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Industry Relationships and Institutional Affiliations

Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolaemia ( h eFH ) not adequately controlled with current lipid-lowering therapy: Results of ODYSSEY FH I and FH II studies.

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Industry Relationships and Institutional Affiliations

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  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,6Fernando Civeira,7 Michel Krempf,8Michel 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 RecherchesCliniques 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 - HȏpitalNord Laennec, Saint-Herblain, France; 9Point Médical, Dijon, France

  2. Industry Relationships and Institutional Affiliations

  3. Heterozygous Familial Hypercholesterolaemia (heFH) NordestgaardBG et al. Eur Heart J. 2013;34:3478–90 PijlmanAH et al. Atherosclerosis. 2010;209(1):189-194. • 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 atherosclerosisand cardiovascular disease (CVD)1 • A large proportion (~80%) of adult patients with heFHon 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

  4. ODYSSEY FH I and FH II Study Design Double-Blind Treatment Period (78 Weeks) Alirocumab 75 mg Q2W SC with potential ↑to150 mg Q2W SC(single 1-mL injection using prefilled pen for self-administration) OLE/8 week FU HeFHpatients 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/dLat W8 Primary efficacy endpoint Pre-specified analysisEfficacy: All Patients To W52 Safety: Baseline-W78 (all patients at least W52) Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT01623115; ODYSSEY FH II: NCT01709500.

  5. Baseline Characteristics †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 †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.

  7. Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-CAll 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 FH I FH I Placebo: Alirocumab: FH II FH II 4.0 mmol/L 4.0 mmol/L 3.7 mmol/L mg/dL 3.5 mmol/L LDL-C, LS mean (SE), mmol/L 1.9 mmol/L 1.8 mmol/L 1.8 mmol/L 1.7 mmol/L Week Dose ↑ if LDL-C >70 mg/dLat W8 Intent-to-treat (ITT) Analysis LLT = lipid-lowering therapy

  9. 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. Safety Analysis (Pooled Data from FH I and FH II)All Data Collected Until Last Patient Visit at Week 52 • 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 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.

  12. Conclusions • In heFHpatients 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

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

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