PCSK9 Inhibitors: Narnia vs. Medicare Bankruptcy Sergio Fazio, MD, PhD William and Sonja Connor Professor of Preventive Cardiology Professor of Medicine, Physiology & Pharmacology Director, Center for Preventive Cardiology Knight Cardiovascular Institute Oregon Health and Science University Portland, Oregon
2013: ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults Identified four groups of patients with most extensive evidence of benefit of statin therapy for ASCVD prevention 1. Individuals with clinical ASCVD 2. Individuals with primary elevations of LDL-C 190 mg/dl 3. Individuals 40-75 years of age with diabetes and LDL-C 70-189 mg/dl 4. Individuals without ASCVD or diabetes, 40-75 years of age, with LDL-C 70-189 mg/dl and an estimated 10-year ASCVD risk of 7.5% by the Pooled Risk Equations ACC = American College of Cardiology; AHA = American Heart Association; ASCVD = atherosclerotic cardiovascular disease. Stone NJ, et al. Circulation. 2014;129(25 Suppl2):S1-45; Goff DC, et al. Circulation. 2014;129(25 Suppl 2):S49-73.
High, Moderate, and Low-intensity Statin Therapy Used in Clinical Trials High-Intensity Statin Therapy Daily dose lowers LDL-C on average, by approximately 50% Moderate-Intensity Statin Therapy Daily dose lowers LDL-C on average, by approximately 30 to <50% Low-Intensity Statin Therapy Daily dose lowers LDL-C on average, by approximately <30% Atorvastatin 40*-80* mg Rosuvastatin 20*-40** mg Atorvastatin 10* (20**) mg Rosuvastatin (5**) 10* mg Simvastatin 20*-40* mg Pravastatin 40* (80**) mg Lovastatin 40* mg Fluvastatin XL 80** mg Fluvastatin 40 mg BID* Pitavastatin 2-4** mg *Statins demonstrated reduction in major CVD events *Statins **FDA demonstrated approved reduction doses in major not tested CVD events. in clinical trials **FDA approved doses not tested in clinical trials. FDA = Food and Drug Administration. Stone NJ, et al. Circulation. 2014;129(25 Suppl2):S1-45; Goff DC, et al. Circulation. 2014;129(25 Suppl 2):S49-73. Simvastatin 10** mg Pravastatin 10*-20* mg Lovastatin 20* mg Fluvastatin 20**-40** mg Pitavastatin 1** mg
Studies That Show The Superiority of High-Intensity, High-Dose Statin Make the Case For Value of Achieved LDL Level of <80 mg/dl More Than for Value of LDL Reduction of >50% H Bays. J ClinLipidol, 2015
Achieving Low Levels of LDL With High-Intensity Statin Is Hard TNT, IDEAL, SPARCL, JUPITER 13% >100 mg/dl 40% >70 mg/dl 78% >50 mg/dl On Treatment LDL Boekholdt et al. JACC, 2014
Achieved Low Levels of LDL Are Predictors of CVD Risk Reduction Boekholdt et al. JACC, 2014
Statin Rx at Discharge After MI in Sweden ButLDL <70 mg/dl -10 weeksaftermi achievedin only52% ofpatients Courtesy of Dr. Olov Wiklund
Lipid Modulating Agents Statins Niacin (Vitamin B3) Fibrates (PPARα agonists) Resins (BA-binding agents) Ezetimibe(Chol absorption inhib) Omega 3 fats PCSK9 inhibitors
Fibrates Reduce CHD Risk in Patients with HTG and Low HDL-C A meta-analysis of randomized fibrate trials Subjects without Dyslipidemia Study (treatment) OR (95% CI) ACCORD (simvastatin + fenofibrate) FIELD (fenofibrate) BIP (bezafibrate) HHS (gemfibrozil) VA-HIT (gemfibrozil) Subjects with Dyslipidemia Study (treatment) ACCORD (simvastatin + fenofibrate) FIELD (fenofibrate) BIP (bezafibrate) HHS (gemfibrozil) VA-HIT (gemfibrozil) OR (95% CI) TG 204 mg/dl, HDL-C 34mg/dL Sacks FM et al. N Engl J Med.2010;33:92-4.
AIM-HIGH Results Primary Outcome 1 o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.105/NEJMoa1107579.
