LEQVIO
inclisiran
Quick Facts
Brand Name
LEQVIO
Generic Name
inclisiran
Indication
LEQVIO is used with diet and exercise to lower bad cholesterol (LDL-C) in: Adults with high cholesterol; Adults and children ages 12 and older with heterozygous familial hypercholesterolemia (HeFH).
Key Contraindications
LEQVIO should not be used in patients who have had a serious allergic reaction to inclisiran or any other ingredients in LEQVIO. Serious allergic reactions include anaphylaxis and angioedema.
Common Side Effects
injection site reaction (8%), arthralgia (5%), bronchitis (4%)
How to Take
The dose is 284 mg given as a shot under the skin. First dose, then another dose at 3 months, then every 6 months after that.
LEQVIO is used with diet and exercise to lower bad cholesterol (LDL-C) in:
– Adults with high cholesterol
– Adults and children ages 12 and older with heterozygous familial hypercholesterolemia (HeFH)
– Children ages 12 and older with homozygous familial hypercholesterolemia (HoFH)
LEQVIO® is indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in:
• adults with hypercholesterolemia.
• adults and pediatric patients aged 12 years and older with heterozygous familial hypercholesterolemia (HeFH).
• pediatric patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH).
Recommended Dose
– The dose is 284 mg given as a shot under the skin. First dose, then another dose at 3 months, then every 6 months after that.
– If you miss a dose by less than 3 months, give the dose right away. Keep the same schedule.
– If you miss a dose by more than 3 months, start over. Give the first dose, then another at 3 months, then every 6 months.
– Your doctor may check your cholesterol as needed. The medicine starts working about 30 days after the first dose.
How to Give the Shot
– A healthcare professional should give this injection.
– Give the shot under the skin in the belly, upper arm, or thigh. Do not give the shot in areas with skin problems or injury, such as sunburn, skin rashes, swelling, or skin infections.
– Look at the medicine before use. It should look clear, with no color or a slight yellow color. Do not use if you see particles or the color looks wrong.
2.1 Recommended Dosage
• The recommended dosage of LEQVIO for adults and pediatric patients aged 12 years and older is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months.
• If a planned dose is missed by less than 3 months, administer LEQVIO and maintain dosing according to the patient’s original schedule.
• If a planned dose is missed by more than 3 months, restart with a new dosing schedule – administer LEQVIO initially, again at 3 months, and then every 6 months.
• Assess LDL-C when clinically indicated. The LDL-lowering effect of LEQVIO may be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose.
2.2 Important Administration Instructions
• LEQVIO should be administered by a healthcare professional.
• Inject LEQVIO subcutaneously into the abdomen, upper arm, or thigh. Do not inject in areas of active skin disease or injury, such as sunburns, skin rashes, inflammation, or skin infections.
• Inspect LEQVIO visually before use. It should appear clear and colorless to pale yellow. Do not use if particulate matter or discoloration is seen.
For more detailed instruction on administration of the prefilled syringe, see Instructions for Use.
Injection
Shot: 284 mg in 1.5 mL of inclisiran. The liquid is clear or pale yellow. It comes in a prefilled syringe for one dose.
Injection: 284 mg/1.5 mL (189 mg/mL) of inclisiran as a clear, and colorless to pale yellow solution in a single-dose prefilled syringe.
When Not to Use This Medicine
LEQVIO should not be used in patients who have had a serious allergic reaction to inclisiran or any other ingredients in LEQVIO. Serious allergic reactions include anaphylaxis and angioedema.
LEQVIO is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any of the excipients in LEQVIO. Serious hypersensitivity reactions have included anaphylaxis and angioedema [see Adverse Reactions (6.2)].
Hypersensitivity Reactions
Allergic reactions, including serious ones, have happened in patients taking LEQVIO. Tell your doctor right away if you have signs of an allergic reaction like:
– Hives or itching
– Trouble breathing
– Swelling of your face, lips, tongue, or throat
If you had a serious allergic reaction to LEQVIO or any of its ingredients before, you should not take this medicine.
5.1 Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients treated with LEQVIO [see Adverse Reactions (6.2)]. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to seek medical attention promptly. LEQVIO is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any of the excipients in LEQVIO.
Adverse Reactions
Other side effects are discussed in other parts of the label:
– Hypersensitivity Reactions [see Warnings and Precautions]
Clinical Trials Experience
Studies were done under different conditions, so results from one study cannot be compared directly to other studies.
