PCSK9 inhibition – Ready for prime time?
Scott Shurmur MD
Corresponding author: Scott Shurmur
Contact Information: Scott.email@example.com
Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a glycoprotein that promotes the destruction of LDL cholesterol receptors in the liver. Thus, high levels of PCSK9 result in reduced activity of LDL receptors in the liver and higher LDL cholesterol levels. Conversely, loss of function mutations in PCSK9 results in lower LDL cholesterol and is associated with a reduction in coronary events.
Two commercially available monoclonal antibodies to PCSK9, alirocumab and evolocumab, have been developed. Evidence of the lipid-lowering efficacy of these agents has been robust,2 and evidence of clinical cardiovascular event reduction has begun to arrive.
Through 2016, the available data included prespecified but exploratory analyses of two open-label randomized extension studies. The OSLER clinical trial program evaluated evolocumab, and the ODYSSEY LONG TERM trial evaluated alirocumab, each studied against a background of statin therapy. Both trials showed a reduced incidence of major cardiovascular events with the active PSCK9 inhibitor therapy, though the total number of events was small.3,4 In both studies, the event reduction was found via post-hoc analysis, and neither trial was powered to detect a difference in clinical ASCVD events.
The FOURIER trial, published in early 2017, is a randomized study of the addition of evolocumab, in either of its two clinical dosing regimens (140 mg s.c. every two weeks or 420 mg s.c. monthly) added to a background of optimized statin therapy. The trial was appropriately powered to assess clinical cardiovascular events, with over 13,000 patients enrolled in each group. Both groups were well-treated by traditional lipid criteria, with a median baseline LDL-C of 92 mg/dl. The addition of evolocumab lowered LDL-C by an additional 59% at 48 weeks with a median on-treatment LDL-C of 30 mg/dl in the active treatment arm. The primary end point, a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, was reduced by 15% over the median duration of follow-up of 26 months. The prespecified secondary endpoint, the “harder” components of the primary endpoint—a composite of cardiovascular death, myocardial infarction, or stroke—was reduced by 20%. And the benefits of evolocumab therapy appeared to increase over time, with a 25% reduction in the secondary endpoint after the first year.5
Cardiovascular death was not reduced with evolocumab therapy, however. Cause for concern? Perhaps not. Most cardiovascular event trials of lipid-lowering therapies have included much longer subject follow up, around five years. And in many of those trials, CV death benefit did not emerge until after two years of active treatment.6-12
Early in the PCSK9 clinical trial development programs, some concern arose as to whether the very low on-treatment LDL levels achieved by PCSK9 inhibitor therapy would lead to a decline in neurocognitive function.13 In the EBBINGHAUS study, an objective assessment of neurocognitive function in nearly 2,000 patients enrolled in the FOURIER trial, no decline in neurocognitive function was found with evolocumab therapy.14
The FOURIER trial population included patients with clinical atherosclerotic cardiovascular disease, and additional characteristics placed them at increased cardiovascular risk. A slightly different patient population is being studied in the ongoing ODYSSEY OUTCOMES trial, a randomized investigation of alirocumab therapy, against a background of standard lipid-lowering therapy, in reducing major cardiovascular events. Approximately 18,000 patients 4-16 weeks post-acute coronary syndromes have been enrolled, and results are anticipated by early 2018.15
Table. PCSK9 Inhibitor Clinical Trials
|Trial Name||FOURIER||ODYSSEY OUTCOMES||SPIRE 1 & 2||ORION-1|
|Mechanism of Action vs. PCSK9||Human monoclonal antibody||Human monoclonal antibody||“Humanized” monoclonal antibody||Interfering RNA|
|Patient Population||High Risk ASCVD||Recent ACS||High Risk ASCVD||Hyperlipidemia|
|Endpoint||CV events||CV events||CV events (Spire 2)||Lipid effects|
A third PCSK9 inhibitor, bococizumab, was well into clinical development until its clinical trial program was halted in November 2016 after neutralizing antidrug antibodies developed in a large number of patients, significantly diminishing the LDL lowering effects.16 Unlike the other two available monoclonal antibodies to PCSK9, this agent is not fully “human” but instead “humanized”, likely explaining the greater propensity for antibody formation. No neutralizing antibodies developed with evolocumab therapy in the FOURIER trial.5
Another mechanism of action of PCSK9 inhibition is in early clinical development. Inclisiran, a small “interfering RNA” which targets PCSK9 mRNA, has been shown in a phase II trial to produce sustained reductions in PCSK9 and LDL-C levels for up to six months, with a single subcutaneous injection, with greater efficacy demonstrated if a second injection is administered after 90 days.17 Further investigations are moving forward in the ORION clinical trial program.
