In a post-hoc, pooled analysis of the ORION-10 and -11 trials among ASCVD patients with dyslipidemia, inclisiran resulted in LDL-c reduction ≥50% for up to 18 months compared with placebo, irrespective of MI status.

This summary is based on the publication of Landmesser U, Koenig W, Leiter LA, et al. - Inclisiran in patients with prior myocardial infarction: A post hoc pooled analysis of the ORION-10 and ORION-11 Phase 3 randomised trials. Atherosclerosis. 2023 Dec:386:117354. Doi: 10.1016/j.atherosclerosis.2023.117354

Introduction and methods

Background

In patients with clinical ASCVD, current European and American guidelines recommend LDL-c reduction by ≥50%, in addition to lowering LDL-c levels to <1.4 mmol/L (55 mg/dL) [1-3]. To achieve these more stringent LDL-c goals, optimization of lipid management—including prescription of and adherence to both statin and non-statin lipid-lowering therapies—may be required in this population, including patients with prior MI [4-6]. The ORION-10 and ORION-11 trials have shown that inclisiran, an siRNA molecule targeting hepatic PCSK9 mRNA, provided effective and consistent LDL-c lowering when administered twice yearly (after an initial dose and a dose at 3 months) and was well-tolerated in patients with ASCVD [7].

Aim of the study

In a post-hoc, pooled analysis of the ORION-10 and ORION-11 trials, the authors evaluated the lipid-lowering efficacy and safety of inclisiran in ASCVD patients with and with no prior MI.

Methods

The ORION-10 (Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol) and ORION-11 (Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol) trials were 2 multicenter, double-blind, placebo-controlled, parallel-group, phase 3 RCTs. In these trials, 3178 ASCVD patients with LDL-c ≥1.8 mmol/L (≥70 mg/dL) at screening despite maximally tolerated statin therapy were randomized to inclisiran 284 mg (equivalent to inclisiran sodium 300 mg) subcutaneously or placebo on day 1, day 90, and 6-monthly thereafter over a period of 540 days, in addition to maximally tolerated background oral lipid-lowering therapy.

This post-hoc-analysis comprised 2636 patients, of whom 122 (4.6%) had a recent MI (>3 months to <1 year prior to randomization), 1521 (57.7%) had a remote MI (≥1 year before randomization), and 993 (37.7%) did not have a prior MI.

Outcomes

The protocol prespecified co-primary endpoints were the percentage change in LDL-c level from baseline to 510 days and the time-adjusted percentage change in LDL-c level from baseline after 90 days and up to 540 days. Key protocol prespecified secondary endpoints were the absolute change in LDL-c level from baseline to 510 days; time-adjusted absolute change in LDL-c level from baseline after 90 days and up to 540 days; and percentage change in PCSK9, total cholesterol, non–HDL-c, and apoB levels from baseline to 510 days. Post-hoc exploratory endpoints included the proportion of patients achieving predefined LDL-c thresholds (<1.0, <1.4, <1.8, and <2.6 mmol/L) at 90 days. Safety analyses included the proportions of patients with treatment-emergent adverse events (TEAEs); treatment-emergent serious adverse events (TESAEs); TEAEs leading to study discontinuation; clinically relevant TEAEs at the injection site; and clinically relevant laboratory measurements, such as liver and renal function tests, creatine kinase levels, and platelet counts.

Main results

Efficacy

• The mean placebo-corrected percentage LDL-c reduction from baseline to day 510 with inclisiran was 52.6% (95%CI: 40.1%–65.1%) for patients with recent MI, 50.4% (95%CI: 47.0%–53.8%) for those with remote MI, and 51.6% (95%CI: 47.4%–55.9%) for those with no prior MI (all P for inclisiran vs. placebo<0.0001).
• The corresponding mean placebo-corrected time-adjusted percentage LDL-c reductions (from baseline after 90 days and up to 540 days) were 50.0% (95%CI: 41.4%–58.7%), 52.2% (95%CI: 49.8%–54.7%), and 51.2% (95%CI: 48.1%–54.2%), respectively (all P for inclisiran vs. placebo<0.0001).
• Mean placebo-corrected (time-adjusted) absolute changes in LDL-c level were also similar across the 3 MI strata.
• Percentage changes in total cholesterol, non–HDL-c, apoB, and Lp(a) levels from baseline to 510 days (540 days for Lp(a)) were significantly greater in inclisiran-treated patients compared with placebo-treated patients for all MI strata (all P<0.001). Triglyceride levels were significantly reduced with inclisiran vs. placebo in patients with remote and no prior MI only (both P<0.001).
• Compared with the placebo group, greater proportions of patients achieved the LDL-c <1.4 mmol/L threshold after a single dose of inclisiran (at 90 days), irrespective of MI status (2.9% vs. 60.8% for recent MI, 2.4% vs. 67.8% for remote MI, and 3.1% vs. 73.5% for no prior MI).

