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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:
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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.
Leqvio is indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in:
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.
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.
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.
Leqvio injection is a clear, colorless to pale yellow solution, 284 mg/1.5 mL (189 mg/mL) of inclisiran supplied as:
Carton containing 1 single-dose prefilled syringe: NDC 0078-1000-60
Store Leqvio at controlled room temperature 20°C to 25°C (68°F to 77°F) with allowable excursions between 15°C and 30°C (59°F and 86°F) [see USP, Controlled Room Temperature (CRT)].
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.
The data in Table 1 are derived from 3 placebo-controlled trials that included 1,833 adults with hypercholesterolemia treated with Leqvio, including 1,682 exposed for 18 months (median treatment duration of 77 weeks). The mean age of the population was 64 years, 32% of the population were female, 92% were White, 6% were Black or African American, 1% were Asian, and
Adverse reactions reported in at least 3% of Leqvio-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1.
| Adverse Reactions | Placebo (N=1,822) % | Leqvio (N=1,833) % |
| Injection site reaction†| 2 | 8 |
| Arthralgia | 4 | 5 |
| Bronchitis | 3 | 4 |
†includes related terms such as: injection site pain, erythema and rash
Adverse reactions led to discontinuation of treatment in 2.5% of patients treated with Leqvio and 1.9% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with Leqvio were injection site reactions (0.2% versus 0% for Leqvio and placebo, respectively).
In a 24-month, two-part trial of 141 pediatric patients aged 12 years and older with HeFH (Trial 4), the safety profile reported was consistent with the description above for adult patients with hypercholesterolemia, with the exception of headache. In pediatric patients with HeFH, the incidence of headache was 6% among patients who received placebo versus 13% of Leqvio-treated patients during the double-blind study period.
In a 24-month, two-part trial of 13 pediatric patients aged 12 years and older with HoFH (Trial 5), the safety profile reported in pediatric patients was consistent with adult patients with hypercholesterolemia.
The following adverse reactions have been identified during post-approval use of Leqvio. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity: anaphylaxis, angioedema, rash, pruritus, and urticaria.
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.
Included as part of the PRECAUTIONS section.
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 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.
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. 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. 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.
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 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. 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.
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.
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.
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.
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.
No dose adjustments are necessary for patients with mild, moderate, or severe renal impairment. Leqvio has not been studied in patients with end stage renal disease.
No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Leqvio has not been studied in patients with severe hepatic impairment.
No Information Provided.
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.
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.
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.
At a dose 3 times the maximum recommended dose, inclisiran does not prolong the QT interval to any clinically relevant extent.
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 Cmax of 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 bound in vitro at 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.
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). 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 Cmax and 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 Cmax and 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.
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.
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of inclisiran.
The immunogenicity of Leqvio has been evaluated using screening and confirmatory immunoassays for the detection of binding anti-inclisiran antibodies. Samples from 1,830 adult patients in the placebo-controlled clinical trials were tested for ADA. Confirmed positivity was detected in 33/1,830 (2%) patients prior to receiving Leqvio and in 90/1,830 (5%) patients during the 18 months of treatment with Leqvio. Approximately 31/1,830 (2%) Leqvio-treated adult patients with a negative sample at baseline had a persistent anti-inclisiran antibody response, defined as two confirmed positive samples separated by at least 16 weeks or a single confirmed positive final sample.
In pediatric patients with HeFH, confirmed positivity was not detected in Year 1 (12 months of double-blind period), but was detected in 8/139 (6%) patients in Year 2 (12 months of open-label period). In pediatric patients with HoFH, confirmed positivity was detected in 1/13 (8%) patient at pre-dose and throughout the trial (12 months of double-blind period and 12 months of open-label period). There was no identified clinically significant effect of anti-inclisiran antibodies on pharmacodynamics, safety, or effectiveness of Leqvio in adults and pediatrics during the placebo-controlled studies. However, the long-term consequences of continuing Leqvio treatment in the presence of anti-inclisiran binding antibodies are unknown.
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.
Trial 1 (ORION-10) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in 1,561 adults with ASCVD 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. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 510 was -52% (95% CI: -56%, -49%; p
| Treatment Group | LDL-C | Total Cholesterol | Non-HDL-C | ApoB |
| 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) |
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Trial 2 (ORION-11) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in 1,617 adults with ASCVD or increased risk for ASCVD randomized 1:1 to receive subcutaneous injections of either Leqvio 284 mg (n=810) or placebo (n=807) on Day 1, Day 90, Day 270, and Day 450. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 510 was -50% (95% CI: -53%, -47%; p
| Treatment Group | LDL-C | Total Cholesterol | Non-HDL-C | ApoB |
| 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) |
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Trial 3 (ORION-9) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in 482 adults with HeFH randomized 1:1 to receive subcutaneous injections of either Leqvio 284 mg (n=242) or placebo (n=240) on Day 1, Day 90, Day 270, and at Day 450. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 510 was -48% (95% CI: -54%, -42%; p
| Treatment Group | LDL-C | Total Cholesterol | Non-HDL-C | ApoB |
| 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) |
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Trial 4 (ORION-16) was a 12-month randomized, double-blind, placebo-controlled trial in 141 pediatric patients aged 12 years and older with HeFH. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 330 was -29% (95% CI: -36%, -21%; p
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
| 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) |
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Trial 5 (ORION-13) was a 12-month randomized, double-blind, placebo-controlled trial in 13 pediatric patients aged 12 years and older with HoFH. The difference between the Leqvio and placebo groups in mean percentage change in LDL-C from baseline to Day 330 was -33% (95% CI: -80%, 13%).
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
| 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) |
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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.
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.
Advise patients that injection site reactions can occur with Leqvio.
