What Role do the New PCSK9 Inhibitors Have in Lipid Lowering Treatment?

Transcription

1 What Role do the New PCSK9 Inhibitors Have in Lipid Lowering Treatment? Jennifer G. Robinson, MD, MPH Professor, Departments of Epidemiology & Medicine Director, Prevention Intervention Center University of Iowa Iowa City, Iowa

2 Disclosures Vice-Chair, 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease in Adults Member, 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk Received in the past year: Research grants to the institution: Amarin, Amgen, Astra-Zeneca, Eli Lilly, Esai, Glaxo-Smith Kline, Merck, Pfizer, Regeneron/Sanofi, Takeda Consultant : Akcea/Ionis, Amgen, Eli Lilly, Esperion, Merck, Pfizer, Regeneron/Sanofi

3 Proprotein Convertase Subtilisin-like/kexin type 9 (PCSK9) Targets the LDL-Receptor for Lysosomal Degradation LDL=low-density lipoprotein; LDL-R=LDL receptor; mab=monoclonal antibody; PCSK9=proprotein convertase subtilisin/kinexin type 9; SREBP-2=sterol regulatory element-binding protein-2. Adapted from: Catapano AL, Papadopoulos N. Atherosclerosis 2013;228:18 28.

4 PCSK9 Inhibitory Monoclonal Antibodies Increase LDL- Receptor Expression LDL=low-density lipoprotein; LDL-R=LDL receptor; mab=monoclonal antibody; PCSK9=proprotein convertase subtilisin/kinexin type 9; SREBP-2=sterol regulatory element-binding protein-2. Adapted from: Catapano AL, Papadopoulos N. Atherosclerosis 2013;228:18 28.

5 PCSK-9 Monoclonal Antibody (mab) Indications Alirocumab & Evolocumab Use as an adjunct to diet and maximally tolerated statin therapy in patients who require additional LDL-C lowering: Adults with heterozygous familial hypercholesterolemia Adults with clinical cardiovascular disease Evolocumab Patients with homozygous familial hypercholesterolemia on statins, ezetimibe, and/or LDL apheresis The FDA further noted as a limitation of use that the effect of alirocumab or evolocumab on cardiovascular morbidity and mortality has not yet been determined. Sanofi Aventis, Regeneron Pharmaceuticals Inc. Praluent (alirocumab injection) PI.. July Amgen. Repatha (evolocumab) injection PI. August

6 LDL-C lowering efficacy of PCSK-9 mabs Background statin therapy Alirocumab 75 mg q2w Alirocumab 75/150 mg q2w Alirocumab 150 mg q2w Evolocumab 140 mg q2w Evolocumab 420 mg q4w -48%-47% -46% -54% -63%-62% -61% -60% -63% -71% Heterozygous Familial Hypercholesterolemia Clinical ASCVD Alirocumab prescribing information, July Accessed 10/29/15. Evolovumab prescribing information, September pi.amgen.com/united_states/repatha/repatha_pi_hcp. Accessed 10/29/15; Kereiakes D, et al. Am J Cardiol 2015;169: ; Robinson JG, et al. NEJM 2015;372:

7 Achieved LDL-C with PCSK-9 mabs HeFH Added to background statin/lipid-lowering therapy ODYSSEY FH I & II Alirocumab 75/150 mg LDL-C % Statin/LLT+ Alirocumab Mean LDL-C mg/dl 69 mg/dl RUTHERFORD 2 - Evolocumab 140 mg q2w or 420 mg q4w LDL-C % Statin/LLT + Evolocumab Mean LDL-C mg/dl mg/dl High CV Risk Added to background statin therapy LAPLACE-2 Evolocumab: High risk LDL-C >70 mg/dl Randomized to moderate or high intensity statin Re-randomized to Evolocumab (140 mg q2w vs 420 q4w)or placebo X 12 weeks LDL-C % vs placebo Moderate intensity statin + Evolocumab Mean LDL-C mg/dl mg/dl High intensity statin + Evolocumab Mean LDL-C mg/dl mg/dl Robinson JG, et al. JAMA 2014; 311: ; Kastelein JJP, et al. Eur Heart J 2015; /eurheartj/ehv370; Raal et al. Lancet 2015; 385:

8 LDL-C lowering efficacy of PCSK-9 mabs Monotherapy Ezetimibe Alirocumab 75/150 mg Ezetimibe Evolocumab 140 mg q2w Evolocumab 420 mg q4w -20% -18% -53% -57% -56% Roth E,et al. Int J Cardiol, 2014; 176: Koren M, et al. J Am Coll Cardiol 2014; 63,

