Long-term safety of inclisiran among high-risk CVS patients demonstrated in a pooled safety analysis

17 Apr 2023

Inclisiran is a first-in-class small interfering ribonucleic acid (siRNA) targeting hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) and lowering low-density lipoprotein-cholesterol (LDL-C).1 Administered subcutaneously at a dose of 284mg initially, at 3 months, and every 6 months thereafter, the drug has been approved for the treatment of adults with hypercholesterolemia or mixed dyslipidemia, helping patients achieve the targeted LDL-C goals.2 The approval in >60 countries was based on the positive findings of the placebo-controlled studies up to 18 months of duration, with some of which followed up open-label extensions.1

In order to provide long-term safety data of inclisiran, a pooled post-hoc analysis which included patient-level data from a total of 7 clinical trials was performed, with a total of 3,576 patients and 9,982 patient-years (PYs) in the inclisiran pool.1 More than 1,500 patients (43.3%) had been treated with inclisiran for 3 years.1 Safety of inclisiran was assessed via the rates of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) leading to treatment discontinuation in comparison with placebo (n=1,968; 2,645 PYs).1 TEAEs of scientific relevance, including hepatic, muscular, renal, diabetic, and major adverse cardiovascular events (MACE)-related safety events, were also investigated.1 In the American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023, Dr. Scott Wright and his colleagues, presented the positive results of the post-hoc study.1

Results from the pooled post-hoc analysis showed that the rates of TEAEs and TESAEs leading to drug discontinuation were comparable between patients treated with inclisiran and placebo.1 The rates of scientifically relevant TEAEs of inclisiran, including hepatic events, muscular events, incident diabetes, and kidney events, were also similar to placebo.1 Notably, the MACE-related safety events were numerically lower with inclisiran vs. placebo.1

Regarding immunogenicity, 4.4% of patients exhibited inclisiran-associated anti-drug antibody (ADA) responses, and persistent ADA increase was observed in 1.3% of patients.1 Nonetheless, the presence of ADA was not associated with a difference in the cumulative incidence of TESAEs or TEAEs leading to study drug discontinuation.1  

In summary, prolonged inclisiran exposure with a median exposure of 2.8 years is shown to be safe without elevated risks of TEAEs or TESAEs leading to treatment discontinuation vs. placebo.1 These data support the long-term safety of inclisiran among high-risk patients with cardiovascular (CV) diseases.1 Some large trials of inclisiran are ongoing and will provide more safety data on the use of the drug for a longer duration.1

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