PCSK9 siRNA effective and safe in high-risk patients with elevated LDL-c irrespective of PVD status

Efficacy and safety of inclisiran in patients with polyvascular disease: pooled, post hoc analysis of the ORION-9, ORION-10, and ORION-11 phase 3 randomized controlled trials

Literature - Koenig W, Conde LG, Landmesser U, et al. - Cardiovasc Drugs Ther. 2022 Dec 23. doi: 10.1007/s10557-022-07413-0.

Introduction and methods

Background

Approximately 15-30% of patients with ASCVD have polyvascular disease (PVD), defined as atherosclerotic plaques in at least 2 major artery beds [1-3]. PVD is an independent risk factor for cardiovascular events [1-3], stronger than diabetes and prior ischemic events [3-5]. Therefore, patients with PVD require intensive lipid-lowering therapy. Previously, a pooled analysis of ORION-9, ORION-10 and ORION-11 showed that twice-yearly subcutaneous injection of inclisiran (after an initial dose at day 1 and 90) – compared with placebo – reduces LDL-c in patients with heterozygous FH, ASCVD and ASCVD risk equivalent [6].

Aim of the study

This pooled post hoc analysis of ORION-9, ORION-10 and ORION-11 examined the efficacy and safety of inclisiran versus placebo in patients with and without PVD.

Methods

The researchers conducted a pooled post hoc analysis of data from 3 double-blind, randomized phase 3 trials in which adult patients with HeFH (ORION-9), ASCVD (ORION-10 and ORION-11) or an ASCVD risk equivalent (ORION-11) were randomized to 284 mg inclisiran or placebo on day 1, day 90 and every 6 months thereafter. Only patients with elevated LDL-c, despite receiving maximal statin therapy with or without other lipid-lowering agents, were eligible to participate. In this pooled post hoc analysis, 3454 patients were divided into a group with (n=470) and a group without (n=2984) PVD, where PVD was defined as the presence of at least 2 of the following conditions: PAD, CAD, or cerebrovascular disease (CeVD).

Outcomes

The pre-specified co-primary outcomes were the percentage change in LDL-c from baseline to day 510 and the time-corrected percentage change in LDL-c from baseline after day 90 up to day 540. Key secondary outcomes were the absolute change in LDL-c from baseline to day 510, the time-corrected absolute change in LDL-c from baseline after day 90 and up to day 540, and the percentage change in PCSK9, total cholesterol, apo-B and non-HDL-c from baseline to day 510. Changes were expressed as least square mean. Safety was assessed in 3449 patients over 540 days, including treatment-emergent (serious) adverse events (TE(S)AEs) and clinically relevant laboratory measurements.

Main results

Efficacy

  • The placebo-corrected percentage change in LDL-c from baseline to day 510 was -48.9% (95%CI: -55.6 to -42.2) in patients with PVD and -51.5% (95%CI: -53.9 to -49.1) in patients without PVD; the treatment effect was independent of PVD status (P-interaction=0.80).
  • The time- and placebo-corrected percentage change in LDL-c from baseline after day 90 up to day 540 was -50.6% (95%CI: -55.3 to -46.0) in patients with PVD and -51.2% (95%CI: -53.0 to -49.5) in patients without PVD.
  • Compared with the placebo group, both absolute and percentage and time-corrected absolute and percentage changes were significantly higher in the inclisiran group, irrespective of PVD status.
  • For patients with and without PVD, the placebo-corrected percentage change in LDL-c from baseline to day 510 was -48.9 mg/dL (95%CI: -55.6 to -42.2) and -51.5 mg/dL (95%CI: -53.9 to -49.1), and the time- and placebo-corrected percentage change was -50.6 mg/dL (95%CI: -55.3 to -46.0) and -51.2 mg/dL (95%CI: -53.0 to -49.5), respectively.
  • For patients with and without PVD, the placebo-corrected absolute change in LDL-c from baseline to day 510 was -50.2 mg/dL (95%CI: -56.8 to -43.6) and -53.5 mg/dL (95%CI: -56.1 to -51.0), and the time- and placebo-corrected absolute change was-53.1 mg/dL (95%CI: -56.1 to -51.0) and -54.1 mg/dL (95%CI: -56.1 to -51.0), respectively.
  • Treatment with inclisiran resulted in significant reductions in PCSK9, total cholesterol, apo-B and non-HDL-c, irrespective of PVD status.

Safety

  • The percentage of patients with a TEAE or TESAE was similar between treatment groups, irrespective of PVD status, with the exception of an excess of mild or moderate clinically relevant TEAEs at the injection site in the inclisiran group.
  • The percentage of patients with clinically relevant laboratory measurements was low and similar between treatment groups, irrespective of PVD status.

Conclusion

This pooled post hoc analysis of ORION-9, ORION-10 and ORION-11 shows that twice-yearly subcutaneous injection (after initial and 90-day doses) of inclisiran results in effective and sustained lipid-lowering in high-risk patients with elevated LDL-c, irrespective of PVD status.

References

1. Yakubov S. Polyvascular atherosclerotic disease: recognizing the risks and managing the syndrome. Curr Med Res Opin. 2009;25:2631-41.

2. Weissler EH, Jones WS, Desormais I, et al. Polyvascular disease: a narrative review of current evidence and a consideration of the role of antithrombotic therapy. Atherosclerosis. 2020;315:10-7.

3. Gutierrez JA, Aday AW, Patel MR, et al. Polyvascular disease: reappraisal of the current clinical landscape. Circ Cardiovasc Interv. 2019;12:e007385.

4. Aday AW, Matsushita K. Epidemiology of peripheral artery disease and polyvascular disease. Circ Res. 2021;128:1818-32.

5. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350-7.

6. Wright RS, Ray KK, Raal FJ et al. Pooled patient-level analysis of inclisiran trials in patients withfamilial hypercholesterolemia or Atherosclerosis.J Am Coll Cardiol.2021;77:1182-93.

Find this article online at Cardiovasc Drugs Ther.

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