Side Effects in Adults with High Cholesterol
Data came from 3 studies with 1,833 adults with high cholesterol. Most people took the medicine for about 77 weeks (over 1 year). The average age was 64 years. Most patients were White. About 12% had a type of high cholesterol called HeFH, and 85% had heart disease.
Side effects that happened in at least 3% of patients taking LEQVIO, and more often than with placebo (inactive pill), are shown in Table 1.
Table 1: Side Effects in Adults with High Cholesterol
Side Effects | Placebo (1,822 patients) | LEQVIO (1,833 patients)
Injection site reaction | 2% | 8%
Joint pain | 4% | 5%
Bronchitis | 3% | 4%
About 2.5% of patients stopped taking LEQVIO because of side effects, compared to 1.9% with placebo. The most common reason for stopping was injection site reactions.
Side Effects in Pediatric Patients with HeFH
A 24-month study tested LEQVIO in 141 pediatric patients aged 12 years and older with HeFH. The first 12 months compared LEQVIO to placebo. The next 12 months, all patients received LEQVIO. Side effects in children were similar to adults, except more children reported headaches. Headaches affected 13% of children taking LEQVIO versus 6% on placebo.
Side Effects in Pediatric Patients with HoFH
A 24-month study tested LEQVIO in 13 pediatric patients aged 12 years and older with HoFH. Side effects were similar to adults with high cholesterol.
Side Effects After Approval
Additional side effects have been reported since the drug was approved. These include:
– Severe allergic reactions (anaphylaxis)
– Swelling
– Rash
– Itching
– Hives
These reactions were reported voluntarily, so it is not known how often they happen.
| Adverse Reactions | Placebo (N = 1,822)
% |
LEQVIO (N = 1,833)
% |
|---|---|---|
| †includes related terms such as: injection site pain, erythema and rash | ||
| Injection site reaction† | 2 | 8 |
| Arthralgia | 4 | 5 |
| Bronchitis | 3 | 4 |
The following adverse reactions are also discussed in other sections of the label:
• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
| Adverse Reactions | Placebo (N = 1,822)
% |
LEQVIO (N = 1,833)
% |
|---|---|---|
| †includes related terms such as: injection site pain, erythema and rash | ||
| Injection site reaction† | 2 | 8 |
| Arthralgia | 4 | 5 |
| Bronchitis | 3 | 4 |
Risk Summary
Stop taking LEQVIO if you become pregnant. This drug lowers cholesterol in your blood. Cholesterol is needed for a developing baby. So LEQVIO may harm an unborn baby.
There are no studies in pregnant women. We don’t know if this drug causes birth defects or miscarriage.
Animal Studies
Studies in pregnant rats and rabbits showed no harm to the babies. The doses tested were 5 to 10 times higher than the human dose.
Background Risk
In general, 2 to 4 out of 100 pregnancies have birth defects. And 15 to 20 out of 100 pregnancies end in miscarriage. We don’t know if LEQVIO changes these risks.
Animal Data
In rats and rabbits, pregnant animals received LEQVIO shots daily during organ formation. No harm to the babies was seen at doses up to 5 to 10 times the human dose.
In another study, pregnant rats received LEQVIO through pregnancy and nursing. The babies grew normally. They had normal development, behavior, and ability to have babies. This was seen at doses up to 5 times the human dose.
Risk Summary
Discontinue LEQVIO when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Inclisiran increases LDL-C uptake and lowers LDL-C levels in the circulation, thus decreasing cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LEQVIO may cause fetal harm when administered to pregnant patients based on the mechanism of action[see Clinical Pharmacology (12.1)]. In addition, treatment of hypercholesterolemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of hypercholesterolemia for most patients.
There are no available data on the use of LEQVIO in pregnant patients to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
In animal reproduction studies, no adverse developmental effects were observed in rats and rabbits with subcutaneous administration of inclisiran during organogenesis at doses up to 5 to 10 times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison (see Data). No adverse developmental outcomes were observed in offspring of rats administered inclisiran from organogenesis through lactation at 5 times the MRHD based on BSA comparison (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
Data
Animal Data
In embryo-fetal development studies conducted in Sprague-Dawley rats and New Zealand White rabbits, inclisiran was administered by subcutaneous injection at dose levels of 50, 100, and 150 mg/kg once daily during organogenesis (rats: Gestation Days 6 to 17; rabbits: Gestation Days 7 to 19). There was no evidence of embryo-fetal toxicity or teratogenicity at doses up to 5 and 10 times, respectively, the MRHD based on BSA comparison/dose. Inclisiran crosses the placenta and was detected in rat fetal plasma at concentrations that were 65 to 154 times lower than maternal levels.
