Inclisiran - A Tailored Approach to Cholesterol Imbalance

Overview

Inclisiran is a pharmaceutical drug prescribed for treating elevated low-density lipoprotein (LDL) cholesterol and atherosclerotic cardiovascular disease (ASCVD), particularly heterozygous familial hypercholesterolemia (a form of genetic condition manifesting with higher cholesterol levels). Inclisiran was approved for use in December 2020 in the European Union. It was sanctioned for its medical use in the United States in December 2021. The United States Food and Drug Administration (FDA) regarded this drug as a first-class medication. Subsequently. Inclisiran was approved by the National Institute for Health and Care Excellence (NICE) in the United Kingdom. The National Medical Products Administration sanctioned the medical use of Inclisiran in China in August 2023.

Drug Group:

Proprotein convertase subtilisin kexin type nine (PCSK9) is a protein involved in regulating cholesterol levels in the body. PCSK9 interference with messenger RNA (mRNA) refers to developing RNA-based therapies that target PCSK9 at the mRNA level. Using techniques like RNA interference (RNAi) or antisense oligonucleotides, these therapies aim to inhibit the production of PCSK9, ultimately reducing its levels in the bloodstream. Lowering PCSK9 levels can lead to increased clearance of low-density lipoprotein (LDL) cholesterol, offering a potential approach for treating hypercholesterolemia and cardiovascular diseases.

Available Doses and Dosage Forms:

Inclisiran injection is a clear and colorless to pallid yellow solution supplied with 284 milligrams per 1.5 milliliter packed in a carton with one single-dose prefilled syringe.

For Patients

What Is Familial Heterozygous Hypercholesterolemia?

High cholesterol, or hypercholesterolemia, is a condition signified by increased concentration of good or bad cholesterol in the blood. Cholesterol is a fatty substance crucial for building cell membranes and hormones. However, excessive amounts can accumulate in blood vessels, forming plaques that narrow and obstruct arteries, leading to atherosclerosis. This condition raises the risk of cardiovascular diseases, such as heart attacks and strokes. High cholesterol often results from a combination of genetic factors, a diet abundant in fats like saturated and trans, a lack of physical activity, and other lifestyle choices.

Heterozygous familial hypercholesterolemia (HeFH) refers to an inherited genetic condition attributed to dangerously increased cholesterol levels in the blood. This condition can eventually result in life-threatening complications like heart attack, cardiovascular disease, or stroke at a very early stage if left unaddressed.

How Does Inclisiran Work?

Inclisiran injection is used adjunctively with diet alone or with certain other cholesterol-lowering medications called statins. It aids in reducing the amount of low-density lipoprotein (LDL) cholesterol, called bad cholesterol, in the blood. It is typically prescribed for individuals with familial heterozygous hypercholesterolemia (a genetic disorder causing extremely high levels of cholesterol). It can also be prescribed with diet modifications and other therapies for reducing the LDL cholesterol levels in individuals with clinical atherosclerotic cardiovascular disease (ASCVD).

Atherosclerotic cardiovascular disease is characterized by the build-up of fatty deposits, cholesterol, and other substances within the arteries. Inclisiran medication belongs to a group of drugs called the proprotein convertase subtilisin kexin type nine (PCSK9) interfering m-ribonucleic acid (RNA). This medication functions by regulating and decreasing the LDL cholesterol concentration in the blood to eventually decrease the cholesterol level that might accumulate within the walls of the blood vessels, impeding the blood flow to the heart, lungs, brain, and other vital parts of the body.

What Is the Dosage of Inclisiran?

Inclisiran is a subcutaneous (beneath the skin) injection typically administered by healthcare professionals in a clinical setting. The dosage of Inclisiran for hypercholesterolemia in adults is 284 milligrams as one dosage initially. This is repeated every three months and then every six months thereafter.

How Effective Is Inclisiran?

Inclisiran is a novel medication designed to lower cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C), often called "bad" cholesterol. It belongs to a class of drugs known as PCSK9 inhibitors. Inclisiran works by inhibiting the PCSK9 protein, which regulates LDL-C receptors in the liver. By reducing PCSK9 activity, Inclisiran increases the number of receptors available to clear LDL-C from the bloodstream, lowering cholesterol levels. Clinical trials have shown promising results, demonstrating significant reductions in LDL-C levels. Its effectiveness lies in its unique mechanism of action, providing a potential alternative for individuals with high cholesterol who may not tolerate or respond well to traditional cholesterol-lowering medications. However, as with any medication, individual responses may vary, and ongoing research is essential to evaluate its long-term safety and effectiveness further.

What Are the Things to Inform the Doctor Before Taking Inclisiran?

• Allergy: It is crucial to inform the doctor of any previous allergic reaction to Inclisiran or any ingredient in the prescribed medication. Moreover, it uncovers the allergy to any other medication in general.

• Medications: It is also important to disclose the medication one takes or intends to take in the future. This includes prescription drugs, over-the-counter medications, nutritional supplements, vitamins, and herbal remedies.

• Medical Conditions: One must confess to the doctor about the medical illness one has or has ever had in the past few days. Be certain to inform if one has end-stage and severe liver or kidney disease.

• Pregnancy: Inform the doctor if one is pregnant, has plans to become pregnant, or is breastfeeding. Call and inform the concerned doctor if one becomes pregnant while on Inclisiran therapy.

How Is Inclisiran Administered?

• Inclisiran comes in an injection form to be given under the skin tissue of the thigh, abdomen, or upper arm.

• The healthcare provider will administer this injection in a hospital or office setting.

• One should not put an end to Inclisiran therapy without the doctor's consent. This, at times, leads to an increase in LDL cholesterol.

• Inclisiran is part of an extensive treatment program that also incorporates statin medication (cholesterol-lowering drugs), diet, and routine blood testing.

• It is crucial to follow the doctor’s prescription and advise conscientiously.

What Are the Side Effects of Inclisiran?

Inclisiran is a safe and effective drug for the treatment of high cholesterol levels in the system. However, it can cause certain undesirable reactions, like any other drug. The common side effects are as follows. These side effects usually get resolved over time. But one must seek medical attention if these reactions do not improve or distress daily life.

• Injection site reactions include rash, redness, swelling, itching, pain, warmth, and drainage at the site.

• Diarrhea.

• Pain in extremities.

Serious Side Effects:

The serious side effects of Inclisiran that require medical and supportive care include the following.

• Hives.

• Difficulty breathing.

• Swelling of the lips, face, throat, and tongue.

• Increased urge for urination.

• Blood in the urine.

• Pain with urination.

• Chest pressure.

• Fatigue.

• Mild degrees of headache.

• Body aches.

• Cough with or without mucus.

• Sore throat.

• Extreme tiredness.

It can also induce certain other serious issues. In the following cases, reaching out to the healthcare professional and getting the appropriate treatment is pivotal.

• Severe headaches, slurred speech, leg weakness, confusion, unsteadiness, stiffened muscles, loss of coordination, high fever, tremors, or excessive sweating.

• Serious eye-related concerns like blurred vision, tunnel vision (peripheral vision loss), abrupt total loss of vision, eye pain, swelling around the eyes, or enduring halos around the lights.

• Serious heart-related symptoms include pounding heartbeats, shortness of breath, lightheadedness, palpitations in the chest, or the sensation of passing out.

Dietary Considerations: One can stick to the routine classic diet unless the doctors impose dietetic restrictions. However, it is crucial to focus on a diet containing low saturated and trans fats to manage cholesterol levels. Incorporate more fruits, whole grains, vegetables, and lean proteins. It is stated that omega-3 fatty acids found in fish are beneficial. Limiting processed foods while prioritizing a balanced and heart-healthy diet is also important.

Missed Dose:

Inclisiran is an injection to be given only through the subcutaneous (immediate layer under the skin) into the upper arm, thigh, or abdomen. The Inclisiran injection is inadvertently given by healthcare professionals in a clinic setting for once initially. The dosage will be administered again within three months after the initial dose, and a schedule for every six months follows. Hence, a missed dose is less likely to happen with Inclisiran treatment. However, reach out to the doctor if one misses any appointment for an Inclisiran injection.

Overdose:

An overdose of Inclisiran is less likely to happen since a qualified healthcare professional administers it in a medical setting. However, any case of overdose can be addressed and treated abruptly with pertinent treatment.

For Doctors

Clinical Data of Inclisiran

Drug Name: Inclisiran.

Generic Name: Inclisiran.

Drug Class: Proprotein convertase subtilisin or kexin type 9 (PCSK9).

Route of Administration: Subcutaneous injection.

Chemical Formula: C529H664F12N176O316P43S6

Molar Mass: 16296.26 g.mol-1

Indication:

In the United States, Inclisiran is indicated as an adjunct treatment to diet. Addedly, it is regarded as an optimally endured statin therapy for the treatment of a genetic condition called heterozygous familial hypercholesterolemia and clinical atherosclerotic cardiovascular disease (ASCVD) in adults who require supplemental decline of low-density lipoprotein cholesterol (LDL-C).

In Europe, Inclisiran is indicated for the management of both heterozygous familial and non-familial primary hypercholesterolemia or mixed dyslipidemia (abnormal levels of lipid in the blood) as an adjunct therapy to diet in adults. This drug can also be used with a statin or other lipid-lowering agents in people whose normal low-density cholesterol levels are not attained with the maximum tolerated dose of a statin. Moreover, Inclisiran can be used as an exclusive therapy for individuals who cannot tolerate statins or certain circumstances associated with statin contraindications.

Associated Conditions:

• Atherosclerotic cardiovascular disease.

• Heterozygous familial hypercholesterolemia (HeFH).

• Mixed dyslipidemia.

• Primary hypercholesterolemia.

Dose:

The drug Inclisiran is available as an injectable subcutaneous solution with a dosage of 284 milligrams per 1.5 milliliters in a pre-filled syringe.

For Hypercholesterolemia:

• Inclisiran is indicated as an adjunct treatment to diet and conventional statin therapy for primary hypercholesterolemia, incorporating heterozygous familial hypercholesterolemia in adults. It helps reduce the low-density lipoprotein cholesterol levels in the system.

• The recommended dosage is 284 milligrams subcutaneously for one time.

• The standard dosage is repeated over three months and then every six months.

Dosage Modifications:

Renal Impairment:

• No dosage adjustment of Inclisiran is required for mild, moderate, or severe renal impairment.

Hepatic Impairment:

• No dosage adjustment of Inclisiran is necessary in mild and moderate cases of hepatic impairment.

• The safety and efficacy of Inclisiran in severe hepatic impairment cases have not been studied.

Dosing Considerations:

• Monitoring Parameters: Assessing the low-density lipoprotein cholesterol levels is crucial when clinically necessary. Assessment of LDL levels can be considered as early as thirty days after Inclisiran treatment initiation.

• Limitation of Use: The effect of Inclisiran on cardiovascular health, including mortality and morbidity, has not been determined.

What Are the Pharmacological Aspects of Inclisiran?

Pharmacodynamics

Inclisiran is a long-acting and small interfering ribonucleic acid (RNA) that functions to decrease the plasma low-density cholesterol levels in the system. Clinical trial studies show that the marked reduction was notable within 14 days following the last dose. The average reductions of low-density cholesterol levels by about 48 to 50 percent were noticed in one to two months following the dose. A decline in LDL cholesterol levels by 53 percent persisted after 180 days of the dose. Inclisiran has been shown to reduce LDL cholesterol levels by 28 to 52 percent in clinical trials investigating individuals with atherosclerotic cardiovascular disease with and without diabetes.

Therefore, though the reduction in low-density cholesterol levels has been attributed to the reduction of cardiovascular risks, the long-term impact of Inclisiran on cardiovascular health has not yet been determined.

Mechanism of Action:

Small interfering ribonucleic acid (so-RNA) is transferred to the proprotein convertase subtilisin kexin type nine (PCSK9). Inclisiran is typically conjugated on this strand type in conjunction with triantennary N-acetylgalactosamine to facilitate effective hepatocyte uptake.

Low-density lipoprotein cholesterol is eliminated from the circulation substantially by means of the LDL receptor pathway. PCSK9 is a form of serine protease that slays the low-density lipoprotein receptor in the liver, contributing to a state of reduced LDL cholesterol clearance and raised plasma LDL cholesterol.

Inclisiran is known to utilize the ribonucleic acid interference process and facilitate the catalytic breakdown of mRNA in hepatocytes for PCSK9. As a result, the LDL cholesterol recycling mechanism and their expression on the hepatocyte's surface are significantly uplifted. This, in turn, results in increased LDL cholesterol uptake, reducing the overall LDL cholesterol level in the circulation.

Pharmacokinetics

Absorption:

• Inclisiran shows a prolonged duration of action after its uptake into the liver.

• Systemic exposure to Inclisiran is raised in a dose-proportional manner following a subcutaneous administration of a single dosage of Inclisiran (24 to 756 milligrams).

• The mean peak serum concentration (Cmax) of Inclisiran is determined to be 509 ng/mL. The time to attain peak serum concentration is about four hours after administering a dosage of 284 milligrams.

• The mean area under the curve (AUC) of Inclisiran is 7980 ng/mL.

• The plasma concentrations of Inclisiran were imperceptible after 48 hours of dosing.

• The pharmacokinetic findings of Inclisiran following a single dosage and multiple doses are of equivalent quality.

Distribution:

• The presumed volume of distribution was nearly 500 liters following subcutaneous administration of a single 284-milligram dosage of Inclisiran in healthy individuals.

• Inclisiran is significantly taken up by the liver, as per the non-clinical studies.

Metabolism:

• Inclisiran undergoes metabolization by nucleases to transform into smaller nucleotides of distinct lengths.

• However, the nucleotides are not expected to be substrates for cytochrome P450 enzymes.

• The protein binding capacity of Inclisiran is 87 percent and is clinically pertinent to plasma concentrations.

Elimination:

• The clinical findings show that nearly 16 percent of the total Inclisiran dosage is eliminated through the kidney.

Half-Life and Clearance:

• The terminal half-life period of Inclisiran is determined to be nine hours.

• There needs to be more extensive and appropriate information on the clearance process and rate of Inclisiran.

Toxicity:

• There is no or limited data about the median lethal dose (LD50) values of Inclisiran.

• The clinical trials show no clinically significant adverse reactions in healthy people who endured Inclisiran at a certain dosage up to three times.

• It is recommended to initiate the symptomatic and supportive measures promptly if there is any suspicion of overdose adverse reaction.

Adverse Effects:

Inclisiran can induce certain less severe adverse reactions. The following are the potential and rare adverse effects of Inclisiran, accounting for one to ten percent of cases.

• Arthralgia (pain in the joint).

• Injection site reactions.

• Diarrhea.

• Bronchitis.

• Pain in extremities.

• Dyspnea (shortness of breath).

• Urinary tract infection.

Clinical Studies: Clinical trials assessing the safety and efficacy of Inclisiran in individuals with high cholesterol levels have contributed valuable insights into its potential as a cholesterol-lowering medication. In the pivotal ORION clinical trial program, which includes ORION-9, ORION-10, and ORION-11 trials, researchers investigated the impact of Inclisiran on LDL-C reduction. These trials involved a diverse population, including patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who had elevated LDL-C levels despite maximally tolerated statin therapy.

Results from these trials demonstrated that Inclisiran consistently and significantly lowered LDL-C levels when administered as a subcutaneous injection with a biannual dosing schedule. The safety profile of Inclisiran appeared favorable, with a low incidence of adverse events. Common side effects included mild injection site reactions, but overall, the incidence of adverse effects was comparable to the control groups. Importantly, the sustained reduction in LDL-C observed in these studies suggests a potential long-term benefit for individuals with high cholesterol.

The outcomes of these clinical trials underscore Inclisiran's promise as an innovative approach to managing high cholesterol levels, offering a novel option for individuals who may face challenges with existing treatments. As research continues, ongoing monitoring and exploration of Inclisiran's safety and efficacy will be crucial for a comprehensive understanding of its role in cardiovascular risk management.

Administration of Inclisiran:

• Injections are to be strictly administered by a healthcare professional.

• Administer Inclisiran subcutaneously into the upper arm, abdomen, or thigh.

• Refrain from injecting Inclisiran into the areas of any active skin infection, disease, or injury, like skin rashes, inflammation, and pruritus.

• It is crucial to inspect the area of injection before any use.

• The Inclisiran injection seems clear and colorless to pallid yellow. Discarding the solution in the presence of particulate matter or discoloration is advisable.

Missed Dose:

• Less Than Three Months: Administer Inclisiran subcutaneously and maintain the dosing and other things according to the routine schedule.

• Greater Than Three Months: It is stated to restart with a new dosing Inclisiran schedule. Hence, administer the initial dose of Inclisiran, repeat the dosing at three months, and then every six months.

Storage:

Store Inclisiran injections at a controlled or regulated room temperature of nearly 68 to 77 Fahrenheit. The allowable excursion for storage can be between 59 and 86 Fahrenheit.

Drug Interactions:

The drug, Inclisiran, is not determined to have any clinically significant effects or interactions with other drugs.

Specific Considerations:

• Pediatrics: The safety and efficacy of Inclisiran in children have not yet been studied and determined.

• Pregnancy: No clinical data is available on the use of Inclisiran in pregnant women and the drug-ass paired risks, including miscarriage, major birth defects, or any adverse fetal outcome. However, Inclisiran treatment might cause harm to the fetus based on the mechanism of action. Hence, it is preferable to discontinue the treatment as soon as the pregnancy is recognized.

• Lactation: No data presents information on the passing of Inclisiran drugs in human milk and their associated effects on infants. Nevertheless, the studies show that Inclisiran was determined in the milk of lactating rats. So, it is also practicable for humans. Consideration is to be taken for Inclisiran use in lactating women.