In high-risk primary prevention individuals, RNAi against PCKS9 reduces LDL-c

Effect of inclisiran on atherogenic lipoproteins in high-risk primary prevention populations

Presented at the virtual EAS 2020 by Kausik Ray (Imperial College, London, UK)

Introduction and methods

High-risk primary prevention refers to subjects without existing atherosclerotic CVD, but have a single high risk condition, such as T2DM or FH, or a combination of risk factors. Many of these patients fail to achieve LDL-c targets despite recommendations for diet and lifestyle changes and use of maximally tolerated statins. There is therefore a need for additional lipid-lowering therapies.

This analysis examined the effect of inclisiran on LDL-c levels and other atherogenic lipids in the primary prevention cohort of the ORION-11 trial.

The ORION-11 trial was a randomized, double-blind, parallel-group phase III trial. Enrolled patients received either inclisiran 300 mg or placebo (1:1 ratio) at day 1, day 90 and then every 6 months until day 540. The primary endpoint was the percentage change in LDL-c at day 510. Because of the infrequent dosing regiment, the co-primary endpoint of time-averaged change from baseline after day 90 to day 540 was assessed.

For this analysis, those in the primary prevention cohort were included (n=203). These subjects had either T2DM (65%), FH (11.3%) or a 10-year CV risk ≥20% (23.6%) with LDL-c ≥2.6 mmol/L.

Main results

• Placebo-corrected percentage change in LDL-c from baseline to day 510 with inclisiran was 47.2%. This reduction was consistent with that observed in the overall cohort and in the secondary prevention cohort.
• Placebo-corrected time-averaged change from baseline after day 90 to day 540 with inclisiran was 42.3% and again similar to that observed in the overall cohort and in the secondary prevention cohort.
• Bigger placebo-corrected absolute reductions in LDL-c were observed with inclisiran (from baseline to day 510 and from baseline after day 90 to day 540) in the primary prevention cohort vs. the secondary prevention cohort and the overall cohort.
• There were significant reduction in % change of total cholesterol, non-HDL-c, ApoB and Lp(a) from baseline to day 510 with inclisiran vs. placebo (-28.4%, -39.5%. -35,9%, -28,5% respectively). Also, significant reductions of absolute change in these lipoproteins were observed with inclisiran vs. placebo.
• Placebo-corrected time-averaged reductions in total cholesterol, non-HDL-c, ApoB and Lp(a) and an increase in HDL-c with inclisiran from day 90 to day 540 were observed (-25.1%, -35.3%, -34.8%, -28.9%, +5.0%, respectively). Also, significant time-averaged placebo-corrected absolute change from day 90 to day 540 with inclisiran were observed for total cholesterol, non-HDL-c, ApoB, Lp(a) and an increase in HDL-c.
• 49.4% Of patients on inclisiran achieved LDL-c target of <1.8 mmol/L at day 510 compared to 1.1% of patients on placebo.
• Adverse events were equally balanced between the inclisiran and placebo groups. There was a small increase in injection site reactions in the inclisiran group.

Conclusion

In a high-risk primary prevention cohort in the ORION-11 trial, 6-monthly injections with inclisiran resulted in reductions of LDL-c (42% reduction over 15 months) compared to placebo. In addition, inclisiran reduced total cholesterol, non-HDL-c, ApoB and Lp(a) compared to placebo in this cohort of primary prevention subjects.

Discussion

In response to the question which specific patient type would be included in the label of inclisiran, Ray answered that this includes all patient populations studied (with high CV risk), and in those in whom maximally tolerated statins do not provide sufficient LDL-c reduction.

Our reporting is based on the information provided at the EAS 2019 congress.