Presented By Bobbie Theodore Alliance Director clinicaltrials@btheodore
Clinicaltrials no. NCT01288443
description
Transcript of Clinicaltrials no. NCT01288443
A Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Efficacy of a Monoclonal Antibody to PCSK9, SAR236553/REGN727, in Patients with Primary Hypercholesterolemia
James M. McKenney, PharmD,1 Michael J. Koren, MD, FACC,2 Dean J. Kereiakes, MD, FACC,3 Corinne Hanotin, MD,4
Anne-Catherine Ferrand,4 Evan A. Stein, MD, PhD5
1National Clinical Research-Richmond, Inc., Richmond, VA, USA; 2Jacksonville Center for Clinical Research, Jacksonville, FL, USA; 3The Carl and Edyth Lindner Center for Research and
Education at the Christ Hospital, Cincinnati, OH, USA; 4Sanofi, Paris, France; 5Metabolic and Atherosclerotic Research Center, Cincinnati, OH, USA.
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Clinicaltrials.gov no. NCT01288443
Industry Relationships and Institutional Affiliations
Author Disclosure
James M. McKenney Is an employee of a research company that has received research funding from Regeneron and/or SanofiMichael J. Koren
Dean J. Kereiakes Has no relationships to disclose
Corinne HanotinAre employees of Sanofi
Anne-Catherine Ferrand
Evan A. Stein Is an employee of a research company that has received research funding from Regeneron and/or Sanofi, as well as consultancy fees from Sanofi
LDL Receptor Function and Life Cycle
For illustration purposes only
The Role of PCSK9 in the Regulation
of LDL Receptor Expression
For illustration purposes only
Impact of an PCSK9 mAb
on LDL Receptor ExpressionFor illustration purposes only
Background and Rationale
Despite the widespread availability of statins, many patients fail to reach recommended LDL-C targets in clinical practice, even in combination with other lipid lowering agents
In PCSK9 human population studies:– Gain-of-function mutations result in hypercholesterolemia– Loss-of-function mutations associated with low LDL-C and low
prevalence of CHD events
SAR236553/REGN727 is a highly specific, fully human monoclonal antibody (mAb) to PCSK9
A SAR236553/REGN727 Phase 1 trial* in familial and non-familial hypercholesterolemia:– Demonstrated dose dependently reduced LDL-C by 36% to 58% either
with or without atorvastatin– Safe and well-tolerated
*Stein EA, Mellis S, Yancopoulos GD et al. NEJM 2012; 366: 1108-1118.
Study Design
LDL-C ≥ 100 mg/dL at Wk-1 while taking
atorva 10, 20, or 40 mg for ≥ 6wks
Placebo Q2W
W-7V1a
SAR236553 50mg Q2W
SAR236553 100mg Q2W
SAR236553 150mg Q2W
SAR236553 200mg Q4W w/alt placebo
SAR236553 300mg Q4W w/alt placebo
N=31
N=30
N=31
N=31
N=30
N=30
Diet*
*NCEP ATP-III TLC or equivalent diet
Treatment Period (12 weeks) Follow-up Period (8 weeks)
W-1V1
W0V2
W2V3
W4V4
W6V5
W8V6
W10V7
W12V8
W16V9
W20V10
Screening Period (7 weeks)
Primary Endpoint% calculated LDL-C
from baseline to week 12
Secondary Endpoints% in other
lipoproteins and apolipoproteins and % patients reaching pre-specified LDL-C
levels
Patient Disposition
Screening/run-in (n=514)
Randomized (n=183)
Safety population (n=182)
Efficacy population (mITT [LOCF]; n=179)
Dosing allocation
Analysis
Enrollment
Patient Demographic and Baseline Characteristics
Age, mean 57 years
Female 52%
White race 86%
Hispanic/ Latino ethnicity 22%
On lipid-lowering treatment 86%
Coronary artery disease 5%
Type 2 diabetes 12%
Peripheral vascular disease 3%
Hypertension 45%
Current smoker 20%
Intervention Baseline LDL-C (mg/dL)
% ChangeLDL-C1
Placebo 130.2 –5.1 (3.1)
SAR236553 50mg Q2W 123.2 –39.6 (3.2)*
SAR236553 100mg Q2W 127.0 –64.2 (3.1)*
SAR236553 150mg Q2W 123.9 –72.4 (3.2)*
SAR236553 200mg Q4W 128.2 –43.2 (3.3)*
SAR236553 300mg Q4W 131.6 –47.7 (3.2)*
Changes in LDL-C from Baseline to Week 12 by Treatment Group (mITT Population)
*P<0.0001 for % change SAR236553 vs. placebo1LS mean (SE), using LOCF method
BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12
-80
-70
-60
-50
-40
-30
-20
-10
0
Placebo SAR236553 50 mg Q2W SAR236553 100 mg Q2W SAR236553 150 mg Q2W
Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 12
11
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.
LD
L-C
Mea
n (S
E)
% C
ha
ng
e fr
om
Ba
seli
ne
∆ - 8.5%
∆ - 30.5%
∆ - 53.6%
∆ - 62.9%
∆ - 64.2%
∆ - 5.1%
∆ - 39.6%
∆ - 72.4%
Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 12
12
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.
