ODYSSEY FH I and FH II studies

Report
Efficacy and safety of alirocumab in patients with
heterozygous familial hypercholesterolaemia
(heFH) not adequately controlled with current lipidlowering 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
1
Industry Relationships and
Institutional Affiliations
2
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, BoehringerIngelheim, Genzyme, Kowa, Merck and Co, Novartis, Pfizer, Recordati, Roche, Sanofi-Aventis, and
SMB
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
1. Nordestgaard BG et al. Eur Heart J. 2013;34:3478–90
2. Pijlman AH et al. Atherosclerosis. 2010;209(1):189-194.
3
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
HeFH patients on
max tolerated statin
± other lipidlowering therapy
n=323 (FH I); n=167 (FH II)
LDL-C ≥1.81 mmol/L
[70 mg/dL]
(history of CVD)
or
2.59 mmol/L
[100 mg/dL]
(no history of CVD)
Assessments
Per-protocol dose ↑ possible based
on pre-specified LDL-C level
R
n=163 (FH I); n=82 (FH II)
Placebo Q2W SC
W0
W8
W4
W16
W12
Dose ↑ if
LDL-C >70 mg/dL
at W8
W36
W24
Primary
efficacy
endpoint
W64
W52
W78
Pre-specified analysis
Efficacy: All Patients To W52
Safety: Baseline-W78 (all patients at least W52)
Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT01623115; ODYSSEY FH II: NCT01709500.
4
OLE/8 week FU
(single 1-mL injection using prefilled pen for self-administration)
Baseline Characteristics
FH I
FH II
All patients on background
of max-tolerated statin ±
other lipid-lowering therapy
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)
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)
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)
34.1% (57)
29.3% (24)
9.6% (31)
15.3% (25)
4.2% (7)
3.7% (3)
Age, years, mean (SD)
BMI, kg/m2, mean (SD)
Type 2 diabetes, % (n)
†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.
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)
100%
100%
100%
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)
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)]
Any statin†, % (n)
LDL-C, mean (SD), mmol/L
[mg/dL]
†Patients
should receive either rosuvastatin 20-40 mg, atorvastatin 40-80 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 40-80 mg or rosuvastatin 20-40 mg daily.
6
Alirocumab Significantly Reduced LDL-C from
Baseline to Week 24 versus Placebo
Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C
LS mean (SE) % change from baseline
to Week 24
All patients on background max-tolerated statin ±other lipid-lowering therapy
7
FH I
20
9.1%
Alirocumab
FH II
10
Placebo
2.8%
0
-10
N=322
-20
N=163
N=166
43.4%
had dose
increase at
W12
-30
-40
N=81
38.6%
had dose
increase at
W12
-50
-48.7%
-48.8%
-60
LS mean
difference (SE)
vs. placebo:
Intent-to-treat (ITT) Analysis
−57.9% (2.7)
P<0.0001
−51.4% (3.4)
P<0.0001
Alirocumab Maintained Consistent LDL-C
Reductions Over 52 Weeks
Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ±Other LLT
FH I
Placebo:
FH I
Alirocumab:
FH II
FH II
4.0 mmol/L
4.0 mmol/L
4
155
3.5
3.7 mmol/L
3.5 mmol/L
3
135
116
2.5
97
1.9 mmol/L
1.8 mmol/L
77
2
1.5
1.8 mmol/L
1.7 mmol/L
58
39
1
0
4
8
12
16
20
Dose ↑ if LDL-C >70 mg/dL at W8
8
174
24
28
Week
32
36
40
44
48
52
Intent-to-treat (ITT) Analysis
LLT = lipid-lowering therapy
mg/dL
LDL-C, LS mean (SE), mmol/L
4.5
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
90
FH II
81.4%
80
Alirocumab
72.2%
70
% patients
Placebo
60
50
40
30
20
11.3%
10
2.4%
0
P<0.0001
†Very
9
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
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)
0
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)
9.0% (22)
0.2% (1)
1.2% (3)
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)
Neurocognitive disorders

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
10
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.
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
11
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.
Conclusions

In heFH patients not well controlled on maximallytolerated statin ± other lipid-lowering therapy:
– Self-administered alirocumab produced significantly greater
LDL-C ↓ vs. placebo at W24 (LS mean difference of 51.4-57.9%)
– Majority of pts (>70%) achieved their LDL-C goals at W24
– Mean achieved LDL-C levels of 1.7-1.9 mmol/L
(65.9-74.3 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
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Thank you to all principal investigators
and national coordinators!
Norway:
1 site
Canada:
5 sites
Denmark:
3 sites
Sweden:
2 sites
Netherlands:
8 sites
Austria:
3 sites
13 sites
UK:
4 sites
USA:
23 sites
1 site
Spain:
9 sites
Russia:
10 sites
2 sites
Czech Republic:
4 sites
6 sites
France:
4 sites
Israel:
4 sites
South Africa:
9 sites
FHI ‒ 89 sites worldwide
FHII – 26 sites worldwide
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