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PCSK9 inhibitor (ALN-PCS)

Indications: - dyslipemia, with increased LDL cholesterol - may be used with statin - very high-risk of cardiovascular disease with multiple prior major cardiovascular events or a single such event plus multiple high-risk conditions when LDL choleseterol is >= 70 mg/dL on maximally tolerated statin + ezetimibe [10] - hypercholesterolemia regardless of 10-year cardiovascular risk if LDL >= 190 mg/dL & does not decrease to < 100 mg/dL on a high-intensity statin + ezetimibe [10] - statin intolerant, LDL cholesterol above goal, taking ezetimibe Benefit/risk: - statistically significant reduction in myocardial infarction in patients with hypercholesterolemia - reduction in mortality in patients with hypercholesterolemia - number needed to treat = 455 [5] - for secondary prevention of cardiovascular events, cost effectiveness ratio of $681,000/quality-adjusted life-year [7] (not cost-effective) - alirocumab added to statin after myocardial infarction not cost-effective [12] - PCSK9 inhibitor added to statin +/- ezetimibe of benefit vs placebo in high-risk patients [13] - data on PCSK9 inhibitors vs statins inconclusive [13] Dosage: - 0.40 mg/kg IV infusion (ALN-PCS) * MK-0616 is an investigational oral PCSK9 inhibitor [14] Adverse effects: - nasopharyngitis - injection site reactions - uncertain effects on cognitive function [8] - increased incidence of cataracts with LDL cholesterol < 25 mg/dL [8] Mechanism of action: - inhibits PCSK9 - decreases LDL cholesterol (50%) - inclisiran (ALN-PCS) has an siRNA-based action [3] - may reduce risk of cardiovascular events when used in combination with statin [4] Notes: - a single infusion of ALN-PCS (0.40 mg/kg IV), results in a 40% reduction of LDL cholesterol after 28 days [3] - annual cost (2015) = $14,000 [7] - cost-effectiveness in question [9]

Interactions

drug adverse effects (more general classes)

Related

proprotein convertase subtilisin/kexin type 9; neural apoptosis-regulated convertase 1; NARC-1; Proprotein convertase 9; PC9; subtilisin/kexin-like protease PC9 (PCSK9 NARC1 PSEC0052)

Specific

alirocumab (Praluent) bococizumab evolocumab (Repatha) inclisiran (Leqvio, ALN-PCS) monoclonal antibody AMG 145 monoclonal antibody SAR2365535

