Can RNAi, gene therapy, targeted drugs, etc. open a new chapter in lipid-lowering therapy in the post-statin era?

"Every festive season, you gain three pounds, and after three pounds, you gain another three pounds

This is just one example of many scientific findings on cholesterol

Cholesterol and the Nobel Prize

Back in time more than 200 years ago, cholesterol had not been officially named

In the 20th century, it was found that cholesterol is widely present in animals and is an important living substance

Among them, the famous German chemist Adolf Windaus began to study and determine the structure of cholesterol and related steroids in 1901, and won the Nobel Prize in 1928 for studying the structure of cholesterol and its relationship with vitamins.

Since then, biochemists Konrad Bloch and Feodor Lynen have worked with colleagues to study how cholesterol and fatty acids are formed and converted in the body

By 1973, scientists Michael Brown and Joseph Goldstein had discovered cholesterol-absorbing receptors in cells and elucidated how the body's genes and other substances regulate the conversion of cholesterol

The metabolic transport mechanism of cholesterol is complex

Studies have found that low-density lipoprotein plays a leading role in cholesterol transport, and its transport volume accounts for up to 2/3, so it has the greatest relationship with cholesterol metabolism and atherosclerosis

There are many reasons for high cholesterol levels

The era of statin development

In 1973, a biochemist named Akira Endo accidentally extracted a new secondary metabolite, ML-236B, also called mevastatin, in a fungal culture solution.

Although the subsequent development of mevastatin was not smooth, the era of statins has already begun

The advent of the statin era not only revolutionized the treatment of blood lipids, but also gradually became an ideal drug for the treatment of hypercholesterolemia in the world

In 1987, a large-scale simvastatin survival study (also known as the 4S study) initiated in northern Europe, for the first time confirmed that the application of statins for lipid-lowering therapy can significantly reduce the overall mortality of patients with coronary heart disease

According to reports in the literature, the importance of statins lies in their significant pleiotropic effects, such as lipid-lowering effect, anti-inflammatory effect, improvement of vascular endothelial function, stabilization of atherosclerotic plaque, and anti-platelet aggregation

In the post-statin era, various innovative therapies have emerged one after another

It is worth noting that although the various clinical effects of statins are well tolerated and widely used, there are still safety limitations

In order to overcome these problems, a new generation of lipid-lowering therapies, such as cholesterol absorption inhibitors, preprotein convertase subtilisin 9 (PCSK9) inhibitors, ATP citrate lyase (ACL) inhibitors, and siRNA therapy, have appeared in drug development.
stage
.

Among them, a class of products represented by Merck & Co.
(MSD) ezetimibe can act on the Niemann-Pick C1-like1 protein receptor on the surface of intestinal and liver cells, selectively inhibiting Absorption of cholesterol, thereby reducing the transport of cholesterol in the small intestine to the liver, reducing the storage of cholesterol in the liver, and reducing the amount of cholesterol in the blood
.
In addition, this mechanism of action can be complementary to that of statins, which can be more effective in improving various cholesterol levels through combination therapy
.

Another type of PCSK9 inhibitors represented by Sanofi/Regeneron alirocumab and Amgen evolocumab have also become cardiovascular inhibitors.
Frontier research and development targets in the field
.
Studies have found that inhibiting PSCK9 can reduce the level of LDL-C in the body and achieve the purpose of treating diseases
.
A number of large clinical studies have also shown that LDL-C levels are significantly reduced in hyperlipidemia patients who are poorly treated by statins after treatment with PCSK9 inhibitors, and PCSK9 inhibitors combined with statins are more effective
.

In December 2020, the siRNA therapy inclisiran developed by Novartis received the world's first batch in Europe for the treatment of adult hypercholesterolemia and mixed dyslipidemia
.
As a "first-in-class" therapy, inclisiran binds to the mRNA encoding the PCSK9 protein, reduces its levels through RNA interference, and prevents the liver from producing PCSK9 protein
.
After the initial injection and the third month of injection, patients are expected to lower their "bad cholesterol" levels with just two treatments a year
.

Since then, bempeoic acid, an ATP citrate lyase (ACL) inhibitor developed by Esperion Therapeutics, and evinacumab-dgnb, a targeted therapy developed by Regeneron that can bind and block the function of angiopoietin-like protein 3 (ANGPTL3), have been successively launched in the United States.
Approved for adults with heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia (HoFH)
.

At the same time, a number of innovative lipid-lowering therapies are under clinical development, including RNAi therapy, gene editing therapy, antisense oligonucleotide (ASO) drugs, cholesteryl ester transfer protein (CETP) inhibitors,
etc.

For example, the RNAi therapy ARO-APOC3 developed by Arrowhead Pharmaceuticals aims to reduce the level of triglyceride (TG) and very low-density lipoprotein by reducing the expression level of the targeted apolipoprotein C3 (APOC3) protein.
High-density lipoprotein levels
.
Another example is the gene editing therapy VERVE-101 developed by Verve Therapeutics, which inactivates the PCSK9 gene by making a single A to G change in the DNA genetic sequence of PCSK9
.
There is also Ionis Pharmaceuticals' investigational antisense oligonucleotide (ASO) drug ION449 targeting PCSK9, which significantly reduced PCSK9 levels and LDL cholesterol levels in patients in Phase 1 clinical trials.
.
.

In addition, there are other innovative therapies that have been approved for marketing or are undergoing clinical trials.
Due to limited space, they will not be introduced here
.
We also expect that these next-generation lipid-lowering therapies can progress smoothly in clinical research, bringing more treatment options to the field of lipid-lowering therapy as soon as possible, and ultimately benefiting the majority of patients
.

References:

[1] Yongfeng S , Junjun L , Ke Z , et al.
Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases[J].
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33, Issue 10:1911-1925 Page.

[2] Chen Zhengwang.
Cholesterol research and Nobel Prize[J].
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[3] Mu ̈ller, C.
(1938).
Xanthomata, hypercholesterolemia, angina pectoris.
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[4]Nobel Prize official website.
Retrieved from https:// A.
, Kuroda, M.
, and Tanzawa, K.
(1976).
Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity.
FEBS Lett.
72, 323–326.

[6] Scandinavian Simvastatin Survival Study Group (1994).
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandi- navian Simvastatin Survival Study (4S).
Lancet 344, 1383–1389.

[7] Yang Xiaofen, Liu Xia.
Has the statin era really come? [J].
Medical Contention, 2016,7(06):33-36.
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[8] Press releases and public information of each company