Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels

Ray, Kausik K.; Stoekenbroek, Robert M.; Kallend, David; Nishikido, Toshiyuki; Leiter, Lawrence A.; Landmesser, Ulf; Wright, R. Scott; Wijngaard, Peter; Kastelein, John J.P.

doi:10.1001/jamacardio.2019.3502

Cited by 129 publications

(82 citation statements)

References 16 publications

(34 reference statements)

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“…3 Data from the same trial following the same patients over a period of 360 days suggested that inclisiran might provide sustained reductions in LDL cholesterol levels, with the potential for a dosing schedule of once every 6 months. 4…”

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Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

et al. 2020

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BACKGROUND Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.

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Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

et al. 2020

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“…In addition, these results may be explained by the enhanced permeability and retention effect that is more prominent in early, developing atherosclerosis compared to late-stage plaques (35). Interestingly, inclisiran, an investigational siRNA-based therapy in clinical trials as a PCSK9 inhibitor for atherosclerosis, has also shown a single dose to have long-term benefits in humans for up to a year (36). Overall, our results demonstrate miR-145 therapy as a viable and safe strategy for treating atherosclerosis, and the benefit of infrequent dosing may be used to supplement patients who are intolerant of current firstline, atherosclerosis therapies.…”

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Nanoparticle-mediated microRNA-145 Delivery for Vascular Smooth Muscle Cell Phenotype Modulation and Atherosclerosis Treatment

Chin

Poon

Wang

et al. 2020

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Vascular smooth muscle cells (VSMCs) change from contractile to the synthetic phenotype during atherogenesis and 30-70% of cells that make up plaques have been elucidated to be of VSMC origin. MicroRNA-145 (miR-145) is responsible for regulating VSMC phenotypic switching, and low miR-145 levels in circulation have been linked with atherosclerosis. Hence, we developed nanoparticles for targeted delivery of miR-145 by synthesizing micelles co-assembled with miR-145 and the CCR2-binding peptides for plaque targeting. The miR cargo was protected in micelles from premature endosomal degradation and rescued contractile markers in synthetic VSMCs and SMCs isolated from patient arteries in vitro. In ApoE-/- mid-stage atherosclerotic mice, miR-145 micelles halted plaque growth and maintained contractile phenotypes similar to baseline levels. In early-stage atherosclerosis, a single dose of miR-145 micelles prevented lesion growth by 49%. We present the potential of miR-145 micelles as a therapeutic that can be applied longitudinally and intervene throughout atherosclerosis pathogenesis.

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“…Previous clinical studies consistently demonstrated the effectiveness of inclisiran in reducing the plasma proprotein convertase subtilisin kexin type 9 and LDL cholesterol levels in healthy individuals and patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels ( Fitzgerald et al, 2014 , 2017 ; Ray et al, 2017 ). Moreover, a single-dose treatment with inclisiran was shown to cause a durable reduction in LDL cholesterol levels among the subjects over 1 year ( Ray et al, 2019 ), and inclisiran showed similar efficacy and safety profiles among individuals with normal and impaired renal functions ( Wright et al, 2020 ). A double-blind, placebo-controlled, and open-label phase II/III study (NCT03851705) is ongoing to evaluate the safety and efficacy of inclisiran in patients with HoFH.…”

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confidence: 99%