Inclisiran and cardiovascular events: a patient-level analysis of phase III trials

Literature - Ray KK, Raal FJ, Kallend DG, et al; ORION Phase III investigators - Eur Heart J. 2022 Nov 4:ehac594. doi: 10.1093/eurheartj/ehac594.

Introduction and methods

Background

Inclisiran is a small interfering ribonucleic acid (siRNA) that prevents translation of PCSK9 messenger RNA to PCSK9 in the liver, thereby decreasing serum LDL-c levels [1]. Three placebo-controlled, double-blind, randomized phase 3 studies (ORION-9, -10, and -11) investigated the efficacy and safety of inclisiran in high-risk patients with elevated LDL-c levels receiving maximal statin therapy [2,3]. A previous pooled analysis of these trials showed that twice-yearly subcutaneous treatment with inclisiran – compared with placebo – reduced LDL-c levels [4]. However, it is not clear whether inclisiran also reduces the risk of cardiovascular events.

Aim of the study

While dedicated CV outcomes trials with inclisiran are ongoing, the aim of this pooled analysis of individual patient data from ORION-9, -10 and -11 was to provide early insights into the potential of inclisiran and investigate whether in high-risk patients with elevated LDL-c levels, treatment with inclisiran results in a lower risk of CV events, compared with placebo.

Methods

The researchers performed a pooled analysis of individual patient data from 3 placebo-controlled, double-blind, randomized phase 3 studies investigating the efficacy and safety of inclisiran in patients with HeFH (ORION-9), ASCVD (ORION-10 and ORION-11) or an ASCVD risk equivalent (ORION-11). Participants were randomized (1:1) to subcutaneous injection of 284 mg inclisiran or placebo on day 1 and day 90, and every 6 months thereafter for 18 months. Participants were ≥18 years and had elevated LDL-c levels despite receiving maximal statin therapy with or without other lipid-lowering agents, such as ezetimibe.

Outcomes

The researchers were interested in the mean placebo-adjusted percentage and absolute change in LDL-c levels from baseline to day 90 and day 540; these efficacy outcomes were examined in the intention-to-treat population (n=3660). The prespecified exploratory outcome was the occurrence of MACE (composite of cardiovascular death, cardiac arrest, non-fatal myocardial infarction, and fatal and non-fatal stroke), with events reported as adverse events. Relevant adverse events were identified using standard nomenclature (MedDRA). This outcome was examined in the safety population (n=3655), as were 2 outcomes that were not prespecified: fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke.

Main results

LDL-c levels

• At day 90, treatment with inclisiran resulted in a mean placebo-corrected percentage and absolute change in LDL-c levels of -50.6% (95%CI: -52.3 to -49.0) and -1.37 mmol/L (95%CI: -1.42 to -1.33), respectively (both P<0.0001).
• At day 540, treatment with inclisiran resulted in a mean placebo-corrected percentage and absolute change in LDL-c levels of -51.4% (95%CI: -53.4 to -49.9) and -1.38 mmol/L (95%CI: -1.44 to -1.33), respectively (both P<0.0001).

Cardiovascular events

• MACE occurred in 131 (7.1%) patients in the inclisiran group, compared with 172 (9.4%) patients in the placebo group (OR: 0.74; 95%CI: 0.58-0.94).
• The frequency of fatal and non-fatal myocardial infarction (1.8 vs. 2.3%; OR: 0.80; 95%CI: 0.50-1.27) and fatal and non-fatal stroke (0.7 vs. 0.8%; OR: 0.86; 95%CI: 0.41-1.81) did not differ significantly between the inclisiran and placebo groups.

Other safety parameters

• Inclisiran was generally well-tolerated, but clinically relevant reactions at the injection site were more frequent in the inclisiran group than in the placebo group (5 vs. 0.7%; risk ratio: 7.54; 95%CI: 4.14-13.71); none of these reactions were severe or persistent.
• There were also more patients with mild-to-moderate bronchitis in the inclisiran group than in the placebo group (4.3 vs. 2.7%; risk ratio: 1.55; 95%CI: 1.09-2.20).

Conclusion

References

Find this article online at Eur Heart J.