9 Effect on Other Blood Lipids and Proteins DESCARTES 52 weeks: Evolocumab 420 mg Q4W Percent change from baseline Baseline 38 nmol/l 87 mg/dl 124 mg/dl 20 mg/dl 177 mg/dl 105 mg/dl 53 mg/dl 152 mg/dl 1.0 mg/dl (median) (mean) (mean) (mean) (mean) (median) (mean) (mean) (median) Apo B=apoliporotein B; HDL-C=high-density lipoprotein cholesterol; hs-crp= high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; Lp(a)= lipoprotein(a); VLDL-C=very low density liporotein cholesterol. Blom DJ, et al. New Eng J Med. 2014; 370:

10 ODYSSEY LONG TERM Placebo vs Alirocumab 150 mg Q2W, 80 weeks Safety of PCSK9 mabs DESCARTES Placebo vs Evolocumab 420 mg, 52 weeks OSLER I & II Standard careevolocumab 420 mg Q4W or 140 mg Q2W, 11 months Injection site reactions 4.2% vs. 5.9%; P=0.10 Mylagia 2.9% vs. 5.4%; P=0.006 Neurocognitive AEs 0.5% vs 1.2%; P=0.17 Opthalmologic AEs 1.9% vs 2.9%; P=0.65 Post hoc CVD events 3.3% vs 1.7% HR 0.52 ( ;P=0.02) Adverse events Injection site reaction 5.0% vs 5.7% Mylagia 3.0% vs 4.0% URIs 6.3% vs 9.3% ALT > 3X ULN 1.0% vs 0.8% Injection site reactions NA vs 4.3% Muscle AEs 6.0% vs 6.4% Neurocognitive AEs 0.3% vs 0.9% Exploratory CVD events 2.18% vs 0.95% HR 0.47 ( ; p=0.003) AEs=adverse events; ALT=alanine aminotransferase; CVD=cardiovascular disease; HR=hazard ratio; Q2W=every 2 weeks; Q4W=every 4 weeks; SC=standard care; ULN=upper limit of normal; URIs=upper respiratory infections. Robinson JG, et al. N Engl J Med 2015;372: ; Blom DJ, et al. N Engl J Med 2014; 370: ; Sabatine MS, et al. N Engl J Med 2015;372:

11 PCSK9 mabs: Preliminary data - CVD event reduction ODYSSEY LONG TERM Alirocumab 150 mg q2w Mean 80 week follow-up OSLER Evolocumab 140 q2w/420 q4w Mean 11 month follow-up HR 0.52 (95% CI ) Nominal P =0.02 HR 0.47 (95% CI ) P=0.003 From N Engl J Med, Robinson JG et al, Efficacy and safety of alirocumab in reducing lipids and cardiovascular events, 372, From N Engl J Med, Sabatine MS et al, Efficacy and safety of evolocumab in reducing lipids and cardiovascular events, 372, CVD=cardiovascular disease; HR=hazard ratio; PCSK9=proprotein convertase subtilisin/kexin Type 9.

12 Magnitude of PCSK-9 mab CV Risk Reduction & Longer-term Safety Awaits CV Outcomes Trials Alirocumab ODYSSEY OUTCOMES N ACS 18,000 Min LDL-C (mg/dl) Evolocumab N 70 FOURIER CVD 27,500 Min LDL-C (mg/dl) Bococizumab N 70 SPIRE-1 SPIRE-2 CVD HR PP 12,000 CVD HR PP 6300 Min LDL-C (mg/dl) 70 & <100 >100 ClinicalTrials.gov. Accessed November 2015.

13 PCSK9 mabs in clinical practice

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15 2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD Risk Major recommendations for initiating statin therapy based on patient s level of RISK I A I A 4.9 mmol/l I B I A IIa B Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):

16 2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD Risk Major recommendations for initiating statin therapy based on patient s level of RISK (cont) I B I A IIa B IIb C IIa B Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):

17 2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD Risk Monitoring Therapeutic Response and Adherence Regularly measure lipid panel I A High intensity statin >50% LDL-C Mod intensity statin 30-<50% LDL-C * IIa B If baseline LDL-C unknown, may use LDL-C <100 mg/dl Nonstatins shown to reduce ASCVD events in RCTs preferred IIa B * * Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):

