▎ WuXi AppTec content team editor
Although scientists have conducted extensive basic research and clinical trials for atherosclerotic cardiovascular disease (ASCVD), ASCVD remains one of the most deadly diseases worldwide. It is now widely believed that low-density lipoprotein cholesterol (LDL-C) is the most important risk factor for atherosclerosis and plays a key role in the development of ASCVD.
Although a variety of effective and safe lipid-lowering drugs have been widely used in the treatment of ASCVD, most patients still have circulating LDL-C at a reasonable level. As a result, the primary prevention of ASCVD remains a difficult goal to achieve. Recently, the European Heart Journal published a blockbuster paper.
The paper points out that with the deepening of our understanding of the pathogenesis of ASCVD, how to achieve more efficient and convenient control of LDL-C through new treatment options with greater accessibility and compliance has also become the key to the treatment and prevention of ASCVD. With the advent of small interfering ribonucleic acid (siRNA) drugs, maintaining long-term lipid-lowering effects with a single injection is expected to become a reality. In the future, we may be able to prevent as much as vaccines at a young age to fully delay the arrival of ASCVD!
Screenshot source: European Heart Journal
How can the age of onset of ASCVD be delayed by 30 years?
The occurrence of ASCVD is mainly related to the deposition and aggregation of LDL-C in the lining of arteries, resulting in the formation of atherosclerotic plaques, and its pathogenesis depends on the level of circulating LDL-C and the duration of this level. Therefore, patients with familial hypercholesterolemia may develop ASCVD at an early age, and individuals with deletional variants in PCSK9-related genes have a significantly lower risk of DEVELOPING ASCVD.
Combining LDL-C levels and their duration, we can use "cholesterol-years" or "LDL-C-years" to represent atherosclerotic load. When the cumulative load reaches a certain threshold, the clinical symptoms associated with ASCVD will become apparent.
The paper cites three different categories of individuals, represented by A, B, and C:
▲ Three different groups of people, with age to increase atherosclerotic load changes (image source: reference [1])
A: In healthy adults or adults receiving statin therapy, the average LDL-C is 100 mg/dL (2.6 mmol/L), and the ASCVD threshold (7 g-years) is reached at age 70 years;
B: Individuals with familial heterozygous hypercholesterolemia who received no treatment and had an LDL-C level of 200 mg/dL (5.2 mmol/L), who reached the ASCVD threshold at age 35;
C: Class A population receiving long-acting lipid-lowering drugs delayed reaching the ASCVD threshold for 30 years.
The authors suggest that by giving an annual long-acting lipid-lowering drug therapy to such individuals represented by A starting at age 30, LDL-C levels are expected to be reduced from 100 mg/dL to 60 mg/dL (i.e., C line), and the rate of progression of atherosclerotic load will also decrease.
This segment of the population will reach the 7 g-year ASCVD threshold in 30 years, at the age of 100.
The authors emphasize that a better delay in reaching the ASCVD threshold depends on the age at which subjects begin receiving long-acting lipid-lowering drugs. The earlier the age of initiation of treatment, the better without taking into account possible adverse effects of long-term administration and possible changes in LDL-C levels during long-term treatment.
In addition, if there are other factors that may increase the risk of atherosclerosis (such as hypertension, diabetes, and family history), the THRESHOLD for the onset of ASCVD will be reached early, and a healthy lifestyle will delay the threshold for the onset of ASCVD.
Exploration of targeted PCSK9 therapeutic strategies
The pro-protein invertase licorticin 9 (PCSK9) is a protein synthesized primarily in the liver that affects its lysosomal degradation by interacting with low-density lipoprotein receptors (LDL-R), thereby affecting the amount of LDL-C in the blood. Studies have shown that "functionally acquired mutations" in the PCSK9 gene can cause severe hypercholesterolemia and early-onset ASCVD, while "functional deletion mutations" in the PCSK9 gene can cause the opposite effect.