JELIS: EPA Reduced Major Coronary Events* in Hypercholesterolemic Patients on Statins No. at Risk Control EPA Cumulative Incidence of Major Coronary Events (%) 4 3 2 1 0 0 1 2 3 4 5 Years 9319 8931 871 8433 8192 7958 932 8929 858 8389 8153 7924 Yokoyama M et al. Lancet. 2007;39:1090-8. Statin only Statin + EPA 1.8g/day HR (95% CI): 0.81 (0.9 0.95) P=0.011 19% N=18,45 Japanese pts with TC 251 mg/dl prior to baseline statin Rx. Baseline TG=153 mg/dl. Statin up-titrated to 20 mg pravastatin or 10 mg simvastatin for LDL-C control. *Primary endpoint: sudden cardiac death, fatal and non-fatal MI, unstable angina pectoris, angioplasty, stenting, or coronary artery bypass graft.
IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT): Design Patients stabilized post-acs 10 days LDL-C 125 mg/dl (or 100 mg/dl if prior statin) Double-blind N ~ 18,000 ASA + Standard Medical Therapy Simvastatin 40 mg* Ezetimibe/ Simvastatin 10/40 mg* Follow-up visit day 30, every 4 months *uptitrated to 80 mg if LDL-C > 79 mg/dl Duration: Minimum 2.5 year follow-up (5250 events) Primary Endpoint: CV death, MI, Hospitalization for UA, Revascularization (> 30 days after randomization), or Stroke New Engl J Med, June 3, 2015DOI: 10.105/NEJMoa1410489
IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT) Mean LDL-C (mg/dl) 100 90 80 70 0 50 40 Number at risk 1 yr mean LDL-C TC TG HDL-C hs-crp Simva 9.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dl -1.7-19.3-1.7 +0. -0.5 Time since randomization (months) QE R 1 4 8 12 1 24 3 48 0 72 84 9 Median Time avg 9.5 vs. 53.7 mg/dl Simva 9009 8921 830 7843 7289 939 07192 584 527 4395 3387 259 108 Ez/Simva 8990 88998230 7701724 84583 25 5734 5354 4508 3484 208 1078 New Engl J Med, June 3, 2015DOI: 10.105/NEJMoa1410489
IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT) Primary Endpoint - ITT Event Rate (%) 40 30 20 10 HR 0.93 CI (0.887, 0.988) p=0.01 Simva 34.7% 2742 events NNT = 50 EZ/Simva 32.7% 2572 events 7-year event rates 0 0 1 2 3 4 5 Time Since Randomization(years) 7 New Engl J Med, June 3, 2015DOI: 10.105/NEJMoa1410489
Percent Change in HDL-C and LDL-C HDL-C LDL-C 150 * 10 128.8 3.9 Percent Change (%) 120 90 0 30 0 * 53. * 94. Percent Change (%) 0-10 -20-30 -13. * -22.3 * -30-3.0 Placebo 30 mg 100 mg 500 mg -40 Placebo 30 mg 100 mg -35.9 * 500 mg Evacetrapib Evacetrapib *P<.001 compared with placebo. Nicholls SJ, et al. JAMA. 2011;30(19):2099-109.
Impact of a PCSK9 mab on LDL Receptor Expression Qian YW, et al. J Lipid Res. 2007;48(7):1488-1498; Horton JD, et al. J Lipid Res. 2009;50:S172-S177; Zhang DW, et al. J Biol Chem. 2007;282(55):1802-1812.
PCSK9 Loss-of-Function Mutations Resulted in Low LDL-C Levels and Reduced CHD Rates Wild-type PCSK9 degrades LDL receptoprs.1,2 Loss-of-function mutations increase hepatic LDL receptor expression, reducing LDL-C levels by 15%-40%. 2,3 CHD was reduced 47% to 88% in PCSK9 loss-offunction mutation carriers compared with normal individuals.3 CHD (%) 12 10 8 4 2 Black Subjects P=.008 9.7 1.2 White Subjects 11.8 P=.008.3 0 n=3278 n=85 n=9223 n=301 Normal Subject Mutation Carrier 1. Peterson AS, Fong LG, Young SG. J Lipid Res.2008;49(7):1595-1599. 2. Cohen J, et al. Nature Genetics. 2005;37(2):11-15. 3. Cohen JC, et al. N Engl J M ed. 200;354(12):124-1272.
