▎ WuXi AppTec content team editor
Last December, the U.S. FDA approved Novartis' Leqvio, a "first-in-class" siRNA therapy that significantly reduces the expression of the PCSK9 protein with just two injections per year, thereby significantly reducing the level of low-density lipoprotein cholesterol (LDL-C). After the monoclonal antibody therapy targeting PCSK9 was first approved in 2015, there was a renaissance in the development of new drugs for PCSK9. Several pharmaceutical and biotechnology companies are targeting this target using almost all conceivable therapeutic models. Recently, the C&EN website of the American Chemical Society took stock of the progress of new drug development in this field.
For the past 15 years, drug discovery scientists have been looking for ways to inhibit PCSK9. In 2003, researchers discovered that mutations in the PCSK9 gene lead to elevated expression of the PCSK9 protein and drive up LDL-C levels, leading to the development of familial hypercholesterolemia (FH).
Shortly thereafter, another team of researchers reported the presence of naturally occurring mutations in genes that inhibit PCSK9 expression in a small number of people. These people have very low LDL-C and a significant reduction in the incidence of cardiovascular disease, and no other adverse effects have been shown. The discovery of the PCSK9 target exemplifies the power of human genetics in the development of new drugs.
Image credit: 123RF
In addition to being verified by human genetics, several other features of PCSK9 make it a particularly attractive target. The PCSK9 protein is mainly expressed in the liver, which is an organ that is easily targeted by multiple treatment models. "It's a highly validated target expressed in the right tissue from a drug delivery perspective." Dr Robert Garbaccio, head of Merck's discovery chemistry, said, "This opens the door for the industry to drive innovation. ”
Cardiovascular disease is the leading cause of death in the world, and even today, when statins are widely used, it still causes a third of all deaths each year. There are still significant unmet medical needs in this area. Typically, the PCSK9 protein regulates the degradation of LDL receptors on the cell surface, inhibiting the activity of this protein so that more LDL receptors reside on the surface of liver cells, allowing them to remove more LDL-C from the bloodstream. The FDA-approved anti-PCSK9 monoclonal antibody can reduce LDL-C levels by 60%, showing excellent activity and safety.
▲Anti-PCSK9 antibody and pcSK9 mechanism of action (Image source: Reference[4])
The current therapies in research mainly further improve the inhibition of PCSK9 from two directions. One direction is to use innovative treatment models to extend the effective time of PCSK9 inhibitors, thereby improving patient adherence to medication. In the prevention of cardiovascular disease, patient medication adherence is crucial. The currently approved antibody therapy requires injections every two weeks, which is inconvenient for patients to use, while the approved siRNA therapy Leqvio only needs to be injected every 6 months to continuously reduce LDL-C levels by about 50%, which makes it convenient for patients to receive treatment.
In addition to siRNAs, antisense oligonucleotide therapy can also reduce the expression of PCSK9 proteins in the long term by targeting mRNA encoding the PCSK9 protein. The gene editing therapy developed by Verve Therapeutics takes it a step further, and the company's single-base editing therapy Verve-101 aims to achieve a single treatment by editing the PCSK9 gene, permanently reducing the expression of the PCSK9 protein. Dr Sekar Kathiresan, CEO of Verve, said: "Our goal is to finally tackle atherosclerotic cardiovascular disease. ”
Dr. Sekar Kathiresan, CEO of Verve, shares insights into gene editing therapy development at WuXi AppTec Global Forum