CONFIDENTAIL & DRAFT PRESENTATION – PLEASE DO NOT DISTRIBUTE (DATA EMBARGOED FOR 08:00 AM CET ON MONDAY, AUGUST 29 Effect of alirocumab on the frequency of lipoprotein apheresis: A randomised Phase III trial Patrick M. Moriarty , 1 * Klaus G. Parhofer, 2 * Stephan P. Babirak, 3 Marc-Andre Cornier, 4 P. Barton Duell, 5 Bernd Hohenstein, 6 Josef Leebmann, 7 Wolfgang Ramlow, 8 Volker Schettler, 9 Vinaya Simha, 10 Elisabeth Steinhagen-Thiessen, 11 Paul D. Thompson, 12 Anja Vogt, 13 Berndt von Stritzky, 14 Yunling Du, 15 Garen Manvelian 16 1 Department of Internal Medicine, Division of Clinical Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA; 2 Medical Department II - Grosshadern, University of Munich, Munich, Germany; 3 Metabolic Leader, LLC, Scarborough, MA, USA; 4 Division of Endocrinology, Metabolism, and Diabetes, Anschutz Health and Wellness Centre, Anschutz Medical Campus, Aurora, CO, USA; 5 Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA; 6 Extracorporeal Treatment and Lipoprotein Apheresis Center, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; 7 Apherese Zentrum Passau, Passau, Germany; 8 Apheresis Center Rostock, Rostock, Germany; 9 Apheresis centre, Nehologisches Zentrum Göttingen GbR, Göttingen, Germany; 10 Mayo Clinic, Rochester, MN, USA; 11 Charite, Universitätsmedizin Berlin-Campus Virchow-Klinikum, Berlin, Germany; 12 Cardiology, Hartford Hospital, Hartford, CT, USA; 13 Medizinische Klinik und Poliklinik IV, LMU Klinikum der Universität München, Munich, Germany; 14 Medical Department, Sanofi-Aventis Deutschland GmbH, Berlin, Germany; 15 Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 16 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA *These joint authors contributed equally to this presentation This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
CONFIDENTAIL & DRAFT PRESENTATION – PLEASE DO NOT DISTRIBUTE (DATA EMBARGOED FOR 08:00 AM CET ON MONDAY, AUGUST 29 Industry Relationships and Institutional Affiliations Author Disclosure Patrick M. Moriarty Grants from Regeneron Pharmaceuticals Inc., Sanofi, Amgen, Ionis, Genzyme, Pfizer, Catabasis, Novartis and Kaneka; personal fees from Regeneron Pharmaceuticals Inc., Sanofi, Amgen, Ionis, Genzyme, Duke, Esperion, Eliaz Therapeutics, Alexion, Aegerion, Amarin and Lilly. Klaus G. Parhofer Grants from Sanofi and Regeneron Pharmaceuticals Inc.; personal fees from Sanofi and Regeneron Pharmaceuticals Inc., Sanofi-Aventis and Aegerion. Stephan P. Babirak Speaker/consultant honoraria from Sanofi; speaker honoraria from Amgen Marc-Andre Cornier Grants from Regeneron Pharmaceuticals Inc. P. Barton Duell Grants from Regeneron Pharmaceuticals Inc.; personal fees from Regeneron Pharmaceuticals Inc., Amgen and Kaneka. Bernd Hohenstein Grants from Kaneka Pharma Europe N.V., B. Braun Avitum and Novartis; personal fees from Amgen, Kaneka Pharma Europe N.V., Miltenyi Biotec GmbH, Fresenius Medical Care GmbH, B. Braun Avitum, Sanofi Aventis, Novartis and Alexion Pharma Josef Leebmann None. Wolfgang Ramlow Grants from Amgen, Fresenius and Kaneka; personal fees from Amgen, Fresenius, Kaneka, Aegerion. B. Braun, Merck Sharp & Dohme, Regeneron Pharmaceuticals Inc. and Sanofi. Volker Schettler Speaker honoraria from Sanofi-Aventis. Vinaya Simha None. Elisabeth Steinhagen-Thiessen None. Paul D. Thompson Grants, consultation and speaker honoraria from Regeneron Pharmaceuticals Inc., Sanofi and Amgen. Anja Vogt Compensation for trial activity, advisory board and speaking honoraria from Sanofi and Regeneron Pharmaceuticals, Inc. Berndt von Stritzky Employee of Sanofi. Yunling Du and Garen Manvelian Employees of and stockholders in Regeneron Pharmaceuticals, Inc. 2
