Table 2.

Clinical studies investigating inclisiran effect on lipid parameters.

Study (year) [NCT registration number]	Number of patients	Population	Design	Study strategy (intervention duration)	Therapeutic regimen	Study start/ completion dates	Key findings
Fitzgerald et al., 2017 [19] [NCT02314442]	69	Healthy individuals with LDL-C $\ge$100 mg/dL $\pm$ statin therapy.	RCT, single blind	Patients 3:1 randomly assigned to inclisiran or placebo (180 days)	Single-increasing-dose (25, 100, 300, 500, or 800 mg) vs a multiple-dose (four doses of 125 mg once a week, followed by two doses of 250 mg once a week, or two doses of 300 or 500 mg once a month)	December 2014/ November 2015	In the single-dose group, inclisiran $\ge$300 mg decreased PCSK9 levels (up to a 74.5% least-squares mean decrease at day 84 compared to basal values), doses $\ge$100 mg decreased LDL-C levels (up to a 50.6% least-squares mean decrease compared to basal value). Decreased PCSK9 and LDL-C levels persisted at day 180 for inclisiran doses $\ge$300 mg. All multiple-dose regimens lowered PCSK9 levels (up to an 83.8% least-squares mean decrease at day 84 compared to basal levels) and LDL-C (up to a 59.7% least-squares mean decrease at day 84 compared to basal levels).
Ray et al., 2017 [13] (ORION-1, 2017) [NCT02597127]	501	Patients at high risk for ASCVD with high LDL-C levels despite the maximum statin dose $\pm$ other lipid-lowering agents.	RCT, double-blind	1:1 randomization to receive inclisiran or placebo (240 days)	Administration of a single dose of placebo vs inclisiran 200, 300, or 500 mg or two doses (at days 1 and 90) of placebo was two doses of inclisiran 100, 200, or 300 mg	January 2016/ June 2017	At day 180, inclisiran single dose reduced LDL-C least-squares mean by 27.9–41.9% and by 35.5–52.6% after two doses. The greatest decrease in LDL-C was obtained with two-dose 300 mg regimen: 48% of patients reached LDL-C 50 mg/dL. At day 240, patients maintained PCSK9 and LDL-C levels lower than basal values with all treatment regimens.
							Serious adverse events were observed in 11% of patients treated with inclisiran and in 8% of patients of the placebo group. Reactions at the site of injection were observed in 5% of patients treated with inclisiran
Ray et al., 2018 [21] [NCT02597127]	501	Patients at high risk for ASCVD	Prespecified analysis of an RCT study	1:1 randomization placebo or inclisiran (210 days)	Administration of a single dose of placebo or inclisiran 200, 300, or 500 mg or two doses) of placebo or inclisiran 100, 200, or 300 mg (the first at day 1 and the second at day 90)	January 2016/ June 2017	Inclisiran single dose decreased, non–HDL-C, VLDL-C, and apo B over 210 days. At day 180, a dose-dependent reduction in non–HDL-C was observed: –25% with single-dose of inclisiran 200 mg; –46% with two doses of inclisiran 300 mg. Apo B was also reduced (–23% and –41%) with the above-mentioned dose schemes.
Ray et al., 2019 [22] [NCT02597127]	501	Patients with high CVD risk	Prespecified analysis of an RCT study	Follow-up at 1 year of ORION-1 study patients (360 days)	Monthly check of LDL-C and PCSK9 levels.	January 2016/ June 2018	Decrease in LDL-C after inclisiran single dose was 29.5%, 38.7% and 29.9%–46.4% after inclisiran two doses. The 2-dose regimen of inclisiran 300 mg led to the highest rate of responders and the greatest LDL-C decrease over one year.
Raal et al., 2020 [23] (ORION-9) [NCT03397121]	482	Patients with heterozygous FH	RCT, double-blind	1:1 randomization to inclisiran or placebo (540 days)	Inclisiran 300 mg subcutaneous injections or placebo at day 1, 90, 270, and 450.	November 2017/ September 2019	At day 510, a 39.7% LDL-C reduction was observed in the inclisiran group, with substantial decrease in LDL-C levels in all FH genotypes.
Ray et al., 2020 [24] (ORION-10) [NCT03399370]	1561	Patients with ASCVD and high LDL-C with maximum tolerated statin dose $\pm$ other lipid- lowering agents	RCT, double-blind	1:1 randomization to receive inclisiran or placebo (540 days)	Subcutaneous administration of inclisiran 284 mg or placebo at day 1, 90, and every six months thereafter over 540 days	December 2017/ September 2019	At day 510, a 51.3% reduction in LDL-C was observed in the group treated with inclisiran.
Ray et al., 2020 [24] (ORION-11) [NCT03400800]	1617	Patients with ASCVD or ASCVD equivalent and high LDL-C despite maximum tolerated statin dose $\pm$ other lipid- lowering agents	RCT, double-blind	1:1 randomization to inclisiran or placebo (540 days)	Subcutaneous administration of inclisiran 284 mg or placebo at day 1, 90, and every six months thereafter over a period of 540 days	November 2017/ August 2019	At day 510, a 45.8% LDL-C reduction was observed in patients treated with inclisiran.

ASCVD, atherosclerotic cardiovascular disease; Apo B, apolipoprotein B; CI, confidence interval; CVD, cardiovascular disease; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin-kexin type 9; RCT, randomized controlled trial; VLDL-C, very-low-density lipoprotein cholesterol.