PCSK9 monoclonal antibody
The paper notes that PCSK9 has been shown to be an effective target for reducing cyclic LDL-C, and blocking PCSK9 by monoclonal antibodies can improve clinical prognosis in ASCVD or its high-risk patients. The results of large clinical studies confirm that monoclonal antibodies targeting PCSK9 are not only safe and well tolerated, but also have considerable effectiveness in reducing LDL-C and improving clinical outcomes. However, lipid-lowering therapy with monoclonal antibody-like PCSK9 inhibitors, or primary prevention of ASCVD in asymptomatic populations, also faces two new problems:
The relatively short half-life of antibodies, with patients requiring subcutaneous injections every 2 or 4 weeks, and treatment often lasting a lifetime, is a cause for concern long-term adherence to this approach;
For people who do not have SYMPTOMSVD-related symptoms, the application of this method for primary prevention may lead to higher treatment costs.
siRNA drugs
In 1998, Andrew Fire, Professor Craig C. Mello and their research team published an article in the journal Nature describing the genetic interference caused by double-stranded RNA in Caenorhabditis elegans (that is, double-stranded RNA activates the relevant enzyme mechanism to cause gene silencing), a finding that has far-reaching biological and pharmacological implications for the future treatment of ASCVD.
In 2006, Andrew Fire and Professor Craig C. Mello also received the Nobel Prize in Physiology or Medicine for the discovery, while in the same year, Professor Bumcrot et al. recognized the potential role of interfering with specific RNAs in the treatment of diseases. Based on this, the research team has developed a new class of drugs, that is, siRNA drugs.
siRNAs are characterized by small molecules (21-23 nucleotides) and double-stranded interfering RNA. The first siRNA was the cardiovascular therapeutic drug patisiran, which has been shown to have a therapeutic effect in myocardial amyloidosis.
inclisiran is a siRNA drug that targets PCSK9, which can be rapidly uptaken by liver cells and reduce the expression of PCSK9, thereby inhibiting lysosomal degradation of LDL-R, increasing the number of LDL-R in cell membranes, and ultimately reducing the level of LDL-C in the circulation. Overall, inclisiran acts similarly to the "loss-of-function mutation" that caused the PCSK9 gene.
The results of phase 3 clinical studies (ORION-10 and ORION-11) confirm that subcutaneous injection of inclisiran every 6 months not only reduces LDL-C levels by up to 50% in patients with patients with atherosclerotic cardiovascular disease or the same risk factors, but also significantly reduces levels of non-hdL-protein cholesterol (HDL-C), apolipoprotein B (ApoB), triglycerides, and lipoprotein (a) in patients.
The ORION-4 trial is an ongoing clinical outcome study in patients with ASCVD. The study found that if administered only once a year, patient lDL-C levels would drop to a minimum about 2 months after inclisiran injection, then gradually increase, and at the next injection, patients would have LDL-C levels decrease by about 20%. By repeating injections each year, patients can average nearly 40% below baseline.
In addition, other clinical trials in the ORION series have confirmed that inclisiran has considerable safety, tolerability, and efficacy in reducing circulating PCSK9 and LDL-C levels in normal subjects, patients with ASCVD, familial or other forms of hypercholesterolemia.
It is worth mentioning that the half-life of inclisiran is up to nearly 300 days, and for patients with ASCVD who receive the maximum tolerated dose of statin therapy, subcutaneous injection of inclisiran (300 mg) every 6 months can reduce their LDL-C level by up to 50 mg/dL. Currently, the drug regulatory authorities in Europe and the United States have approved the use of inclisiran in adult patients with hypercholesterolemia and specific types of mixed dyslipidemia.
Summary
Based on the relatively long duration of action of the siRNA drug Inclisiran and the relatively convenient mode of administration, its application may bring hope for delaying the age of onset of ASCVD in the future.
For asymptomatic people, primary prevention of ASCVD with long-term (or even lifelong) daily statins or bi-weekly monoclonal antibodies for asCVD is clearly low. In contrast, it is relatively simple and convenient to inject long-acting lipid-lowering drugs subcutaneously once a year, like vaccination.
The authors emphasize that without affecting the use of other lipid-lowering drugs, the primary prevention method of siRNA-based drugs in the future is expected to significantly delay the occurrence of ASCVD in a large proportion of the population on the basis of further controlling LDL-C levels!