Inclisiran, marketed as Leqvio, represents a novel approach to lowering low-density lipoprotein cholesterol (LDL-C) levels. It belongs to a class of drugs known as RNA interference (RNAi) therapeutics and is indicated as an adjunct treatment alongside statin therapy for patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease who require additional LDL-C lowering. It's particularly beneficial for patients with uncontrolled cholesterol levels despite maximal statin therapies.
What is Leqvio?
Leqvio (inclisiran) is a first-in-class medication indicated for treating hypercholesterolaemia or mixed dyslipidaemia in adults. The drug is available as a 284mg clear, colourless to pale yellow injectable solution in a prefilled syringe. Leqvio is the first and only siRNA treatment used for elevated LDL-C levels via RNA interference.
Composition and Structure
Inclisiran is a synthetic, chemically modified, double-stranded small interfering RNA (siRNA). Its molecular formula is C529H664F12N176Na43O316P43S6, and its molecular weight is 17 284.75 g/mol. The molecule comprises 32 ribonucleotides chemically modified with 2′-O-methyl-ribonucleotide (2′-O-methyl), 11 modified with 2′-fluoro-ribonucleotide (2′-fluoro), and one 2′-deoxy-ribonucleotide. The sense strand is conjugated with a triantennary N-acetylgalactosamine (GalNAc) ligand to enable targeting of hepatocytes via the asialoglycoprotein receptor (ASGPR).
Mechanism of Action: Silencing PCSK9
Inclisiran functions by interfering with RNA (genetic material) to inhibit the development of proprotein convertase subtilisin Kexin type 9 (PCSK9), a protein that can raise LDL cholesterol levels. The proprotein convertase, PCSK9, is a liver-produced and secreted serine protease whose binding and action on LDL receptors results in their increased lysosomal degradation in hepatocytes, a consequence of which is an increase in the level of circulating LDL cholesterol (and inhibition of which, the decrease in this level).
The drug’s active ingredient, inclisiran, interferes with RNA (genetic material) to inhibit the development of proprotein convertase subtilisin Kexin type 9 (PCSK9), a protein that can raise LDL cholesterol levels. In hepatocytes, inclisiran uses the RNA interference mechanism to guide catalytic mRNA breakdown for PCSK9.
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Here's a step-by-step breakdown of how inclisiran works:
- Targeting Hepatocytes: After subcutaneous administration, inclisiran is transported into the bloodstream and subsequently to the liver, the target organ. This is facilitated by the GalNAc ligand, which binds to the ASGPR expressed on the surface of hepatocyte cell membranes, inducing internalization via endocytosis.
- Endocytosis and Intracellular Trafficking: During endocytosis, inclisiran is trapped in endocytic vesicles, which fuse with endosomes/lysosomes.
- Release of siRNA: The GalNAc ligand of inclisiran is degraded, and the double-stranded siRNA is slowly released into the cytoplasm from endosomes/lysosomes, while the ASGPR is recycled to the cell surface.
- RISC Loading: The double-stranded siRNA part of inclisiran is then loaded into the RNA-induced silencing complex (RISC), which leads to the removal of the sense strand.
- mRNA Targeting and Degradation: The antisense strand containing active RISC scans for and binds to the complementary sequence in its target mRNA of PCSK9 in the cytoplasm. The RISC utilizes the catalytic slicer activity that degrades PCSK9 mRNA, resulting in less mRNA available for translation.
- Increased LDLR Availability: As a result of reduced PCSK9 levels, less PCSK9 is available to bind low-density lipoprotein cholesterol receptors (LDLR), minimizing their targeting for degradation. This leads to an increased number of LDLRs on the surface of liver cells, which can then remove more LDL-C from the bloodstream.
By blocking production of the PCSK9 enzyme, the receptors in the liver can remove more bad cholesterol (LDL-C) from the blood. This can help decrease your risk of heart disease, stroke, and heart attack.
Clinical Use and Dosage
Inclisiran is indicated as an adjunct to diet and statin therapy in adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C.
Inclisiran is given by a healthcare professional as a subcutaneous injection of 284 mg initially, again at 3 months, and then every 6 months. This infrequent dosing schedule offers convenience for patients and may improve adherence.
Clinical Trials and Efficacy
Data from phase III trials focusing on LDL-C reduction have seen early data that suggests the potential for cardiovascular benefits and a reduction in major cardiovascular events (MACEs). These cardiovascular benefits were only observed as non-adjudicated adverse events rather than pre-defined outcomes, meaning further, intentional studies are required to determine statistical significance. Landmark trials are currently underway focusing on reducing cardiovascular risk in patients with history of a MACE (ORION-4) or at high risk of one (VICTORION-2).
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Leqvio showed an effective and sustained decrease in LDL-C level of up to 52% in patients with elevated LDL-C, despite maximally tolerated statin therapy. The global ORION-9 trial was conducted at 46 sites across eight countries. In ORION-9, 482 patients with clinical or genetic evidence of HeFH were recruited. Inclisiran was administered three months after the initial dose, followed by one every six months. A total of 1,561 participants with ASCVD were enrolled in ORION-10. In the study, the patients treated with Leqvio maintained a significant reduction in LDL-C levels over a four-year period. The average reduction in LDL-C from baseline to Day 210 was 47.5%.
Side Effects
The most common adverse reaction is injection site reactions in 8% of patients, including erythema, pain, and rash. About 5% of patients have an increased arthralgia and development of antidrug antibodies to Leqvio. Lastly, approximately 4% of patients experience bronchitis during treatment. Less than 2% of patients experience myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea, and dizziness.
The most common side effects of Leqvio are listed below. Tell your health care provider if you have any of these side effects that bother you:
- Pain, itching, swelling, or redness near the injection site
- Joint pain
- Bronchitis
While less common, the most serious side effects of Leqvio are described below, along with what to do if they happen:
- Severe Allergic Reactions. Leqvio may cause allergic reactions, which can be serious. Stop using Leqvio and get help right away if you have any of the following symptoms of a serious allergic reaction:
- Breathing problems or wheezing
- Racing heart
- Fever or general ill feeling
- Swollen lymph nodes
- Swelling of the face, lips, mouth, tongue, or throat
- Trouble swallowing or throat tightness
- Itching or skin rash
- Bumps on the skin called hives that can be red, pink, white, or brown depending on your skin tone
- Nausea or vomiting
- Dizziness, feeling lightheaded, or fainting
- Stomach cramps
- Joint pain
Contraindications
People who are allergic to any of the following should not use Leqvio:
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- Leqvio
- Inclisiran
- Any of the ingredients in the specific product dispensed
Your pharmacist can tell you all of the ingredients in Leqvio.
Precautions
Leqvio is usually given by a health care provider in a hospital or clinic. This medicine is injected under the skin of the abdomen, upper arm, or thigh. Tell your health care provider if you have any skin problems where you will get the medicine. Leqvio should not be injected into painful, damaged, or infected areas of skin.
Your health care provider will likely check your low-density lipoprotein cholesterol (LDL-C) levels. Keep all appointments to have your blood checked. Diet and exercise are important when you have high LDL-C levels even when you use Leqvio. Talk with your health care provider before starting any diet or exercise program.
This medicine may be used alone or with certain other medicines to lower LDL-C. Use all medicines that are prescribed for you.
Interactions
There are no known interactions between Leqvio and foods or drinks. There are no known interactions between Leqvio and alcohol. There are no known interactions between Leqvio and other medicines. Always tell your health care provider about any prescription or over-the-counter (OTC) medicines, vitamins/minerals, herbal products, and other supplements you are using.
Market and Regulatory Approval
In October 2020, Leqvio received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use to treat adults with hypercholesterolaemia or mixed dyslipidaemia. Novartis resubmitted the NDA to the FDA in July 2021, addressing the CRL. On December 22, 2021, the Food and Drug Administration (FDA) approved Leqvio for use in the United States. Novartis successfully completed acquisition of The Medicines Company, adding a potentially first-in-class, investigational cholesterol-lowering therapy inclisiran.
Ongoing Research
VICTORION is one of the largest cardiovascular clinical trial programmes designed to generate data consistently and comprehensively. Landmark trials are currently underway focusing on reducing cardiovascular risk in patients with history of a MACE (ORION-4) or at high risk of one (VICTORION-2).
Leqvio vs Repatha
Leqvio and Repatha are both injectable medicines that are used for the treatment of high cholesterol, by specifically lowering low density lipoprotein (LDL) levels. Although they both inhibit PCSK9 they work by different mechanisms. Repatha is a monoclonal antibody that binds directly to PCSK9 in the liver preventing it from binding to LDL receptors. Leqvio blocks the PCSK9 protein by interfering with the translation of PCSK9 messenger RNA. The PCSK9 inhibitors are used for the treatment of patients with elevated cholesterol, especially when statins aren't adequate.