MedImpact MedConnect | Drug Info | PCSK9 Inhibitors

Drug Info icon

Drug Info

PCSK9 Inhibitors: A Glimpse at the Future Treatment of High Cholesterol

This past summer saw the FDA approval of two new agents in the novel class of drugs called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Praluent® (alirocumab), approved July 24th, and Repatha™ (evolocumab), approved August 27th, are the first two humanized monoclonal antibody medications belonging to this unique drug class for the treatment of hyperlipidemia. Both Praluent and Repatha are indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) and those with clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-cholesterol (LDL-C). Repatha carries the additional approval for use with other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

Statins remain the mainstay of LDL-lowering therapy for most patients due to the proven cardiovascular risk reduction that accompanies LDL reduction with statin therapy. With generic statin agents being priced at pennies per day, statins are an extremely cost-effective method to lower LDL-C. Despite the potential for low-cost treatment with statins and their widespread use, some patients may be statin-intolerant or may need additional cholesterol-lowering activity despite maximal statin doses.

The PCSK9 protein is synthesized by several organs in the body and is secreted by the liver where it can bind to LDL receptors on liver cells. This binding prevents the LDL receptors from continuously clearing LDL from the plasma, resulting in elevated LDL-C levels. The PCSK9 inhibitor drugs serve to improve the liver’s ability to clear LDL from the plasma, reducing LDL-C levels and reducing the risk of cardiovascular events. When added to a maximized statin regimen, PCSK9 inhibitors work synergistically with statins to provide additional LDL-lowering via a different mechanism of action.

There are approximately 18 additional PCSK9 inhibitors currently in development. Pfizer’s® bococizumab (RN316) is currently in phase 3 trials and could file for FDA approval as early as 2016. Eli Lilly® has also entered the PCSK9 inhibitor race with LY3015014, which has completed phase 2 trials. Pending trial outcomes, it could still be a year or more before Eli Lilly seeks approval for their product.

One potential drawback of Praluent, Repatha, and several other PCSK9 inhibitors in development is the need for repeated injections of the drugs. Drug development will potentially bring forth oral PCSK9 inhibitors, vaccines and gene therapy as modalities to treat dyslipidemia. With the hope of providing non-injectable options, Pfizer is developing an oral PCSK9 inhibitor, currently in phase 1 trials. In addition, Serometrix’s oral PCSK9 inhibitor, SX-PCK9, has entered preclinical trials.

In efforts to reduce the number of injections required for effective treatment, vaccines to PCSK9 are being explored. Clinical trials are expected to begin in mid-2016 for an anti-PCSK9 vaccine that Pfizer is developing to stimulate the immune system into producing long-lasting PCSK9 antibodies. Two PCSK9 vaccine candidates (ATH04 and ATH06) from AFFiRiS AG have begun recruiting participants for phase 1 clinical trials, with a third vaccine candidate (ATH05) showing promising data in animal models. Alnylam Pharmaceuticals® and The Medicines Company recently reported positive results from their phase I clinical trial with ALN-PCSsc, an investigational RNAi therapeutic targeting PCSK9 which would likely be dosed quarterly. Approval of these vaccines and non-injectable anti-PCSK9 agents are, however, likely still several years away.

Although the forthcoming data from the clinical trials appears to be promising in the reduction of LDL-C and theoretically, a reduction in cardiovascular events, it is not known what the absolute cardiovascular benefit will be with this new class of drugs. Results from the outcomes trials with the newly approved PCSK9 inhibitors are anticipated to report out in 2017/2018. Given the lack of long-term safety and efficacy data for PCSK9 inhibitors; the fact that most patients can tolerate statins rather well; the steep price of PCSK9 inhibitors compared to statins; and the current recommendation that they be used in conjunction with statins, the exact role of PCSK9s in cholesterol treatment remains to be seen.


Jora Sliwinski, PharmD
Drug Information Pharmacist

Sources: