Today we had our manuscript on the pre-protein convertase subtilisin kexin (PCSK)-9 approach to the treatment of hyperlipidaemia published [1]. PCSK-9 is a newly discovered protein involved in intracellular and extracellular regulation of low-density lipoprotein receptor (LDLR) expression. For some time, we have known that autosomal dominant activating mutations in PCSK-9 cause familial hypercholesterolaemia whereas inactivating mutations in man reduce LDL cholesterol (LDL-C) and are associated with a decreased lifetime risk of cardiovascular events. Clearly, this identifies a potential target for a new therapeutic approach to hypercholesterolaemia.
Based on in vitro and in vivo data antibodies targeting PCSK-9 have emerged as a novel treatment option in patients with cardiovascular disease. We have reviewed how several approaches involving small molecule or peptide inhibition of binding, antibody-mediated inactivation of binding and the use of antisense oligonucleotides are being investigated as therapeutic approaches to lower LDL-C in man [1].
Until 2011 the literature had been relatively quiet on the advancement of this new treatment paradigm [2]. Our article reviews the biochemistry and physiology of PCSK-9 and details the efforts made to design novel molecules with the ability to inhibit PCSK-9 activity [1]. The potential therapeutic benefits have been investigated in animal models, which has confirmed that reducing PCSK-9 expression can reduce atherosclerosis in mice, rats and primates. Monoclonal antibodies such as REGN-727 and AMG-145 have been shown to reduce LDL-C in patients with familial hypercholesterolaemia already treated with statins or healthy normocholesterolaemic controls. Potential benefits to be gained from PCSK-9's include:
- Reduction in LDL-C in the range of 40-70% from baseline either in combination with statins or given as a monotherapy
- Significant reductions in apoB and total cholesterol
- Modest increases in HDL-C/reduction in triglycerides
- Once/twice monthly subcutaneous injection
- Acceptable safety and tolerability profile
Our timely literature review highlights how PCSK-9 inhibition is a potentially interesting novel addition to the armamentarium of LDL-C reducing drugs. Its effects in reducing LDL-C will need to be confirmed to reduce CVD events in large-scale clinical trials.
- Wierzbicki AS, Hardman TC, Viljoen A. Inhibition of pro-protein convertase subtilisin kexin 9 (PCSK-9) as a treatment for hyperlipidaemia. Expert Opin Investig Drugs. 2012;21:667-76.
- Tibolla G, Norata GD, Artali R, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition. Nutr Metab Cardiovasc Dis 2011;21:835-43.
