Brand Name
Leqvio
Generic Name
Inclisiran
View Brand Information FDA approval date: December 22, 2021
Form: Injection
What is Leqvio (Inclisiran)?
LEQVIO ® is indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia , to reduce low-density lipoprotein cholesterol . LEQVIO is a small interfering RNA directed to proprotein convertase subtilisin kexin type 9 mRNA indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia , to reduce low-density lipoprotein cholesterol .
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Brand Information
LEQVIO (inclisiran)
1INDICATIONS AND USAGE
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).
2DOSAGE FORMS AND STRENGTHS
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.
3CONTRAINDICATIONS
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)].
4ADVERSE REACTIONS
The following adverse reactions are also discussed in other sections of the label:
- Hypersensitivity Reactions
4.1Clinical 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 in Adults with Hypercholesterolemia
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)
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 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).
Adverse Reactions in Pediatric Patients with HeFH
In a 24-month, two-part trial of 141 pediatric patients aged 12 years and older with HeFH (Trial 4), consisting of a 12-month randomized, double-blind, placebo-controlled part (Part 1/Year 1), followed by a 12-month open-label part (Part 2/Year 2), 93 patients received 284 mg of LEQVIO subcutaneously during Part 1 and 139 patients were treated with LEQVIO during Part 2
Adverse Reactions in Pediatric Patients with HoFH
In a 24-month, two-part trial of 13 pediatric patients aged 12 years and older with HoFH (Trial 5), consisting of a 12-month randomized, double-blind, placebo-controlled part (Part 1/Year 1), followed by a 12-month open-label part (Part 2/Year 2), 9 patients received 284 mg of LEQVIO administered subcutaneously during Part 1 and 13 patients were treated with LEQVIO during Part 2
4.2Postmarketing Experience
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.
5DESCRIPTION
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 C
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.
6CLINICAL STUDIES
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.
The primary efficacy outcome measure in Trial 1 was the percent change from baseline to Day 510 in LDL-C. 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 < 0.0001). For additional results, see Table 2 and Figure 1.
Figure 1: Mean Percent Change from Baseline in LDL-C Over 18 Months in Adults with Hypercholesterolemia and ASCVD on Maximally Tolerated Statin Therapy (Trial 1)
Trial 2 (ORION-11, NCT03400800) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 1,617 adults with ASCVD or increased risk for ASCVD were 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. 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 country and 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 65 years (range: 20 to 88 years), 55% were ≥65 years old, 28% were female, 98% were White, 1% were Black or African American, and <1% were Asian; <1% identified as Hispanic or Latino ethnicity. Thirty-five percent (35%) of patients had diabetes at baseline. The mean baseline LDL-C was 105 mg/dL. At the time of randomization, 95% of patients were receiving statin therapy and 78% were receiving high-intensity statin therapy.
The primary efficacy outcome measure in Trial 2 was the percent change from baseline to Day 510 in LDL-C. 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 < 0.0001). For additional results, see Table 3 and Figure 2.
Figure 2: Mean Percent Change from Baseline in LDL-C Over 18 Months in Adults with Hypercholesterolemia and ASCVD or Increased Risk for ASCVD on Maximally Tolerated Statin Therapy (Trial 2)
In a pooled analysis of Trial 1 and Trial 2, the observed treatment effect was similar across predefined subgroups, such as sex, age, race, disease characteristics, geographic regions, presence of diabetes, body mass index, baseline LDL-C levels, and intensity of statin treatment.