Safety

• In the inclisiran and placebo arms, similar proportions of patients experienced ≥1 TEAE (ranging from 73.1% to 79.7%), regardless of MI status.
• The TESAE rate was also generally comparable between the treatment groups and ranged from 17.3% in inclisiran-treated patients with recent MI to 31.4% in placebo-treated patients with recent MI (ranging from 22.3% to 29.6% in patients with remote or no MI).
• Clinically relevant TEAEs at the injection site were more frequently observed in the inclisiran group compared with the placebo group across all MI strata, but these events were all mild or moderate in severity.
• The incidence rates of clinically relevant laboratory test values were largely similar between the 2 treatment arms and across MI strata.

Conclusion

In this post-hoc, pooled analysis of the ORION-10 and ORION-11 trials among ASCVD patients with elevated LDL-c levels despite maximally tolerated statin therapy, twice-yearly administration of inclisiran (after the initial and 3-month doses)—in addition to maximally tolerated background oral lipid-lowering therapy—resulted in a placebo-corrected LDL-c reduction ≥50% for at least 18 months (end of follow-up), regardless of whether they had had an MI or the time since the last MI. Inclisiran treatment also reduced non-HDL-c, apoB, and Lp(a) levels in ASCVD patients with recent, remote, or no MI.

The drug was generally well-tolerated, although a higher proportion of patients in the inclisiran group reported mild to moderate TEAEs at the injection site compared with the placebo group.

The authors remark that “the impact of inclisiran on events is currently being evaluated in the larger and longer VICTORION-2 PREVENT and ORION-4 studies. [...] [T]he LDL-c reduction demonstrated with inclisiran in the present analysis would be expected to translate to a corresponding reduction in cardiovascular risk.”

References

1. F. Mach, C. Baigent, A.L. Catapano, K.C. Koskinas, M. Casula, et al., ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), Eur. Heart J. 41 (2019) 111–188, https://doi.org/10.1093/eurheartj/ehz455, 2019.

2. M. Lloyd-Jones Donald, B. Morris Pamela, M. Ballantyne Christie, K. Birtcher Kim, M. Covington Ashleigh, et al., ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk, J. Am. Coll. Cardiol. 80 (2022) 1366–1418, https://doi.org/10.1016/j.jacc.2022.07.006, 2022.

3. M. Grundy Scott, J. Stone Neil, L. Bailey Alison, C. Beam, K. Birtcher Kim, et al., AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of Blood cholesterol: executive summary, J. Am. Coll. Cardiol. 73 (2018) 3168–3209, https://doi.org/10.1016/j.jacc.2018.11.002, 2019.

4. U. Landmesser, J. McGinniss, P.G. Steg, D.L. Bhatt, V.A. Bittner, et al., Achievement of ESC/EAS LDL-C treatment goals after an acute coronary syndrome with statin and alirocumab European, J. Prevent. Cardiol. 29 (2022) 1842–1851, https://doi.org/10.1093/eurjpc/zwac107.

5. J. Brandts, K.K. Ray, Low density lipoprotein cholesterol-lowering strategies and population Health: time to move to a cumulative exposure model, Circulation 141 (2020) 873–876, https://doi.org/10.1161/circulationaha.119.043406.

6. K.K. Ray, B. Molemans, W.M. Schoonen, P. Giovas, S. Bray, et al., EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study, Eur. J. Prev. Cardiol. 28 (2021) 1279–1289, https://doi.org/10.1093/eurjpc/zwaa047.

7. K.K. Ray, R.S. Wright, D. Kallend, W. Koenig, L.A. Leiter, et al., Two Phase 3 trials of inclisiran in patients with elevated LDL cholesterol, N. Engl. J. Med. 382 (2020) 1507–1519, https://doi.org/10.1056/NEJMoa1912387.

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