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Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran: An Analysis of the ORION-7 and ORION-1 Studies

Published:October 17, 2019DOI:https://doi.org/10.1016/j.mayocp.2019.08.021

      Abstract

      Objective

      To investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI).

      Patients and Methods

      The analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo.

      Results

      In ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.1%±12.4%), mild RI group (74.2%±12.3%), moderate RI group (79.8%±4.9%), and severe RI group (67.9%±16.4%) (P<.001 vs placebo in all groups). Low-density lipoprotein cholesterol levels were significantly reduced versus placebo: normal renal function, 57.6%±10.7%; mild RI, 35.1%±13.5%; moderate RI, 53.1%±21.3%; severe RI, 49.2%±26.6% (P<.001 for all). In ORION-1, PCSK9 level reductions at day 180 were 48.3% to 58.6% in the 300-mg single-dose groups and 67.3% to 73.0% in the 300-mg 2-dose groups (P<.001 vs placebo in all groups). The corresponding low-density lipoprotein cholesterol level reductions were 35.7% to 40.2% in the 300-mg single-dose groups and 50.9% to 58.0% in the 300 mg 2-dose groups (P<.001 vs placebo in all groups). In ORION-7, exposure to inclisiran was proportionally greater in individuals with increasing RI; inclisiran was undetectable in plasma 48 hours after administration in any group.

      Conclusion

      The pharmacodynamic effects and safety profile of inclisiran were similar in study participants with normal and impaired renal function. Dose adjustments of inclisiran are not required in these patients.

      Trial Registration

      Abbreviations and Acronyms:

      ASCVD (atherosclerotic cardiovascular disease), AUC0-inf (area under the curve of the inclisiran plasma concentration from time 0 hour to infinity), CKD (chronic kidney disease), Cmax (maximum plasma concentration), CrCl (creatinine clearance), CVD (cardiovascular disease), eGFR (estimated glomerular filtration rate), LDL-C (low-density lipoprotein cholesterol), PCSK9 (proprotein convertase subtilisin-kexin type 9), PD (pharmacodynamic), PK (pharmacokinetic)
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