What is the current status, pharmacology, and trial data for Inclisiran (Leqvio) in the treatment of primary hypercholesterolemia (high cholesterol) or mixed dyslipidemia?

Inclisiran: Current Status, Pharmacology, and Clinical Trials

Inclisiran (Leqvio®) is a first-in-class small interfering RNA (siRNA) therapy that effectively reduces LDL-C by approximately 50% with a convenient twice-yearly dosing schedule after initial doses, and is FDA-approved as an adjunct to diet and statin therapy for adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). 1

Pharmacology and Mechanism of Action

Inclisiran works through a novel mechanism compared to other lipid-lowering therapies:

• It is a synthetic small interfering RNA (siRNA) that targets PCSK9 mRNA in hepatocytes
• Unlike PCSK9 monoclonal antibodies that bind to circulating PCSK9 protein, inclisiran prevents PCSK9 synthesis at the source
• By silencing PCSK9 mRNA translation, inclisiran decreases PCSK9 production, which:
  • Reduces degradation of LDL receptors
  • Increases LDL receptor availability on hepatocyte surfaces
  • Enhances clearance of LDL-C from circulation 2, 3

Current Regulatory Status

• FDA approved in December 2021 for use as an adjunct to diet and statin therapy 4
• Indicated for treatment of adults with:
  • Primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH)
  • To reduce low-density lipoprotein cholesterol (LDL-C) 1

Dosing and Administration

• Recommended dosage: 284 mg administered subcutaneously:
  • Initially
  • Again at 3 months
  • Then every 6 months thereafter
• Must be administered by a healthcare professional
• Injection sites include abdomen, upper arm, or thigh
• LDL-lowering effect may be measured as early as 30 days after initiation 1

Clinical Trial Evidence

Phase 3 ORION Trials

The efficacy and safety of inclisiran were demonstrated in multiple phase 3 trials:

• ORION-9, ORION-10, and ORION-11: In a pooled patient-level analysis of 3,660 patients:

  • Mean placebo-corrected change in LDL-C at day 510: 50.7% reduction
  • Time-adjusted mean change in LDL-C: 50.5% reduction
  • Injection site reactions were more common with inclisiran (5.0% vs 0.7% with placebo) but predominantly mild 4

• ORION-10 (US) and ORION-11 (Europe and South Africa): Evaluated inclisiran in patients with ASCVD or ASCVD risk equivalents:

  • Placebo-corrected percentage change in LDL-C from baseline to day 510: 52.3% in ORION-10 and 49.9% in ORION-11
  • Significant proportions of patients with diabetes were included (47.5% in ORION-10 and 36.5% in ORION-11) 4

• VICTORION-Mono: Recently evaluated inclisiran as monotherapy in primary prevention:

  • Mean percentage change in LDL-C from baseline at day 150: -46.5% with inclisiran vs 1.4% with placebo and -11.2% with ezetimibe
  • Demonstrated superiority over both placebo (-47.9%) and ezetimibe (-35.4%) 5

Safety Profile

Inclisiran has demonstrated a favorable safety profile across clinical trials:

• Most common adverse reactions (≥3%): injection site reactions, arthralgia, and bronchitis
• Discontinuation rate due to adverse events: 2% of patients
• Contraindicated in patients with prior serious hypersensitivity reactions to inclisiran or its excipients 1
• Overall safety profile similar to placebo in major trials 4, 6

Ongoing Cardiovascular Outcomes Trials

While inclisiran effectively lowers LDL-C, cardiovascular outcomes data are still pending:

• ORION-4: Enrolling ~15,000 participants aged ≥55 years with pre-existing ASCVD and LDL-C ≥100 mg/dL

  • Primary endpoint: composite of CHD death, nonfatal MI, fatal/nonfatal ischemic stroke, or urgent coronary revascularization
  • Planned median follow-up: ~5 years 4

• VICTORION-2P: Enrolling ~15,000 participants aged ≥40 years with established ASCVD on high-intensity statin therapy and LDL-C ≥70 mg/dL

  • Primary endpoint: major adverse cardiac events (CV death, nonfatal MI, nonfatal ischemic stroke) 4

Practical Considerations and Positioning in Therapy

• Advantages over PCSK9 monoclonal antibodies:

  • Less frequent dosing (twice yearly vs biweekly/monthly)
  • Potentially better adherence due to administration schedule
  • Administered by healthcare professionals, ensuring compliance 7

• Limitations:

  • Must be administered by healthcare professionals
  • Billed under medical benefit rather than pharmacy benefit
  • Higher initial year cost compared to PCSK9 mAbs (though cost difference lessens in subsequent years) 4

• Current positioning:

  • The American College of Cardiology recommends inclisiran as a non-statin therapy option in addition to maximally tolerated statin therapy for patients at very high risk of ASCVD or with LDL-C levels above target
  • Particularly valuable for patients with demonstrated poor adherence to PCSK9 mAbs, adverse effects, or inability to self-inject 7
  • LDL-C lowering response appears approximately 10% less than that seen with PCSK9 mAbs based on indirect comparisons 4

Key Considerations for Clinical Practice

• Inclisiran offers a novel approach to LDL-C reduction with the convenience of twice-yearly dosing
• Patient selection should prioritize those with established ASCVD or HeFH who require additional LDL-C lowering beyond maximally tolerated statin therapy
• The lack of cardiovascular outcomes data is an important limitation, with results from ORION-4 and VICTORION-2P expected in the coming years
• Consider inclisiran particularly for patients with adherence challenges to daily or more frequent therapies