CONFIDENTAIL & DRAFT PRESENTATION – PLEASE DO NOT DISTRIBUTE (DATA EMBARGOED FOR 08:00 AM CET ON MONDAY, AUGUST 29 Background – HeFH • The prevalence of HeFH is thought to be 1:200 to 1:500 1 – Untreated FH is associated with severely elevated LDL-C levels and a high risk for premature CHD 2 • Recent guidelines have recommended pharmacotherapy with statins ± other LLT, such as ezetimibe, bile acid sequestrants, and niacin 3,4 • Despite LDL-C-lowering drug therapy, many patients with FH do not reach their target LDL-C levels 5 – LDL-C treatment goals for patients with FH are <1.8 mmol/L (<70 mg/dL) in the presence of CHD and <2.6 mmol/L (<100 mg/dL) in those without CHD 2,4 1. Nordestgaard BG et al. Eur Heart J . 2013; 34:3478 – 3490; 2. Ito MK et al. J Clin Lipidol. 2011;5:S38 – S45; 3. Bays HE et al. J Clin Lipidol . 2014;8:S1 – S36; 4. Reiner Z et al. Eur Heart J . 2011; 32:1769 – 1818; 5. Huijgen et al. PLoS One . 2010;5:e9220; CHD, coronary heart disease; FH, familial hypercholesterolemia; He, heterozygous; LDL-C, low-density lipoprotein cholesterol; LLT; lipid-lowering therapies; PCSK9, proprotein convertase subtilisin kexin type 9; Q2W, every 2 weeks 3
CONFIDENTAIL & DRAFT PRESENTATION – PLEASE DO NOT DISTRIBUTE (DATA EMBARGOED FOR 08:00 AM CET ON MONDAY, AUGUST 29 Background – Apheresis • Lipoprotein apheresis may be considered for hypercholesterolemia inadequately controlled by maximally tolerated drug therapy 1,2 – However, the procedure is time-consuming (up to 4 hours), conducted weekly or every other week, costly, and can only be performed in highly specialized apheresis centres 2,3 – Lipoprotein apheresis can acutely reduce LDL-C and Lp(a) levels by 50 – 75% 4 Regeneration Re-priming Heparin pump solution solution Plasma separator LDL adsorption columns Blood return Plasma line Waste line 1. Jacobson TA et al. J Clin Lipidol. 2015;9:129 – 169; 2. Reiner Z et al. Eur Heart J . 2011; 32:1769 – 1818; 3. Bays HE et al. J Clin Lipidol . 2014;8:S1 – S36; 4. Nordestgaard BG et al. Eur Heart J . 2013; 34:3478 – 3490 Lp(a), lipoprotein (a) 4
CONFIDENTAIL & DRAFT PRESENTATION – PLEASE DO NOT DISTRIBUTE (DATA EMBARGOED FOR 08:00 AM CET ON MONDAY, AUGUST 29 Alirocumab ODYSSEY Phase 3 Programme • Alirocumab is a fully human monoclonal antibody to PCSK9 – In patients with and without HeFH, LDL-C levels were reduced by 44 – 48% (alirocumab 75 mg Q2W [with possible dose adjustment to 150 mg Q2W]) and 61% (alirocumab 150 mg Q2W) in Phase 3 studies as monotherapy or on background of statin ± other LLT 1 – 8 With background statin Without background statin ODYSSEY Alirocumab 75/150 mg Q2W OUTCOMES Control: ezetimibe COMBO II 1 OPTIONS I 2 OPTIONS II 3 ALTERNATIVE 4 MONO 5 Study 9 10 mg/day Control: placebo COMBO I 6 FH I 7 FH II 7 Alirocumab 150 mg Q2W Alirocumab 75 mg Q2W (with possible dose Control: placebo ESCAPE † LONG TERM 8 HIGH FH † adjustment to 150 mg Q2W) versus placebo Alirocumab 300 mg Q4W/150 mg Q2W Control: placebo CHOICE I † Alirocumab 150 mg Q4W/150 mg Q2W Control: placebo CHOICE II † † NCT numbers for studies not published yet: NCT01617655 (HIGH FH); NCT02326220 (ESCAPE); NCT01926782 (CHOICE I); NCT02023879 (CHOICE II). 1. Cannon CP et al. Eur Heart J . 2015; 36:1186 – 1194; 2. Bays et al. J Clin Endocrinol Metab . 2015; 100:3140 – 3148; 3. Farnier M et al. Atherosclerosis . 2016;244:138 – 146; 4. Moriarty PM et al. 2015 J Cin Lipidol . 2015;9:758 – 769; 5. Roth EM et al. Int J Cardiol . 2014;176:55 – 61; 6. Kereiakes DJ et al. Am Heart J 2015;169:906 – 915; 7. Kastelein JJ et al. Eur Heart J 2015;36:2996 – 3003; 8. Robinson JG et al . N Eng Med 2015;372:1489 – 1499; 9. Schwartz GG et al. Am Heart J . 2014;168:682 – 689 LLT; lipid-lowering therapies; PCSK9, proprotein convertase subtilisin kexin type 9; Q2W, every 2 weeks 5
CONFIDENTAIL & DRAFT PRESENTATION – PLEASE DO NOT DISTRIBUTE (DATA EMBARGOED FOR 08:00 AM CET ON MONDAY, AUGUST 29 ODYSSEY ESCAPE – Study Objectives • To evaluate the effect of alirocumab 150 mg Q2W on the frequency of lipoprotein apheresis treatments in patients with HeFH (comparator: placebo) – ≥30% reduction was chosen to present comparable exposure to LDL -C between apheresis procedures – Lipoprotein apheresis acutely lowers LDL-C levels by 50 – 75%, which translates to a time- averaged reduction of LDL-C that approximates 30% between the apheresis procedures • Primary efficacy endpoint: frequency of apheresis treatments over 12 weeks, normalised according to the number of planned apheresis treatments • Secondary endpoints: effect of alirocumab on other lipids, safety and tolerability of alirocumab and its effect on patient well-being 6
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