In a pre- and postnatal development study conducted in Sprague-Dawley rats, inclisiran was administered once daily by subcutaneous injection at levels of 50, 100, and 150 mg/kg from Gestation Day 6 through Lactation Day 20. Inclisiran was well-tolerated in maternal rats, with no evidence of maternal toxicity and no effects on maternal performance. There were no effects on the development of the F1 generation, including survival, growth, physical and reflexological development, behavior, and reproductive performance at doses up to 5 times the MRHD, based on BSA comparison/dose.
Risk Summary
There is no information on whether inclisiran passes into human breast milk or how it might affect a breastfeeding baby. Studies in rats showed the drug passes into breast milk. When a drug is found in animal milk, it is likely to be found in human milk too. The drug is not easily absorbed by the mouth, so it is unlikely to harm a breastfeeding baby. The benefits of breastfeeding for the baby should be weighed against the mother’s need for LEQVIO.
Data
In rats, inclisiran was found in breast milk. The amount in milk was lower than in the mother’s blood. There was no sign that the baby rats absorbed the drug into their bodies.
Risk Summary
There is no information on the presence of inclisiran in human milk, the effects on the breastfed infant, or the effects on milk production. Inclisiran was present in the milk of lactating rats in all dose groups. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Oligonucleotide-based products typically have poor oral bioavailability; therefore, it is considered unlikely that low levels of inclisiran present in milk will adversely impact an infant’s development during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEQVIO and any potential adverse effects on the breastfed infant from LEQVIO or from the underlying maternal condition.
Data
In lactating rats, inclisiran was detected in milk at mean maternal plasma: milk ratios that ranged between 0.361 and 1.79. However, there is no evidence of systemic absorption in the suckling rat neonates.
HeFH in Patients 12 and Older
LEQVIO is approved for teens ages 12 and older with HeFH (a type of high cholesterol that runs in families). It is used with diet and other cholesterol medicines. This approval was based on a study of 141 teens with HeFH that lasted 12 months. Adult studies also supported this use. The side effects in teens were similar to adults. The main difference was headache[see Adverse Reactions (6.1), Clinical Studies (14)].
HoFH in Patients 12 and Older
LEQVIO is also approved for teens ages 12 and older with HoFH (another type of inherited high cholesterol). This approval was based on a study of 13 teens with HoFH that lasted 12 months[see Adverse Reactions (6.1), Clinical Studies (14)].
Patients Under 12
LEQVIO is not approved for children younger than 12 years old with HeFH or HoFH. It is also not approved for children with other types of high cholesterol.
The safety and effectiveness of LEQVIO as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HeFH have been established in pediatric patients aged 12 years and older. Use of LEQVIO for this indication is based on data from a 12-month, randomized, placebo-controlled, double-blind study in 141 pediatric patients with HeFH. This indication is also supported by evidence from an adequate and well-controlled study in adults with HeFH. The safety profile reported in pediatric patients aged 12 years and older with HeFH was consistent with adult patients with hypercholesterolemia, with the exception of headache[see Adverse Reactions (6.1), Clinical Studies (14)].
The safety and effectiveness of LEQVIO as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HoFH have been established in pediatric patients aged 12 years and older. Use of LEQVIO for this indication is based on data from a 12-month, randomized, placebo-controlled, double-blind study in 13 pediatric patients with HoFH[see Adverse Reactions (6.1), Clinical Studies (14)].
The safety and effectiveness of LEQVIO have not been established in pediatric patients with HeFH or HoFH younger than 12 years of age. The safety and effectiveness of LEQVIO has not been established in pediatric patients with other types of hypercholesterolemia.
Older Patients in Studies
Of 1,833 patients who took LEQVIO in studies, 981 (54%) were 65 or older, and 239 (13%) were 75 or older.
Safety and Effectiveness
The medicine worked the same way and was equally safe for older patients and younger patients.
Of the 1,833 patients treated with LEQVIO in clinical trials, 981 (54%) patients were 65 years of age and older, while 239 (13%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.
