1. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolaemia (heFH) not adequately controlled with current lipid-lowering therapy: Results of ODYSSEY FH I and FH II studies
John J.P. Kastelein,1 Henry N. Ginsberg,2 Gisle Langslet,3 G. Kees Hovingh,1 Richard Ceska,4 Robert Dufour,5 Dirk Blom,6 Fernando Civeira,7 Michel Krempf,8 Michel Farnier9
1Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Columbia University, New York, NY, USA; 3Lipid Clinic, Oslo University Hospital, Oslo, Norway; 4Center of Preventive Cardiology, 1st School of Medicine and University Hospital, Charles University, Prague, Czech Republic; 5Institut de Recherches Cliniques de Montréal, Montreal, Canada; 6Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group, Cape Town, South Africa; 7Lipid Unit, Hospital Universitario Miguel Servet, Zaragoza, Spain; 8CHU de Nantes - Hȏpital Nord Laennec, Saint-Herblain, France; 9Point Médical, Dijon, France

2. Industry Relationships and Institutional Affiliations
Author
Disclosure
John J.P. Kastelein
Consultant/honoraria for Regeneron, Sanofi, Eli Lilly, Pfizer, Amgen, Isis, Genzyme, Aegerion and Esperion
Henry N. Ginsberg
Research support from Genzyme (Sanofi) and Sanofi-Regeneron, is a consultant on an advisory board for Sanofi and Regeneron and is or has been a consultant for Amarin, Amgen, AstraZeneca, BristolMyersSquibb, GlaxoSmithKline, ISIS, Kowa, Merck, Novartis, and Pfizer
Gisle Langslet
Advisory board fees from Amgen, Sanofi-Aventis and Janssen Pharmaceuticals
G. Kees Hovingh
KHs institution has received payment for conducting clinical trials from Sanofi, Regeneron, Amgen, Pfizer, Kowa, Genzyme, ISIS, Genzyme, Roche, Ely Lilly, Aegerion, Synageva, AstraZeneca and for lectures and/or advisory panel participation of KH from Amgen, Sanofi, Pfizer and Roche
Richard Ceska
Consultant/honoraria for Regeneron, Sanofi, Amgen, Genzyme, Aegerion, Kowa
Robert Dufour
Received consultancy fees from Sanofi
Dirk Blom
Consultant or on an advisory panel for Aegerion, Amgen, AstraZeneca, MSD, and Sanofi Aventis. DB’s institution has received payment for conducting clinical trials from Aegerion, Amgen, Eli Lilly, Novartis, and Sanofi/Regeneron; DB has participated in a lecture/speaker’s bureau or received honoraria from Aegerion, Amgen, AstraZeneca, MSD, Pfizer, Sanofi Aventis, Servier, and Unilever
Fernando Civeira
Grants, consulting fees and/or honoraria from Amgen, Merck, Pfizer and Sanofi Aventis
Michel Krempf
Grants, consulting fees and/or honoraria and delivering lectures for Abbott, Amgen, Astra Zeneca, BMS, Merck and Co, Novartis, Pfizer, Roche, Sanofi-Aventis
Michel Farnier
Grants, consulting fees and/or honoraria and delivering lectures for Abbott, Amgen, Boehringer-Ingelheim, Genzyme, Kowa, Merck and Co, Novartis, Pfizer, Recordati, Roche, Sanofi-Aventis, and SMB

3. Heterozygous Familial Hypercholesterolaemia (heFH)
HeFH is one of the most common genetic diseases (prevalence 1/200 to 1/500) characterised by:
extremely high levels of low-density lipoprotein cholesterol (LDL-C)1
premature atherosclerosis and cardiovascular disease (CVD)1
A large proportion (~80%) of adult patients with heFH on lipid-lowering treatment do not reach the LDL-C goal of <2.5 mmol/L (100 mg/dL)2
The treatment goal for adult patients with heFH who also have coronary heart disease or diabetes is <1.8 mmol/L (70 mg/dL)1 
Nordestgaard BG et al. Eur Heart J. 2013;34:3478–90
Pijlman AH et al. Atherosclerosis. 2010;209(1):

