of lipoprotein apheresis: A randomised Phase III trial Patrick M. - - PowerPoint PPT Presentation

Effect of alirocumab on the frequency

• f 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 Manvelian16

1Department of Internal Medicine, Division of Clinical Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA; 2Medical Department II - Grosshadern, University of Munich, Munich,

Germany; 3Metabolic Leader, LLC, Scarborough, MA, USA; 4Division of Endocrinology, Metabolism, and Diabetes, Anschutz Health and Wellness Centre, Anschutz Medical Campus, Aurora, CO, USA;

5Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA; 6Extracorporeal Treatment and Lipoprotein Apheresis Center, Department of Internal Medicine III, University

Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; 7Apherese Zentrum Passau, Passau, Germany; 8Apheresis Center Rostock, Rostock, Germany; 9Apheresis centre, Nehologisches Zentrum Göttingen GbR, Göttingen, Germany; 10Mayo Clinic, Rochester, MN, USA; 11Charite, Universitätsmedizin Berlin-Campus Virchow-Klinikum, Berlin, Germany; 12Cardiology, Hartford Hospital, Hartford, CT, USA; 13Medizinische Klinik und Poliklinik IV, LMU Klinikum der Universität München, Munich, Germany;

14Medical Department, Sanofi-Aventis Deutschland GmbH, Berlin, Germany; 15Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA; 16Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA

*These joint authors contributed equally to this presentation

This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.

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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.

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Background – HeFH

• The prevalence of HeFH is thought to be 1:200 to 1:5001

– Untreated FH is associated with severely elevated LDL-C levels and a high risk for premature CHD2

• Recent guidelines have recommended pharmacotherapy with statins ± other LLT, such as ezetimibe,

bile acid sequestrants, and niacin3,4

• Despite LDL-C-lowering drug therapy, many patients with FH do not

reach their target LDL-C levels5

– 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 CHD2,4

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• 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

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Background – Apheresis

• Lipoprotein apheresis may be considered for hypercholesterolemia inadequately

controlled by maximally tolerated drug therapy1,2

– 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 centres2,3 – Lipoprotein apheresis can acutely reduce LDL-C and Lp(a) levels by 50–75%4

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• 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)

Regeneration solution LDL adsorption columns Waste line Plasma line Blood return Plasma separator Heparin pump Re-priming solution

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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 LLT1–8

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Alirocumab 75/150 mg Q2W Alirocumab 150 mg Q2W Alirocumab 300 mg Q4W/150 mg Q2W Alirocumab 150 mg Q4W/150 mg Q2W Control: ezetimibe 10 mg/day Control: placebo Control: placebo Control: placebo Control: placebo

COMBO II1 OPTIONS I2 OPTIONS II3 COMBO I6 FH I7 FH II7 LONG TERM8 HIGH FH† ALTERNATIVE4 MONO5 Without background statin With background statin CHOICE I† 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

ESCAPE†

ODYSSEY OUTCOMES Study9

Alirocumab 75 mg Q2W (with possible dose adjustment to 150 mg Q2W) versus placebo

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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

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ESCAPE: Study Design

• Patients with HeFH were on stable background LLT and had undergone consistent lipoprotein

apheresis QW for ≥4 weeks or Q2W for ≥8 weeks (14 study sites in US and Germany)

7 Apheresis only performed if LDL-C <30% lower than baseline LDL-C (pre-apheresis LDL-C during regular apheresis)

FU 8 weeks/OLE

Screening (2 weeks)

W12

Alirocumab 150 mg Q2W (s.c.)

W-2

Double-blind treatment period (18 weeks) Alirocumab 150 mg Q2W (s.c.) Placebo Q2W (s.c.)

W9† W6 W4 W0 W1† W13† W2 W5† W7† W8 W10 W11† W3† W18 W16 W14 W17† W15† W26

Fixed apheresis frequency‡ Randomization

†Visits at these times are mandatory for patients undergoing apheresis QW, but not for patients undergoing apheresis Q2W; ‡Based on individual patient’s established schedule; OLE optional for patients in Germany

• nly; FU includes patients who chose not to enter the open-label extension study after the end of the double-blind treatment period, or who prematurely discontinued from study treatment

FU, follow-up; OLE, open-label extension; QW, weekly; Q2W, every 2 weeks; s.c., subcutaneous; W, week

Male and female patients ≥18 years of age with HeFH undergoing QW/Q2W lipoprotein apheresis therapy

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ESCAPE: Key Inclusion and Exclusion Criteria

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• 1. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991;303:893–896; 2. World Health Organization. Familial Hypercholesterolemia (FH). Report of a second WHO Consultation. 1998.

http://apps.who.int/iris/bitstream/10665/66346/1/WHO_HGN_FH_CONS_99.2.pdf. LLT, lipid-lowering therapy; WHO, World Health Organization

Inclusion criteria Diagnosis of HeFH by genotyping or clinical criteria (Simon Broome criteria1 or the WHO/Dutch Lipid Network criteria2) Stable lipoprotein apheresis QW for ≥4 weeks or Q2W for ≥8 weeks Background LLT, diet, and exercise level stable for ≥8 weeks Lipoprotein apheresis techniques: Double membrane filtration, immunoadsorption, heparin-induced LDL precipitation, direct adsorption of lipids, dextran sulfate adsorption (plasma), and dextran sulfate adsorption (whole blood) Exclusion criteria Diagnosis of HoFH Lipoprotein apheresis schedule other than QW and Q2W