Results: Single-Dose SQ Subcutaneous Administration Mean Change from Baseline in LDL Cholesterol (%) 20 10 0-10 -20-30 -40-50 -0-70 No. at Risk: Placebo 50 mg 100 mg 150 mg 250 mg Mean Percent Change from Baseline in LDL Cholesterol Values among Healthy Volunteers in Single-Dose Studies 124 81115 22 29 43 4 85 10 8 8 8 5 8 5 8 5 5 8 5 8 5 8 5 7 5 5 5 Study Day 7 4 7 5 5 Placebo 50 mg 100 mg 150 mg 250 mg Among subjects receiving increasing single doses of REGN727, values are shown for subcutaneous administration. LDL cholesterol values were calculated with the use of the Friedwald formula. The I bars indicate standard errors. Stein EA, et al. N Engl J Med. 2012;3(12):1108-1118.
Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 12 LDL-C Mean (±SE) % Change from Baseline Mean percentage change in calculated LDL-C from baseline to weeks 2, 4,, 8, 10, and 12 in the modified intent-to-treat (mitt) population, by treatment group. Week 12 estimation using LOCF method. 0-10 -20-30 -40-50 -0-70 -80 Baseline Week 2 Week 4 Week Week 8 Week 10 Week 12-8.5% -30.5% -53.% -2.9% -5.1% Placebo -39.% SAR23553 50 mg Q2W -4.2% SAR23553 100 mg Q2W -72.4% SAR23553 150 mg Q2W LOCF = last observation carried forward. McKenneyJM. A Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of a Monoclonal Antibody to ProproteinConvertaseSubtilisin/KexinType 9 Serine Protease, REGN727/SAR23553, in Patients with Primary Hypercholesterolemia(NCT: 01288443). American Cardiology Conference 2012, Chicago, IL.
Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 12 Mean percentage change in calculated LDL-C from baseline to weeks 2, 4,, 8, 10, and 12 in the modified intent-to-treat (mitt) population, by treatment group. Week 12 estimation using LOCF method. LDL-C Mean (±SE) % Change from Baseline 0-10 -20-30 -40-50 -0-70 -80 Baseline Week 2 Week 4 Week Week 8 Week 10 Week 12-5.1% Placebo -39.% SAR23553 50 mg Q2W -43.2% SAR23553 200 mg Q4W -47.7% SAR23553 300 mg Q4W -4.2% SAR23553 100 mg Q2W -72.4% SAR23553 150 mg Q2W McKenneyJM. A Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of a Monoclonal Antibody to ProproteinConvertaseSubtilisin/KexinType 9 Serine Protease, REGN727/SAR23553, in Patients with Primary Hypercholesterolemia(NCT: 01288443). American Cardiology Conference 2012, Chicago, IL.
Change in Lipids/Lipoproteins from Baseline to Week 8 LOCF 10 TC LDL-C Apo B non-hdl-c Lp (a) HDL-C Apo AI TG 0 Percent Change (%) -10-20 -30-40 -50-0 * * a b -70 * -80 Placebo + A80 mg SAR23553 + A10 mg SAR23553 + A80 mg Percent change from baseline median data are reported. Clinicaltrials.gov no. NCT0128849. *P<.001 vs Placebo + A80mg; P=.051 vs Placebo + A80mg; a P=.0003 vs Placebo + A80mg; b P<.05 vs Placebo + A80mg. McKenney JM. A Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease, REGN727/SAR23553, in Patients with Primary Hypercholesterolemia (NCT: 01288443). American Cardiology Conference 2012, Chicago, IL.
OSLER Trial: Effect of Evolocumab on LDL Cholesterol 140 Standard of care alone Median LDL-C(mg/dL) 120 100 80 0 40 20 1% reduction(95% CI 59%-3%), P<0.0001 Absolute reduction: 73 mg/dl(95% CI 71-7%) Evolocumab plus standard of care 0 Baseline (Parent study) N=445 4 weeks (OSLER) N=1258 12 weeks 24 weeks 3 weeks 48 weeks N=4259 N=4204 N=1243 N=3727 SabatineMS, et al. N EnglJ Med. 2015;372:1500-1509.
