Long-term safety and tolerability of PCSK9 siRNA


A patient-level post-hoc analysis of 7 ORION clinical trials in a diverse population of patients with dyslipidemia showed inclisiran versus placebo was safe and generally well tolerated.

This summary is based on the publication of Wright R et al. - Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials. J Am Coll Cardiol. 2023 Dec 12;82(24):2251-2261. doi: 10.1016/j.jacc.2023.10.007.

Introduction and methods


Several studies have shown that twice-yearly administration (after an initial dose and a dose at 3 months) of PCSK9 siRNA inclisiran, in combination with maximum-tolerated oral lipid-lowering therapy reduced LDL-c levels by ∼50% compared with placebo [1-4]. Although the safety and tolerability of inclisiran have been demonstrated [3,5], more information on its long-term safety profile is desired.

Aim of the study

The authors investigated the long-term safety and tolerability of inclisiran in a large, pooled data set from completed and ongoing studies.


This was a post-hoc analysis of patient-level data from 6 completed clinical trials (ORION-1, -3, -5, -9, -10, and -11) and 1 ongoing clinical trial (ORION-8) in which a total of 3576 patients were treated with inclisiran sodium 300 mg (equivalent to inclisiran 284 mg) subcutaneously for up to 6 years (mean follow-up duration: 2.8 years; SD: 1.1) (i.e., 9982.1 exposed patient-years) and 1968 patients received placebo for up to 1.5 years (mean follow-up duration: 1.3 years; SD: 0.3) (i.e., 2647.7 exposed patient-years), in addition to statins and/or other oral lipid-lowering therapy. The study population comprised patients with elevated LDL-c levels who had ASCVD, ASCVD risk equivalent (this was a high-risk primary prevention cohort of individuals with T2D, familial hypercholesterolemia, or 10-year CVD risk ≥20%), or heterozygous or homozygous familial hypercholesterolemia.


The endpoints included the cumulative incidence and exposure-adjusted incidence rate (EAIR) of treatment-emergent serious adverse events (TESAEs); treatment-emergent adverse events (TEAEs) leading to study drug discontinuation; scientifically relevant TEAEs (such as liver-, muscle-, and kidney-related events, incident diabetes, and MACE); and changes in related laboratory parameters. Additionally, the incidence of treatment-induced antidrug antibodies was assessed.

Main results

Treatment-emergent adverse events

  • In the first 1.5 years, TESAEs and TEAEs leading to study drug discontinuation accumulated at a comparable rate over time in the inclisiran and placebo groups. Thereafter, the cumulative incidence of TESAEs and TEAEs leading to study drug discontinuation followed similar trajectories in the inclisiran group.
  • At least 1 TESAE was reported in 32.2% of the patients treated with inclisiran (EAIR: 13.80 per 100 patient-years; 95%CI: 13.01–14.62) and 22.1% of those receiving placebo (EAIR: 18.14 per 100 patient-years; 95%CI: 16.48–19.93; difference: −4.34; 95%CI: −6.30 to −2.51).
  • The most common TESAEs were cardiac in both the inclisiran (EAIR: 4.39 per 100 patient-years; 95%CI: 3.98–4.84) and placebo (EAIR: 6.90 per 100 patient-years; 95%CI: 5.92–7.99) groups.
  • At least 1 TEAE leading to study drug discontinuation occurred in 3.2% of the patients in the inclisiran group (EAIR: 1.12 per 100 patient-years; 95%CI: 0.93–1.35) and 1.7% of those in the placebo group (EAIR: 1.27 per 100 patient-years; 95% CI: 0.88–1.77; difference: −0.14; 95%CI: −0.68 to 0.29).
  • The most common TEAEs leading to study drug discontinuation were neoplasms (EAIR for inclisiran: 0.36 per 100 patient-years; 95%CI: 0.25–0.49; EAIR for placebo: 0.37 per 100 patient-years; 95%CI: 0.18–0.68).
  • Injection site TEAEs were observed more frequently with inclisiran (EAIR: 3.54 per 100 patient-years; 95%CI: 3.17–3.95) compared with placebo (EAIR: 1.31 per 100 patient-years; 95%CI: 0.91–1.83; difference: 2.23; 95%CI: 1.61–2.79).