Kidney Problems
No dose changes are needed for patients with mild, moderate, or severe kidney problems. LEQVIO has not been studied in patients with end stage kidney disease.
No dose adjustments are necessary for patients with mild, moderate, or severe renal impairment[see Clinical Pharmacology (12.3)]. LEQVIO has not been studied in patients with end stage renal disease[see Clinical Pharmacology (12.3)].
Liver Problems
No dose change is needed for patients with mild to moderate liver problems. LEQVIO has not been studied in patients with severe liver problems.
No dose adjustment is necessary in patients with mild to moderate hepatic impairment. LEQVIO has not been studied in patients with severe hepatic impairment[see Clinical Pharmacology (12.3)].
What LEQVIO Contains
LEQVIO contains inclisiran sodium. This is a small interfering RNA (siRNA) medicine. It targets the PCSK9 protein in the body. Inclisiran has a special sugar (called GalNAc) attached that helps it reach liver cells. Most parts of inclisiran are modified with fluorine or methyl groups. Some parts have special linkages (phosphorothioate) for stability.
Molecular Details
The molecular formula is C529H664F12N176Na43O316P43S6. The molecular weight is 17,284.72 g/mol.
What It Looks Like
LEQVIO is a clear, colorless to pale yellow liquid. It is sterile and contains no preservatives. It comes in a prefilled syringe for injection under the skin. Each syringe contains 1.5 mL of solution with 284 mg of inclisiran (equivalent to 300 mg inclisiran sodium salt). The solution is made with Water for Injection and may contain small amounts of sodium hydroxide or phosphoric acid to adjust the pH to 7.0.
LEQVIO contains inclisiran sodium, a small interfering RNA (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9) mRNA. Inclisiran contains a covalently linked ligand containing three N-acetylgalactosamine (GalNAc) residues to facilitate delivery to hepatocytes. With one exception, the 2’ribose moieties of the inclisiran sodium are present as 2′-F or 2′-OMe ribonucleotide. In addition, six of the terminal phosphodiester backbones are present as phosphorothioate linkages as indicated below.
The molecular formula of inclisiran sodium is C529H664F12N176Na43O316P43S6 and its molecular weight is 17,284.72 g/mol. It has the following structural formula:
Abbreviations: Af = adenine 2′-F ribonucleotide; Cf = cytosine 2′-F ribonucleotide; Gf = guanine 2′-F ribonucleotide; Am = adenine 2′-OMe ribonucleotide; Cm = cytosine 2′-OMe ribonucleotide; Gm = guanine 2′-OMe ribonucleotide; Um = uracil 2′-OMe ribonucleotide; L96 = triantennary GalNAc (N-acetyl-galactosamine)
LEQVIO is a sterile, preservative-free, clear, and colorless to pale yellow solution for subcutaneous use in a prefilled syringe. Each syringe contains 1.5 mL of solution containing the equivalent of 284 mg inclisiran (present as 300 mg inclisiran sodium salt). LEQVIO is formulated in Water for Injection and may also contain sodium hydroxide and/or phosphoric acid for pH adjustment to a target pH of 7.0.
How This Medicine Works
Inclisiran is a medicine that lowers LDL (bad) cholesterol. It works inside liver cells to reduce a protein called PCSK9. When this protein is reduced, more cholesterol receptors become active on liver cells. These receptors remove LDL cholesterol from the blood, which lowers LDL cholesterol levels.
Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.
How This Medicine Works
After one injection of 284 mg of inclisiran, LDL cholesterol (the “bad” cholesterol) starts to go down within 14 days. Over the next 30 to 180 days, LDL cholesterol dropped by 38% to 51%. At 180 days (about 6 months), LDL cholesterol was still about 53% lower.
After doses on Day 1 and Day 90 of 284 mg inclisiran, PCSK9 protein levels went down by about 75% at Day 120 and 69% at Day 180.
In clinical studies, after four doses given at Day 1, Day 90 (3 months), Day 270 (6 months), and Day 450 (12 months), LDL cholesterol, total cholesterol, ApoB, and non-HDL cholesterol were all lowered.
Heart Safety
At a dose 3 times higher than the recommended dose, inclisiran does not cause any meaningful change in heart rhythm.
Following a single subcutaneous administration of 284 mg of inclisiran, LDL-C reduction was apparent within 14 days post dose. Mean reductions of 38% to 51% for LDL-C were observed 30 to 180 days post dose. At Day 180, LDL-C levels were still reduced by approximately 53%.
