Evolving Concepts on Lipid Management from Ezetimibe (IMPROVE IT) to PCSK9 Inhibitors

Transcription

1 Evolving Concepts on Lipid Management from Ezetimibe (IMPROVE IT) to PCSK9 Inhibitors Sidney C. Smith, Jr. MD, FACC, FAHA, FESC Professor of Medicine/Cardiology University of North Carolina at Chapel Hill Nothing to Disclose

2 Institute of Medicine Report: Quality Chasm In its current form, habits, and environment, American health care is incapable of providing the public with the quality health care it expects and deserves. Design Rule 5: Current: Decision making is based on training and experience. New: Decision making is based on evidence. Patients should receive care based on the best available scientific knowledge. Care should not vary illogically form clinician to clinician or from place to place. Institute of Medicine, Crossing the Quality Chasm: A New Health System for the Twenty-first Century. Washington: National Academy Press, 2001

3 2013 ACC/AHA Guidelines for Treating Hypercholesterolemia ( Summary)

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5 Management Considerations

6 Non-Statin Therapy is Not First-Line but to be considered by Guidelines Use the maximum tolerated intensity of statin But consider adding non-statin drug therapy if: A less-than-anticipated therapeutic response persists ASCVD risk-reduction benefits outweigh the potential for adverse effects in higher-risk persons: Clinical ASCVD <75 years of age Baseline LDL C 190 mg/dl Diabetes mellitus 40 to 75 years of age Non-statin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs are preferred

7 Non Statin Therapy: IMPROVE-IT Study: Randomized Double Blind Controlled Trial for 6-7 yrs Population: High Risk Secondary Prevention (Acute Coronary Syndrome with One High Risk Feature) Intervention/Comparator Simvastatin 40 + Ezetemibe 10 mg / Simvastatin 40 + Placebo Outcomes: No effect on total mortality (not powered to do so) -reduced rate of ischemic stroke (RRR -21%) -reduced rate of MI (RRR -13%) -LDL-C lowered 69 to about 54 in intervention group -No safety signal of harm Cannon CP, Blazing MA, Gugliano RP et al. IMPROVE-IT Investigators. N Engl J Med Jun 18;372(25):

8 LDL-C and Lipid Changes in IMPROVE-IT 1 Yr Mean LDL-C TC TG HDL hscrp Simva EZ/Simva Δ in mg/dl IMPROVE-IT slide set with permission

9 Individual Cardiovascular Endpoints and CVD/MI/Stroke HR Simva* EZ/Simva* p-value All-cause death CVD CHD MI Stroke Ischemic stroke Cor revasc 30d UA CVD/MI/stroke Ezetimibe/Simva Better Simva Better *7-year event rates (%) IMPROVE-IT slide set with permission

10 IMPROVE-IT and ACC/AHA GLs IMPROVE-IT fits with 2013 ACC-AHA Guidelines Proves that moderate intensity statin therapy + ezetimibe safely reduces further rates of stroke & MI Does not include a high intensity statin arm. A high intensity statin lowering LDL-C 50% would have lowered LDL-C approximately the same or more than simvastatin 40 + ezetimibe 10 mg. Since ezetimibe proved to be safe and effective in a high risk group it would be the non-statin of choice if a high intensity statin could not be used or the response to a high intensity statin was not adequate

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12 IMPROVE-IT Considerations Adding ezetimibe most likely to benefit Very high risk CAD patient (eg diabetes)even if LDL-C 70 mg/dl High risk CAD patient who can t take high intensity statin High risk patient much higher LDL-C than seen in IMPROVE IT Adding ezetimibe to a statin might not benefit greatly High risk patient tolerating a high intensity statin whose LDL-C is mildly above the arbitrary 70 mg/dl cutoff (much higher NNT) Clinician-Patient risk discussion should be part of treatment decision Ref: Robinson JG, Stone NJ. Eur Heart J. 2015; 36(31):

13 IMPROVE-IT Study reaffirms central role of intensive LDL-C reduction to prevention of recurrent cardiac events (heart attack and stroke) Results expand the options for additional proven * lipid lowering therapies *Shown to add incremental benefit and are safe when taken as directed

14 Does This Change the Guidelines? No! 2013 ACC-AHA Guidelines recommended highintensity statin therapy for those with ACS, but expressly state: Clinicians treating high risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin or who are completely statin intolerant, may consider the addition of non-statin cholesterol lowering therapy

15 PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9)

16 PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) A. PCSK9 binds LDL receptor leads to LDL receptor degradation B. PCSK9 Inhibition restores LDL receptor to hepatocyte wall causing increased uptake of LDL - C

17 PCSK9 First Recognition of clinical association of gain of function mutation of PCSK9 gene with hypercholesterolemia in French family

18 Population Studies: PCSK9 Loss of Function Mutations Patients with loss-of-function mutations in PCSK9 or total lack of PCSK9 Have naturally low levels of LDL-C and reduced Coronary Heart Disease ( efficacy) Are not associated with other detectable abnormalities ( safety) PCSK9 Mutation LDL-C Reduction CHD Reduction Population Benn et al, JACC 2010 R46L 12% 46% 1) Copenhagen City Heart Study 2) Copenhagen General Population Study 3) Copenhagen Ischemic Heart Disease Study (DK) Cohen et al, NEJM 2006 R46L Y142X or C679X 14% 28% 47% 88% Atherosclerosis Risk Community Study (US) Benn, M. et al. J Am Coll Cardiol. 2010;55(25): ; Cohen, JC. et al. N Engl J Med. 2006;354(12):