OSLER Trial: Effect of Evolocumab on Cardiovascular Outcomes 3 Composite Endpoint: Death, MI, UA hosp, coronary revasc, stroke, TIA, or CHF hosp Cumulative Incidence(%) 2 1 HR 0.47 95% CI 0.28-0.78 P=0.003 Standard of care alone (n=1489) 2.18% 0.95% Evolocumab plus standard of care (n=297) 0 30 0 90 120 150 180 210 240 270 300 330 35 Days Since Randomization TIA = transient ischemic attack; CHF = congestive heart failure; MI = myocardial infarction; UA = unstable angina. SabatineMS, et al. N EnglJ Med. 2015;372:1500-1509
Cardiovascular Outcomes Trials of PCSK9 Inhibitors Alirocumab Evolocumab Bococizumab Sponsor Sanofi/Regeneron Amgen Pfizer Trial ODYSSEY Outcomes FOURIER SPIRE I SPIRE II Sample Size 18,000 22,500 12,000 300 Patients 4-1 weeks post-acs MI, stroke, or PAD High risk of CV event Statin Evidence-based Rx Atorvastatin 20 mg or equivalent Lipid-lowering Rx LDL-C 70 mg/dl 70 mg/dl 70-99 mg/dl 100 mg/dl PCSK9i Dosing Endpoint Every 2 weeks Every 2 or Every 4 weeks Every 2 weeks CHD death, MI, ischemic stroke, or UA hospitalization Primary: CV death, MI, stroke, UA hospitalization or coronary revascularization Key Secondary: CV death, MI, or stroke CV death, MI, stroke, or urgent revascularization Completion March 2018 December 2017 August 2017
FDA Indications As adjunct to diet and maximally tolerated statin therapy for the treatment of adults not at LDL goal and with 1. heterozygous familial hypercholesterolemia or 2. clinical atherosclerotic cardiovascular disease Estimated US market size 1. Heterozygous familial hypercholesterolemia: 1 million people 2. Clinical atherosclerotic cardiovascular disease: 8 million people
Medication cost issues $14,00 per year If 25% of eligible patients are prescribed the medication, cost to insurances will be unsustainable EMA also approved the medication for use in Europe, but actual availability in member countries is decided based on cost Cost in Europe less than half compared with the US No real knowledge of cardiovascular benefits yet Assumptions of large effects based on preliminary studies Even so, cost per QALY considered way too high
Cost effectiveness and real use Predictions that guidelines will change again to make the market even larger
Cost effectiveness and real use To bring cost per QALY in the reasonable range (<$100K), cost of medication should be brought below $5500 per year. Real use of medication much slower than expected, with most recent data showing 15,000 prescriptions worldwide
Sergio Fazio, MD, PhD Bart Duell, MD Michael Shapiro, DO Jonathan Purnell, MD Tina Kaufman, PhD, PA-C Alissa Augustus, RN Tracy Severson, RD, LD
The KCVI Center for Preventive Cardiology Cardiac Rehab. Diagnostic laboratory for state-of-the-art risk assessment and novel biomarker testing. Genetic counseling and testing. LDL apheresis. Novel medications in clinical trials. Pediatric/Family management of dyslipidemia. Non-invasive imaging at controlled cost. Top prescribing center for PCSK9 agents in the Northwest.
The KCVI Experience 100+ prescriptions Coverage ranging from no copay to no coverage Only one approval without appeal (<1%) Donut hole problem with Medicare patients Excellent results with LDL (-40-70%) No obvious complaints (site of injection, memory)
Patients You May Consider Referring to Us The patient without obvious risk factors who needs additional lab and non-invasive testingbecause of significant family history. The high-risk patient who refuses or cannot tolerate statins. The diabetic patient with severe combined dyslipidemia not responding to statin only. The patient with LDL>200 despite therapy. The patient with TG>500 not responding to fibrates and fish oil. The patient with progressive CAD despite all parameters at goal. The patient with extremely low HDL (<20) The patient who needs a preventive visit that includes a session with our dietitian The patient who needs a PCSK9 inhibitor
Conclusion Guidelines endorse LDL lowering via use of statin Inability to reach LDL goal and statin intolerance make it necessary to consider combo therapy or non-statin therapy None of the non-statin drugs (including PCSK9 inhibitors) have indication for CVD prevention New PCSK9 agents reduce LDL by up to 5%but cost an arm and a leg Absence of CV benefit data makes it impossible to evaluate cost effectiveness, but it seems price should be adjusted down by a lot even with optimistic prediction of benefits This is turning out not to be a real problem, since prescriptions are coming in very slowly and for a tiny fraction of patients with indications