ORION-10 STUDY
ORION-9 STUDY

Coprimary Endpoints

In ORION-10, LEQVIO® significantly reduced LDL-C vs. placebo in patients who have non-familial hypercholesterolemia with ASCVD^1,3†‡

Adapted from the LEQVIO® Product Monograph.

LEQVIO® was also studied in the ORION-11 (N=1,617) clinical trial in a mixed population (patients who had non-familial hypercholesterolemia with ASCVD and/or ASCVD risk equivalent patients).¹  
Note: LEQVIO® is not indicated for the treatment of patients with ASCVD risk equivalents.

ASCVD=atherosclerotic cardiovascular disease; LDL-C=low-density lipoprotein cholesterol.

† In the ORION-10 (N=1,561) and ORION-11 (N=1,617) clinical trials, patients who received 284 mg of LEQVIO® (inclisiran injection) administered subcutaneously at baseline, 3 months, and every subsequent 6 months exhibited an average between-group difference in LDL-C reduction of 52% (95% CI: -55.7%, -48.8; p<0.001) and -49.9% (95% CI: -53.1, -46.6; p<0.0001) when compared to placebo, respectively. The reduction in LDL-C was maintained across each 6-month dosing interval up to trial Day 510.¹
‡ Patients in each study arm in the ORION-10 clinical trial were receiving a maximally tolerated dose of statin, with or without other lipid-modifying therapy, such as ezetimibe.

Other Secondary Outcomes

At Day 510 in ORION-10:

Proportion who achieved an LDL-C <1.8 mmol/L (70 mg/dL):¹

ASCVD=atherosclerotic cardiovascular disease; LDL-C=low-density lipoprotein cholesterol.

Trial Design

ORION-10^1,3,4

Features	Multicentre, double-blind, randomized (1:1), placebo-controlled
Location	United States
Population	Non-familial hypercholesterolemia With ASCVD

Treatment Arms	LEQVIO® 284 mg SC (n=781) Matched placebo (n=780)
Coprimary Endpoints	Percent change in LDL-C from baseline to Day 510   Time-adjusted percent change in LDL-C from Day 90 up to Day 540

ASCVD=atherosclerotic cardiovascular disease; LDL-C=low-density lipoprotein cholesterol; SC=subcutaneous.

† Patients in each study arm in the ORION-10 phase 3 clinical trials were receiving a maximally tolerated dose of a statin, with or without other lipid-modifying therapy, such as ezetimibe.^1,3

Indications and Clinical Use:

LEQVIO® (inclisiran injection) is indicated as an adjunct to lifestyle changes, including diet, to further reduce low-density lipoprotein cholesterol (LDL-C) level in adults with the following conditions who are on a maximally tolerated dose of a statin, with or without other LDL-C-lowering therapies:

Non‐familial hypercholesterolemia with atherosclerotic cardiovascular disease (ASCVD), or
Heterozygous familial hypercholesterolemia (HeFH).

The effect of LEQVIO® on cardiovascular morbidity and mortality has not been determined.

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥65 years of age): Of the 1,833 patients treated with inclisiran in the Phase 3 program, 981 (54%) patients were 65 years of age and older, while 239 (13%) patients were 75 years of age and older. Elderly subjects with heterozygous familial hypercholesterolemia were however less represented (22% were aged ≥65 years). No overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients.

Contraindications:

Hypersensitivity to LEQVIO® or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
For lipid-lowering therapies such as statin or other lipid-lowering therapies used in combination with LEQVIO®, see the CONTRAINDICATIONS section of the Product Monographs for those medications.

Relevant warnings and precautions:

Endocrine and metabolism: Disturbances in glucose metabolism homeostasis have been observed in patients treated with LEQVIO®. Periodic monitoring of patients at high risk of diabetes mellitus is recommended (e.g., metabolic syndrome).
Hepatic/Biliary/Pancreatic: The safety and efficacy of LEQVIO® in patients with severe hepatic impairment have not been studied. Patients with active liver disease were excluded from the pivotal trials. Transaminase elevations have been observed in patients treated with LEQVIO®. Transaminase elevations generally occurred after 6 months following initiation of treatment. The effect was usually transient, although some patients experienced a sustained effect (i.e., for at least 2 consecutive visits). Patients with an active liver disease or unexplained elevations in ALT, AST, >3x the ULN, or total bilirubin >2x ULN, were excluded from the pivotal trials. Treatment should be discontinued for severe or clinically significant transaminase elevations. For resumption of dosing after interruption see DOSING AND ADMINISTRATION in the Product Monograph.
Injection-site reactions: Injection-site reactions have been reported in approximately 8% of patients receiving LEQVIO® in the placebo-controlled trials. Symptoms included erythema, pain, pruritus, rash, bruising, or discolouration around the injection site. The severity of the reaction was predominantly mild. Monitor for reactions and manage clinically as needed.
Renal: Due to limited data, the safety and efficacy of LEQVIO® in patients with severe renal impairment could not be established. The safety and efficacy of LEQVIO® in patients with end-stage renal disease with or without hemodialysis have not been studied. The pivotal trials only included patients with calculated glomerular filtration rate >30 mL/min and no current or planned renal dialysis or renal transplantation.
Pregnant or breastfeeding women: There are no or limited amount of data from the use of inclisiran in pregnant women. Inclisiran should not be used during pregnancy. It is unknown if inclisiran is excreted in human milk; however, a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from inclisiran therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility: There are no data on the effect of LEQVIO® on human fertility. No effects on fertility were observed in female and male rats at doses equivalent to 20.4-fold and 44.1-fold based on area under the curve (AUC), compared to exposures observed at the maximum recommended human dose – MRHD.

For more information:

Consult the Product Monograph at www.novartis.com/ca-en/Leqviomonograph for important information relating to adverse drug reactions, drug interactions and dosing information which have not been discussed in this piece. The Product Monograph is also available by calling 1-800-363-8883 or emailing [email protected].

References

LEQVIO® Product Monograph. Novartis Pharmaceuticals Canada Inc.
Data on File. First siRNA PCSK9i. Novartis Pharmaceuticals Inc., 2023.
Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507-1519.
Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16_Suppl):1-32.

LEQVIO® is a registered trademark.
© Novartis Pharmaceuticals Canada Inc.

February/2025 - 425307E

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Coprimary Endpoints

In ORION-9, LEQVIO® significantly reduced LDL-C vs. placebo in patients with HeFH^1,3†‡

Adapted from the LEQVIO® Product Monograph.

HeFH=heterozygous familial hypercholesterolemia; LDL-C=low density lipoprotein cholesterol.

† In the ORION-9 clinical trial (N=482), patients who received 284 mg of LEQVIO® (inclisiran injection) administered subcutaneously at baseline, 3 months, and every subsequent 6 months exhibited an average between-group difference in LDL-C reduction of 47.9% (95% CI: -53.5%, -42.3%; p<0.0001) when compared to placebo. The reduction in LDL-C was maintained across each 6-month dosing interval up to trial Day 510.¹
‡ Patients in the ORION-9 clinical trial were on a maximally tolerated dose of a statin, with or without other lipid-lowering therapies, such as ezetimibe.¹

Other Secondary Outcomes

At Day 510 in ORION-9:

Proportion who achieved an LDL-C <1.8 mmol/L (70 mg/dL):¹

Proportion who achieved an LDL-C <2.6 mmol/L (100 mg/dL):¹

ASCVD=atherosclerotic cardiovascular disease; HeFH=heterozygous familial hypercholesterolemia; LDL-C=low-density lipoprotein cholesterol.

Trial Design

ORION-9^1,3

Features	Multicentre, double-blind, randomized (1:1), placebo-controlled
Location	International
Population	HeFH Diagnosis made via genotyping or clinical criteria (Simon Broome or WHO/Dutch Lipid Network criteria)

Treatment Arms	LEQVIO® 284 mg SC (n=242) Matched placebo (n=240)
Coprimary Endpoints	Percent change in LDL-C from baseline to Day 510 Time-adjusted percent change in LDL-C from Day 90 up to Day 540

HeFH=heterozygous familial hypercholesterolemia; LDL-C=low-density lipoprotein cholesterol; SC=subcutaneous; WHO=World Health Organization.

† Patients in each study arm in the ORION-9 clinical trial were taking a maximally tolerated dose of a statin, with or without other lipid-modifying therapy, such as ezetimibe.¹

Indications and Clinical Use:

Non‐familial hypercholesterolemia with atherosclerotic cardiovascular disease (ASCVD), or
Heterozygous familial hypercholesterolemia (HeFH).