Following a dose at Day 1 and Day 90 of 284 mg of inclisiran, mean serum PCSK9 levels were reduced by approximately 75% and 69% at Day 120, and Day 180, respectively.
In the clinical trials, following four doses of LEQVIO at Day 1, Day 90 (3 months), Day 270 (~6 months) and Day 450 (~12 months), LDL-C, total cholesterol, ApoB, and non-HDL-C were reduced[see Clinical Studies (14)].
Cardiac Electrophysiology
At a dose 3 times the maximum recommended dose, inclisiran does not prolong the QT interval to any clinically relevant extent.
Absorption
After a single injection under the skin, the amount of medicine in your blood increases with the dose. With the standard dose of 284 mg, the highest level in your blood is reached in about 4 hours. The medicine is mostly gone from your blood within 24 to 48 hours after the dose. The body absorbs the medicine in a predictable way. Taking more doses works the same as a single dose.
Distribution
About 87% of the medicine binds to proteins in your blood. The medicine spreads through your body to reach about 500 liters of fluid. It goes mainly to your liver, which is the organ that lowers cholesterol.
Elimination
The medicine stays in your body for about 9 hours on average. No buildup occurs when you take doses more often.
Metabolism
Your body breaks down the medicine into smaller pieces using natural enzymes called nucleases. The medicine is not processed by liver enzymes called CYP450.
Excretion
About 16% of the medicine leaves your body through your kidneys.
Specific Populations
Age, body weight, gender, race, and kidney function do not significantly change how this medicine works in your body.
Children
The medicine works the same in children age 12 and older as it does in adults.
Kidney Problems
In patients with kidney problems, more medicine stays in the blood. However, the medicine still lowers cholesterol the same amount.
Liver Problems
In patients with mild to moderate liver problems, more medicine stays in the blood. The medicine still lowers cholesterol in patients with mild liver problems. In patients with moderate liver problems, the effect on cholesterol is slightly less. This medicine has not been studied in patients with severe liver problems.
Drug Interactions
This medicine does not interact with other common cholesterol medicines like atorvastatin or rosuvastatin. It is not expected to cause drug interactions.
Absorption
Following a single subcutaneous administration, systemic exposure to inclisiran increased in a linear and dose proportional manner over a range from 25 mg to 800 mg of inclisiran sodium. At the recommended dosing regimen of 284 mg of LEQVIO, plasma concentrations reached peak in approximately 4 hours post dose with a mean Cmaxof 509 ng/mL. Concentrations reached undetectable levels after 24 to 48 hours post dosing. The mean area under the plasma concentration-time curve from dosing extrapolated to infinity was 7,980 ng*h/mL. Pharmacokinetic findings following multiple subcutaneous administrations of LEQVIO were similar to single-dose administration.
Distribution
Inclisiran is 87% protein boundin vitroat the relevant clinical plasma concentrations. Following a single subcutaneous 284 mg dose of LEQVIO to healthy adults, the apparent volume of distribution is approximately 500 L. Inclisiran has been shown to have high uptake into, and selectively for the liver, the target organ for cholesterol lowering.
Elimination
The terminal elimination half-life of LEQVIO is approximately 9 hours, and no accumulation occurs with multiple dosing.
Metabolism
Inclisiran is primarily metabolized by nucleases to shorter nucleotides of varying length. Inclisiran is not a substrate for CYP450 or transporters.
Excretion
Approximately 16% of LEQVIO is cleared through the kidney.
Specific Populations
Male and Female Patients and Racial or Ethnic Groups
A population pharmacodynamic analysis was conducted on data from 4,328 patients. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence inclisiran pharmacokinetics.
Pediatric Patients
The pharmacokinetics of LEQVIO were evaluated in pediatric patients aged 12 years and older with HeFH (Trial 4) or HoFH (Trial 5)[see Use in Specific Populations (8.4), Clinical Studies (14)]. Inclisiran plasma concentrations in pediatric patients at the clinically recommended dose were similar to adults.
Patients with Renal Impairment
Pharmacokinetic analysis of data from a dedicated renal impairment study reported increases in inclisiran Cmaxand AUC of approximately 2.3 to 3.3-fold and 1.6 to 2.3-fold, respectively, in patients with mild, moderate or severe renal impairment, relative to patients with normal renal function. Despite the higher plasma exposures, reductions in LDL-C were similar across all groups based on renal function.
