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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
2
3
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
4
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
0
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
5
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
Endosome
Hepatocyte cytoplasm
Clathrin-coated vesicle
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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
perc
en
t ch
an
ge (±
95%
CI)
-60
-50
-40
-30
-20
-10
0
10
0 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
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P-value for all comparisons to placebo <0.0001
-60
-50
-40
-30
-20
-10
0
10
0 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
perc
en
t ch
an
ge (±
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
Tim
e a
dju
ste
d p
erc
en
t ch
an
ge
in
LD
L-C
to
Day 3
60
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
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Q1
Q3
Mean Median
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Q1
Q3
Mean Median
Day 90
% C
han
ge in
LD
L-C
fro
m B
aseli
ne
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
-40
0
40
100 mg
N = 41
200 mg
N = 48
300 mg
N = 53
-200
-160
-120
-80
-40
0
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 0 0 1 (1.6) 1 (0.5)
Injection site reaction 0 7 (3.8) 0 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
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