Adults with HeFH
Trial 3 (ORION-9, NCT03397121) was a multicenter, double-blind, randomized, placebo-controlled 18-month trial in which 482 adults with HeFH were 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. Patients with HeFH were taking a maximally tolerated dose of statin with or without other lipid modifying therapy and required additional LDL-C reduction. The diagnosis of HeFH was made either by genotyping or clinical criteria using either the Simon Broome or WHO/Dutch Lipid Network criteria. Patients were stratified by country and 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 55 years (range: 21 to 80 years), 22% were ≥65 years old, 53% were female, 94% were White, 3% were Black or African American, and 3% were Asian; and 3% identified as Hispanic or Latino ethnicity. Ten percent (10%) of patients had diabetes at baseline. The mean baseline LDL-C was 153 mg/dL. At the time of randomization, 90% of patients were receiving statin therapy and 74% were receiving high-intensity statin therapy. Fifty-two percent (52%) of patients were treated with ezetimibe. The most commonly administered statins were atorvastatin and rosuvastatin.
The primary efficacy outcome measure in Trial 3 was the percent change from baseline to Day 510 in LDL-C. 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 < 0.0001). For additional results, see Table 4 and Figure 3.
Figure 3: Mean Percent Change from Baseline in LDL-C Over 18 Months in Adults with HeFH on Maximally Tolerated Statin Therapy (Trial 3)
Pediatric Patients with HeFH
Trial 4 (ORION-16, NCT04652726) was a 12-month randomized, double-blind, placebo-controlled trial in 141 pediatric patients aged 12 years and older with HeFH and elevated LDL-C. Patients were receiving maximally tolerated statin therapy with or without additional LDL-C-lowering therapies. The diagnosis of HeFH was made either by genetic testing or clinical criteria. Patients were randomized in a 2:1 ratio to receive subcutaneous injections of either LEQVIO 284 mg (n = 93) or placebo (n = 48) on Day 1, Day 90, and Day 270.
The mean age at baseline was 15 years (range: 12 to 17 years), 53% were female, 91% were White, 4% were Black or African American, 3% were Asian, and 3% were other races; 9% identified as Hispanic or Latino ethnicity. The mean LDL-C at baseline was 183 mg/dL; 93% of patients were taking statins and 23% were on ezetimibe.
The primary efficacy outcome measure in Trial 4 was the percent change from baseline to Day 330 in LDL-C. 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 < 0.0001). For additional results, see Table 5 and Figure 4.
Figure 4: Mean Percent Change from Baseline in LDL-C Over 12 Months in Pediatric Patients aged 12 Years and Older with HeFH (Trial 4)
Pediatric Patients with HoFH
Trial 5 (ORION-13, NCT04659863) was a 12-month randomized, double-blind, placebo-controlled trial in 13 pediatric patients aged 12 years and older with HoFH and elevated LDL-C. All patients were taking LDL-C-lowering therapies. Patients with a null (negative) variant in both low-density lipoprotein receptor (LDLR) alleles, who were considered unlikely to benefit from a reduction in PCSK9, were excluded. The diagnosis of HoFH was made by genetic testing. Patients were randomized in a 2:1 ratio to receive subcutaneous injections of either LEQVIO 284 mg (n = 9) or placebo (n = 4) on Day 1, Day 90, and Day 270.
The mean age at baseline was 15 years (range: 12 to 17 years), 69% were female, 85% were White, and 15% were Asian; 8% identified as Hispanic or Latino ethnicity. The mean LDL-C at baseline was 272 mg/dL; all patients were taking statins and 85% were on ezetimibe.
The primary efficacy outcome measure in Trial 5 was the percent change from baseline to Day 330 in LDL-C. 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%). For additional results, see Table 6 and Figure 5.
Figure 5: Mean Percent Change from Baseline in LDL-C Over 12 Months in Pediatric Patients aged 12 Years and Older with HoFH (Trial 5)
7HOW SUPPLIED/STORAGE AND HANDLING
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)].
8PATIENT COUNSELING INFORMATION
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
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
Injection Site Reactions
Advise patients that injection site reactions can occur with LEQVIO
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9PRINCIPAL DISPLAY PANEL
LEQVIO
(inclisiran) injection
Contains One Single-dose Prefilled Syringe
For subcutaneous use
For administration by a healthcare professional only
284 mg/1.5 mL
(189 mg/mL)
NDC 0078-1000-60
Sterile Solution
Rx only
NOVARTIS