General

anti-hyperlipidemic agent enzyme inhibitor

References

  1. Roth EM et al Atorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia. N Engl J Med. Oct 31, 2012 PMID: 23113833 http://www.nejm.org/doi/full/10.1056/NEJMoa1201832
  2. Giugliano RP et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study The Lancet, Early Online Publication, 6 November 2012 PMID: 23141813 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61770-X/abstract - Koren MJ et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study The Lancet, Early Online Publication, 6 November 2012 PMID: 23141812 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61771-1/abstract - Tonkin AM and Watts GF Into the future: diversifying lipid management The Lancet, Early Online Publication, 6 November 2012 PMID: 23141810 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61888-1/fulltext
  3. Fitzgerald K et al Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. The Lancet, Early Online Publication, 3 October 2013 PMID: 24094767 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61914-5/abstract - Fitzgerald K, White S, Borodovsky A et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2016 Nov 13 PMID: 27959715 http://www.nejm.org/doi/10.1056/NEJMoa1609243
  4. Krumholz HM More Promising Results for PCSK9 Inhibitors. NEJM Journal Watch. March 15 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Robinson JG et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015 Mar 15; PMID: 25773378 http://www.nejm.org/doi/full/10.1056/NEJMoa1501031 - Sabatine MS et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015 Mar 15 PMID: 25773607 http://www.nejm.org/doi/full/10.1056/NEJMoa1500858 - Stone NJ and Lloyd-Jones DM. Lower LDL cholesterol is better, but it matters how you get there, and in whom. N Engl J Med 2015 Mar 15 PMID: 25773740 http://www.nejm.org/doi/full/10.1056/NEJMe1502192
  5. Navarese EP et al Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. Published online 28 April 2015 PMID: 25915661 http://annals.org/article.aspx?articleid=2279798 - Cainzos-Achirica M PCSK9 Inhibitors: A New Era in Lipid-Lowering Treatment? Ann Intern Med. Published online 28 April 2015 PMID: 25915768 http://annals.org/article.aspx?articleid=2279799
  6. Prescriber's Letter 22(8): 2015 PCSK9 Inhibitors for High Cholesterol Detail-Document#: 310813 http://www.prescribersletter.com (subscription needed)
  7. New England Comparative Effectiveness Public Advisory Council (CEPAC) PCSK9 Inhibitors for Treatment of High Cholesterol. http://cepac.icer-review.org/adaptations/cholesterol/ - Kazi DS, Moran AE, Coxson PG. Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease. JAMA. 2016;316(7):743-753 PMID: 27533159 http://jama.jamanetwork.com/article.aspx?articleid=2544639
  8. Khan AR, Bavishi C, Riaz H et al. Increased risk of adverse neurocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ Cardiovasc Qual Outcomes 2017 Jan; 10:e003153 PMID: 28073851 http://circoutcomes.ahajournals.org/content/10/1/e003153 - Everett BM Low-Density Lipoprotein Cholesterol and the On-Target Effects of Therapy. How Low Is Too Low? J Am Coll Cardiol 69(5) Feb 2017 PMID: 28153103
  9. Arrieta A, Hong JC, Khera R et al Updated Cost-effectiveness Assessments of PCSK9 Inhibitors From the Perspectives of the Health System and Private Payers. Insights Derived From the FOURIER Trial. JAMA Cardiol. Published online October 18, 2017. PMID: 29049467 https://jamanetwork.com/journals/jamacardiology/article-abstract/2657541 - Kazi DS, Lu CY, Lin GA et al Nationwide Coverage and Cost-Sharing for PCSK9 Inhibitors Among Medicare Part D Plans. JAMA Cardiol. 2017;2(10):1164-1166 PMID: 28903137 https://jamanetwork.com/journals/jamacardiology/article-abstract/2653354 - Mark DB, Richman I, Hlatky MA. Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy - Breakthrough in Low-Density Lipoprotein Cholesterol Lowering, Breakdown in Value. JAMA Cardiol. 2017;2(10):1066-1068 PMID: 28832860 https://jamanetwork.com/journals/jamacardiology/article-abstract/2649270 - Bonow RO, Harrington RA, Yancy CW Cost-effectiveness of PCSK9 Inhibitors. Proof in the Modeling. JAMA Cardiol. Published online October 18, 2017. PMID: 29049827 https://jamanetwork.com/journals/jamacardiology/article-abstract/2657544
  10. Phend C. AHA: Revised Lipid Guide Boosts PCSK9s, Coronary Calcium Scans. New recommendations aim to cut statins in low-risk primary prevention. Med Page Today. Nov 10, 2018 https://www.medpagetoday.com/meetingcoverage/aha/76250 - Grundy SM, Stone NJ, Bailey AL et al 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. J Am Coll Cardiol. 2018 Nov 8. pii: S0735-1097(18)39034-X. PMID: 30423393 - Lloyd-Jones DM, Braun LT, Ndumele CE et al Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease: A special report from the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2018 Nov 3. pii: S0735-1097(18)39036-3. PMID: 30423392 - Grundy SM, Stone NJ, Bailey AL et al 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. Circulation. 2019 Jun 18;139(25):e1082-e1143. PMID: 30586774 - Grundy SM, Stone NJ, Bailey AL et al 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1046-e1081. PMID: 30565953 - Forman DE, Stone NJ, Grundy SM. Treating Hypercholesterolemia in Older Adults. JAMA. 2019 Aug 20;322(7):695. No abstract available. PMID: 31429891-
  11. Medical Knowledge Self Assessment Program (MKSAP) 18, American College of Physicians, Philadelphia 2018
  12. Kazi DS, Penko J, Coxson PG, et al. Cost-effectiveness of alirocumab: A just-in-time analysis based on the ODYSSEY outcomes trial. Ann Intern Med 2019 Jan 1; PMID: 30597485 - Hlatky MA. A pound of prevention? Assessing the value of new cholesterol- lowering drugs. Ann Intern Med 2019 Jan 1; PMID: 30597487
  13. Carter JP et al. Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Heart 2022 Jan; 108:14. PMID: 34815331 https://heart.bmj.com/content/108/1/14
  14. Ballantyne et al Efficacy and safety of the oral PCSK9 inhibitor MK-0616: a phase 2b randomized controlled trial J Am Coll Cardiol. Mar 06, 2023. PMID: 36889610 https://www.jacc.org/doi/10.1016/j.jacc.2023.02.018