Newest kid on the block – Cholesterol lowering PCSK9 inhibitors

The FDA recently announced approval of two cholesterol lowering drugs which both work by inhibiting PCSK9 or proprotein convertase subtilisin/kexin type 9.

PCSK9 is an enzyme from the subtilisin-like proprotein convertase family which include proteases that process proteins trafficking through various constitutive secretory pathways. PCSK9 increases blood cholesterol levels by binding to low densitiy lipoprotein (LDL) receptors, targeting them for lysosomal degradation. PCSK9 inhibitors therefore increase the number of LDL receptors on the surface of liver cells, increasing uptake of LDL, hence lowering bad cholesterol levels.

Pralauent (alirocumab) by Sanofi and Regeneron Pharmaceuticals and Repatha (evolocumab) by Amgen are both monoclonal antibody treatments that bind and inhibit PCSK9. They have shown pretty high efficacy, lowering LDL levels by nearly 60% compared to statins which on average reduce LDL by about 35%. Both treatments can be taken together, having complementary mechanism of actions. Statins reduce cholesterol by inhibiting HMG-CoA reductase, reducing cholesterol production. PCSK9 inhibitors are administrated by injection about twice monthly. They are however very costly, US$14 600 for Praluent and USD$14 100 for Repatha, every year for life. This translates into 36 billion dollars per annum in spending for US alone, assuming they are taken by 200,000 patients with familial hypercholesterolemia and another 2.3 million high-risk patients who are statin intolerant or not adequately controlling their cholesterol levels on current therapy.

Statin intolerance is hard to nail down though. Patients often complain of muscle aches from statin treatment but some of this can be psychological and not due to the drug. Statins however do come with side effects of muscle cramping and in some cases can cause rhabdomyolysis or muscle injury. Much concern has been raised about the price of these new PCSK9 inhibitors. Insurance agencies and doctors alike will find it difficult to substantiate the need for costly PCSK9 inhibitor treatment on top of current statin treatment if the need is not severe. Health agencies are setting up evaluation committees to appraise the cost-effectiveness of these treatments.

This is not stopping pharma from developing more cholesterol-lowering alternatives though. Pfizer, Eli Lily and Alnylam have their own PCSK9 inhibitors in the pipeline with the latter providing an RNA interference therapeutic that may afford more infrequent dosing. An alternative cholesterol-lowering mechanism is also currently being developed – Cholesteryl ester transfer protein (CETP) inhibitors lower LDL-c (the form that is transported in the blood) by preventing the transfer of cholesteryl esters from HDL to LDL, thereby also increasing concentration of “good cholesterol” or HDL.

This bodes well for patients with a high risk of cardiovascular problems due to elevated cholesterol but if prices are as high as PCSK9 inhibitors, statins which are also now available in many generic forms (and available for $50 per month), will likely still be the main drug of choice. Of course its also important to remember that cholesterol can be reduced by other simple cheap ways also known as exercise and healthy eating. 🙂


Cormac Sheridan, “New class PCSK9 blockers stride into cholesterol market” Nature Biotechnology 33, 785–786 (2015)