) Two dose starting regimen (N = 142)

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Safety

• By day 360, patients are predictably returning towards baseline
• No safety signals at 1 year (>250 patient-years of observation)

Dose and dose frequency

• 300 mg given s.c. at Day 1 and Day 90 represents the optimal starting dose
• 300 mg given s.c. at Day 270 then every 180 days is the maintenance dose

This dosing schedule provides robust and consistent LDL-C lowering

• 46% time-averaged reduction over 12 months
• 51% time-averaged reduction over 6-monthly dosing interval
• Minimal within-patient variability in LDL-C reduction over time

Conclusions

Robust LDL-C with 6 monthly inclisiran dosing

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LDL-C lowering trials underway

• 3,000 subjects with ASCVD/ risk equivalents (ORION-10, -11)
• 400 subjects with HeFH (ORION-9)
• 60 subjects with HoFH (ORION-5)

Parallel cardiovascular outcomes trial in preparation

• 15,000 subjects with high risk ASCVD (ORION-4)

Implications

Inclisiran has moved into Phase III

Backup

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Safety

No safety concerns in follow up to Day 360

Safety population One dose starting regimen Two dose starting regimen Placebo Inclisiran Placebo Inclisiran

N=65 N=186 N=62 N=184 n (%) n (%) n (%) n (%)

Any TEAE 51 (78.5) 155 (81.3) 51 (82.3) 153 (83.2) Serious 3 (4.6) 30 (16.1) 7 (11.3) 31 (16.8) Severe 2 (3.1) 18 (9.7) 7 (11.3) 22 (12.0) Related 12 (18.5) 39 (21.0) 19 (30.6) 52 (28.3) AE discontinuation 1 (1.6) 1 (0.5) Injection site reaction 7 (3.8) 12 (6.5)

TEAEs (treatment emergent adverse events) - similar incidence placebo vs inclisiran: One dose starting regimen: Nasopharyngitis, myalgia, back pain, cough, arthralgia, headache Two dose starting regimen: Myalgia, headache, diarrhea, nasopharyngitis, arthralgia, back pain