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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

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John J.P. Kastelein,1 Henry N. Ginsberg,2 Gisle Langslet,3 G. KeesHovingh,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

Author Disclosure

John J.P. KasteleinConsultant/honoraria for Regeneron, Sanofi, Eli Lilly, Pfizer, Amgen, Isis, Genzyme, Aegerion and Esperion

Henry N. GinsbergResearch 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 HovinghKHs 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 KrempfGrants, consulting fees and/or honoraria and delivering lectures for Abbott, Amgen, Astra Zeneca, BMS, Merck and Co, Novartis, Pfizer, Roche, Sanofi-Aventis

Michel FarnierGrants, 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

Industry Relationships and Institutional Affiliations

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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

Heterozygous Familial Hypercholesterolaemia (heFH)

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1. Nordestgaard BG et al. Eur Heart J. 2013;34:3478–902. Pijlman AH et al. Atherosclerosis. 2010;209(1):189-194.

4Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT01623115; ODYSSEY FH II: NCT01709500.

Placebo Q2W SC

R

n=323 (FH I); n=167 (FH II)

n=163 (FH I); n=82 (FH II)

HeFH patients on max tolerated statin

± other lipid-lowering

therapy

OLE

/8w

eek

FU

Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC(single 1-mL injection using prefilled pen for self-administration)

AssessmentsW0 W8 W16 W36

W52

Double-Blind Treatment Period (78 Weeks)

Primaryefficacy endpoint

W64

W4 W12 W24 W78

LDL-C ≥1.81 mmol/L [70 mg/dL]

(history of CVD)

or

2.59 mmol/L [100 mg/dL]

(no history of CVD)

Dose ↑ if LDL-C >70 mg/dL

at W8

Pre-specified analysisEfficacy: All Patients To W52Safety: Baseline-W78 (all patients at least W52)

Per-protocol dose ↑ possible based on pre-specified LDL-C level

ODYSSEY FH I and FH II Study Design

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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)GenotypingClinical 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) 34.1% (57) 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.

Baseline Characteristics

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Any statin†, % (n) 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)

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)]

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)

†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.

Lipid Medication and LDL-C at Baseline

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Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo

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-48.8% -48.7%

9.1%

2.8%

-60

-50

-40

-30

-20

-10

0

10

20

LS

mea

n (

SE

) %

ch

ang

e fr

om

bas

elin

e to

Wee

k 24

LS mean difference (SE)

vs. placebo:

N=163

Alirocumab

N=322

−57.9% (2.7) P<0.0001

N=81N=166

−51.4% (3.4) P<0.0001

FH IPlacebo

FH II

43.4% had dose

increase at W12

38.6% had dose

increase at W12

Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-CAll patients on background max-tolerated statin ±other lipid-lowering therapy

Intent-to-treat (ITT) Analysis

LD

L-C

, LS

mea

n (

SE

), m

mo

l/L

39

58

77

97

116

135

155

174

1

1.5

2

2.5

3

3.5

4

4.5

0 4 8 12 16 20 24 28 32 36 40 44 48 52

3.5 mmol/L

1.8 mmol/L

3.7 mmol/L

1.9 mmol/L mg

/dL

1.8 mmol/L 1.7 mmol/L

4.0 mmol/L 4.0 mmol/L

Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks

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Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ±Other LLT

Placebo: FH I

FH II

Alirocumab: FH I

FH II

Week Intent-to-treat (ITT) AnalysisLLT = lipid-lowering therapy

Dose ↑ if LDL-C >70 mg/dL at W8

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Most heFH Patients Receiving Alirocumab on Background Statin Other LLT Achieved LDL-C Goals

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72.2%

81.4%

2.4%

11.3%

0

10

20

30

40

50

60

70

80

90

P<0.0001

% p

atie

nts

Placebo

†Very high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy.

Proportion of patients reaching LDL-C goal† at Week 24

FH I FH II

Alirocumab

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

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% (n) of patientsAll 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)

Neurocognitive disorders 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)

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.

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% (n) of patientsAll 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)

Safety AnalysisTEAEs 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)

Statistical analyses have not been performed.

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 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

Conclusions

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Thank you to all principal investigators and national coordinators!

