Industry Relationships and Institutional Affiliations Author - - PDF document

8/31/2014 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

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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

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

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;34:3478–90
• 2. Pijlman AH et al. Atherosclerosis. 2010;209(1):189-194.

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Clinicaltrials.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/8 week FU

Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC

(single 1-mL injection using prefilled pen for self-administration) Assessments W0 W8 W16 W36 W52 Double-Blind Treatment Period (78 Weeks)

Primary efficacy endpoint

W64 W4 W12 W24 W78

LDL-C ≥1.81 mmol/L [70 mg/dL] (history of CVD)

• r

2.59 mmol/L [100 mg/dL] (no history of CVD) Dose ↑ if LDL-C >70 mg/dL at W8 Pre-specified analysis Efficacy: All Patients To W52 Safety: Baseline-W78 (all patients at least W52)

Per-protocol dose ↑ possible based

• n pre-specified LDL-C level

ODYSSEY FH I and FH II Study Design

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All patients on background

• f max-tolerated statin ±
• ther 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) 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

• f >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

10 20 LS mean (SE) % change from baseline to Week 24 LS mean difference (SE)

• vs. placebo:

N=163 Alirocumab N=322

−57.9% (2.7) P<0.0001

N=81 N=166

−51.4% (3.4) P<0.0001

FH I

Placebo

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-C

All patients on background max-tolerated statin ±other lipid-lowering therapy

Intent-to-treat (ITT) Analysis

LDL-C, LS mean (SE), mmol/L 39 58 77 97 116 135 155 174

1 1.5 2 2.5 3 3.5 4 4.5 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) Analysis LLT = lipid-lowering therapy Dose ↑ if LDL-C >70 mg/dL at W8

8/31/2014 5 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% 10 20 30 40 50 60 70 80 90

P<0.0001

% patients

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 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) 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 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)

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)

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

20 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); Prediman Shah (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); Suat Simsek (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