Inhibition of pre-protein convertase serine kexin-9 (PCSK-9) as a treatment for hyperlipidaemia

Abstract

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.

Clinical Management of Familial Hypercholesterolemia: New Insights from International Guidelines and Recent Studies

“…The latest innovation in treatment in FH is the future introduction of PCSK-9 inhibitors. These inject able agents are superior to ezetimibe in reducing LDL-C by 50-65% in FH 42 compared to the 20%. However no outcome of surrogate outcome studies are planned with PCSK-9 inhibitors in FH so the utility of these drugs in this common genetic condition will not be established and will have to be extrapolated from general CVD.…”

Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia

“…Antibody therapies to PCSK-9 have been developed and reduce plasma LDL-C by 48-56%. An ASO therapy for PCSK-9 has also been developed and has the theoretical advantage that it will inhibit the intracellular activity of PCSK-9 as well as plasma-secreted form [6].…”

“…The pharmacology of antibody-based therapies is well understood given the extensive experience gathered in autoimmune disease in rheumatology and hemato-oncology. The new antibody-based PCSK-9 inhibitors show great promise with a high efficacy reducing LDL-C by 50% and good safety profiles and can even be used to treat some patients with HoFH where statins are less effective [6]. Less is known about ASO therapies than with antibodies or small molecules and experience with mipomersen in HOFH suggests that tolerability may be an issue.…”

“…More recently, antibodybased therapies directed against small molecules, e.g. tumor necrosis factor-alpha, or pro-protein convertase subtilisin kexin (PCSK)-9 [6], or cellular receptor targets, have become available. These are typically very effective and given as injections weekly to monthly but can lead to the induction of antibody responses including the production of neutralizing antibodies though clinically these do not seem to cause problems in the short term.…”

Novel insights on the treatment of hypercholesterolemia

“…The inhibition of PCSK9 pathway immediately appears one of the most promising novel targets for additional LDL-C reduction [11]. Alirocumab (REGN-727), evolocumab (AMG-145) and bococizumab (RN-316) are human monoclonal antibodies that bind circulating PCSK9 and block its interactions with surface LDLR.…”