Canada: 5 sites

USA: 23 sites

FHI ‒ 89 sites worldwide

FHII – 26 sites worldwide

Austria: 3 sites

Czech Republic: 4 sites

Denmark: 3 sites

France: 4 sites

Israel: 4 sites

Netherlands: 8 sites

Sweden: 2 sites

Russia: 10 sites

Spain: 9 sites

Norway: 1 site

South Africa: 9 sites

UK: 4 sites

2 sites

6 sites

13 sites

1 site

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FH I:Austria: Rudolf Prager (Wien); Hermann Toplak (Graz); Evelyn Fliesser-Goerzer (St Stefan)

Canada: Robert DuFour (Montreal, Quebec); Jean Bergeron (Sainte-Foy, Quebec); Daniel Gaudet (Montreal, Quebec); Patrice Perron (Sherbrooke, Quebec); Lawrence Leiter (Toronto, Ontario)

Czech Republic: Marketa Galovcova (Praha 4); Josef Machacek (Zlin); Jan Zeman (Praha 8); Stanislav Zemek (Uherské Hradiště)

Denmark: Erik Schmidt (Aalborg); Kristian Thomsen (Esbjerg); Pernille Correll(Roskilde)

France: Eric Bruckert (Paris); Michel Krempf (Saint-Herblain); Michel Farnier(Dijon); Gerald Luc (Lille)

Israel: Hofit Cohen (Tel-Hashomer); Dov Gavish (Holon); Osamah Hussein (Safed); Daniel Schurr (Jerusalem)

Netherlands: S.H.J. Donders (Groningen); G. Kees Hovingh (Amsterdam); P. Viergever (Den Helder); H.H. Vincent (Nieuwegein); A. Loualidi (Delfzijl); S.C.C. Hartong (Sliedrecht); A.A. Kroon (Maastricht); Jacqueline De Graaf (Nijmegen)

Norway: Anders Hovland (Bodo)

Russia: Evgenia Akatova (Moscow); Vadim Arkhipovsky (Arkhangelsk); Elena Demchenko (St. Petersburg); Victor Gurevich (St. Petersburg); Gadel Kamalov(Kazan); Anastasia Lebedeva (Moscow); Viacheslav Marasaev (Yaroslavl); Svetlana Mustafina (Novosibirsk); Andrey Susekov (Moscow)

Spain: Luis Alvarez-Sala (Madrid); Fernando Civeira (Zaragoza-Aragon); Jose Luis Diaz Diaz (La Coruna- Galicia); Nuria Plana Gil (Reus-Tarragona); Rodrigo Alonso (Madrid); Francisco Fuentes Jimenez (Cordoba); Xavier Pinto Sala (Barcelona); Emilio Ros (Barcelona); Jose Luis Mostaza Prieto (Madrid)

FH I contd.:South Africa: F.C.J. Bester (Bloemfontein);Dirk Blom(Cape Town); Lesley Burgess (Cape Town); Shaunagh Emanuel (Cape Town); Nyda Fourie (Bloemfontein); Maria Pretorius (Cape Town); Frederick Raal (Johannesburg); Prashilla Soma (Pretoria); Shirley Middlemost (Western Cape)

Sweden: A. Ohlsson-Önerud (Stockholm); Stefano Romeo (Goteborg)

United Kingdom: Graham Bayly (Bristol); Jacob George (Dundee); Basil Issa (Manchester); Gordon Ferns (Brighton)

United States: Thomas Barringer (Charlotte, NC); Robert Fishberg (Summit, NJ); Henry Ginsberg (New York, NY); Anne Goldberg (St Louis,MO); John Guyton (Durham,NC); LindaHemphill (Boston,MA); John Homan (Newport Beach, CA); Patrick Moriarty (Kansas City, KS); Galal Salem (Bell Gardens, CA); Erich Schramm (Ponte Vedra, FL); PredimanShah (Los Angeles, CA); Chad Wadell (Mission Viejo, CA); Ralph Wade (Bountiful, UT); Jonathan Purnell (Portland, OR); Robert Weiss (Lewiston, ME); Marina Cuchel (Philadelphia, PA); Emanuel Shaoulian (Newport Beach, CA); Robert Greenfield (Fountain Valley, CA); Traci Turner (Cincinnati, OH); Alan Brown (Oakbrook Terrace, IL); Jeffrey Geohas (Evanston, IL); Frederick Dunn (Dallas, TX)

FH II:Czech Republic: Richard Ceska (Praha 2); Vladmir Blaha (Hradec Kralove); Jana Cepova(Praha 5); Hana Halamkova (Vyskov); Lucie Solcova (Trutnov); Jana Jirouskova (Praha 8).

Netherlands: G. Kees Hovingh (Amsterdam); Stan Peter Janssen (Utrecht); H.W.O. Roeters van Lennep (Goes); Roel P.T. Troquay (Venlo); B.E. Groenemeijer (Apeldoorn); J.W. Hans Louwerenburg (Enschede); Marcel A. van de Ree (Utrecht); Adriaan Kooy (Hoogeveen); SuatSimsek (Alkmaar); Ben P.M. Imholz (Waalwijk); P.W. Kamphuisen (Groningen); Castro Cabezas (Rotterdam); Dick Basart (Hoorn).

Norway: Gisle Langslet (Oslo); Eli Heggen (Oslo).

UK: See Kwok (Manchester); D.D.R. Nair (London); Alan Rees (Cardiff); R.D.G. Neely (Newcastle upon Tyne); Elizabeth Hughes (West Bromwich).

Acknowledgments:Principal Investigators and National Coordinators