Antibody-Based Therapeutics for Hypercholesterolemia

Statins have provided the first line treatment for hypercholesterolemia for over two decades with the addition of ezetimibe if low-density lipoprotein (LDL) cholesterol targets are not achieved with statins alone. However, treatment with statins and other oral small molecules is often insufficient to attain the target levels of LDL cholesterol. This review describes the monoclonal antibodies (mAbs) that have been produced to overcome the residual cardiovascular risk related to uncontrolled LDL cholesterol. In recent years the mAbs, alirocumab and evolocumab, targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have become established worldwide as an additional treatment for patients not achieving LDL cholesterol goals on statins and ezetimibe, or sometimes as an alternative treatment in those with statin intolerance. They have been shown to be safe and effective in reducing cardiovascular events in patients at high cardiovascular risk. More recently, four new mAbs targeting PCSK9 have been developed and approved in China. Some of these mAbs offer the benefit of less frequent subcutaneous dosing and some are humanized mAbs and it remains to be seen whether their efficacy will be retained with long term use. New drug targets were identified to potentially reduce elevated triglyceride levels and the mAb angiopoietin-like 3 (ANGPTL3) inhibitor, evinacumab, was found to be effective in reducing LDL cholesterol in patients with homozygous familial hypercholesterolemia (FH) and has been approved for that indication. SHR-1918 is another mAb targeting ANGPTL3 being developed in China which may also be effective to treat homozygous FH. These drugs are expensive and may not be suitable for a wider indication and there are antisense oligonucleotides and small interfering RNA treatments in development which may prove more cost effective. Another mAb at an early stage of development is MAR001 targeting angiopoietin-like 4 (ANGPTL4). The role for this remains to be established.