The New Age of Hypercholesterolaemia Treatment

In 2003, a scientist in Montreal named Nabil Seidah discovered a novel human proprotein convertase protein that was located on the short arm of chromosome 1. At this same time, a lab in Paris had been researching families with the condition familial hypercholesterolaemia (FH). FH causes CAD in 90% of patients and in 60% of patients will lead to an early death based on the FRAMINGHAM study. The group in Paris identified a mutation in some FH patients that lied on chromosome 1 but were not able to ID the gene. Both labs ended up getting together and published their work in 2003 that linked mutations in the gene, now known as PCSK9 to FH. Additionally, a study in 2004 was released showing that statin therapy induced mRNA expression and could significantly increase PCSK9 levels in a dose-dependent manner

These publications led to a flood of research on the PCSK9 gene. In 2009 a group at UT-Southwestern used this new information about the PCSK9 gene and sequenced the relevant region on chromosome 1 in patients with very low cholesterol. They found nonsense mutations that led to very low cholesterol. This study and various case studies quickly validated the potential of PCSK9 as a therapeutic target. Nearly a decade after the discovery, PCSK9 rapidly became one of the most promising targets for lowering cholesterol and preventing CV diseases.

              
In 2015, the FDA approved Repatha (evolucumab) and Praluent (alirocumab) as the first PCSK9 inhibitor drugs. These monoclonal antibodies against PCSK9 can reduce LDL by over 50%, non-HDL, and triglycerides, while also increasing HDL by about 7-15%. Although highly effective, the use of these new agents has been limited to mainly FH due to high costs and limited data/clinical experience. They are currently only indicated adjunct to statin therapy in individuals with heterozygous FH.

              
A lot of interest has now shifted to RNA-based targeting approaches to decrease expression of PCSK9. Small interfering RNA (SiRNA) molecules are being studied extensively and work by interfering with the expression of hepatic PCSK9 expression. The most promising of these agents, Inclisiran is a long-acting synthetic siRNA made by The Medicines Company that is now undergoing phase III clinical trials for hypercholesterolemia. In the ORION-1 trial subjects were randomized to either one dose of placebo or inclisiran on day 1  (200, 300, or 500 mg) or two doses (100, 200, or 300 mg) on days 1 and 90. The primary efficacy endpoint was percent change from baseline LD at day 180 after treatment. The results showed very robust reductions in mean LDL-C levels form Day 14 to 210 of therapy. Max LDL-C changes were greater on the two dose regimen and the return to baseline was slower up to 210 days. In the phase III trial, the dosing regimen moving forward will be 300 mg on days 1 and 90, then every 180 days thereafter.

The major advantages of siRNA treatment for hypercholesterolemia is the use of twice yearly therapy to increase adherence and a predicted lower cost. Unfortunately, none of these studies have been done without adjunct statin treatment, so the adverse effects of statins may still be of concern. It remains to be determined whether patients taking Inclisiran will experience diminished CV risk, but outcomes trials are underway.