Clinical Trials for PCSK9 - Lipid. McKenney is an employee of National Clinical Research which has...
Transcript of Clinical Trials for PCSK9 - Lipid. McKenney is an employee of National Clinical Research which has...
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James M. McKenney, PharmDPresident and CEO, National Clinical Research, Inc.
Professor Emeritus, Virginia Commonwealth University Richmond, VA
Clinical Trials for PCSK9
2014 NLA Scientific Sessions, Orlando, FL
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Dr. McKenney is an employee of National Clinical Research which has received research funding from Sanofi, Regeneron, Amgen, Pfizer, BMS, Novartis, and Lilly which are developing PCSK9 therapies
Speaker Disclosure
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The Interplay Between LDL-C, Hepatocyte Cholesterol Synthesis, LDL-R, and PCSK9
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9am 12pm 3pm 6pm 9pm 12am 3am 6am 9am
% C
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m B
asel
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9)
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PCSK9
Lathosterol
Total Cholesterol
Persson et al. Arterioscler Thromb Vasc Biol 2010; 30: 2666-2672
Diurnal Variation of Cholesterol Synthesis and PCSK9
Food Intake
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PCSK9 Inhibitors in Development
Investigational Product Company Stage of
Development
Monoclonal antibodies
Alirocumab (SAR236553, REGN727) Sanofi (Regeneron) Phase III
Evolocumab (AMG 145) Amgen Phase III
Bococizumab (PF-0490615, RN316) Pfizer (Rinat) Phase IlI
LY3015014 Lilly Phase II
Other PCSK9 biologics
ALN-PCS (siRNA) Alnylam, The Medicines Comp Phase I
Revised from Stein et al Annu Rev Med. 2014; 65: 417-431
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Effect of ALN-PCS on LDL-C AfterA Single 0.400 mg/kg Dose
0 5 10 15 20 25 30
1.2
1.0
0.8
0.6
LDL-
C r
elat
ive
to b
asel
ine
(mg/
dL)
Days
Findings: Mean PCSK9 reduction = 70% Mean LDL-C reduction = 40% Effect duration ~ 30 days
32 normal volunteers received doses ranging from 0.015-0.400 mg/kg (#24) or normal saline (#8) via IV infusion over one hour
144 mg/dL
Fitgerald et al Lancet 2014; 383: 60-68
iRNA discovered in 1998Nobel Prize in 2006First POC study with siRNA
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Impact of mAb on LDL-C Homeostasis
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0
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0 500 1000 1500 2000 2500
Free/Total PCSK9
Con
c. (n
g/mL)
Total R
EGN727 (ng/mL) X
0.01
Time (hours)
Free PCSK9, Total REGN727/SAR236553 Concentration and Mean % Change LDL-C vs Time
Total REGN727/SAR236553
10 20 40 60 80 100
(days)
Unbound alirocumab concentration
ALIROCUMAB 150 mg SCDynamic Relationship Between mAb Levels, PCSK9 and LDL-C
Stein EA et al. NEJM 2012; 366: 1008-1118.
(days)
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Free/Total PCSK9
Con
c. (n
g/mL)
Total R
EGN727 (ng/mL) X
0.01
Time (hours)
Free PCSK9, Total REGN727/SAR236553 Concentration and Mean % Change LDL-C vs Time
free PCSK9
(days)
10 20 40 60 80 100
Unbound alirocumab concentrationStein EA et al. NEJM 2012; 366: 1008-1118.
ALIROCUMAB 150 mg SCDynamic Relationship Between mAb Levels, PCSK9 and LDL-C
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‐70
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‐10
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LDL‐‐C m
ean % cha
nge
Free/Total PCSK9
Con
c. (n
g/mL)
Total R
EGN727 (ng/mL) X
0.01
Time (hours)
Free PCSK9, Total REGN727/SAR236553 Concentration and Mean % Change LDL-C vs Time
Total REGN727/SAR236553 free PCSK9 LDL‐c
(days)
10 20 30 40 60 80 100
Unbound alirocumab concentration
Stein EA et al. NEJM 2012; 366: 1008-1118.
