clinical trials for pcsk9 - lipid. mckenney is an employee of national clinical research which has...
TRANSCRIPT
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
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
The Interplay Between LDL-C, Hepatocyte Cholesterol Synthesis, LDL-R, and PCSK9
9am 12pm 3pm 6pm 9pm 12am 3am 6am 9am
% C
hang
e fro
m B
asel
ine
(PC
SK
9)
20
10
0
-10
-20
40
20
0
-20
-40 % C
hang
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ine
(Lat
host
erol
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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
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
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
Impact of mAb on LDL-C Homeostasis
0
20
40
60
80
100
120
140
160
180
200
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)
0
20
40
60
80
100
120
140
160
180
200
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
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
‐70
‐60
‐50
‐40
‐30
‐20
‐10
0
0
20
40
60
80
100
120
140
160
180
200
0 500 1000 1500 2000 2500
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
Impact of Statin Therapy on PCSK9 & LDL-R
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
Impact of mAb + Statin on LDL-C Homeostasis
x
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
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
-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
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
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
-20
-30
-40
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-60
-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
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
The Statin Intolerant Patient
PCSK9 mAb in the Statin Intolerant Patient
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
Impact of HeFH on LDL-C Homeostasis
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
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
Impact of HoFH on LDL-C Homeostasis
% ∆ 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)
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
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
Backup Slides
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
> 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
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
Dosing of Evolocumab
140 mg Q2W 420 mg Q4W
►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
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
-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