What is the current status and pharmacology of Inclisiran (inclisiran) for primary hypercholesterolemia (high cholesterol) management?

Inclisiran for Primary Hypercholesterolemia Management: Current Status and Pharmacology

Inclisiran is a first-in-class small interfering RNA (siRNA) therapy that reduces LDL-C by approximately 45-50% with twice-yearly dosing, and should be considered in patients with demonstrated poor adherence to PCSK9 monoclonal antibodies, adverse effects from PCSK9 mAbs, or those unable to self-inject. 1

Pharmacology and Mechanism of Action

Inclisiran represents a novel approach to lipid management with unique pharmacological properties:

• Mechanism: Inclisiran is a double-stranded small interfering RNA (siRNA) conjugated with triantennary N-Acetylgalactosamine (GalNAc) that facilitates uptake by hepatocytes 2
• Target: It utilizes RNA interference to direct catalytic breakdown of mRNA for PCSK9, increasing LDL-C receptor recycling and expression on hepatocyte cell surfaces 2
• Pharmacokinetics:
  • Terminal elimination half-life of approximately 9 hours
  • No accumulation with multiple dosing
  • Approximately 16% cleared through kidneys
  • Primarily metabolized by nucleases to shorter nucleotides 2
  • Plasma concentrations reach peak in approximately 4 hours post-dose 2

Clinical Efficacy

Inclisiran demonstrates consistent and significant LDL-C reduction across various patient populations:

• LDL-C Reduction: Provides sustained LDL-C reduction of approximately 45-50% with twice-yearly dosing 1, 3
• Onset of Action: LDL-C reduction becomes apparent within 14 days post-dose 2
• Duration: Following a single dose, LDL-C levels remain reduced by approximately 53% at Day 180 2
• PCSK9 Suppression: Mean serum PCSK9 levels are reduced by approximately 75% at Day 120 and 69% at Day 180 following doses at Day 1 and Day 90 2
• Monotherapy: Recent data from the VICTORION-Mono trial demonstrated 46.5% LDL-C reduction as monotherapy in primary prevention patients without ASCVD, significantly superior to both placebo and ezetimibe 4

Current Status and Indications

Inclisiran has received regulatory approval with specific positioning in treatment algorithms:

• FDA Approval: Received in 2021 5
• EMA Approval: Received in 2020 5
• Indication: Adjunct to diet and statin therapy for treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia 5
• Guideline Position: The 2022 ACC Expert Consensus Decision Pathway includes inclisiran as a non-statin therapy option in addition to maximally tolerated statin therapy for:
  • Patients at very high risk of ASCVD
  • Patients with LDL-C >190 mg/dL 6, 5

Dosing Schedule

Inclisiran offers a convenient dosing regimen that may improve adherence:

• Initial subcutaneous injection
• Second dose at 3 months
• Maintenance doses every 6 months thereafter 5

Clinical Considerations and Limitations

Important considerations when prescribing inclisiran include:

• Preferred PCSK9 Inhibitor: PCSK9 monoclonal antibodies (mAbs) are preferred as initial PCSK9 inhibitors due to demonstrated cardiovascular outcomes benefits in the FOURIER and ODYSSEY Outcomes trials 6
• Appropriate Patient Selection: Inclisiran may be considered in patients with:
  • Demonstrated poor adherence to PCSK9 mAbs
  • Adverse effects from both PCSK9 mAbs
  • Inability to self-inject 6
• No Outcome Data: Currently, no cardiovascular outcome studies exist for inclisiran 6
• Ongoing Outcome Trials: ORION-4, VICTORION-1 PREVENT, and VICTORION-2 PREVENT trials are evaluating inclisiran's ability to reduce major cardiovascular events but will not be completed for several years 5
• Combination Therapy: No evidence supports additional efficacy or cardiovascular outcomes benefit for combination therapy with a PCSK9 mAb and inclisiran when added to maximally tolerated statin therapy 6

Safety Profile

Inclisiran demonstrates a favorable safety profile:

• Generally well-tolerated with a safety profile similar to placebo 3
• Most common adverse effects are mild to moderate, transient injection-site reactions 3
• No dose adjustments necessary for patients with mild, moderate, or severe renal impairment 2
• No dose adjustment necessary for patients with mild to moderate hepatic impairment 2
• Not studied in patients with end-stage renal disease or severe hepatic impairment 2

Cost-Effectiveness Considerations

• Inclisiran is suggested to be cost-effective based on the presumed cardiovascular benefit commensurate with LDL-C reduction, though definitive data are pending 7
• The convenient twice-yearly dosing regimen may provide an advantage over other non-statin lipid-lowering therapies 3

Practical Application in Treatment Algorithm

Inclisiran should be positioned in the treatment algorithm as follows:

1. Maximize statin therapy as first-line treatment
2. Add ezetimibe if LDL-C targets not achieved
3. Consider PCSK9 mAbs (alirocumab, evolocumab) as first-choice PCSK9 inhibitors
4. Consider inclisiran as an alternative to PCSK9 mAbs in patients with adherence issues, injection difficulties, or adverse effects from PCSK9 mAbs 6, 1