Table 1.

Summary of Inclisiran Clinical Trials

Trial	Design	Participants	Intervention	Results
Fitzgerald K et al16	Phase 1, randomized, single-blind, placebo-controlled study.	Men and women (18 to 60 years of age in the single-dose phase and 18 to 75 years of age in the multiple-dose phase) who had a serum LDL-C level of at least 100 mg/dl and a fasting triglyceride level of less than 400 mg/dl (4.5 mmol/L).	Single-ascending-dose phase of inclisiran or placebo: at a dose of 25, 100, 300, 500, or 800 mg. Multiple-ascending-dose phase of inclisiran or placebo: 125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy.	Single-dose phase: showed reduction of LDL-C up to 50.6% from baseline with inclisiran dose of 100 mg or more. Also, reduction in PCSK9 level up to 74.5% from baseline with inclisiran dose of 300 mg or more. The reductions were maintained at day 180 for doses 300 mg or more. Multiple-dose phase: showed reduction of LDL-C up to 59.7% from baseline to day 84. Also, reduction in PCSK9 level up to 83.8% from baseline. No serious adverse events observed with inclisiran.
ORION-115	Phase 2, multicenter, double-blind, placebo-controlled study.	501 men and women, 18 years of age or older with LDL level at screening higher than 70 mg/dl (for patients with a history of atherosclerotic cardiovascular disease) or higher than 100 mg/dl (for patients without a history of atherosclerotic cardiovascular disease).	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.	At day 180, the mean reductions in LDL-C levels were 27.9% to 41.9% after a single dose of inclisiran and 35.5% to 52.6% after two doses (P<0.001 for all comparisons vs placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL-C levels: 48% of the patients who received the regimen had an LDL-C level below 50 mg/dl (1.3 mmol/L) at day 180. At day 240, PCSK9 and LDL-C levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo.
ORION-1 1-year follow-up18	Phase 2, multicenter, double-blind, placebo-controlled study.	501 men and women, 18 years of age or older with LDL-C level at screening higher than 70 mg/dl (for patients with a history of atherosclerotic cardiovascular disease) or higher than 100 mg/dl (for patients without a history of atherosclerotic cardiovascular disease).	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.	One dose of inclisiran on day 1 and two doses of inclisiran on days 1 and 90 lowered time-averaged LDL-C levels over 1 year by 29.5% to 38.7% and by 29.9% to 46.4%, respectively, in a dose-dependent manner. A 50% LDL-C reduction was maintained for at least 6 months after 2 doses of 300 mg of inclisiran on days 1 and 90, producing the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year.
ORION-319	Phase 2, open-label, long-term extension study of the ORION-1 study.	490 participants who completed the ORION-1 study and were previously treated with any dose of inclisiran.	Patients were treated with 300 mg inclisiran sodium twice per year (n = 290) or 140 mg evolocumab (Repatha, Amgen) every 2 weeks for 1 year followed by 300 mg inclisiran sodium on day 360, day 450 and every 6 months after that (n = 92)	At day 210 of ORION-3 trial, LDL-C was reduced by a mean of 51% and PCSK9 levels were decreased by a mean of 77%. A consistent long-term effect of the 300 mg dose of inclisiran on LDL-C lowering was observed in ORION-3 over ~22 months and the time-averaged lowering of LDL-C was ~60 mg/dL. During at least 3 years of follow-up, there were no changes in the overall safety profile and no laboratory test abnormalities associated with the treatment.
ORION-1020	Phase 3, randomized, double-blind, placebo-controlled, parallel group study.	1561 adults in the United States with atherosclerotic cardiovascular disease and LDL-C levels at screening 70 mg/dL or higher.	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.	At day 510, inclisiran reduced LDL-C levels by 52.3% with corresponding time-adjusted reductions of 53.8% (P<0.001 for all comparisons vs placebo). Adverse events were generally similar in the inclisiran and placebo groups, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs 0.9%).
ORION-1120	Phase 3, randomized, double-blind, placebo-controlled, parallel group study.	1617 adults in Europe and South Africa with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent and LDL-C levels at screening 70mg/dl and 100 mg/dL or higher, respectively.	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.	At day 510, inclisiran reduced LDL cholesterol levels by 49.9% with corresponding time-adjusted reductions of 49.2% (P<0.001 for all comparisons vs placebo). Adverse events were generally similar in the inclisiran and placebo groups, although injection-site adverse events were more frequent with inclisiran than with placebo (4.7% vs 0.5%).
ORION-921	Phase 3, double-blind, randomized, placebo-controlled study.	482 adults with diagnosis of heterozygous familial hypercholesterolemia with LDL of at least 100 mg/dL, despite receiving a maximally accepted dose of statin therapy with or without ezetimibe.	The patients were assigned in a 1:1 ratio to receive inclisiran sodium (at a dose of 300 mg) or matching placebo, which were both administered as a 1.5-mL subcutaneous injection on days 1, 90, 270, and 450.	At day 510, the percent change in the LDL-C level was a reduction of 39.7% in the inclisiran group and an increase of 8.2% in the placebo group, for a between-group difference of −47.9 percentage points. Adverse events and serious adverse events were similar in the two groups.
ORION-522 (Ongoing)	Phase 3, double-blind, placebo-controlled, open-label, multicenter study.	45 adults with diagnosis of homozygous familial hypercholesterolemia with LDL of at least 100 mg/dL, despite receiving a maximally accepted dose of statin therapy with or without ezetimibe.	Part one: patients will receive two 300-mg doses of inclisiran sodium or placebo at day one and day 90 (three months). Part two: patients will receive a 300-mg dose of inclisiran sodium on day 270 (nine months), day 450 (15 months) and day 630 (21 months).	Estimated study completion date: September 2021.
ORION-424 (Ongoing)	Phase 3, double-blind, randomized, placebo-controlled study.	15,000 participants aged 55 years or older with pre-existing ASCVD.	Patients will receive inclisiran 300 mg or placebo on the day of randomization, at 3 months and then every 6 months.	Estimated primary completion date: December 2024. Estimated study completion date: December 2049.