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

Ray, Kausik K.; Troquay, Roel P T; Visseren, Frank L J; Leiter, Lawrence A.; Wright, R. Scott; Vikarunnessa, Sheikh; Talloczy, Zsolt; Zhang, Xiao; Maheux, Pierre; Lesogor, Anastasia; Landmesser, Ulf

doi:10.1016/s2213-8587(22)00353-9

Cited by 163 publications

(94 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the pooled safety analysis of the ORION-9, -10, and -11 trials that included 3655 patients, the safety findings were similar in the inclisiran and placebo groups for 18 months, but injection site reactions were more frequent in patients receiving inclisiran (5.0% vs. 0.7%) [ 48 ]. Additionally, the results of the ORION-3 trial showed well-tolerated safety profile consistent with other trials during 4 years of follow-up [ 44 ]. The network meta-analysis of PCSK9 inhibitors revealed that inclisiran was identified as the top ranked drug in association with less serious adverse events by the surface under the cumulative ranking curve, and there were no findings that LDL-C lowering therapies with PCSK9 mAbs and inclisiran were associated with new-onset diabetes and neurocognitive disorders [ 55 ].…”

Section: Inclisiran: a Small Interfering Ribonucleic Acid-based Inhib...supporting

confidence: 74%

“…The ORION-3 trial (NCT03060577), a phase 2 open-label extension of the ORION-1 trial, assessed the long-term efficacy and safety of inclisiran for up to 4 years in patients who previously received inclisiran in the ORION-1 trial and patients who received evolocumab for 1 year [ 44 ]. The median duration of exposure to inclisiran from baseline through ORION-3 was 4.5 years.…”

Section: Inclisiran: a Small Interfering Ribonucleic Acid-based Inhib...mentioning

confidence: 99%

See 1 more Smart Citation

Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease

Nishikido

2023

Cardiovasc Diabetol

View full text Add to dashboard Cite

Elevated low-density lipoprotein cholesterol (LDL-C) level is associated with an increased risk of atherosclerotic cardiovascular disease. Although high-intensity lipid-lowering therapies with statins and ezetimibe are highly effective for reducing LDL-C levels, over half of high-risk patients do not achieve guideline-recommended LDL-C goals. Thus, there is a significant gap between treatment guidelines and their implementation in daily clinical practice. The major causes are individual variability in the response to lipid-lowering therapies and variation in treatment adherence. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies combined with statins provide marked and consistent reduction in LDL-C levels; however, poor adherence due to the need for subcutaneous injections every 2 or 4 weeks and high cost are major obstacles to their use in real-world clinical settings. Inclisiran, a recently approved novel small interfering ribonucleic acid (siRNA) molecule that inhibits PCSK9 synthesis, provides robust and long-term reduction in LDL-C levels with a low inter-individual variability in the LDL-C-lowering response. Moreover, its administration by biannual injection is expected to greatly improve treatment adherence. Clinical trials of this drug lasting for up to 4 years showed acceptable safety profiles, and ongoing studies accumulate evidence of its longer-term safety. This narrative review summarizes the available evidence on the efficacy and safety of inclisiran and analyzes its potential to overcome the gap between guideline recommendations and real-world clinical practice in current LDL-C-lowering therapies, with a focus on reduced LDL-C level variability and improved treatment adherence.

show abstract

Section: Inclisiran: a Small Interfering Ribonucleic Acid-based Inhib...supporting

confidence: 74%

Section: Inclisiran: a Small Interfering Ribonucleic Acid-based Inhib...mentioning

confidence: 99%

Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease

Nishikido

2023

Cardiovasc Diabetol

View full text Add to dashboard Cite

show abstract

“…The long-awaited results were published a few days ago in Lancet. The above-mentioned study outcomes showed that twice-yearly inclisiran provided sustained reductions in LDL-C and PCSK9 levels and was well tolerated for 4 years [ 93 ]. Patients receiving inclisiran in ORION-1 received inclisiran during ORION-3 as well, whereas patients receiving placebo in ORION-1 received evolocumab for up to 1 year and then transitioned to inclisiran for the remainder of the study.…”

Section: Safety and Side-effect Profilementioning

confidence: 99%

“…A hepatic enzyme increase occurred in 4 patients (1,4%), as well as muscle spasms. Treatment-emergent serious adverse events, possibly related to the study drug (as reported by the investigator), occurred in 4 patients and included sinus tachycardia, acute cholecystitis (in a patient known with gallstones), hepatic fibrosis (in a patient with fatty liver disease) and hepatic enzyme increased (in a patient with chronic hepatitis C and high alcohol intake) [ 93 ]. In the ORION-3 study, each reported side effect was summarized in detail in the supplementary material to Lancet’s article.…”

Section: Safety and Side-effect Profilementioning

confidence: 99%

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

et al. 2023

View full text Add to dashboard Cite

Dyslipidemia is listed among important cardiovascular disease risk factors. Treating lipid disorders is difficult, and achieving desirable levels of LDL-cholesterol (LDL-C) is essential in both the secondary and primary prevention of cardiovascular disease. For many years, statins became the basis of lipid-lowering therapy. Nevertheless, these drugs are often insufficient due to their side effects and restrictive criteria for achieving the recommended LDL-C values. Even the addition of other drugs, i.e., ezetimibe, does not help one achieve the target LDL-C. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has triggered intensive research on a new class of protein-based drugs. The protein PCSK9 is located mainly in hepatocytes and is involved in the metabolism of LDL-C. In the beginning, antibodies against the PCSK9 protein, such as evolocumab, were invented. The next step was inclisiran. Inclisiran is a small interfering RNA (siRNA) that inhibits the expression of PCSK9 by binding specifically to the mRNA precursor of PCSK9 protein and causing its degradation. It has been noticed in recent years that siRNA is a powerful tool for biomedical research and drug discovery. The purpose of this work is to summarize the molecular mechanisms, pharmacokinetics, pharmacodynamics of inclisiran and to review the latest research.

show abstract

“…The results of the ORION-3 study were recently published [ 25 ]. The ORION-3 trial was an open-label extension study of ORION-1 trial with a 4 year follow-up.…”

Section: Four Years Of Efficacy and Safety Of Inclisiran—orion-3 Trialmentioning

confidence: 99%

Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus

Rakočević

Dobrić

Vučić

et al. 2023

IJMS

View full text Add to dashboard Cite

The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) enzyme interferes with the metabolism of low-density lipoprotein (LDL) cholesterol. Inhibition of PCSK9 results in lower LDL cholesterol levels, which can be achieved by different molecular pathways. Monoclonal antibodies targeting circulating PCSK9 have shown strong and persistent effects on lowering the LDL cholesterol level, while reducing the risk of future cardiovascular events. However, this therapy requires once- or twice-monthly administration in the form of subcutaneous injection. This dosing regimen might impact the therapy adherence in cardiovascular patients who often require multiple drugs with different dosing intervals. Small interfering ribonucleic acid (siRNA) represents a promising therapy approach for patients with elevated LDL cholesterol level despite optimized background statin therapy. Inclisiran is a synthesized siRNA which inhibits PCSK9 synthesis in the liver and provides sustained and durable lowering of LDL cholesterol with twice-yearly application and a good tolerability profile. Herein, we present an overview of the current available data and critical review of the major clinical trials which assessed safety and efficacy of inclisiran in different groups of patients with elevated LDL cholesterol level.

show abstract

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

Cited by 163 publications

References 28 publications

Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease

Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus

Contact Info

Product

Resources

About