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20 PCSK9 Inhibitors in Development Adapted from

21 Ongoing PCSK-9 Inhibitor Trials Swiger & Martin, Drug Saf (2015) 38:

22 Evolocumab vs Alirocumab: Who will be first in the $10 billion market?!

23 PCSK-9 Monoclonal Antibody (mab) Indications Approved by FDA 2015 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

24 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 Praluent prescribing information, July Accessed 10/29/15. Repatha 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:

25 Evolocumab: Changes in Other Lipids OSLER Trial - Koren MJ, et al. Circulation. 2014;129:

26 Achieved LDL-C with PCSK-9 mabs High 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 Percent reduction LDL-C 63-64% vs placebo Moderate intensity statin + Evolocumab Mean LDL-C mg/dl mg/dl High intensity statin + Evolocumab Mean LDL-C mg/dl mg/dl HeFH Added to background statin/lipid-lowering therapy ODYSSEY FH I & II Alirocumab 75/150 mg Percent reduction LDL-C 51-58% vs placebo LLT+ Alirocumab Mean LDL-C mg/dl 69 mg/dl RUTHERFORD 2 - Evolocumab 140 mg q2w or 420 mg q4w Percent reduction LDL-C 60-66% LLT + 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:

27 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,

28 Muscle symptoms in statin intolerant patients ODYSSEY ALTERNATIVE Alirocumab double-blind RCT Medical record documentation intolerant to 2 statins, including one at the lowest daily starting dose 33% 41% 46% 78% tolerated blinded atorvastatin 20 mg 8% 7% 16% 20% 22% 24% 98% tolerated open-label alirocumab 2% Placebo Alirocumab Ezetimibe Atorvastatin 20 mg Any musculoskeletal symptoms Musculoskeletal symptoms leading to discontinuation Open label Alirocumab Moriarity PM, et al. J Clin Lipidol 2015; /j.jacl

29 Safety of PCSK9 mabs ODYSSEY LONG TERM Alirocumab 150 mg Q2W vs placebo, 80 weeks (Placebo vs Alirocumab) 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 DESCARTES Evolocumab 420 mg Q4W vs placebo, 52 weeks (Placebo vs Evolocumab) 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% OSLER I & II Evolocumab 420 mg Q4W or 140 mg Q2W, patient preference vs standard care, 11 months (SC vs Evolucumab %) Injection site reactions NA vs 4.3% Muscle AEs 6.0% vs 6.4% Neurocognitive AEs 0.3% vs 0.9% Post hoc CVD events - 80 wks 3.3% vs 1.7% HR 0.52 ( ;P=0.02) Exploratory CVD events -1 yr 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:

30 PCSK9 mabs: Preliminary data CVD event reduction ODYSSEY LONG TERM - Alirocumab Mean 80 week follow-up OSLER - Evolocumab 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.

31 Ongoing PCSK-9 mab CV outcomes trials PCSK-9 mab vs placebo added to maximal lipid-lowering therapy Trial Population Lipid criteria N Completion FOURIER CVD+ Age y LDL-C >70 mg/dl or Non-HDL-C >100 mg/dl 27,500 (Feb 2018) ODYSSEY OUTCOMES ACS within 1 yr Age >40 y LDL-C >70 mg/dl or Non-HDL-C >100 mg/dl 18,000 Dec 2017 SPIRE-1 Very high risk with CVD or diabetes LDL-C 70 mg/dl and <100 mg/dl or Non-HDL-C >100 mg/dl and < 130 mg/dl 12,000 June 2018 SPIRE-2 Very high risk with CVD or diabetes LDL C 100 mg/dl or Non- HDL C 130 mg/dl 6,3000 March Accessed November Accessed November Accessed November Accessed November 2015

32 Ezetimibe, PCSK-9 mabs and the CTT statin line OSLER I & II mg/dl ODYSSEY LONGTERM mg/dl ODYSSEY pooled IMPROVE-IT mg/dl 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:

33 PCSK-9 Inhibitor Rx - Considerations Cost -Praluent (alirocumab) and Repatha (evolucumab) have been priced at $14,600 and $14,100 per year, respectively. Compliance with Injections good in RCTs need long term data on monthly or twice monthly injections Long-term safety No major problems, small neurocognitive signal, further information needed (FDA) on possible neurocognitive changes. Outcomes Key RCTs evaluating outcomes may not be available until 2018

34 Issues for Non-Evidence Based Therapy When it comes to unproven therapy, just because lower LDL-C is better does not mean that any cholesterol lowering agent will do. The guidelines recommend that a non-statin show incremental net benefit (safety and efficacy). These are important therapeutic tenets Recall that Torcetrapib, hormone replacement, niacin trials; all lowered LDL-C, but lower was not better for the patient.

35 N Engl J Med 2015;372: Adverse Events (OSLER)