1 Treatment of severe Familial Hypercholesterolemia PCSK9 inhibitors 2 nd Severe FH Course: Recognize, Diagnose and Treat Severe Familial Hypercholesterolemia December 2-3, 2018 Muscat, Oman Dr. Khalid Al-Waili, MD, FRCPC, DABCL Senior Consultant Medical Biochemist & Lipidologist Sultan Qaboos University Hospital
2 Disclosures Received honorariums for giving lectures for AstraZeneca and Pfizer. Attended conferences sponsored by Sanofi Amgen, Pfizer and Abbott.
3 Background Cardiovascular Disease (CVD) remains the biggest killer worldwide Reducing levels of low-density lipoprotein (LDL) cholesterol is a cornerstone of the prevention of CVD. Despite the proven efficacy of statins in lowering CV events, many patients fail to reach recommended LDL-C goals
4 Putting Into Perspective the Hazards of Untreated Familial Hypercholesterolemia Paul N. Hopkins, J Am Heart Assoc. 2017;6:e006553
5 Are Statins Enough? Statins are effective, potent, inexpensive and generally well tolerated Residual Risk
6 Achieving LDL-c target with Statins 25 Percent (%) of subjects Residual Risk 19, ,2 13,3 8,2 8,3 5,6 3,2 3,2 1,7 2,1 1,4 0,1 0,5 Achieved LDL (mg/dl) Wiviott SD et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol Oct 18;46(8):1411-6
7 Perez de Isla et al. JACC VOL. 67, NO. 11, 2016 MARCH 22, 2016: The SAFEHEART Registry
8 Perez de Isla et al. JACC VOL. 67, NO. 11, 2016 MARCH 22, 2016: The SAFEHEART Registry
9 Perez de Isla et al. JACC VOL. 67, NO. 11, 2016 MARCH 22, 2016: The SAFEHEART Registry
10 PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) the 9th member of the proprotein convertase family of proteins that activate other proteins involved in the degradation of low-density lipoprotein (LDL) receptors in the liver.
11 The Role of PCSK9 in the Regulation of LDL Receptor Expression 1) Tibolla G et al. Nutr Metab Cardiovasc Dis 2011;21: ) Akram ON et al. Arterioscler Thromb VascBiol 2010;30: ) Duff CJ et al. Expert Opin Ther Targets 2011;15: ) Horton JD et al. J Lipid Res 2009;50 Suppl:S ) Cariou B et al. Atherosclerosis 2011;216:
16 PCSK9, LDL levels and coronary heart disease Risk of CHD low high PCSK9 LOF alleles PCSK9 GOF alleles 11. PCSK9 GOF alleles: increased LDL levels PCSK9 LOF alleles: decreased LDL levels PCSK9 LOF alleles: protect against CHD PCSK9 LOF alleles: no obvious adverse events 2006 low LDL levels high
17 PCSK9, LDL levels and coronary heart disease Risk of CHD low high PCSK9 LOF alleles PCSK9 GOF alleles 11. PCSK9 GOF alleles: increased LDL levels PCSK9 LOF alleles: decreased LDL levels PCSK9 LOF alleles: protect against CHD PCSK9 LOF alleles: no obvious adverse events Clinical trials: monoclonal antibody to PCSK low LDL levels high
18 Impact of a PCSK9 mab on LDL Receptor Expression 1) Tibolla G et al. Nutr Metab Cardiovasc Dis 2011;21: ) Akram ON et al. Arterioscler Thromb VascBiol 2010;30: ) Duff CJ et al. Expert Opin Ther Targets 2011;15: ) Horton JD et al. J Lipid Res 2009;50 Suppl:S ) Cariou B et al. Atherosclerosis 2011;216:
19 Impact of Statin Therapy on PCSK9 Levels 1. Welder et al. J Lipid Res 2010; 51: Careskey et al. J Lipid Res 2008; 49: Awan et all. Clin Chem 2012; 58: Dubuc et al. J Lipid Res 2010; 51:
20 Statins Also Upregulate the Expression of PCSK9 Statins SREBP2 PCSK9 LDLR LDL-C SREBP2 = sterol regulatory element-binding protein 2
21 PCSK9 inhibition with mabs in clinical trials reduces LDLC by 60% on top of standard therapy Alirocumab Evolocumab Robinson JG et al. N Engl J Med 2015;372: Sabatine MS et al. N Engl J Med 2015;372:
22 >70% decrease in LDL-C and % of patients reach predefined levels with150 mg Q2W + 80 mg atorvastatin % of LDL-C change % of patients at predefined LDL-C target Placebo + Atorvastatin 80 mg SAR mg Q2W + atorvastatin 10 mg (N=29) SAR mg Q2W + atorvastatin 80 mg (N=30) Placebo + A80 SAR A10 SAR A80 Mean Percent Change in LDL-C % 66.2% ,7 * * 17,2 96, % Baseline Week 2 Week 4 Week 6 Week 8 LOCF 0 LDL-C <100 mg/dl LDL-C <70 mg/dl SAR atorva 80 mg resulted in 73% reduction in mean LDL-C vs 17% for atorva 80 mg only SAR stable dose of atorva 10 mg resulted in 66% LDL-C reduction SAR was generally well tolerated p< vs Placebo + A80
23 Most hefh Patients Receiving Alirocumab on Background Statin Other LLT Achieved LDL-C Goals % patients % 2.4% P< % 11.3% 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 Proportion of patients reaching LDL-C goal at Week 24 FH I FH II Alirocumab Placebo
24 Most of These High CV-Risk Patients Receiving Alirocumab on Background Statin Achieved LDL-C Goal Proportion of Patients Reaching LDL-C <1.8 mmol/l (70 mg/dl) at Week 24 All patients on background of maximally-tolerated statin % Alirocumab % patients % Ezetimibe Intent-to-treat (ITT) analysis P<0.0001
25 Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia Undergoing Lipoprotein Apheresis: the ODYSSEY ESCAPE 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 manuscript This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. Moriarty PM et al. Eur Heart J (in press).
