What is the indication and dosing regimen for Leqvio (inclisiran) in patients with primary hypercholesterolemia or mixed dyslipidemia?

Leqvio (Inclisiran) for Primary Hypercholesterolemia and Mixed Dyslipidemia

Leqvio (inclisiran) is indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C). 1

Dosage and Administration

The recommended dosage regimen for Leqvio is:

• Initial dose: 284 mg administered as a single subcutaneous injection
• Second dose: 284 mg at 3 months after the initial dose
• Maintenance doses: 284 mg every 6 months thereafter 1

Key administration points:

• Must be administered by a healthcare professional
• Subcutaneous injection into the abdomen, upper arm, or thigh
• Do not inject in areas of active skin disease or injury
• If a planned dose is missed by less than 3 months, administer Leqvio and maintain the original schedule
• If a planned dose is missed by more than 3 months, restart with a new dosing schedule 1

Mechanism of Action

Inclisiran is a first-in-class small interfering RNA (siRNA) that:

• Selectively silences the translation of PCSK9 messenger RNA
• Inhibits hepatic production of PCSK9 protein
• Increases LDL receptor density on hepatocytes
• Enhances clearance of LDL-C from circulation 2

Efficacy

• Reduces LDL-C by approximately 50% in clinical trials 3
• Maintains LDL-C reduction through 4 years of treatment 3
• The LDL-lowering effect may be measured as early as 30 days after initiation 1

Patient Selection

Leqvio is appropriate for:

1. Adults with primary hyperlipidemia, including HeFH, who require additional LDL-C lowering despite maximally tolerated statin therapy 1
2. Patients with established ASCVD who have not achieved target LDL-C levels despite maximally tolerated statin therapy plus ezetimibe, with LDL-C ≥55 mg/dL 3
3. Patients with HeFH when LDL-C remains ≥100 mg/dL despite maximally tolerated statin therapy 3
4. Patients with statin intolerance who require significant LDL-C reduction 3

Safety Profile

Common adverse reactions (≥3% and more frequent than placebo):

• Injection site reactions (8% vs 2% with placebo)
• Arthralgia (5% vs 4%)
• Bronchitis (4% vs 3%) 1

Contraindications:

• Prior serious hypersensitivity reaction to inclisiran or any of the excipients in Leqvio 1

Clinical Considerations

Advantages of Inclisiran

• Twice-yearly maintenance dosing improves adherence compared to daily oral medications or more frequent injections 3
• Alternative mechanism for PCSK9 inhibition for patients with adverse effects from PCSK9 monoclonal antibodies 3
• Consistent LDL-C lowering in the range of 44-54% 4

Monitoring Recommendations

• Assess LDL-C when clinically indicated 1
• Regular monitoring with lipid panel every 3-6 months is recommended 3
• Clinical assessment for cardiovascular symptoms and adherence to medication regimen 3

Limitations

• Must be administered by a healthcare professional (unlike PCSK9 mAbs which can be self-administered) 1
• The effect on cardiovascular morbidity and mortality has not yet been determined 2
• Cardiovascular outcomes trials (ORION-4 and VICTORION-2P) are currently in progress 2

Practical Implementation

When initiating Leqvio:

1. Ensure patient is already on maximally tolerated statin therapy
2. Administer initial 284 mg dose subcutaneously
3. Schedule second dose at 3 months
4. Schedule maintenance doses every 6 months thereafter
5. Monitor LDL-C response as clinically indicated

Conclusion

Leqvio represents a novel approach to LDL-C reduction with its unique mechanism of action and convenient twice-yearly dosing schedule after initial doses. It is specifically indicated for adults with primary hyperlipidemia, including HeFH, who require additional LDL-C reduction despite maximally tolerated statin therapy.