Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9
Abstract
:1. Introduction
2. Dyslipidemia
3. PCSK9
4. Anti-PCSK9 Antibodies
5. Small Interfering RNA—Short History and Mechanism
6. siRNA Drugs
7. Pharmacokinetic and Pharmacodynamic Properties
8. Safety and Side-Effect Profile
9. Clinical Trials
10. Familial Hypercholesterolemia (FH)
11. Olpasiran
12. Pediatric Population
13. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug Name | EMA | FDA | Indications |
---|---|---|---|
patisiran | August 2018 | August 2018 | hATTR amyloidosis in patients with stage 1 or stage 2 polyneuropathy |
givosiran | March 2020 | November 2019 | AHP |
lumasiran | November 2020 | November 2020 | PH 1 |
inclisiran | December 2020 | December 2021 | ASCVD, HeFH |
vutrisiran | July 2022 | June 2022 | hATTR amyloidosis in patients with stage 1 or stage 2 polyneuropathy |
Participants | Design | Outcome | |
---|---|---|---|
Completed trials | |||
ORION-1 phase 2 | 501 participants (253 between 18 and 65 years, 248 ≥ 65 years); ASCVD or ASCVD risk equivalents and elevated LDL-C | Multicenter, double-blind, placebo-controlled study. One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo. | Mean percentage change from baseline in LDL-C on Day 180: 38.4% with single dose of inclisiran; 52.6% with two-dose starting regimen of inclisiran |
ORION-3 phase 2 | 382 participants; ASCVD or ASCVD risk equivalents and elevated LDL-C who have completed ORION-1 study | 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial. Patients receiving inclisiran in ORION-1 received inclisiran sodium, 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. | Twice-yearly inclisiran provided sustained reductions in LDL-C and PCSK9 concentrations and was well tolerated over 4 years. |
ORION-10 phase 3 | 1561 participants (630 between 18 and 65 years, 931 ≥ 65 years); ASCVD and elevated LDL-C | Double-blind, randomized, placebo-controlled study. Patients received either inclisiran (284 mg) or placebo, administered subcutaneous on day 1, day 90, and every 6 months thereafter over a period of 540 days. | At day 510, inclisiran reduced LDL-C levels by 52.3% with corresponding time-adjusted reductions of 53.8%. Adverse events and serious adverse events were similar in the two groups. |
ORION-11 phase 3 | 1617 participants (733 between 18 and 65 years, 884 ≥ 65 years); ASCVD or ASCVD risk equivalents and elevated LDL-C; | Double-blind, randomized, placebo-controlled study. Patients received either inclisiran (284 mg)) or placebo subcutaneous on day 1, day 90, and every 6 months thereafter over a period of 540 days. | At day 510, inclisiran reduced LDL-C levels by 49.9% with corresponding time-adjusted reductions of 49.2%. Adverse events and serious adverse events were similar in the two groups. |
Ongoing trials | |||
ORION-4 phase 3 | 15,000 participants; pre-existing ASCVD | Patients will receive inclisiran 300 mg or placebo on day 1, after 3 months and then every 6 months. | Estimated primary completion date: July 2026. Estimated study completion date: December 2049. The purpose of this study is to find out if inclisiran safely lower MACE in people with pre-existing ASCVD. |
ORION-8 phase 3 | 3275 participants (actual enrollment) | Inclisiran sodium 300 milligrams will be administered as a single subcutaneous injection od Day 1, 90, then every 180 days to Day 990. | Estimated primary completion date: 31 December 2023. The purpose of this extension study is to evaluate the efficacy, safety and tolerability of long-term dosing of inclisiran. |
VICTORION-2P | 15,000 participants (estimated enrollment) | Patients will receive inclisiran 300 mg or placebo. | Estimated primary completion date: 13 October 2027 Estimated Study Completion Date 13 October 2027 |
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Wołowiec, Ł.; Osiak, J.; Wołowiec, A.; Wijata, A.; Grześk, E.; Kozakiewicz, M.; Banach, J.; Nowaczyk, A.; Nowaczyk, J.; Grześk, G. Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9. Pharmaceutics 2023, 15, 323. https://doi.org/10.3390/pharmaceutics15020323
Wołowiec Ł, Osiak J, Wołowiec A, Wijata A, Grześk E, Kozakiewicz M, Banach J, Nowaczyk A, Nowaczyk J, Grześk G. Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9. Pharmaceutics. 2023; 15(2):323. https://doi.org/10.3390/pharmaceutics15020323
Chicago/Turabian StyleWołowiec, Łukasz, Joanna Osiak, Anna Wołowiec, Aleksandra Wijata, Elżbieta Grześk, Mariusz Kozakiewicz, Joanna Banach, Alicja Nowaczyk, Jacek Nowaczyk, and Grzegorz Grześk. 2023. "Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9" Pharmaceutics 15, no. 2: 323. https://doi.org/10.3390/pharmaceutics15020323
APA StyleWołowiec, Ł., Osiak, J., Wołowiec, A., Wijata, A., Grześk, E., Kozakiewicz, M., Banach, J., Nowaczyk, A., Nowaczyk, J., & Grześk, G. (2023). Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9. Pharmaceutics, 15(2), 323. https://doi.org/10.3390/pharmaceutics15020323