ALIROCUMAB 150 mg SCDynamic Relationship Between mAb Levels, PCSK9 and LDL-C
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Impact of Statin Therapy on PCSK9 & LDL-R
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Impact of Statin Therapy on PCSK9 Levels
PCSK9 Change
Atorvastatin 80 mg (1) +47%
Atorvastatin 40 mg (2) +34%
Rosuvastatin 20 mg (3) +28% (men)+35% (women)
Controls (4)
Statin therapyStain-ezetimibe therapyTitration of atorva 5 to 80 mg/dTitration of rosuva 5 to 40 mg/d
+45%+77%+30%+37%
1. Welder et al. J Lipid Res 2010; 51: 2714-27212. Careskey et al. J Lipid Res 2008; 49: 394-398
3. Awan et all. Clin Chem 2012; 58: 183-1894. Dubuc et al. J Lipid Res 2010; 51: 140-149
Statin
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Impact of mAb + Statin on LDL-C Homeostasis
x
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Mean % ∆ in LDL-C (Placebo Adjusted) from Baseline to Week 12 With PCSK9 mAb on a Stable Statin Dose
InterventionmAb added to stable atorvadose of 10-40 mg QD with LDL-C ≥ 100 mg/dL
n=183, Duration = 12 wks
% Change LDL-C
InterventionmAb added to stable statin and LDL-C > ~85 mg/dL
n=631, Duration = 12 wks
% Change LDL-C
Alirocumab 50 mg Q2W -35% Evolocumab 70 mg Q2W -42%
Alirocumab 100 mg Q2W -59% Evolocumab 105 mg Q2W -60%
Alirocumab 150 mg Q2W -67% Evolocumab 140 mg Q2W -66%
Alirocumab 200 mg Q4W -38%
Alirocumab 300 mg Q4W -43% Evolocumab 280 mg Q4W -42%
Evolocumab 350 mg Q4W -50%
Evolocumab 420 mg Q4W -50%
McKenney et al. JACC 2012;59 2344-2353 Giugliano et al. Lancet 2012; 380: 2007-17
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3
Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12 in the modified intent-to-treat (mITT) population, by treatment group. Week 12 estimation using LOCF method.
LDL‐C Mean % Cha
nge from
Baseline
-80
-70
-60
-50
-40
-30
-20
-10
0BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12
Placebo SAR 50mg Q2W SAR 100mg Q2W
SAR 200mg Q4W SAR 300mg Q4W SAR 150mg Q2W
∆ ‐ 64.2%
∆ ‐ 47.7%
∆ - 5.1%
∆ ‐ 39.6%
∆ ‐ 72.4%
∆ ‐ 43.2%
% LDL-C ∆ with Alirocumab Administered Q2W in nonFH Hypercholesterolemic Patients
McKenney et al. J Am Coll Cardiol 2012;59 2344-2353
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-40%
-50%
-60%
-70%
-80%
W 8 Wk 9 Wk 10 Wk 11 Wk12
-40%
-50%
-60%
-70%
-80%
-90%
∆ L
DL-
C
LDL-C Reduction with Evolocumab Dose Ranging Study From Week 8 to 12
Q4W
Q2W
Giugliano et al. Lancet 2012; 380: 2007-17
70 mg
105 mg
140 mg
280 mg420 mg350 mg
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Mean % ∆ in LDL-C From Baseline to End of Study With PCSK9 mAbs on a Stable Statin Dose
Intervention8 wks, n=92
Baseline LDL-C = 122 mg/dL
% Change LDL-C
Intervention52 wks, n=901
Baseline LDL-C = 104 mg/dL
% Change LDL-C
Atorvastatin 80 mg QD -17% Diet Evolocumab 420 mg Q4W -52%
Atorvstatin 10 mg QD + Alirocumab 150 mg Q2W -66% Atorvastatin 10 mg QD +
Evolocumab 420 mg Q4W -55%
Atorvastatin 80 mg QD + Alirocumab 150 mg Q2W -73% Atorvastatin 80 mg QD +
Evolocumab 420 mg Q4W -47%
Atorvastatin 80 mg QD +Ezetimibe 10 mg QD +Evolocumab 420 mg Q4W
-47%
Roth et al. NEJM 2012;367: 1891-1900 Blom et al. NEJM 2014; 370: online Mar 29, 14
Evolocumab was added to a stable diet or atorvastatin regimen (4 to 12 wks) in patients with LDL-C ≥ 75 mg/dL.
