Efficacy and Safety of the PCSK9 Monoclonal Antibody Alirocumab versus Placebo in 1257 Patients with Heterozygous Familial Hypercholesterolaemia: Analyses up to 78 Weeks from Four ODYSSEY Trials John J.P. Kastelein 1 , Michel Farnier 2 , G. Kees Hovingh 1 , Gisle Langslet 3 , Marie T. Baccara-Dinet 4 , Daniel A. Gipe 5 , Umesh Chaudhari 6 , Jian Zhao 7 , Christelle Lorenzato 8 , Henry N. Ginsberg 9 1 Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Lipid Clinic, Point Médical, Dijon, France; 3 Lipid Clinic, Oslo University Hospital, Oslo, Norway; 4 Sanofi, Montpellier, France; 5 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 6 Sanofi, Bridgewater, NJ, USA; 7 Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 8 Sanofi, Paris, France; 9 Columbia University, New York, NY, USA This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Transcript
Efficacy and Safety of the PCSK9 Monoclonal Antibody Alirocumab versus Placebo in 1257
Patients with Heterozygous Familial Hypercholesterolaemia: Analyses up to 78 Weeks
from Four ODYSSEY Trials
John J.P. Kastelein1, Michel Farnier2, G. Kees Hovingh1, Gisle Langslet3, Marie T. Baccara-Dinet4, Daniel A. Gipe5, Umesh Chaudhari6, Jian Zhao7, Christelle Lorenzato8, Henry N. Ginsberg9
1Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Lipid Clinic, Point Médical, Dijon, France;
3Lipid Clinic, Oslo University Hospital, Oslo, Norway; 4Sanofi, Montpellier, France; 5Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 6Sanofi, Bridgewater, NJ, USA;
7Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 8Sanofi, Paris, France; 9Columbia University, New York, NY, USA
This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Author Disclosure
John J.P. Kastelein Honoraria from Dezima Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi, Eli Lilly, Pfizer, Amgen, Genzyme, Aegerion, Esperion, and Isis Pharmaceuticals, and consultant/advisory board fees from Dezima Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi, Eli Lilly, Pfizer, Amgen, Genzyme, Aegerion, Esperion, and Isis Pharmaceuticals.
Michel Farnier Received research support from Amgen, Merck, and Sanofi, speaker’s bureau fees from Amgen, Sanofi, and Merck, honoraria from Abbott, Eli Lilly, and Pfizer, and consultant/advisory board fees from AstraZeneca, Roche, Kowa, Recordati, SMB, Amgen, Sanofi, and Merck.
G. Kees Hovingh G.K. Hovingh’s institution has received payment for conducting clinical trials from Sanofi, Regeneron Pharmaceuticals, Inc., Amgen, Pfizer, Kowa, Genzyme, Isis Pharmaceuticals, Roche, Eli Lilly, Aegerion, Synageva, and AstraZeneca, and for lectures and/or advisory panel participation from Amgen, Sanofi, Pfizer, and Roche
Gisle Langslet Consultant/advisory board fees from Amgen, Sanofi-Aventis, and Janssen Pharmaceuticals
Marie T. Baccara-Dinet, Umesh Chaudhari, Christelle Lorenzato
Employees of and stockholders in Sanofi
Daniel A. Gipe, Jian Zhao
Employees of and/or stockholders in Regeneron Pharmaceuticals, Inc.
