KEY POINTS

● Inclisiran is an injectable LDL-C-lowering treatment, with the convenience of two maintenance doses a year (after an initial dose, inclisiran is administered again at 3 months, followed by every 6 months).¹ It is a cholesterol-lowering siRNA therapy targeting PCSK9 mRNA in hepatocytes using GalNAc. It works through RNA interference to direct catalytic breakdown of mRNA for proprotein convertase PCSK9, enhancing LDL-C receptor recycling and expression, leading to increased LDL-C uptake and reduced LDL-C levels in circulation.¹

● In two randomised, double-blind, placebo-controlled, parallel-group, phase III trials (ORION-10 and ORION-11), patients with ASCVD were assigned in a 1:1 ratio to receive 4 doses (at days 1, 90, 270 and 450) of either inclisiran (284mg) or matching placebo, both administered as a 1.5 ml subcutaneous injection, to assess the efficacy, safety and adverse-event profile of inclisiran over a period of 18 months.²

● The co-primary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 and up to day 540. In combination with a maximally tolerated statin, at day 510, inclisiran reduced LDL-C levels by 52.3% in the ORION-10 trial and by 49.9% in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% and 49.2%, respectively (p<0.001 for all comparisons vs placebo).² In ORION-10, baseline LDL-C levels were 2.70 ± 1.02 mmol/l and 2.71 ± 0.96 mmol/l for the inclisiran and placebo groups, respectively. In ORION-11, baseline LDL-C levels were 2.77 ± 1.08 mmol/l and 2.68 ± 0.94 mmol/l for the inclisiran and placebo groups, respectively.²

● Adverse events were generally similar among treatment groups; however, more injection-site adverse events occurred with inclisiran than with placebo (2.6% vs 0.9% in the ORION-10 trial and 4.7% vs 0.5% in the ORION-11 trial). Adverse reactions were generally mild.²

● A long-term extension trial (ORION-8), conducted across 268 centres in 13 countries, followed a total of 2,446 patients with ASCVD or ASCVD risk equivalent or heterozygous familial hypercholesterolaemia and elevated LDL-C. Patients received open-label inclisiran twice yearly (after initial and 3-month doses) and the mean cumulative exposure to inclisiran (including parent trials) was 3.7 years, with a maximum exposure of 6.8 years.⁴

● Inclisiran demonstrated consistent LDL-C lowering efficacy in combination with a maximally tolerated statin, with approximately 78% of patients treated with inclisiran achieving prespecified LDL-C goals, with a mean percentage change in LDL-C of 49.4% from baseline (2.9 ± 1.2 mmol/l). No reduction in LDL-C lowering was observed over time.⁴

● Inclisiran demonstrated a long-term safety data and tolerability profile up to day 540, with treatment-emergent adverse events at the injection site (including pain, redness and rash) occurring in 8.2% of patients, compared with 1.8% of patients receiving placebo.^1,4

● NHS England (NHSE) has collaborated with stakeholders to work towards addressing the potential barriers to the treatment of patients with ASCVD with inclisiran. The new NHSE Commercial Agreement provides practices with a total net income of ~£17.40 per Leqvio injection. This consists of a £15 reimbursement supplement and an approximate £2.40 dispensing fee. The reimbursement supplement is the difference between the reimbursed amount of £60 and the nominal purchase price of £45.^1,3

● This new reimbursement supplement offers a sustainable model for helping with lipid management with inclisiran in primary care, enabling long-term, cost-effective lipid management in eligible patients diagnosed with ASCVD.^1,3

REFERENCES

1. Leqvio Summary of Product Characterisitics.
2. Ray KK et al; ORION-10 and ORION-11 Investigators. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020; 382: 1507–19.
3. NHS England. Funding and supply of inclisiran (Leqvio^®). March 2025 (accessed May 2025).
4. Wright RS et al. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial. Cardiovasc Res 2024; 120: 1400–10.