Alirocumab and atorva 80 uptitration was given to randomized patients who were receiving a stable atorva 10 mg QD regimen and had a LDL-C ≥ 100 mg/dL
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McKenney et al. J Am Coll Cardiol 2012;59 2344-2353
% C
hang
e fro
m B
asel
ine
to W
eek
12
10
0
-10
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-70
Apo B nonHDL-C Lp(a)
-2% -2%
-34%*
-56%*
-63%*
-0%
-13%†
-26%*-29%*-27%*
-48%*
-56%*
Placebo50 mg Q2W100 mg Q2W150 mg Q2W
1LS mean (SE)2median (Q1-Q3)* p < 00001† p = 0.0022
Changes in Apo B, nonHDL-C, and Lp(a) from Baseline to Week 12 with Alirocumab
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McKenney et al. J Am Coll Cardiol 2012;59 2344-2353
% C
hang
e fr
om B
asel
ine
to W
eek
12
1LS mean (SE)2median (Q1-Q3)* p < 0.05† p = 0.0006
10
0
-10
-20
-30
-40
-50
-60
-70
Trig2 HDL-C1 Apo A11
10%
-1%
7%* 4% 6%0% 1% 1%
-7% -6%
-19%†
0%
Placebo50 mg Q2W100 mg Q2W150 mg Q2W
Changes in Trig, HDL-C, and Apo A1 from Baseline to Week 12 with Alirocumab
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The Statin Intolerant Patient
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PCSK9 mAb in the Statin Intolerant Patient
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Mean % ∆ in LDL-C (Placebo Adjusted) from Baseline to Week 12 With PCSK9 mAb
InterventionIntolerance to one statin
mAb or Exe alone or in combination
n=160, Duration = 12 wks
% Change LDL-C
InterventionIntolerance to 2 statins
mAb alone Q2W or Q4W vs Eze
n=160, Duration = 12 wks
% Change LDL-C
Evolocumab 280 mg Q4W -41% Ezetimibe 10 mg qd -18%
Evolocumab 350 mg Q4W -43% Evolocumab 140 mg Q2W -56%
Evolocumab 420 mg Q4W -51% Ezetimibe 10 mg qd -15%
Evolocumab 420 mg Q4W
Ezetimibe 10 mg qd-63% Evolocumab 420 mg Q4W -53%
Exetimibe 10 mg qd -15%
Stokes et al JACC 2014, in pressSullivan et al JAMA 2012; 308: 2497-2506
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Impact of HeFH on LDL-C Homeostasis
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Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, 12 , 16 and 20 in the modified intent-to-treat (mITT) population, by treatment group. All patients receiving stable statin therapy
Mea
n (S
E) %
Cha
nge
in L
DL-
C f
rom
Bas
elin
e
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12 WEEK 16 WEEK 20
Placebo 150 mg Q4W 200 mg Q4W 300 mg Q4W 150 mg Q2W
Visit
-68%
-43%
-32%
-29%
-11%
FH Patient Profile (n=77) >70% on max dose statin >70% on ezetimibe Baseline LDL-C = ~155 mg/dL
Rx Results On-Rx LDL-C = ~ 50 mg/dL LDL-C < 100 = 97% LDL-C < 70 = 81%
Stein et al Lancet 2012; 380: 29-36
% ∆ LDL-C from Baseline to Wk 12 with Alirocumab in HeFH Patients
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Efficacy of LDL-C Reduction With PCSK9 mAb in FH and non-FH Patients Receiving Statin Therapy
McKenney et al. JACC 2012; 59: 2344-53Stein et al. Lancet 2012; 380: 29-36
Alirocumab 150 mg Q2W
non- FH -67.3%FH -57.3%
Evolocumab 420 mg Q4W
non-FH -50.3%FH -56.4%
Giugliano et al. Lancet 2012; 380: 2007-17 Raal et al. Circulation 2012; 126: 2408-2417
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Impact of HoFH on LDL-C Homeostasis
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% ∆ LDL-C
Evolocumab420 mg Q4W
% ∆ LDL-C
Evolocumab420 mg Q2W
All subjects (n=8) -16.5% -13.9%
Receptor defective (n=6) -22.9% -23.6%
Receptor negative (n=2) 2.6% 15.3%
Homozygous FH PatientsMean % in LDL-C from Baseline to Week 12 With Evolocumab
Stein et al. Circulation 2013; 128: 21123-2120
Patients
Mean age 34Receiving intensive statin + ezetimibe Rx
Mean Baseline LDL-C = 442 mg/dL (218-563)
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Phase III PCSK9 Development Plans
■ Familial hypercholesterolemia
■ Patients with high CVD risk and not at goal with statin Rx
■ Patients intolerant to statin therapy
■ Reduction of ASCVD events when added to a statin
Clintrials.gov (9/1/13)
Seeking indications for
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Conclusions
■ Having an understanding of the interplay between cholesterol synthesis, LDL-R, PCSK9, and LDL-C helps us interpret the efficacy results with anti-PCSK9 therapies.