Henry N. Ginsberg Research support from Genzyme (Sanofi), Merck, and Sanofi-Regeneron, consultant on advisory boards for Merck, Sanofi, and Regeneron Pharmaceuticals, Inc., and consultant for Amarin, Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, ISIS, Kowa, Merck, Novartis, and Pfizer
Industry Relationships and Institutional Affiliations
2
HeFH is the most common autosomal dominant genetic dyslipidaemia disorder (estimated prevalence 1:200 to 1:500)1
Despite treatment with LDL-C-lowering therapies, many patients with HeFH do not achieve sufficient LDL-C reductions
– Only ~20% of patients with HeFH treated with LLTs reached a pre-defined LDL-C target level of ≤2.59 mmol/L (100 mg/dL)2,3
– An LDL-C target level of <1.8 mmol/L (70 mg/dL) has been recommended for patients with HeFH who are at very high CV risk4,5
Alirocumab is a fully human monoclonal antibody to PCSK9, which has shown significant LDL-C reductions in Phase 2 and 3 studies6–10
Background
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1. Nordestgaard BG et al. Eur Heart J. 2013;34:3478–90a; 2. Huijgen R et al. PLoS One. 2010;5:e9220; 3. Béliard S et al. Atherosclerosis. 2014;234:136–41; 4. Bays HE et al. J Clin Lipidol. 2014;8:S1–S36; 5. Reiner Z et al. Eur Heart J. 2011,32:1769–1818; 6. Koren MJ et al. Postgrad Med. 2015;127:125–32; 7. Roth EM et al. Int J Cardiol. 2014;176:55–61; 8. Cannon CP et al. Eur Heart J. 2015;36:1186–94; 9. Robinson JG et al. N Engl J Med. 6;372:1489–99; 10. Kereiakes DJ et al. Am Heart J. 2015;169:906–15. CV, cardiovascular; HeFH, heterozygous familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; PCSK9, proprotein convertase subtilisin/kexin type 9.
This analysis determined LDL-C-lowering efficacy and safety of alirocumab in 1257 patients with HeFH on maximally-tolerated statin
± other LLT from four 18-month placebo-controlled ODYSSEY studies
Efficacy and Safety Data Analysed from Four Phase 3 ODYSSEY Studies
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Control: placebo Q2W
FH I, 78 weeks (n=486)Alirocumab, n=323Placebo, n=163
FH II, 78 weeks (n=249)Alirocumab, n=167Placebo, n=82
3183 randomised patients with HeFH or high CV risk receiving stable maximally tolerated statin† ± other LLT
(2115 alirocumab, 1068 control)
Alirocumab 75/150 mg Q2W‡
Background statin
LONG TERM, 78 weeks (n=2341)Alirocumab, n=1553Placebo, n=788
HIGH FH, 78 weeks (n=107)Alirocumab, n=72Placebo, n=35
Primary endpoint in all studies: % change in calculated LDL-C from baseline to Week 24, analysed with an ITT approach§
Control: placebo Q2W
Alirocumab 150 mg Q2W
Patients with HeFH or high CV risk (n=2341) (LDL-C level
≥1.81 mmol/L [70 mg/dL])
Patients with HeFH (n=107)(LDL-C level ≥4.14 mmol/L
[160 mg/dL])
Patients with HeFH (n=735) (LDL-C levels ≥1.81/2.59 mmol/L [70/100 mg/dL], depending on CV
risk)
Patients with HeFH (n=415)Alirocumab, n=276 Placebo, n=139
†Rosuvastatin 20–40 mg, atorvastatin 40–80 mg, or simvastatin 80 mg daily, or lower doses with an investigator-documented reason e.g. intolerance; ‡Dose adjustment to 150 mg Q2W at Week 12 if LDL-C was not at a pre-defined target by Week 8; §Based on ITT analysis – ITT population, includes all lipid data throughout the duration of the study irrespective of adherence to the study treatment.ITT, intent-to-treat; Q2W, every 2 weeks. Figure shows randomised patient population.
Pool of FH I and II studies† Pool of LONG TERM (HeFH patients only) and HIGH FH
Alirocumab 75/150 mg Q2W
PlaceboAlirocumab 150 mg Q2W
Placebo
n 490 245 348 174
Age, years, mean (SD) 52.5 (12.9) 52.2 (12.4) 52.8 (11.8) 53.8 (11.3)
†75 mg Q2W increased to 150 mg Q2W at Week 12 if LDL-C levels at Week 8 were ≥1.81 mmol/L [70 mg/dL].‡Baseline values are means; Week 12 and Week 24 are LS means taken from mixed-effect model with repeated measures analysis. LS, least squares; SE, standard error. Figure shows ITT analysis performed on ITT population.