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Patient Characteristics at Baseline

Alirocumab 150 mg Q2W (n=41) Placebo (n=21) Age, years, mean (SD) 59.5 (9.2) 57.0 (10.5) Male, % (n) 63.4 (26) 47.6 (10) Race, white, % (n) 95.1 (39) 100 (21) BMI, kg/m2, mean (SD) 30.5 (5.0) 30.3 (6.2) Country, % (n) Germany United States 48.8 (20) 51.2 (21) 47.6 (10) 52.4 (11) Frequency of apheresis, % (n) Weekly Every 2 weeks 43.9 (18) 56.1 (23) 42.9 (9) 57.1 (12) Coronary Heart Disease, % (n) 90.2 (37) 85.7 (18) Acute myocardial infarction 46.3 (19) 14.3 (3) Silent myocardial infarction 12.2 (5) 4.8 (1) Unstable angina 24.4 (10) 19.0 (4) Coronary revascularization procedure 85.4 (35) 66.7 (14) Other clinically significant CHD 41.5 (17) 33.3 (7) Background lipid-modifying therapy at randomization, % (n) Any statin Any LLT other than statins (with or without statin) 46.3 (9) 63.4 (26) 61.9 (13) 76.2 (16) LDL-C, mmol/L [mg/dL], mean (SD) 4.5 (1.4) [175.1 (54.6)] 5.0 (1.8) [191.6 (68.9)]

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BMI, body mass index; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; SD, standard deviation

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Standardized Apheresis Treatment Rates from Week 7–18

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†An apheresis rate of 0 indicates that the patient skipped all planned apheresis treatments and an apheresis rate of 1 indicates that the patient received all planned apheresis treatments between Week 7 and Week 18

(apheresis rate of 0.75:, the patient received 75% of planned apheresis treatments)

Hodges-Lehmann estimate of median treatment difference (95% CI): 0.75 (0.67 to 0.83) 0.50 (0.50 to 1.00) p-value versus placebo: p<0.0001 p<0.0001 Weeks 7–18 Weeks 15–18 Standardised apheresis treatment rate in the period: CONFIDENTAIL & DRAFT PRESENTATION – PLEASE DO NOT DISTRIBUTE (DATA EMBARGOED FOR 08:00 AM CET ON MONDAY, AUGUST 29

Time-Averaged Cholesterol Concentrations (Kroon Formula1)

Data labels are expressed in both measurements; 1Kroon AA et al. Atherosclerosis. 2000;152:519–526. LS, least squares

50 100 150 200 250 1 2 3 4 5 6 7 8–10 10–12 12–14 14–16 16–18 mg/dL Average LDL-C value, mean, mmol/L Interval (weeks) Alirocumab 150 mg Q2W (n=41) Placebo (n=21) 4.3/166.0 4.5/174.7 4.3/165.0 4.5/172.6 4.5/175.2 2.4/92.1 2.5/98.1 2.4/93.6 2.5/95.2 2.4/94.3 LDL-C % change from baseline (%), LS mean (SE): Week 6 Week 18 Alirocumab

• 53.7 (2.3)
• 42.5 (4.7)

Placebo 1.6 (3.1) 3.9 (6.3) p-value versus placebo <0.0001 <0.0001

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Safety: Treatment-Emergent Adverse Events

% (n) Alirocumab 150 mg Q2W (n=41) Placebo (n=21) Any TEAE 75.6 (31) 76.2 (16) Treatment emergent SAE 9.8 (4) 9.5 (2) TEAE leading to death TEAE leading to permanent treatment discontinuation 4.9 (2) 4.8 (1) TEAE of interest: Injection site reaction Pruritus 2.4 (1) 4.9 (2) 4.8 (1) TEAE occurring in ≥5% of patients Upper respiratory tract infection 7.3 (3) 19.0 (4) Fatigue 14.6 (6) 9.5 (2) Nausea 4.9 (2) 14.3 (3) Diarrhoea 9.8 (4) Myalgia 9.8 (4) 4.8 (1) Nasopharyngitis 9.8 (4) 9.5 (2) Arthralgia 7.3 (3) 9.5 (2) Back pain 4.9 (2) 9.5 (2) Palpitations 9.5 (2) Headache 7.3 (3) 4.8 (1)

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TEAE, treatment-emergent adverse event; SAE, serious adverse event

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Summary and Conclusions

• In ODYSSEY ESCAPE, alirocumab significantly reduced the frequency of lipoprotein

apheresis in patients with HeFH not achieving recommended LDL-C levels without this treatment

– Lipoprotein apheresis was discontinued in 63.4% of patients receiving alirocumab who were previously undergoing regular apheresis – The standardized rate was reduced by ≥50% in 92.7% of patients on alirocumab – At Weeks 6 and 18, alirocumab significantly reduced the levels of LDL-C, Apo B, non-HDL-C and Apo A1 versus placebo (p<0.0001)

• Alirocumab was generally safe and well tolerated
• Treatment with alirocumab 150 mg Q2W may allow patients with HeFH to

terminate or reduce the frequency of lipoprotein apheresis

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Results from ODYSSEY ESCAPE are now available in The European Heart Journal

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doi: xx.xxxx/eurheartj/xxxxxx eurheartj.oxfordjournals.org Authors: please note that this is a placeholder slide. We will receive a screenshot of the first page of the accepted paper from the European Heart Journal to include here.

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Q&A

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