For 30 years, statins have been the most effective lipid-lowering medication and the only class of drug that improves cardiovascular mortality in randomized trials. However, despite intensive LDL reduction, a portion of patients taking statins still experience cardiovascular events. Many other patients experience side effects with statins, or the drugs do not effectively bring their LDL to goal. But soon, we may have another option.
In June, results from the 10 year IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) were published, showing ezetimibe in combination with simvastatin decreases more cardiovascular events than simvastatin alone in a high-risk population. Although the reduction is small, this is the first time that a non-statin agent showed cardiovascular benefit in an outcome trial. These results support the theory that absolute LDL reduction drives improvement in cardiovascular outcome.
Then later in the summer, two first-in-class human monoclonal antibodies against PCSK9 – the gene that helps regulate the half-life of LDL receptors – were approved by both FDA and EMA. These drugs, called alirocumab and evolocumab, decrease LDL level in the blood by blocking PCSK9-mediated degradation of the LDL receptor leading to more LDL uptake and clearance by the liver.
Both drugs bring down LDL by more than 50% when used alone, or more than 60% when used in combination with statins. Side effect profiles are favorable, with injection site reaction and flu like symptoms being the most common.
To determine whether this LDL lowering will translate into cardiovascular benefit, cardiovascular outcome studies are ongoing and likely to be completed in 2017 for alirocumab, evolocumab. A third agent in the pipeline, bococizumab, is currently in Phase III development with completion of cardiovascular outcome trial in 2018.
The availability of PCSK9 inhibitors is great news for patients who are at high cardiovascular risk with LDL not at goal. The downside is that these two medications will likely be very expensive comparing to the generic statins, with estimated price of $14,000, comparing to $2400 for Vytorin a year.
More good news to come
The development of these drugs signals a turning point for lipid lowering research. Looking ahead, the field targeting PCSK9 continues to be fast-paced as there are many agents in development. They represent a diverse type of molecules, including RNA interference, small molecules, and vaccines. Both Pfizer and AFFiRiS are developing vaccines that could be convenient for this lifelong condition, and several companies have oral PCSK9 inhibitors in the pipeline. One of these — K-312 by Kowa, an agent that down-regulates the expression of PCSK9 while also inhibiting cholesteryl ester transfer protein (CETP) — could potentially open a whole new therapeutic pathway.