So where does PCSk9 inhibition fit in? The answer remains unclear. Currently the agents are labeled for use in patients with familial hypercholesterolemia with LDL-C>190 mg/dl, or in individuals with clinical atherosclerotic cardiovascular disease who require greater reduction in LDL cholesterol beyond that achieved on normally tolerated lipid lowering therapy. At what level of on-treatment LDL PCSK9 is indicated is undefined, and recent and ongoing studies appear to be inching that number downward. In FOURIER, the on-treatment LDL-C before PCSK9 inhibition was 92 mg/dl, and adding evolocumab significantly reduced events. Similar lipid levels are likely to be seen in ODYSSEY OUTCOMES. Stay tuned…
Keywords: PCSK9, outcomes, cognitive function, LDL cholesterol
- Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006 Mar 23:354(12):1264–72.
- Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014 Oct: 11(10):563–75.
- Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, ODYSSEY LONG TERM Investigators. N Engl J Med 2015 Apr 16:372(16):1489–99.
- Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA; Open-label study of long-term evaluation against LDL cholesterol (osler) investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015 April 16; 372(16):1500–9.
- Sabatine MS, Giuglinao RP, Keech AC, Honarpour N, Wiviott SC, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pederson TR; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl J Med 2017 Mar 17. doi:10.1056/NEJMoa1615664.
- 4S group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994 Nov 19; 344(8934):1383–9.
- Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998 Nov 5; 339(19):1349–57.
- Sacks FM, Pfeffer MA, Moyle LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996 Oct 3:335(14):1001–9.
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002 Jul 6:360(9326):7–22.
- Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, Mckillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995 Nov 16; 333(20):1301–7.
- Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorder A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Airforce/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998 May 27; 279(20):1615–22.
- Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorezatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008 Nov 20; 359(21):2195–207.
- Lipinski MJ, Benedetto U, Escarcega RO, Biondi-Zoccai G, Lhermusier T, Baker NC, Torguson R, Brewer HB Jr, Waksman R. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolemia: a network meta-analysis. Eur Heart J 2016 Feb 7; 37(6):536–45.
- American College of Cardiology – 66th Annual Scientific Sessions; Late Breaking Clinical Trial. March 18, 2017.
- Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Mahaffey KW, Moryusef A, Pordy R, Roe MT, Rorick T, Sasiela WJ, Shirodaria C, Szarek M, Tamby Jf, Tricoci P, White H, Zeiher A, Steg PG. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rational and design of the ODYSSEY outcomes trial. Am Heart J 2014 Nov; 168(5):682–9.
- Ridker PM, Tardif JC, Amarenco P, Duggan W, Glynn RJ, Jukema JW, Kastelein JJP, Kim AM, Koenig W, Nissen S, Revkin J, Rose LM, Santos RD, Schwartz PF, Shear CL, Yunis CL, SPIRE Investigators. Lipid-reduction variability and antidrug-antibody formation with Bococizumab. N Engl J Med 2017 April 20; 376(16):1517–1526.
- Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017 Apr 13; 376(15):1430–40. doi: 10.1056/NEJMoa1615758.
From: The Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX
Conflicts of interest: none
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