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Evolocumab PCSK9 inhibitor
- 1. CV Benefits of Evolocumab (a PCSK9 Inhibitor) By: Sara Temkit
- 2. MOA of PCSK9 Inhibitor • mAb binds circulating PCSK9 and prevents degradation of LDLR • Increases LDLR, so they can clear blood LDL-C • 50-70% LDL reduction as monotherapy*
- 3. Background on PCSK9 Inhibitors • Carriers of PCSK9 loss of fxn allele - ↓MI • Indications: adjunct to diet and max. tolerated statin therapy* for pts with FH, or atherosclerotic vascular disease – to further ↓LDL • AE : nasopharyngitis, upper respiratory tract infection, influenza, back pain, myalgia, arthralgia, and injection-site reactions • Long-term concern: • New-onset diabetes • Neurocognitive effects Autoinjector – SC
- 4. History of Dyslipidemia Trials • PROVE-IT : high-dose statin ↓CV events and trend ↓ mortality in pts with established atherosclerotic diseases • IMPROVE-IT: addition of ezetimibe further reduces CV events by 2%*; mechanism: max LDL ↓ • DESCARTES and ODYSSEY LONG-TERM: PCSK9Is reduced LDL by an additional 60% in pts on mod-high intensity statin therapy • Need for a prospective randomized trial investigating whether this LDL reduction results in an improvement in CV outcomes was needed
- 5. FOURIER (Further CV Outcomes Research with PCSK9 in Subjects with Elevated Risk) Trail • Question: Does addition of evolocumab to mod-high intensity statin therapy ↓MCE in pts with artherosclerosis at high CV risk? Inclusion Criteria Exclusion Criteria Established arthrosclerosis: Angina/MI TIA Symptomatic PAD + High risk of CVD: Diabetes ≥65yr, HTN, HLD , active smoker FHx of CVD or Stroke* LVEF <30% Uncontrolled HTN Hyper/Hypothyroidism Severe renal or liver dysfunction CK>5 ULN Active malignancy/infection◊
- 6. FOURIER (Further CV Outcomes Research with PCSK9 in Subjects with Elevated Risk) Trail • Demographic: 63y, white, male, NA, MI • Method: • Randomized, double-blind, placebo-controlled trial (n=27,564) • ITT Analysis • Intervention: Evolucumab (140mg every 2 weeks OR 420 mg monthly)* OR placebo SC injection • Primary Outcome: Major CV events (CV death, MI, stroke, UA hospitalization, or coronary revascularization)
- 7. FOURIER Trial Results • Primary outcome of MCE • ↓nonfatal MI, stroke, coronary revascularization by 20% • NNT=75 over 2 yrs • Mean LDL:0.78* • Secondary Outcomes • No ↓ overall or CV mortality • CV death low (< 2%) in both grps • SE: injection-site reactions (2%) Months Incidence(%)
- 8. Strengths and Limitations of Fourier Trial • Strengths: Effect consistent across major subgroups • age, gender • type of atherosclerotic vascular disease • dosing regime • intensity of baseline statin use and baseline LDL • Limitations: • Mortality detection • Infection? Neurocognitive effects? • Funding: Amgen
- 10. References • Cannon C, Blazing M, Giugliano R, McCagg A, White J, Theroux P, Darius H, Lewis B, Ophuis T, Jukema J, De Ferrari G, Ruzyllo W, De Lucca P, Im K, Bohula E, Reist C, Wiviott S, Tershakovec A, Musliner T, Braunwald E, Califf R, IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015; 372:2387-97. • Cannon C, Braunwald E, McCabe C, Rader D Rouleau J, Belder R, Joyal S, Hill K, Pfeffer M, Skene A, Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. N Engl J Med. 2004; 350:1495-1504 • PCSK9 inhibitor monoclonal antibodies for the treatment of hypercholesterolemia. Ottawa: CADTH; 2015 Dec. (CADTH issues in emerging health technologies; issue 145). • Robinson JG, Farnier M, Krempf M,Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, Shahawy M, Koren MJ, Lepor NE,Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med. 2015; 372 (16): 1489-99. • Sabatine MS , Giugliano RP, Keech A, Honarpour, Wiviott S, Murphy S, Kuder J, Huei Wang MA, Liu T, Wasserman S, Sever P, Pedersen T, and FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Eng J Med. 2017; doi: 10.1056/NEJMoa1615664 • Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R , Legg J , Wasserman SM, Scott R , Koren MJ, and Stein EA. Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. New Eng J Med. 2015: 372 (16): 1500-9. • Todd A, Grégoire J, Pearson G, Barry A, Couture P, Dawes M, Francis G, Genest J, Grover S, Gupta M, Hegele R, Lau D, Leiter L, Lonn E, Mancini G, McPherson R, Ngui D, Poirier P, Sievenpiper J, Stone J, Thanassoulis G, Ward R. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can JCardiol. 2016; 32 (11): 1263-1282.