Patients with Hepatic Impairment
Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported increases in inclisiran Cmaxand AUC of approximately 1.1- to 2.1-fold and 1.3- to 2.0-fold, respectively, in patients with mild and moderate hepatic impairment, relative to patients with normal hepatic function. Despite the higher plasma inclisiran exposures, reductions in LDL-C were similar between the groups of patients administered inclisiran with normal hepatic function and mild hepatic impairment. In patients with moderate hepatic impairment, baseline PCSK9 levels were lower and reductions in LDL-C were less than those observed in patients with normal hepatic function. LEQVIO has not been studied in patients with severe hepatic impairment.
Drug Interaction Studies
No formal clinical drug interaction studies have been performed. The components of LEQVIO are not substrates, inhibitors or inducers of cytochrome P450 enzymes or transporters. In a population pharmacokinetic analysis, concomitant use of inclisiran did not have a clinically significant impact on atorvastatin or rosuvastatin concentrations. LEQVIO is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes or transporters.
[med_microbiology]
[med_pharmacogenomics]
[med_immunogenicity]
[med_references]
Adults with Primary Hypercholesterolemia or HeFH
LEQVIO was studied in 3 main studies with 3,660 adults. All adults had high cholesterol and were already taking cholesterol medicine (statins) but needed more help lowering their LDL (bad) cholesterol. The studies compared LEQVIO to a placebo (inactive treatment).
Trial 1 – Adults with Heart Disease
Trial 1 (ORION-10) included 1,561 adults with heart disease. Patients received LEQVIO 284 mg or placebo as injections under the skin on Day 1, Day 90, Day 270, and Day 450. All patients were taking the highest dose of statin they could tolerate.
Patient details:
– Average age: 66 years
– 60% were 65 years or older
– 31% were female
– 45% had diabetes
– Average LDL-C at start: 105 mg/dL
– 89% were taking statin therapy
Results:
LEQVIO lowered LDL-C by 52% more than placebo at Day 510 (p < 0.0001).
Trial 2 – Adults with Heart Disease or High Risk
Trial 2 (ORION-11) included 1,617 adults with heart disease or high risk for heart disease. Patients received LEQVIO 284 mg or placebo as injections on Day 1, Day 90, Day 270, and Day 450.
Patient details:
– Average age: 65 years
– 55% were 65 years or older
– 28% were female
– 35% had diabetes
– Average LDL-C at start: 105 mg/dL
Results:
LEQVIO lowered LDL-C by 50% more than placebo at Day 510 (p < 0.0001).
Trial 3 – Adults with HeFH
Trial 3 (ORION-9) included 482 adults with HeFH (a genetic form of high cholesterol). Patients received LEQVIO 284 mg or placebo as injections on Day 1, Day 90, Day 270, and Day 450.
Patient details:
– Average age: 55 years
– 22% were 65 years or older
– 53% were female
– 10% had diabetes
– Average LDL-C at start: 153 mg/dL
– 52% were also taking ezetimibe
Results:
LEQVIO lowered LDL-C by 48% more than placebo at Day 510 (p < 0.0001).
Trial 4 – Children with HeFH
Trial 4 (ORION-16) included 141 children ages 12 years and older with HeFH. Patients received LEQVIO 284 mg or placebo as injections on Day 1, Day 90, and Day 270.
Patient details:
– Average age: 15 years
– 53% were female
– Average LDL-C at start: 183 mg/dL
– 93% were taking statins
Results:
LEQVIO lowered LDL-C by 29% more than placebo at Day 330 (p < 0.0001).
Trial 5 – Children with HoFH
Trial 5 (ORION-13) included 13 children ages 12 years and older with HoFH (a severe genetic form of high cholesterol). Patients received LEQVIO 284 mg or placebo as injections on Day 1, Day 90, and Day 270.