Contraindications:

Hypersensitivity to LEQVIO® or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
For lipid-lowering therapies such as statin or other lipid-lowering therapies used in combination with LEQVIO®, see the CONTRAINDICATIONS section of the Product Monographs for those medications.

Relevant warnings and precautions:

Endocrine and metabolism: Disturbances in glucose metabolism homeostasis have been observed in patients treated with LEQVIO®. Periodic monitoring of patients at high risk of diabetes mellitus is recommended (e.g., metabolic syndrome).
Hepatic/Biliary/Pancreatic: The safety and efficacy of LEQVIO® in patients with severe hepatic impairment have not been studied. Patients with active liver disease were excluded from the pivotal trials. Transaminase elevations have been observed in patients treated with LEQVIO®. Transaminase elevations generally occurred after 6 months following initiation of treatment. The effect was usually transient, although some patients experienced a sustained effect (i.e., for at least 2 consecutive visits). Patients with an active liver disease or unexplained elevations in ALT, AST, >3x the ULN, or total bilirubin >2x ULN, were excluded from the pivotal trials. Treatment should be discontinued for severe or clinically significant transaminase elevations. For resumption of dosing after interruption see DOSING AND ADMINISTRATION in the Product Monograph.
Injection-site reactions: Injection-site reactions have been reported in approximately 8% of patients receiving LEQVIO® in the placebo-controlled trials. Symptoms included erythema, pain, pruritus, rash, bruising, or discolouration around the injection site. The severity of the reaction was predominantly mild. Monitor for reactions and manage clinically as needed.
Renal: Due to limited data, the safety and efficacy of LEQVIO® in patients with severe renal impairment could not be established. The safety and efficacy of LEQVIO® in patients with end-stage renal disease with or without hemodialysis have not been studied. The pivotal trials only included patients with calculated glomerular filtration rate >30 mL/min and no current or planned renal dialysis or renal transplantation.
Pregnant or breastfeeding women: There are no or limited amount of data from the use of inclisiran in pregnant women. Inclisiran should not be used during pregnancy. It is unknown if inclisiran is excreted in human milk; however, a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from inclisiran therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility: There are no data on the effect of LEQVIO® on human fertility. No effects on fertility were observed in female and male rats at doses equivalent to 20.4-fold and 44.1-fold based on area under the curve (AUC), compared to exposures observed at the maximum recommended human dose – MRHD.

For more information:

References

LEQVIO® Product Monograph. Novartis Pharmaceuticals Canada Inc.
Data on File. First siRNA PCSK9i. Novartis Pharmaceuticals Inc., 2023.
Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530.

February/2025 - 425307E

Product information

Coprimary Endpoints

In ORION-10, LEQVIO® significantly reduced LDL-C vs. placebo in patients who have non-familial hypercholesterolemia with ASCVD1,3†‡

Other Secondary Outcomes

At Day 510 in ORION-10:

Proportion who achieved an LDL-C <1.8 mmol/L (70 mg/dL):1

Trial Design

ORION-101,3,4

Indications and Clinical Use:

Contraindications:

Relevant warnings and precautions:

For more information:

References

Related content

ORION-10 & -11

ORION-10 & -11

Safety Profile

Safety Profile

Coprimary Endpoints

In ORION-9, LEQVIO® significantly reduced LDL-C vs. placebo in patients with HeFH1,3†‡

Other Secondary Outcomes

At Day 510 in ORION-9:

Proportion who achieved an LDL-C <1.8 mmol/L (70 mg/dL):1

Proportion who achieved an LDL-C <2.6 mmol/L (100 mg/dL):1

Trial Design

ORION-91,3

Indications and Clinical Use:

Contraindications:

Relevant warnings and precautions:

For more information:

References

Related content

ORION-9

ORION-9

Safety Profile

Safety Profile

In ORION-10, LEQVIO® significantly reduced LDL-C vs. placebo in patients who have non-familial hypercholesterolemia with ASCVD^1,3†‡

Proportion who achieved an LDL-C <1.8 mmol/L (70 mg/dL):¹

ORION-10^1,3,4

In ORION-9, LEQVIO® significantly reduced LDL-C vs. placebo in patients with HeFH^1,3†‡

Proportion who achieved an LDL-C <1.8 mmol/L (70 mg/dL):¹

Proportion who achieved an LDL-C <2.6 mmol/L (100 mg/dL):¹

ORION-9^1,3