Editor's Notes
- PCSK9=proprotein convertase subtilisin/kexin type 9 PCSK9 is a protein that is produced in the hepatocyte and in the nucleus and then secreted into the extracellular space. What it does then is bind to the LDL receptor/LDL particle complex on the surface of the hepatocyte. That triad -- PCSK9, the LDL receptor, and LDL -- are then internalized via an endocytotic process into the hepatocyte. When PCSK9 is present in that complex, what ultimately happens is that the LDL receptor is subsequently targeted via the endosome to the lysosome for degradation. Hence, we lose the LDL receptor; it does not recirculate back to the liver. If there is no PCSK9 that is bound to that complex, then once it is internalized, the cholesterol is released, the LDL particle is released from the receptor, and the receptor recirculates back to the surface, where it can then attach to more LDL cholesterol and clear more LDL cholesterol from the circulation. We have known for a long time that after the initial starting dose of a statin, where you get most of the LDL cholesterol lowering, as you double the dose of statin, incrementally much lower reductions in LDL cholesterol are observed. What we understand now is that as you increase a statin dose, you actually also upregulate PCSK9 (by sterol regulatory binding proteins- that sense cholesterol levels) . *With statins, we get 20-60% reduction.
- Carriers of PCSK9 loss of fnx allele have lower LDL levels and reduced risk of MI Familial hypercholesterolemia, an autosomal co-dominant genetic disorder, is the most common form of familial hyperlipidemia and is characterized by very high plasma levels of LDL-C and the development of premature CV disease. For homozygous familial hypercholesterolemia- adjunct to any LDL lowering therapy (statin, ezetimibe) New-onset diabetes is theoretical risk (PCSK9 expressed in pancreatic islet cells) AEs occur in less than 5% of pts. Neurocognitive effects in ≤0.2% (Product Monograph) Autoinjector = single use, preservative free – stored in fridge (2-8C). Taken out, inject thigh, upper arm, stomach (15s)
- PROVE-IT – CV events reduced (14% UA and 29% need for revascularization) The subsequent IMPROVE –IT trial demonstrated that the addition of ezetimibe to statin therapy further reduces CV events in this population (non-fatal MI and stroke by 2%), suggesting that maximal LDL reduction is the key mechanism in improving outcomes in patients with established atherosclerotic disease. In trials DESCARTES and ODYSSEY LONG TERM (alirocumab), use of these agents was shown to reduce LDL by an additional 60% in patients on background moderate- or high-intensity statin therapy with very good tolerability. Exploratory analysis showed potential reduction in CV events (trials were not designed to address CV outcomes)
- MCE= Major CV events = cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization High intensity statin: Atorvastatin 40-80 mg (at lest 20 mg of Atorvastatin) rosuvastatin 20-40 mg Uncontorlled HTN: SBP>180, DSP>110 *1 of the following major risk factors ◊ Infection- nasopharyngitis, URTI, influenza, cough (common with Repatha) http://www.medscape.org/viewarticle/830954_2
- 81% of pts had Hx of MI , 20% stroke Multi-site RCT across 49 Countries *Choice of intervention: based on pt preference Randomization stratified by screening LDL < 85 vs. > 85
- http://www.onlinecjc.ca/article/S0828-282X(16)30732-2/pdf 15% reduction in major cardiovascular events (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) secondary endpoint: nonfatal MI, stroke, coronary revacularization (21-27% reduction) + Conclusion evolocumab in addition to moderate- or high-intensity statin therapy in patients with established atherosclerotic disease results in a modest reduction in CV events including MI and stroke although notably without a reduction in overall or CV-specific mortality *pts with artherosclerotic disease benefit from LDL lowering below current targets Mean LDL: 0.78 (↓59%). Statins alone reduced risk of UA and revascularization, addition of evolocumab enabled reduction in MI and stroke.
- Effects consistent actross Major subgroups: age, gender, type of artherosclerotic disease, dosing regime, baseline statin use, and baseline LDL Mortality detection: Median follow-up 26 months- limits detection of effect on CV events and mortality Very low CV mortality rates (< 2%) in both groups may result in underpowering to detect a mortality benefit with evolocumab Premature D/C in 12.5% of pts. Amgen: design and data collection
- http://www.onlinecjc.ca/article/S0828-282X(16)30732-2/pdf - ccs Algorithm Framingham risk score based on the patient’s age, sex, total cholesterol, HDL-C, blood pressure (treated or untreated), and smoking status. DM – pts ≥40 or T1 >30 for 15 or more yrs The effect of FOURIER on clinical practice remains to be seen, but given the significant cost of PSCK9 inhibitors ($7,263 per year) and lack of established mortality benefit, their routine addition to standard-of-care statin therapy in patients with established atherosclerosis is likely to be reserved (at least initially) for those perceived to be at particularly high risk for CV events, including patients with poorly controlled LDL levels despite maximally-tolerated statin therapy. Trials are underway for other PCSK9is (alirocumab and bococizumab). Results are anticipated in late 2017 OR early 2018.