Patient details:
– Average age: 15 years
– 69% were female
– Average LDL-C at start: 272 mg/dL
Results:
LEQVIO lowered LDL-C by 33% more than placebo at Day 330. This study was very small and could not prove definite results.
| Treatment Group | LDL-C | Total Cholesterol |
Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a11.5% of subjects on LEQVIO and 14.6% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using a mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value. Missing data were imputed using a control-based pattern-mixture model approach. |
||||
| Day 510 (mean percentage change from baseline)a | ||||
| Placebo (n = 780) | 1 | 0 | 0 | -2 |
| LEQVIO (n = 781) | -51 | -34 | -47 | -45 |
| Difference from placebo (LS Mean) (95% CI) | -52 (-56, -49) |
-33 (-35, -31) |
-47 (-50, -44) |
-43 (-46, -41) |
| Treatment Group | LDL-C | Total Cholesterol |
Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a10.6% of subjects on LEQVIO and 8.4% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value. Missing data were imputed using a control-based pattern-mixture model approach. |
||||
| Day 510 (mean percentage change from baseline)a | ||||
| Placebo (n = 807) | 4 | 2 | 2 | 1 |
| LEQVIO (n = 810) | -46 | -28 | -41 | -38 |
| Difference from placebo (LS Mean) (95% CI) | -50 (-53, -47) |
-30 (-32, -28) |
-43 (-46, -41) |
-39 (-41, -37) |
| Treatment Group | LDL-C | Total Cholesterol |
Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a4.5% of subjects on LEQVIO and 4.6% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value as a covariate. Missing data were imputed using a control-based pattern-mixture model approach. |
||||
| Day 510 (mean percentage change from baseline)a | ||||
| Placebo (n = 240) | 8 | 7 | 7 | 3 |
| LEQVIO (n = 242) | -40 | -25 | -35 | -33 |
| Difference from placebo (LS Mean) (95% CI) | -48 (-54, -42) |
-32 (-36, -28) |
-42 (-47, -37) |
-36 (-40, -32) |
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a3.2% of subjects on LEQVIO and 0% of subjects on placebo had missing LDL-C data at primary endpoint (Day 330). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effects for treatment group and baseline age group, and baseline LDL-C as a covariate. Other endpoints were analyzed using same approach. |
||||
| Day 330 (mean percentage change from baseline)a | ||||
| Placebo (n = 48) | 1 | 4 | 2 | 0 |
| LEQVIO (n = 93) | -27 | -21 | -25 | -19 |
| Difference from placebo (LS Mean) (95% CI) | -29 (-36, -21) | -26 (-32, -20) | -27 (-34, -20) | -19 (-25, -14) |
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
The trial was designed as a descriptive trial and was not powered to test any hypothesis. aNo subject in either LEQVIO or placebo had missing LDL-C data at primary endpoint (Day 330). No statistical model was performed. The mean and 95% CI of the difference from placebo were calculated based on a t-distribution for the percent change from baseline in LDL-C and other endpoints. |
||||
| Day 330 (mean percentage change from baseline)a | ||||
| Placebo (n = 4) | 12 | 5 | 9 | 9 |
| LEQVIO (n = 9) | -22 | -19 | -23 | -19 |
| Difference from placebo (Mean) (95% CI) | -33 (-80, 13) | -23 (-50, 4) | -33 (-87, 22) | -28 (-75, 19) |
Adults with Primary Hypercholesterolemia or HeFH
The efficacy of LEQVIO was investigated in three randomized, double-blind, placebo-controlled trials that enrolled 3,660 adults with HeFH, clinical ASCVD, or increased risk for ASCVD, who were taking maximally tolerated statin therapy and who required additional LDL-C lowering. Demographics and baseline disease characteristics were balanced between the treatment arms in all trials.
Adults with Primary Hypercholesterolemia
Trial 1 (ORION-10, NCT03399370) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 1,561 adults with ASCVD were randomized 1:1 to receive subcutaneous injections of either LEQVIO 284 mg (n = 781) or placebo (n = 780) on Day 1, Day 90, Day 270, and at Day 450. Patients were taking a maximally tolerated dose of statin with or without other lipid modifying therapy and required additional LDL-C reduction. Patients were stratified by current use of statins or other lipid-modifying therapies. Patients taking PCSK9 inhibitors were excluded from the trial.
