Efficacy and safety of inclisiran a newly approved FDA drug: a systematic review and pooled analysis of available clinical studies

Abstract

Study objective: This systematic review and meta-analysis aimed to assess the efficacy and safety profile of treatment with inclisiran, a drug that has been recently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Design: A systematic literature search was conducted in order to identify randomized controlled trials (RCTs) assessing the effect on lipoproteins and the safety profile of inclisiran.

Results: Data were pooled from 5 RCTs, which included 4226 subjects. Meta-analyses of data suggested that the multiple-dose regimens of inclisiran yielded a significant reduction in serum levels of proprotein convertase subtilisin/kexin type 9 (MD = -78.23%, 95%CI: -86.74, -69.71) and low-density lipoprotein cholesterol (MD = -45.48%, 95%CI: -50.36%, -40.61%) throughout the studies. Furthermore, treatment with inclisiran significantly affected total cholesterol (MD = -13.67%, 95%CI: -20.78%, -6.57%), high-density lipoprotein cholesterol (MD = 8.29%, 95%CI: 4.66%,11.93%), non-HDL cholesterol (MD = -39.45%, 95%CI: -43.6%, -35.31%), apolipoprotein B (MD = -34.58%, 95%CI: -38.78%, -30.78%) and lipoprotein(a) (MD = -20.9%, 95%CI: -25.8%, -15.99%). Multiple-dose regimens of inclisiran were associated with increased risk of injection-site reactions (any reaction: OR = 5.86, 95%CI: 3.44, 9.98; mild reactions: OR = 5.19, 95%CI: 1.68, 16.07; moderate reactions: OR = 13.37, 95%CI: 3.17, 56.46), and bronchitis (OR = 1.58, 95%CI: 1.10, 2.26), while the incidence of the pre-specified exploratory CV endpoint significantly decreased at 18 months (OR = 0.74, 95%CI: 0.58, 0.94).

Conclusion and relevance: Inclisiran has favourable effects on serum lipid levels and an acceptable safety profile. Further well-designed RCTs are needed to explore its longer-term safety.

Keywords: Hypercholesterolemia;lipoprotein(a); Inclisiran; Low-density lipoprotein cholesterol; Proprotein convertase subtilisin/kexin type 9; Silencing ribonucleic acid.

Graphical abstract

Fig. 1

- Flow chart of the number of studies identified and included into the meta-analysis.

Fig. 2

- Forest plot displaying mean difference and 95% confidence intervals for the effect of inclisiran on plasma levels of PCSK9. Fitzgerald et al. (2017) tested inclisiran at a dose of 125 mg without statin treatment (a), 250 mg without statin treatment (b), 300 mg with statin treatment (c), 300 mg without statin treatment (d), 500 mg with statin treatment (e) and 500 mg without statin treatment (f). Ray et al. (2017) tested inclisiran at a dose of 100 mg (a), 200 mg (b), and 300 mg (c).

Fig. 3

- Forest plot displaying mean difference and 95% confidence intervals for the effect of inclisiran on plasma levels of LDL-C.

Fig. 4

- Forest plot displaying mean difference and 95% confidence intervals for the effect of inclisiran on plasma levels of TC.

Fig. 5

- Forest plot displaying mean difference and 95% confidence intervals for the effect of inclisiran on plasma levels of HDL-C.

Fig. 6

- Forest plot displaying mean difference and 95% confidence intervals for the effect of inclisiran on plasma levels of Non-HDL-C.

Fig. 7

- Forest plot displaying mean difference and 95% confidence intervals for the effect of inclisiran on plasma levels of apoB.

Fig. 8

– Forest plot displaying mean difference and 95% confidence intervals for the effect of inclisiran on plasma levels of Lp(a).

Fig. 9

- Forest plots for the risk of injection site adverse events occurred in patients on the multiple-dose regimens of inclisiran.

Fig. 10

- Forest plot for the risk of bronchitis occurred in patients on the multiple-dose regimens of inclisiran.

Fig. 11

- Forest plots for the incidence of pre-specified exploratory CV endpoint occurred in patients on the multiple-dose regimens of inclisiran.