Scientifically relevant treatment-emergent adverse events and laboratory parameters

  • Kaplan–Meier analyses showed no apparent differences in the cumulative incidence of liver-, muscle-, and kidney-related events between the inclisiran and placebo arms during the first 1.5 years.
  • The EAIR for incident diabetes was lower in the inclisiran group (4.04 per 100 patient-years; 95%CI: 3.54–4.59) compared with the placebo group (7.08 per 100 patient-years; 95%CI: 5.86–8.48; difference: −3.04; 95%CI: −4.53 to −1.74), as was the EIAR for MACE (3.79 per 100 patient-years; 95%CI: 3.41–4.20 vs. 6.75 per 100 patient-years; 95%CI: 5.79–7.83; difference: −2.96; 95%CI: −4.10 to −1.94).
  • After 1.5 years, similar trends in the cumulative incidence of these liver-, muscle-, and kidney-related events, incident diabetes, and MACE continued in the inclisiran group.
  • Elevated creatine kinase levels (>5× upper limit of normal) were less common with inclisiran compared with placebo when corrected for exposure (EAIR: 1.24 per 100 patient-years; 95%CI: 1.03–1.48 vs. 2.41 per 100 patient-years; 95%CI: 1.86–3.08; difference: −1.17; 95%CI: −1.88 to −0.59).

Treatment-induced antidrug antibodies

  • In the inclisiran group, treatment-induced antidrug antibodies were uncommon (4.6%), mostly transient (3.2%), and unrelated to TESAEs or TEAEs leading to study drug discontinuation.


This patient-level post-hoc analysis of 7 ORION clinical trials in a diverse population of patients with dyslipidemia showed that twice-yearly treatment with subcutaneous inclisiran versus placebo, in addition to statins and/or other oral lipid-lowering therapy, was generally well tolerated and did not identify new safety signals for up to 6 years. Of the TEAEs, only injection site TEAEs were observed more frequently with inclisiran compared with placebo, although these events were uncommon, mild, and mostly transient. Contrary to statin therapy, there was no evidence of excess incidence of elevated creatine kinase levels, muscle-related events, or incident diabetes with inclisiran.

Editorial Comment

In an editorial comment, Christie M. Ballantyne, MD, Abdul Mannan Khan Minhas, MD, and Carl E. Orringer, MD shed their light on the current status of treatment with inclisiran for LDL-c reduction [6]. They start off by providing a short introduction of inclisiran and a detailed summary of the results of the study by Wright et al. They then remind the reader that pharmacovigilance programs require pharmaceutical companies to provide safety and periodic benefit/risk reports of potential treatment-related adverse events of new drugs, such as inclisiran—which received EMA approval in 2020 and FDA approval in 2021. Thus far, the FDA Adverse Events Reporting System has received ~2500 adverse event reports about inclisiran. However, Ballantyne, Minhas, and Orringer believe “the lack of systematic reporting and information on the number of individuals who have received inclisiran in the United States and the uncertainty of the quality of the case reports received limits [sic] efforts to assess this drug’s safety in real-world clinical practice.”

They expect the 3 ongoing, large-scale, long-term RCTs of inclisiran (ORION-4, VICTORION-1 PREVENT, and VICTORION-2 PREVENT), together with smaller trials and other data sets, will yield more information on its safety and efficacy. Nonetheless, they believe this research cannot determine whether the frequency of inclisiran administration also improves clinical effectiveness. Unlike PCSK9 monoclonal antibodies, which patients self-administer every 2 or 4 weeks, inclisiran is injected by a health care professional every 6 months (after the initial and 3-month doses), holding the potential of improved patient compliance.

The authors wonder whether the clinical effectiveness of “twice-yearly comprehensive ‘prevention visits’ based around an injection of inclisiran using a team of physicians, nurses, pharmacists, and other health care providers” is greater than that of usual care and also whether such a prevention visit should take place at a local pharmacy with point-of-care testing for lipids, diabetes, and other conditions. To answer these questions, they call for pragmatic trials that examine the clinical effectiveness and cost-effectiveness of novel strategies such as inclisiran compared with the PCSK9 monoclonal antibodies.


  1. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382:1520–1530.
  2. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376:1430–1440.
  3. Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023;11:109–119.
  4. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382:1507–1519.
  5. Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021;77:1182–1193.
  6. Ballantyne CM, Minhas AMK, Orringer CE. Inclisiran: Where Are We on Safety, Efficacy, and Clinical Effectiveness of siRNA Therapies for Prevention? J Am Coll Cardiol. 2023;82:2262–2264.

Find this article online at J Am Coll Cardiol.

Find the editorial comment online at J Am Coll Cardiol.

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free