41.8%had dose
increase at Week 12
Week 12 Week 24 Week 24
All % changes P<0.0001 versus placebo
Baseline‡ 3.66
mmol/L
Week 12 change‡
-1.62 mmol/L
Baseline‡ 3.66
mmol/L
Week 24 change‡
-1.84 mmol/L
Week 12 change‡ +0.14 mmol/L
Baseline‡ 3.65 mmol/L
Week 24 change‡ +0.21 mmol/L
Baseline‡ 3.65 mmol/L
Baseline‡ 4.36
mmol/L
Week 24 change‡
-2.32 mmol/L
Week 24 change‡ -0.11 mmol/L
Baseline‡ 4.19 mmol/L
Alirocumab
Placebo
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Mean Calculated LDL-C Levels (mITT) Pool of FH I and II Studies (Alirocumab 75/150 mg Q2W)
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LS m
ean
LDL-
C le
vel
(SE
), m
mol
/L mg/dL
Study Week
ΔW24‡: -56.1 (2.1)%
†Alirocumab dose 75 mg Q2W increased to 150 mg Q2W in 41.8% of patients at Week 12 as their LDL-C levels at Week 8 were ≥1.81 mmol/L [70 mg/dL]; ‡ΔW24/52/78 defined as LS mean (SE) % difference versus placebo in calculated LDL-C from baseline to Week 24/52/78. Figure shows on-treatment analysis on modified ITT population, including all lipid data throughout the duration of study collected while the patients were still receiving study treatment.
ΔW52‡: -58.4 (2.5)%
ΔW78‡: -56.1 (2.6)%
Per-protocol Week 12 dose increase
(41.8%)
†
Mean Calculated LDL-C Levels (mITT) Pool of LONG TERM (HeFH Patients only) and HIGH FH (Alirocumab 150 mg Q2W)
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ΔW24†: -57.1 (2.4)%)
†ΔW24/52/78 defined as LS mean (SE) % difference versus placebo in calculated LDL-C from baseline to Week 24/52/78. Figure shows on-treatment analysis on modified ITT population, including all lipid data throughout the duration of study collected while the patients were still receiving study treatment.
LS m
ean
LDL-
C le
vel
(SE
), m
mol
/L
Study Week
ΔW52†: -60.1 (2.8)%
ΔW78†: -63.2 (2.8)%
All % changes P<0.0001 versus placebo
mg/dL
Secondary Efficacy Endpoints at Week 24 in Both Pooled Study Groups (ITT)
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Mea
n‡ (S
E)
% c
hang
e fr
om
base
line
to W
eek
24
ApoB Non-HDL-CLp(a)
All P<0.0001 versus placebo
ApoB Non-HDL-CLp(a)
†75 mg Q2W increased to 150 mg Q2W at W12 if LDL-C levels at Week 8 were ≥1.81 mmol/L [70 mg/dL]; ‡LS means for ApoB and non-HDL-C from mixed effects model with repeated measures; combined estimate for adjusted mean for Lp(a) analysed with multiple imputation followed by robust regression. Figures show ITT analyses performed on ITT populations.
Goal Attainment (ITT)Pool of FH I and II Studies (Alirocumab 75/150 mg Q2W)
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<70 mg/dL (1.81 mmol/L)
LDL-C ApoB
<80 mg/dL
Non-HDLC<100 mg/dL
(2.59 mmol/L)<130 mg/dL
(3.37 mmol/L)
All P<0.0001 versus placeboAlirocumab dose 75 mg Q2W increased to 150 mg Q2W in 41.8% of patients at Week 12 as their LDL-C levels at Week 8 were ≥1.81 mmol/L [70 mg/dL]; †Depending on CV risk; goals analysed using multiple imputation followed by logistic regression. Figure shows ITT analysis performed on ITT population.
