Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors

Monoclonal antibodies against PCSK9

• enzyme proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) binds to hepatic LDL receptors, leading to their accelerated degradation and thereby reducing the removal of circulating LDL-C
  
  
  • PCSK9 is a proteinase K-like enzyme of the secretory subtilase family
    • primarily synthesized and secreted by hepatocytes but expressed to a lesser extent in oher tissues,such as intestine and kidney
    • main function of PCSK9 is regulation of cholesterol homeostasis via accelerating the degradation of LDLreceptor
    • reduction in surface LDLR reduces uptake of LDL particles and increases LDL-C concentration in the blood
      
      
  • monoclonal antibodies (mAbs) against the PCSK9 enzyme (PCSK9 inhibitors) are administered subcutaneously every two or four weeks
    • reported mean half-life times for subcutaneous administration have been six to seven days, with minimal differences due to administration site (abdomen or upper arm) and LDL-C reaching its lowest level at 15 days (1)
    • PCSK9 inhibitors bind to the PCSK9 enzyme with high affinity, disrupting its ability to bind with LDLR
      • by preventing PCSK9 from binding to LDLR, inhibitors against PCSK9 maintain surface LDLR expression with the aim of reducing LDL-C serum concentration
    • a systematic review relating to the role of PCSK9 inhibitors in the primary and secondary prevention of cardiovascular disease (2) states:
      • evidence for the clinical endpoint effects of evolocumab and alirocumab versus placebo were graded as high. There is a strong evidence base for the benefits of PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials
      • evidence base of PCSK9 inhibitors compared with ezetimibe and statins is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies
      • finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.

Notes:

• a number of trials have shown that fibrate therapy elevates PCSK9 levels, and this may account for the limited effects of these drugs on plasma LDL-C
• statin use is associated with increased levels of PCSK9
  • statins act through inhibition of HMG-CoA, thereby depleting intrahepatic cholesterol content
    • in turn leads to the up regulation of LDLR via a sterol-regulatory element binding protein-2 (SREBP-2)-mediated transcriptional activation
    • since PCSK9 expression is also regulated by SREBP-2, induction of LDLR - and associated reduction in LDL-C- would be accompanied by a rise in the synthesis and secretion of PCSK9
• evolocumab has had myalgia added to the summary of product characteristics (SPC) as a common adverse event (4)

Reference:

• Lunven C, Paehler T, Poitiers F, Brunet A, Rey J, Hanotin C, et al. A randomized study of the relative pharmacokinetics, pharmacodynamics, and safety of alirocumab, a fully human monoclonal antibody to PCSK9, after single subcutaneous administration at three different injection sites in healthy subjects. Cardiovascascular Therapy 2014;32(6):297-301
• Schmidt AF et al. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Oct 20;10:CD011748.
• MayneJ,DewpuraT,RaymondA, et al.Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis. 2008;7:22.
• NICE - Medicines Awareness Service - 24 May 2021