LD
L-C
Mea
n (S
E)
% C
ha
ng
e fr
om
Ba
seli
ne
BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12
-80
-70
-60
-50
-40
-30
-20
-10
0
Placebo SAR236553 50 mg Q2W SAR236553 100 mg Q2W SAR236553 200 mg Q4W
SAR236553 300 mg Q4W SAR236553 150 mg Q2W
∆ - 64.2%
∆ - 47.7%
∆ - 5.1%
∆ - 39.6%
∆ - 72.4%
∆ - 43.2%
Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 12
13
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.
LD
L-C
Mea
n (S
E)
% C
ha
ng
e fr
om
Ba
seli
ne
BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12
-80
-70
-60
-50
-40
-30
-20
-10
0
Placebo SAR236553 50 mg Q2W SAR236553 100 mg Q2W SAR236553 200 mg Q4W
SAR236553 300 mg Q4W SAR236553 150 mg Q2W
∆ - 64.2%
∆ - 47.7%
∆ - 5.1%
∆ - 39.6%
∆ - 72.4%
∆ - 43.2%
16
93 97 100
8997
3
47
84
100
46
57
0
20
40
60
80
100
120
Placebo 50mg Q2W 100mg Q2W 150mg Q2W 200mg Q4W 300mg Q4W
% LDL-C <100mg/dL % LDL-C <70mg/dL
% P
atie
nts
Ach
ievi
ng
Pre
spe
cifi
ed L
DL
-C L
eve
lAttainment of Prespecified LDL-C Levels
at Week 12 (mITT Population)
Intervention % ChangeApo B
% ChangeNon–HDL-C
% ChangeLp (a)
Placebo 2.2 –2.2 0.0
SAR236553 50mg Q2W –27.3* –33.6* –13.3†
SAR236553 100mg Q2W –48.1* –55.6* –26.1*
SAR236553 150mg Q2W –56.1* –62.5* –28.6*
SAR236553 200mg Q4W –28.7* –37.4* –16.7†
SAR236553 300mg Q4W –33.1* –40.7* –7.9†
Changes in Apo B, Non–HDL-C and Lp (a) from Baseline to Week 12 by Treatment Group (mITT Population)
*P<0.0001 for % change SAR236553 vs. placebo†P=0.05 for % change SAR236553 vs. placebo P values are not adjusted for multiplicity (descriptive only)
Changes in TG, HDL-C, and Apo AI from Baseline to Week 12 by Treatment Group (mITT Population)
TG HDL-C Apo AI
-25
-20
-15
-10
-5
0
5
10
15
Placebo SAR236553 50mg Q2W SAR236553 100mg Q2W
SAR236553 150mg Q2W SAR236553 200mg Q4W SAR236553 300mg Q4W
% C
han
ge
fro
m B
asel
ine
at W
eek
12
1 2 1
1LS mean (SE)2median (Q1-Q3)
Summary of Treatment-Emergent Adverse Events (TEAEs) (Safety Population)
Q2W dosing Q4W dosing
Placebo (N=31)
50mg (N=30)
100mg (N=31)
150mg (N=31)
200mg (N=30)
300mg (N=30)
Overview of all TEAEs – no.
Any TEAE
14
18
20
19 20 14
Any treatment-emergent SAE
1
0
1
0 1 1
Any TEAE leading to permanent treatment d/c
0 0
1
1
3
1
AEs of special interest — no.
ALT or AST >3 x ULN 0 0 0 0 0 0
Muscle (including pain, weakness) 1 1 2 1 1 2
CK >10 x ULN 1 0 0 0 0 0
Injection-site reactions occurred in the SAR236553 groups only and were generally mild and non-progressive.
Serious Adverse Events
57-year-old male developed diarrhea followed by rash on his arms, legs, and abdomen 9 days after receiving his
first injection of SAR236553 300mg.
Leukocytoclastic vasculitis diagnosed by biopsy
Prednisone begun with full resolution
No organ involvement per signs and symptoms
No anti-drug antibodies 2 weeks before or after the incident
ANA, IgG, IgA, IgM, IgE, tryptase, anti-dsDNA, complement 5 WNL
Investigator considered this a “significant medical event” related to IP
SAR236553 produced significant, dose-dependent LDL-C reductions– Up to 72% LDL-C reduction with 150mg Q2W– Improved ability to achieve LDL-C goal cut points– LDL-C reductions were generally unaffected by baseline atorvastatin dose
Consistent and robust reductions for all other Apo B–containing lipoproteins – Important reduction in Lp (a), consistent with prior studies
Trend towards decreases in TG and increases in HDL-C and Apo AI vs placebo
More sustained efficacy with Q2W vs. Q4W regimen
SAR236553 was well tolerated during this short study– No signals for persistent or prevalent clinical or laboratory adverse events
including hepatic and muscle assessments.– One patient experienced an occurrence of leukocytoclastic vasculitis; no similar
reactions reported in prior studies
These results support further evaluation of SAR236553 in larger, more diverse patient populations with different background therapies to fully assess its efficacy and safety.
Summary and Conclusions
Q&A