TY - JOUR
T1 - Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran
T2 - An Analysis of the ORION-7 and ORION-1 Studies
AU - Wright, R. Scott
AU - Collins, Michael G.
AU - Stoekenbroek, Robert M.
AU - Robson, Richard
AU - Wijngaard, Peter L.J.
AU - Landmesser, Ulf
AU - Leiter, Lawrence A.
AU - Kastelein, John J.P.
AU - Ray, Kausik K.
AU - Kallend, David
N1 - Funding Information:
Potential Competing Interests: Dr Wright reports fees from The Medicines Company for his work on the steering committees of several trials as well as fees for serving on advisory boards of Sanofi, Regeneron, Boehringer Ingelheim, and Eli Lilly. He has also received past fees for his work from AstraZeneca for work on the STRENGTH Trial Steering Committee. Dr Collins reports being an employee of Auckland District Health Board and being a consultant for Auckland Clinical Studies Ltd, a clinical research center that conducts early phase clinical studies. He has received investigator-initiated research grant support from Baxter Healthcare Pty Ltd (outside the submitted work). Dr Stoekenbroek and Dr Wijngaard report being an employee of The Medicines Company, Parsippany, NJ. They also own stock options of The Medicines Company (outside the submitted work). Dr Robson reports grants from Christchurch Clinical Studies Trust for the conduct of the study. Dr Landmesser reports personal fees from The Medicines Company, Amgen, and Sanofi. Dr Leiter reports personal fees from The Medicines Company during the conduct of the study. He also reports grants and personal fees from Amgen, Kowa, Merck, Regeneron/Sanofi, and The Medicines Company and personal fees from Esperion and HLS Therapeutics (outside the submitted work). Dr Kastelein reports personal fees from AFFiRiS, Amgen, Akarna, AstraZeneca, Catabasis, Cerenis, Corvidia, CSL Behring, CymaBay, Esperion, Gemphire, Ionis, Kowa, Madrigal, Novartis, Eli Lilly, Pfizer, Regeneron, Roche, and Sanofi. Dr Ray reports personal fees from MedCo during the conduct of the study. He also reports personal fees from AbbVie, AstraZeneca, MedCo, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddy’s, Eli Lilly, and Zuellig Pharma and grants and personal fees from Amgen, Sanofi, Regeneron, MSD, and Pfizer (outside the submitted work). Dr Kallend reports being an employee of The Medicines Company (Schweiz) GmbH, Zurich, Switzerland (outside the submitted work).
Funding Information:
Potential Competing Interests: Dr Wright reports fees from The Medicines Company for his work on the steering committees of several trials as well as fees for serving on advisory boards of Sanofi, Regeneron, Boehringer Ingelheim, and Eli Lilly. He has also received past fees for his work from AstraZeneca for work on the STRENGTH Trial Steering Committee. Dr Collins reports being an employee of Auckland District Health Board and being a consultant for Auckland Clinical Studies Ltd, a clinical research center that conducts early phase clinical studies. He has received investigator-initiated research grant support from Baxter Healthcare Pty Ltd (outside the submitted work). Dr Stoekenbroek and Dr Wijngaard report being an employee of The Medicines Company, Parsippany, NJ. They also own stock options of The Medicines Company (outside the submitted work). Dr Robson reports grants from Christchurch Clinical Studies Trust for the conduct of the study. Dr Landmesser reports personal fees from The Medicines Company, Amgen, and Sanofi. Dr Leiter reports personal fees from The Medicines Company during the conduct of the study. He also reports grants and personal fees from Amgen, Kowa, Merck, Regeneron/Sanofi, and The Medicines Company and personal fees from Esperion and HLS Therapeutics (outside the submitted work). Dr Kastelein reports personal fees from AFFiRiS, Amgen, Akarna, AstraZeneca, Catabasis, Cerenis, Corvidia, CSL Behring, CymaBay, Esperion, Gemphire, Ionis, Kowa, Madrigal, Novartis, Eli Lilly, Pfizer, Regeneron, Roche, and Sanofi. Dr Ray reports personal fees from MedCo during the conduct of the study. He also reports personal fees from AbbVie, AstraZeneca, MedCo, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddy's, Eli Lilly, and Zuellig Pharma and grants and personal fees from Amgen, Sanofi, Regeneron, MSD, and Pfizer (outside the submitted work). Dr Kallend reports being an employee of The Medicines Company (Schweiz) GmbH, Zurich, Switzerland (outside the submitted work).
Publisher Copyright:
© 2019 Mayo Foundation for Medical Education and Research
PY - 2020/1
Y1 - 2020/1
N2 - 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: clinicaltrials.gov
AB - 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: clinicaltrials.gov
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U2 - 10.1016/j.mayocp.2019.08.021
DO - 10.1016/j.mayocp.2019.08.021
M3 - Article
C2 - 31630870
AN - SCOPUS:85073828554
SN - 0025-6196
VL - 95
SP - 77
EP - 89
JO - Mayo Clinic proceedings
JF - Mayo Clinic proceedings
IS - 1
ER -