■ The mAbs currently in development are highly effective at lowering LDL-C, up to 70% on top of statin therapy.
■ These mAbs have a similar efficacy in patients with non-FH and HeFH dyslipidemias
■ Significant reductions are achieved in apo B, nonHDL-C, triglycerides, and Lp(a) levels
■ PCSK9 mAbs appear to be safe and well tolerated
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Backup Slides
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Evolocumab EfficacyMean ∆ in LDL-C from Baseline to Week 12 on Stable Statin
Intervention Baseline LDL-C (mg/dL)
% Change LDL-C
Attained LDL-C (mg/dL)
Placebo 124
Evolocumab 70 mg Q2W 120 -42%* 73
Evolocumab 105 mg Q2W 128 -60%* 54
Evolocumab 140 mg Q2W 120 -66%* 45
Evolocumab 280 mg Q4W 124 -42%* 69
Evolocumab 350 mg Q4W 124 -50%* 60
Evolocumab 420 mg Q4W 120 -50%* 58n = 631* p < 0.0001 for % change in LDL-C vs placebo Giugliano et al. Lancet 2012; 380: 2007-17
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> 40 yo Hospitalization
with ACS in the past 4 months
Alirocumab SQ
Placebo SQ
Up to 64 months
Endpoint:First occurrence of:
CHD death, any non-fatal MI, fatal and non-fatal
ischemic stroke, UArequiring hospitalization
FOURIER
40 to 85 yo CV disease at high risk
for a recurrent event Fasting LDL-C ≥ 70 mg/dL
or non-HDL-C ≥ 100 mg/dL
Evolocumab SC Q2W or QM
Placebo SC Q2W or QM
60 months
Estimated completion:March 2018
Endpoint:Time to CV death, MI, hospitalization for UA,
stroke, or coronary revascularization
Estimated completion:February 2018
www.clinicaltrials.gov Nov 4, 2013
ODYSSEY Outcomes
Phase III PCSK9 Development Plans
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Efficacy of AliocumabReduction in LDL-C With 150 mg SQ Q2W
HeFH Non-FHnonFH –no statin
-55.7%-64.7%
-57.0%
Stein et al. NEJM 2012; 366: 1108-1118
Multiple Dose Study, phase I
n=8n=8n=5
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Dosing of Evolocumab
140 mg Q2W 420 mg Q4W
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►Week 8 Week 9 Week 10 Week 11 Week 12
►0
· 10 —
· 90
►—100 —it— 280 mg n = 25 n = 6 n = 25 n = 16 n = 26
—M— 350 mg n = 27 n = 10 n = 26 n = 18 n = 27
—A— 420 mg n = 27 n = 17 n = 26 n = 19 n = 28
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Week 8 Week 9 Week 10 Week 11 Week 12
10
· 90
—100
—•—• 70 mg n = 22 n=7 n = 23 n=16 n = 22
105 mg n = 25 n = 1 1 n = 28 n = 1 5 n = 28
140 mg n = 29 n = 16 n = 30 n = 20 n = 27
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-40%
-50%
-60%
-70%
-80%
W 8 Wk 9 Wk 10 Wk 11 Wk12
-40%
-50%
-60%
-70%
-80%
-90%
∆ LDL-C
LDL-C Reduction with Evolocumab Dose Ranging Study From Week 8 to 12