Atherosclerosis is a leading cause of cardiovascular diseases worldwide. Understanding its pathophysiology and exploring innovative treatment options like PCSK9 inhibitors are crucial for advancing cardiovascular health.
Atherosclerosis is a chronic condition characterized by the accumulation of fatty and fibrous materials within the innermost layer of the arteries, known as the intima. This process begins with the buildup of low-density lipoprotein cholesterol (LDL-C), which leads to the formation of atherosclerotic plaques. These plaques can become calcified and fibrous over time, narrowing the arterial lumen and restricting blood flow, potentially causing tissue ischemia.
Atherosclerosis is a major contributor to cardiovascular diseases (CVD), which include conditions such as myocardial infarction (heart attack), ischemic stroke, and peripheral artery disease. The pathogenesis of atherosclerosis involves three main phases: initiation, progression, and complications. During the initiation phase, LDL-C infiltrates the arterial wall, leading to plaque formation. Progression involves the continued accumulation of lipids and inflammatory cells, while complications arise when plaques rupture or erode, causing acute cardiovascular events like heart attacks and strokes (Libby et al).
Figure1: Schematic representation of Atherosclerosis stages.
A key player in the development of atherosclerosis is the PCSK9 gene, which regulates the degradation of LDL receptors on liver cells. These receptors are responsible for clearing LDL-C from the bloodstream. Mutations in the PCSK9 gene can lead to higher levels of LDL-C, increasing the risk of atherosclerosis. Conversely, inhibiting PCSK9 can help lower LDL-C levels and reduce the risk of cardiovascular events.
PCSK9 (proprotein convertase subtilisin/kexin type 9) is an essential enzyme involved in cholesterol regulation, particularly low-density lipoprotein cholesterol (LDL-C). It functions by binding to LDL receptors on the surface of liver cells, marking them for degradation. These receptors are vital for clearing LDL-C from the bloodstream. Under normal conditions, LDL receptors bind to LDL particles and internalize them into liver cells, where the particles are broken down, and the receptors are recycled back to the cell surface to repeat the process.
However, when PCSK9 attaches to an LDL receptor, it prevents the receptor from recycling. Instead, the receptor is directed to the lysosome for degradation, reducing the number of LDL receptors available on the cell surface. This reduction leads to higher levels of circulating LDL-C (Roth et al).
Figure2: PCSK9 inhibitions of LDL receptors.
Leqvio (inclisiran) is a novel therapeutic that targets the PCSK9 gene. It works by inhibiting PCSK9, leading to increased LDL receptor availability and enhanced clearance of LDL-C from the blood. Clinical trials have shown that Leqvio significantly lowers LDL-C levels and may provide substantial cardiovascular benefits. By integrating PCSK9 inhibition into treatment regimens, we can offer new hope for patients struggling with high cholesterol and atherosclerosis, potentially reducing the global burden of cardiovascular diseases.
Inclisiran represents a novel approach in cholesterol management, utilizing small interfering RNA (siRNA) to target PCSK9. Unlike monoclonal antibodies such as alirocumab and evolocumab, which inhibit PCSK9 extracellularly by binding to it in the bloodstream, inclisiran works intracellularly. It prevents the translation of PCSK9 messenger RNA (mRNA), effectively reducing the synthesis of PCSK9 within liver cells. This mechanism leads to decreased levels of PCSK9 protein, thereby increasing the number of LDL receptors available to clear LDL cholesterol (LDL-C) from the bloodstream.
The ORION clinical development program has extensively studied inclisiran in various phases of clinical trials. Key studies include ORION-1, ORION-9, and ORION-11. ORION-1, a phase II trial, showed that inclisiran could reduce LDL-C levels by 50% or more with effects lasting for up to six months after a single injection. The ORION-9 trial focused on patients with heterozygous familial hypercholesterolemia (HeFH) and demonstrated similar efficacy. ORION-11 included patients with atherosclerotic cardiovascular disease (ASCVD) and also showed significant LDL-C reductions with biannual dosing.
These trials have shown that inclisiran's siRNA mechanism provides a durable and potent reduction in LDL-C, similar to that achieved with monoclonal antibodies but with less frequent dosing. Patients can receive inclisiran injections every six months, which improves adherence and convenience compared to the biweekly or monthly injections required by monoclonal antibodies.
Inclisiran's unique mechanism of action involves its conjugation to triantennary N-acetylgalactosamine (GalNAc), which facilitates its targeted delivery to liver cells. This targeted approach enhances the drug's efficacy and reduces the likelihood of off-target effects. The reduced PCSK9 levels lead to an increase in LDL receptor recycling, enhancing the liver's ability to remove LDL-C from the blood.
The ORION trials have also demonstrated that inclisiran is well-tolerated, with a safety profile comparable to placebo. Common side effects include mild to moderate injection-site reactions, but serious adverse events are rare.
In summary, inclisiran offers a promising new treatment for hypercholesterolemia by harnessing the power of siRNA technology to inhibit PCSK9 at the mRNA level. This innovative approach not only matches the LDL-C lowering efficacy of monoclonal antibodies but also offers the added benefits of less frequent dosing and improved patient adherence, marking a significant advancement in the management of cardiovascular risk (German et al).
Leqvio is owned by Novartis, a leading global healthcare company that is dedicated to improving patient outcomes through innovative medical solutions. Novartis has been at the forefront of cardiovascular disease research and treatment, consistently developing groundbreaking therapies to address some of the most pressing health challenges. Their commitment to scientific excellence and patient care is evident in their extensive portfolio of cardiovascular drugs and their continuous efforts to advance medical knowledge and treatment options in this critical area.
In this article, I've looked into the realm of cardiovascular disease, with a spotlight on atherosclerosis and the innovative approach of PCSK9 inhibition. The insights presented are grounded in scientific studies and publicly accessible datasets. This is the result of the collective efforts of many, from public institutions to Novartis, and it reflects the dedication of these individuals to develop and bring efficacious drugs to the market for the benefit of all patients. Your feedback and thoughts are immensely appreciated. For further details or to get in touch with me, please visit my personal page.
For those interested in further details, here are some key references:
- Libby, P., Buring, J. E., Badimon, L., Hansson, G. K., Deanfield, J., Bittencourt, M. S., Tokgözoğlu, L., & Lewis, E. F. (2019). Atherosclerosis. Nature Reviews Disease Primers, 5(56). https://doi.org/10.1038/s41572-019-0106-z
- Roth, E. M., & Davidson, M. H. (2018). PCSK9 Inhibitors: Mechanism of Action, Efficacy, and Safety. Reviews in Cardiovascular Medicine, 19(S1), 31-46. https://doi.org/10.3909/ricm19S1S0002
- German, C. A., & Shapiro, M. D. (2019). Small Interfering RNA Therapeutic Inclisiran: A New Approach to Targeting PCSK9. BioDrugs. https://doi.org/10.1007/s40259-019-00399-6