<70/<100 mg/dL† (1.81 /2.59 mmol/L)
Alirocumab W12/W24
Placebo W12/W24
Baselinevalues
3.66 3.66 3.653.65mmol/L
3.66 3.66 3.653.65mmol/L
4.31 4.31 4.294.29mmol/L
4.31 4.31 4.294.29mmol/L
112 112 112112mg/dL
Goal Attainment (ITT)Pool of LONG TERM (HeFH Patients only) and HIGH FH (Alirocumab 150 mg Q2W)
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†Depending on CV risk; goals analysed using multiple imputation followed by logistic regression. Figure shows ITT analysis performed on ITT population.
<70 mg/dL (1.81 mmol/L)
LDL-C ApoB
<80 mg/dL
Non-HDLC<100 mg/dL
(2.59 mmol/L)<130 mg/dL
(3.37 mmol/L)<70/<100 mg/dL†
(1.81 /2.59 mmol/L)
Baselinevalues
4.194.36mmol/L
4.194.36mmol/L
5.06 4.90mmol/L
5.06 4.90mmol/L
123127mg/dL
All P<0.0001 versus placebo
Alirocumab
Placebo
Pooled Safety Data Included in Current Analysis (Pool of HeFH patients)
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Pool of HeFH patients (Pool of FH I and II, LONG TERM [HeFH patients only] and HIGH FH)
Alirocumab (n=837) Placebo (n=418)
TEAEs, n (%) 674 (80.5) 347 (83.0)
Treatment-emergent SAEs 114 (13.6) 55 (13.2)
TEAEs leading to death 7 (0.8) 2 (0.5)
TEAEs leading to discontinuation 33 (3.9) 15 (3.6)
Table shows safety analysis performed on safety population.SAE, serious adverse event; TEAE, treatment-emergent adverse event
Most Frequent TEAEs: Pool of HeFH PatientsTEAEs Recorded in ≥5% of Patients in Any Group
†Placebo-controlled studies: Phase 3 (LTS11717, FH I, FH II, HIGH FH, COMBO I), Phase 2 (DFI11565, DFI11566, CL-1003, DFI12361) Ezetimibe-controlled studies: Phase 3 (COMBO II, MONO, OPTIONS I, OPTIONS II, ALTERNATIVE). Includes all data collected to last patient visit at 52 weeks for COMBO, FH, HIGH FH and LONG TERM studies.‡Safety data pool includes alirocumab 75 mg Q2W and alirocumab 150 mg Q2W doses only.§Includes CHD death, non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalisation, and ischaemia-driven coronary revascularisation procedure. ‖Calculated using n values of 2318 for alirocumab and 1174 for placebo (excludes Phase 2). ALT, alanine aminotransferase; CMQ, custom MedDRA query; HLT, high-level term, PCSA, potentially clinically significant abnormalities; PT, preferred term; ULN, upper limit of normal. Table shows safety analysis performed on safety population.
This analysis represents the single largest collection of patients with HeFH (n=1257) included in a Phase 3 clinical study programme – In on-treatment analyses (using measurements that were
collected while patients were still receiving treatment), alirocumab reduced mean LDL-C levels to <2.2 mmol/L (85 mg/dL) at Weeks 24–78 of treatment, levels hitherto unobtainable with maximum doses of statin and addition of other LLTs in patients with HeFH
– The incidence of TEAEs was generally similar between alirocumab and control group patients
These findings hold potential for reducing LDL-C to levels that were previously unobtainable with existing currently standard-of-care therapy in patients with HeFH
Conclusions
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Results from ODYSSEY FH I and FH II are now Available in The European Heart Journal