18 Nonstatins Shown to reduce CVD events added to background statin therapy Ezetimibe IMPROVE-IT 2015 PCSK9 monoclonal antibodies Preliminary ODYSSEY LONG TERM & OSLER CV outcomes RCTs pending Cannon, C.P., et al., NEJM (25): p ; Robinson, J.G., et al., NEJM (16): p Sabatine, M.S., et al., NEJM (16): p ;

19 Nonstatins Not clearly shown to reduce CVD events added to background moderate intensity statin therapy Niacin (harmful in diabetic subgroup) Fenofibrate (trend to benefit low HDL-C/high TG but harmful in women) The HPS2-THRIVE Collaborative Group, NEJM : p ; The ACCORD Study Group, N Engl J Med, : p ; The AIM-HIGH Investigators, N Engl J Med, : p

20 ACC nonstatin clinical pathway LDL-C thresholds for considering nonstatin therapy Lloyd-Jones D, et al. JACC 2016; 68:

21 ACC nonstatin clinical pathway - Clinical ASCVD with comorbidities (2) Lloyd-Jones D, et al. JACC 2016; 68:

22 How can patients be better identified for added nonstatin therapy? Robinson JG, et al. J Am Coll Cardiol 2016 in press

23 Ezetimibe, PCSK-9 mabs and the CTT Statin line JUPITER OSLER I & II ODYSSEY LONGTERM ODYSSEY pooled IMPROVE-IT ezetimibe hard CVD IMPROVE-IT ezetimibe major CVD CTT Collaboration. Lancet 2005; 366: ; Cannon CP, et al. NEJM 2015;372: ; Robinson JG, et al. NEJM 2015;372: ; Robinson JG, et al. AHA Scientific Sessions 2014, Chicago IL. Nov 2014; Sabatine MS, et al. NEJM 2015;372:

24 Very high risk groups >30% 10-year ASCVD risk ON statin therapy in RCTs Clinical ASCVD + Diabetes Clinical ASCVD + Chronic kidney disease Clinical ASCVD with poorly controlled risk factors Recent acute coronary syndrome (<3 months) Clinical ASCVD + primary LDL-C >190 mg/dl or familial hypercholesterolemia Clinical ASCVD with multiple recurrent events* Clinical ASCVD with elevated lipoprotein (a)* Robinson JG, et al. J Am Coll Cardiol 2016 in press; *Lloyd-Jones DL, et al. ACC expert nonstatin pathway. JACC 68:

25 Very high risk (>30% 10-year ASCVD risk) 5-year NNT to prevent 1 ASCVD event Initial LDL-C 190 mg/dl 160 mg/dl 130 mg/dl 100 mg/dl 70 mg/dl Ezetimibe LDL-C 20% PCSK9 mab LDL-C 50% Reasonable NNT thresholds: Physicians: NNT < 50 PCSK9 mab 65% Patients: NNT <30 Robinson JG, et al. J Am Coll Cardiol 2016 in press; Steel N. Br Med J 2000;

26 PCSK9 mabs Statin intolerant patients

27 Muscle symptoms in statin intolerant patients ODYSSEY ALTERNATIVE Alirocumab double-blind RCT 46% 41% 78% tolerated blinded atorvastatin 20 mg 33% 20% 22% 24% 98% 16% 8% tolerated open-label alirocumab 7% 2% Placebo Alirocumab Any musculoskeletal symptoms Moriarity PM, et al. J Clin Lipidol. 2015;9: Ezetimibe Atorvastatin 20 mg Open label Alirocumab Musculoskeletal symptoms leading to discontinuation

28 Muscle symptoms in statin intolerant patients GAUSS-3 Evolocumab double-blind RCT mean intolerant >2 statins Time to muscle symptoms resulting study drug discontinuation Phase A1: Nocebo effect Power of expectation Phase A2: 20% truly intolerant? Phase B: Ezetimibe 29% vs Evolocumab 21% DC due to intolerable muscle symptoms Nissen et al. JAMA 2016; 315(15):

29 Maximize statin therapy Same rate of muscle & other adverse events in statin trials Most patients with statin-related symptoms can tolerate blinded statin therapy Clinician needs to believe statins are safe and effective to convince the patient Statins reduce nonfatal & fatal coronary & stroke events Statins reduce total mortality in 1 & 2 prevention Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B): ; Nissen et al. JAMA 2016; 315(15): ; Moriarity PM, et al. J Clin Lipidol. 2015;9:758-69

30 Lower might be better It matters how you get there and in whom Robinson, J.G.. Eur Heart J (17): p