4. ODYSSEY FH I and FH II Study Design
Double-Blind Treatment Period (78 Weeks)
Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC (single 1-mL injection using prefilled pen for self-administration)
OLE/8 week FU
HeFH patients on max tolerated statin ± other lipid-lowering therapy
n=323 (FH I); n=167 (FH II)
Per-protocol dose ↑ possible based on pre-specified LDL-C level R
LDL-C ≥1.81 mmol/L [70 mg/dL] (history of CVD) or
2.59 mmol/L [100 mg/dL] (no history of CVD)
n=163 (FH I); n=82 (FH II)
Placebo Q2W SC W0 W8
W16
W36
W64
Assessments W4
W12
W24
W52
W78
Dose ↑ if LDL-C >70 mg/dL at W8
Primary
efficacy endpoint
Pre-specified analysis Efficacy: All Patients To W52
Safety: Baseline-W78 (all patients at least W52)
Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT ; ODYSSEY FH II: NCT

5. Baseline Characteristics
All patients on background of max-tolerated statin ± other lipid-lowering therapy
FH I
FH II
Alirocumab (N=323)
Placebo (N=163)
Alirocumab (N=167)
Placebo (N=82)
Diagnosis of heFH†, % (n)
Genotyping
Clinical criteria
39.9% (129)
59.8% (193)‡
38.0% (62)
62.0% (101)
70.1% (117)
29.9% (50)
81.7% (67)
18.3% (15)
Age, years, mean (SD)
52.1 (12.9)
51.7 (12.3)
53.2 (12.9)
53.2 (12.5)
Male, % (n)
55.7% (180)
57.7% (94)
51.5% (86)
54.9% (45)
Race, white, % (n)
92.9% (300)
88.3% (144)
98.2% (164)
97.6% (80)
BMI, kg/m2, mean (SD)
29.0 (4.6)
30.0 (5.4)
28.6 (4.6)
27.7 (4.7)
CHD history, % (n)
45.5% (147)
47.9% (78)
34.1% (57)
37.8% (31)
Current smoker, % (n)
12.1% (39)
18.4% (30)
21.6% (36)
15.9% (13)
Hypertension, % (n)
43.0% (139)
43.6% (71)
29.3% (24)
Type 2 diabetes, % (n)
9.6% (31)
15.3% (25)
4.2% (7)
3.7% (3)
†Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score of >8 points.
‡In FH I, one patient was categorised as “probable” FH by clinical criteria – genotyping results for this patient are pending.

6. Lipid Medication and LDL-C at Baseline
All patients on background of max-tolerated statin ± other lipid-lowering therapy
FH I
FH II
Alirocumab (N=323)
Placebo (N=163)
Alirocumab
(N=167)
Placebo (N=82)
Any statin†, % (n)
100%
High-intensity statin‡, % (n)
80.8% (261)
82.8% (135)
86.2% (144)
87.8% (72)
Ezetimibe, % (n)
55.7% (180)
59.5% (97)
67.1% (112)
64.6% (53)
LDL-C, mean (SD), mmol/L [mg/dL]
3.7 (1.3) [144.7 (51.2)]
3.7 (1.2) [144.4 (46.8)]
3.5 (1.1) [134.6 (41.3)]
3.5 (1.1) [134.0 (41.6)]
†Patients should receive either rosuvastatin mg, atorvastatin mg daily, or simvastatin 80 mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the investigator.
‡High-intensity statin: atorvastatin mg or rosuvastatin mg daily.

7. Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo
Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background max-tolerated statin ±other lipid-lowering therapy
Alirocumab
FH I
FH II
Placebo
N=322
N=163
N=166
N=81
LS mean (SE) % change from baseline to Week 24
43.4% had dose increase at W12
38.6% had dose increase at W12
LS mean difference (SE) vs. placebo:
−57.9% (2.7) P<0.0001
−51.4% (3.4) P<0.0001
Intent-to-treat (ITT) Analysis

8. Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks
Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ±Other LLT
Placebo:
FH I
Alirocumab:
FH I
FH II
FH II
LDL-C, LS mean (SE), mmol/L
3.5 mmol/L
1.8 mmol/L
3.7 mmol/L
1.9 mmol/L
mg/dL
1.7 mmol/L
4.0 mmol/L
Dose ↑ if LDL-C >70 mg/dL at W8
Week
Intent-to-treat (ITT) Analysis
LLT = lipid-lowering therapy

9. Proportion of patients reaching LDL-C goal† at Week 24
Most heFH Patients Receiving Alirocumab on Background Statin  Other LLT Achieved LDL-C Goals
Proportion of patients reaching LDL-C goal† at Week 24
FH I
FH II
Alirocumab
Placebo
% patients
P<0.0001
†Very high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy.
Intent-to-treat (ITT) Analysis

10. Adverse Events of Interest
Safety Analysis (Pooled Data from FH I and FH II) All Data Collected Until Last Patient Visit at Week 52
% (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy
Alirocumab (N=489)
Placebo (N=244)
TEAEs
74.8% (366)
75.4% (184)
Treatment-emergent SAEs
10.0% (49)
9.0% (22)
TEAEs leading to death
0.8% (4)
TEAEs leading to discontinuation
3.1% (15)
3.7% (9)
Adverse Events of Interest
Adjudicated CV events†
1.6% (8)
1.2% (3)
Injection-site reactions
11.5% (56)
Neurocognitive disorders
0.2% (1)
ALT >3 x ULN
2.1% (10/488)
1.2% (3/244)
Creatine kinase >3 x ULN
3.5% (17/483)
6.2% (15/243)
4 TEAE-related deaths were all in alirocumab arm, 2 due to metastatic cancer (non-small cell lung and pancreatic), 2 due to MI (1 acute, 1 sudden cardiac death)
†Adjudicated CV events include all CV AEs positively adjudicated. The adjudication categories are the following: CHD death, non-fatal MI, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalisation, congestive heart failure requiring hospitalisation, ischaemia-driven revascularisation procedure (PCI, CABG).
Statistical analyses have not been performed.

11. Safety Analysis TEAEs Occurring in ≥5% of Either Alirocumab or Placebo Patients Collected Until Last Patient Visit at Week 52 (Pooled Data from FH I and FH II)
% (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy
Alirocumab (N=489)
Placebo (N=244)
Injection-site reaction
11.5% (56)
9.0% (22)
Nasopharyngitis
10.2% (50)
11.1% (27)
Influenza
8.8% (43)
6.1% (15)
Headache
5.5% (27)
6.6% (16)
Statistical analyses have not been performed.

12. Conclusions
In heFH patients not well controlled on maximally- tolerated statin ± other lipid-lowering therapy:
Self-administered alirocumab produced significantly greater LDL-C ↓ vs. placebo at W24 (LS mean difference of %)
Majority of pts (>70%) achieved their LDL-C goals at W24
Mean achieved LDL-C levels of mmol/L ( mg/dL) at W52 with alirocumab
~50% did not require a dose ↑ to alirocumab 150 mg Q2W
Safety and tolerability were generally comparable in alirocumab and placebo groups

13. Thank you to all principal investigators and national coordinators!
Norway: 1 site
Russia: 10 sites
Denmark: 3 sites
2 sites
Canada: 5 sites
Sweden: 2 sites
Netherlands: 8 sites
Austria: 3 sites
13 sites
UK: 4 sites
France: 4 sites
Czech Republic: 4 sites
USA: 23 sites
Spain: 9 sites
1 site
6 sites
Israel: 4 sites
South Africa: 9 sites
FHI ‒ 89 sites worldwide
FHII – 26 sites worldwide