26 Pre-apheresis LDL-C Over Time Alirocumab 150 mg Q2W (n=41) Average LDL-C value (pre-apheresis), mean (SE), mmol/l 5,5 5 4,5 4 3,5 3 2,5 2 1,5 1 0, mg/dl 175 mg/dl Placebo (n=21) 185 mg/dl 90 mg/dl Week Apheresis rate varied from Week 7 onwards 191 mg/dl 110 mg/dl mg/dl LDL-C % change from baseline, LS mean (SE), %: Week 6 Week 18 Alirocumab (2.3) (4.7) Placebo 1.6 (3.1) 3.9 (6.3) p-value versus placebo < < Raw mean values are provided for baseline. SE, standard error. Moriarty PM et al. Eur Heart J (in press).
27 Time-Averaged Cholesterol Concentrations (Kroon Formula 1 ) Average LDL-C value (interval), mean, mmol/l Alirocumab 150 mg Q2W (n=41) Placebo (n=21) mg/dl Interval (weeks) Time-averaged concentrations are widely regarded to provide the best estimate of the physiologically effective plasma cholesterol concentrations during long-term treatment with lipoprotein apheresis. Data labels are expressed in both measurements. 1 Kroon AA et al. Atherosclerosis. 2000;152: Moriarty PM et al. Eur Heart J (in press).
28 Standardized Apheresis Treatment Rates from Week Alirocumab 150 mg Q2W (n=41) Placebo (n=21) % of patients ,4 33,3 28,6 23,8 17,1 12,2 14,3 2,4 2,4 2, >0 and 25% >25% to 50% >50% to 75% >75% to <100% 100% Standardized Apheresis Rate from Week 7 to Week 18 An apheresis rate of 0 indicates that the patient skipped all planned aphereses and an apheresis rate of 1 indicates that the patient received all planned aphereses; between Week 7 and Week 18 (apheresis rate of 0.75:, the patient received 75% of planned aphereses). Moriarty PM et al. Eur Heart J (in press).
29 Sabatine MS, et al. N Engl J Med Mar 17. [Epub ahead of print]
35 The ODYSSEY OUTCOMES Trial: Topline Results Alirocumab in Patients After Acute Coronary Syndrome Gregory G. Schwartz, Michael Szarek, Deepak L. Bhatt, Vera Bittner, Rafael Diaz, Jay Edelberg, Shaun G. Goodman, Corinne Hanotin, Robert Harrington, J. Wouter Jukema, Guillaume Lecorps, Angèle Moryusef, Robert Pordy, Matthew Roe, Harvey D. White, Andreas Zeiher, Ph. Gabriel Steg On behalf of the ODYSSEY OUTCOMES Investigators and Committees American College of Cardiology 67th Scientific Sessions March 10, 2018 ClinicalTrials.gov: NCT
36 ACC.18 Treatment Assignment Post-ACS patients (1 to 12 months) Run-in periodof2 16 w eeks on high-intensity or maximum-tolerated dose of atorvastatin or rosuvastatin At least one lipid entry criterion met Randomization Alirocumab SC Q2W Placebo SC Q2W Patient and investigators remained blinded to treatment and lipid levels for the entire duration of the study Schwartz GG, et al. Am Heart J 2014;168: e1. 11
37 ACC.18 LDL-C: ITT and On-Treatment Analyses Mean LDL-C (mg/dl) Placebo ITT On-treatment* Alirocumab ITT On-treatment* Months Since Randomization *Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo All LDL-C values, including those after premature treatment discontinuation, blinded down titration, or blinded switch to placebo 28
39 ACC.18 All-Cause Death ARR 0.6% HR 0.85 (95% CI 0.73, 0.98) P=0.026* *Nominal P-value Based on cumulative incidence 34
41 Priority Patient Groups for PCSK9 Inhibition Patients with clinical ASCVD and substantially elevated LDL-C levels. Patients should be on maximally tolerated statin therapy (ideally with concomitant ezetimibe), or unable to tolerate three or more statins. Familial hypercholesterolaemia (FH) patients without clinical ASCVD but with substantially elevated LDL-C levels Patients should be on maximally tolerated statin therapy plus ezetimibe Landmesser U et al. Eur Heart J 2017;
42 Patients with Clinical ASCVD : When to Consider a PCSK9 Inhibitor Two LDL-C thresholds: >3.6 mmol/l (>140 mg/dl) >2.6 mmol/l (>100 mg/dl) with additional indices of risk severity Landmesser U et al. Eur Heart J 2017;
43 Patients with FH: When to Consider a PCSK9 Inhibitor Two LDL-C thresholds: >4.5 mmol/l (>180 mg/dl) >3.6 mmol/l (>140 mg/dl) with additional indices of risk severity Landmesser U et al. Eur Heart J 2017;
44 Grundy SM, et al Cholesterol Clinical Practice Guidelines 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines
47 Recommended Use of PCSK9I s Based on current guidelines, available evidence, and economic considerations: Patients with FH or ASCVD and statin resistance (on max dose) for additional LDL lowering is a reasonable strategy. Discuss with patient costs vs clinical benefit In FH patients to avoid apheresis 2 nd line to addition of ezetimibe for statin intolerant patients No evidence to support use of PCSK9I s as monotherapy or for arbitrary reduction of statin dose In complete statin intolerance, PCSK9I monotherapy should be considered only after careful risk assessment and patient preference