The mean age at baseline was 66 years (range: 35 to 90 years), 60% were ≥65 years old, 31% were female, 86% were White, 13% were Black or African American, 1% were Asian, and 14% identified as Hispanic or Latino ethnicity. Forty-five percent (45%) of patients had diabetes at baseline. The mean baseline LDL-C was 105 mg/dL. At the time of randomization, 89% of patients were receiving statin therapy and 69% were receiving high-intensity statin therapy.
| Treatment Group | LDL-C | Total Cholesterol |
Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a11.5% of subjects on LEQVIO and 14.6% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using a mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value. Missing data were imputed using a control-based pattern-mixture model approach. |
||||
| Day 510 (mean percentage change from baseline)a | ||||
| Placebo (n = 780) | 1 | 0 | 0 | -2 |
| LEQVIO (n = 781) | -51 | -34 | -47 | -45 |
| Difference from placebo (LS Mean) (95% CI) | -52 (-56, -49) |
-33 (-35, -31) |
-47 (-50, -44) |
-43 (-46, -41) |
| Treatment Group | LDL-C | Total Cholesterol |
Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a10.6% of subjects on LEQVIO and 8.4% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value. Missing data were imputed using a control-based pattern-mixture model approach. |
||||
| Day 510 (mean percentage change from baseline)a | ||||
| Placebo (n = 807) | 4 | 2 | 2 | 1 |
| LEQVIO (n = 810) | -46 | -28 | -41 | -38 |
| Difference from placebo (LS Mean) (95% CI) | -50 (-53, -47) |
-30 (-32, -28) |
-43 (-46, -41) |
-39 (-41, -37) |
| Treatment Group | LDL-C | Total Cholesterol |
Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a4.5% of subjects on LEQVIO and 4.6% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value as a covariate. Missing data were imputed using a control-based pattern-mixture model approach. |
||||
| Day 510 (mean percentage change from baseline)a | ||||
| Placebo (n = 240) | 8 | 7 | 7 | 3 |
| LEQVIO (n = 242) | -40 | -25 | -35 | -33 |
| Difference from placebo (LS Mean) (95% CI) | -48 (-54, -42) |
-32 (-36, -28) |
-42 (-47, -37) |
-36 (-40, -32) |
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
a3.2% of subjects on LEQVIO and 0% of subjects on placebo had missing LDL-C data at primary endpoint (Day 330). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effects for treatment group and baseline age group, and baseline LDL-C as a covariate. Other endpoints were analyzed using same approach. |
||||
| Day 330 (mean percentage change from baseline)a | ||||
| Placebo (n = 48) | 1 | 4 | 2 | 0 |
| LEQVIO (n = 93) | -27 | -21 | -25 | -19 |
| Difference from placebo (LS Mean) (95% CI) | -29 (-36, -21) | -26 (-32, -20) | -27 (-34, -20) | -19 (-25, -14) |
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol
The trial was designed as a descriptive trial and was not powered to test any hypothesis. aNo subject in either LEQVIO or placebo had missing LDL-C data at primary endpoint (Day 330). No statistical model was performed. The mean and 95% CI of the difference from placebo were calculated based on a t-distribution for the percent change from baseline in LDL-C and other endpoints. |
||||
| Day 330 (mean percentage change from baseline)a | ||||
| Placebo (n = 4) | 12 | 5 | 9 | 9 |
| LEQVIO (n = 9) | -22 | -19 | -23 | -19 |
| Difference from placebo (Mean) (95% CI) | -33 (-80, 13) | -23 (-50, 4) | -33 (-87, 22) | -28 (-75, 19) |
Pregnancy
Tell your doctor right away if you are pregnant or think you might be pregnant. This medicine may harm your baby. Talk with your doctor about whether you should keep taking LEQVIO.
Hypersensitivity
Serious allergic reactions can happen with this medicine. Call your doctor right away if you have trouble breathing, swelling, or feel like your throat is closing up.
Injection Site Reactions
Reactions can happen where you get the shot, like redness, pain, or swelling.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
For more information, visit www.leqvio.com or call 1-833-LEQVIO2 (1-833-537-8462).
© Novartis
T2026-02
Pregnancy
Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if LEQVIO should be discontinued [see Use in Specific Populations (8.1)].
Hypersensitivity
Inform patients that serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients treated with LEQVIO. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.1)].
Injection Site Reactions
Advise patients that injection site reactions can occur with LEQVIO [see Adverse Reactions (6.1)].
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
For more information, visit www.leqvio.com or call 1-833-LEQVIO2 (1-833-537-8462).
© Novartis
T2026-02
Related Medications
Treats These Conditions
This medication is not currently linked to any conditions.
References
LEQVIO (inclisiran) [prescribing information]. April 2026. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fc0afca-4513-4c35-b594-6544aee29a44
Accessed: July 1, 2026