2.1 Pharmacodynamics
Inclisiran is a double-stranded, chemically synthesised siRNA directed against PCSK9 mRNA and conjugated with triantennary GalNAc on the sense strand [
1,
3]. Specific binding of the GalNAc ligand to asialoglycoprotein receptors (ASGPR) enables targeted uptake of inclisiran into hepatocytes [
1,
3]. Following uptake into hepatocytes, the antisense strand of inclisiran (which specifically corresponds to human PCSK9 mRNA) is integrated into the RNA-induced silencing complex, directing the catalytic breakdown of PCSK9 mRNA and thus preventing PCSK9 protein translation [
3,
11]. In vitro, inclisiran delivered into HeLa and Hep3B cells inhibited PCSK9 synthesis with half-maximal inhibitory concentrations in the picomolar range [
11]. Inhibited PCSK9 synthesis increases the recycling and expression of LDL-C receptors on the hepatocyte cell surface, in turn increasing LDL-C uptake and reducing circulating LDL-C levels [
3].
Following a single subcutaneous dose of inclisiran (25, 100, 300, 500 or 800 mg) in healthy volunteers, least-squares mean PCSK9 reductions from baseline to day 84 of 74.5%, 69.9% and 73.1% were observed with inclisiran doses of 300 mg, 500 mg and 800 mg (all
p < 0.001 vs placebo) [
12]. Least-squares mean LDL-C reductions of 36.7%, 50.0%, 50.6% and 43.4% were observed with inclisiran doses of 100 mg, 300 mg, 500 mg and 800 mg (all
p < 0.05 vs placebo). At inclisiran doses of 300 mg and higher, PCSK9 and LDL-C reductions were maintained over 6 months [
12].
2.2 Pharmacokinetics
Subcutaneous inclisiran exhibits approximately dose-proportional pharmacokinetics over the dose range of 24–756 mg following a single administration [
3,
11]. Peak plasma concentration (C
max) was reached ≈ 4 h after administration of the recommended dose (284 mg) and concentrations were undetectable by 48 h after administration [
3]. After multiple doses, no accumulation was observed. The in vitro plasma protein binding of inclisiran is 87% at clinically relevant plasma concentrations. The apparent volume of distribution was ≈ 500 L after subcutaneous administration of a single 284 mg dose to healthy adults [
3]. Preclinical data suggest that inclisiran is primarily localized in the liver following subcutaneous administration [
3,
11]. Inclisiran is mainly metabolized by non-specific nucleases into inactive shorter nucleotides [
3,
11]. Inclisiran is not a substrate of common drug transporters and is not expected to be a cytochrome P450 substrate [
3]. In addition, inclisiran is neither an inducer nor inhibitor of cytochrome P450 enzymes or common drug transporters; clinically significant interactions between inclisiran and other medicinal products are not anticipated [
3]. Drug interaction assessments showed no clinically meaningful interactions with atorvastatin or rosuvastatin [
11]. Inclisiran has a terminal elimination half-life of ≈ 9 h, with 16% being renally cleared [
3].
In a dedicated renal impairment study, patients with mild [creatinine clearance (CL
CR) 60–89 mL/min], moderate (CL
CR 30–59 mL/min) and severe (CL
CR 15–29 mL/min) renal impairment showed ≈ 2.3-, 2.0- and 3.3-fold increases in inclisiran C
max and ≈ 1.6-, 1.8- and 2.3-fold increases in inclisiran area under the concentration–time curve (AUC) relative to patients with normal renal function [
3]. LDL-C reductions were comparable across renal function groups. No dose adjustments are required in patients with mild, moderate or severe renal impairment or end-stage renal disease, although haemodialysis should not be performed for at least 72 h after administration [
3]. In a dedicated hepatic impairment study, patients with mild (Child–Pugh class A) and moderate (Child–Pugh class B) hepatic impairment showed ≈ 1.1- and 2.1-fold increases in inclisiran C
max and ≈ 1.3- and 2.0-fold increases in AUC relative to patients with normal hepatic function. LCL-C reductions were similar between patients with mild hepatic impairment and those with normal function, while both baseline PCSK9 levels and LDL-C reductions were lower in patients with moderate hepatic impairment. In patients with mild to moderate hepatic impairment, no dose adjustments are required [
3]. The use of inclisiran in patients with severe hepatic impairment (Child–Pugh class C) has not been evaluated and should therefore be approached with caution [
3].
Features and properties of inclisiran
Alternative names | Leqvio; ALN-60212; ALN-PCSsc; KJX-839; PCSK9si |
Class | Amino sugars, antihyperlipidaemics, drug conjugates, siRNA |
Mechanism of Action | RNA interference mechanism directs the breakdown of mRNA for PCSK9 |
Route of Administration | Subcutaneous |
Pharmacodynamics | siRNA conjugate; inhibits PCSK9 synthesis in hepatocytes and reduces LDL-C levels in circulation |
Pharmacokinetics | Dose-proportional pharmacokinetics; peak plasma concentration reached ≈ 4 h after administration |
Common adverse reactions | Adverse reactions at the injection site (including injection site reaction, injection site pain, injection site erythema, injection site rash) |
ATC codes | |
WHO ATC code | C10A-X16 (Inclisiran) |
EphMRA ATC code | C10A9 (All other cholesterol/triglyceride regulators) |
Chemical Name | RNA, (Am-sp-(2′-deoxy-2′-fluoro)C-sp-Am-(2′-deoxy-2′-fluoro)A-(2′-deoxy-2′-fluoro)A-(2′-deoxy-2′-fluoro)A-Gm-(2′-deoxy-2′-fluoro)C-Am-(2′-deoxy-2′-fluoro)A-Am-(2′-deoxy-2′-fluoro)A-Cm-(2′-deoxy-2′-fluoro)A-Gm-(2′-deoxy-2′-fluoro)G-Um-(2′-deoxy-2′-fluoro)C-Um-Am-Gm-sp-Am-sp-Am), complex with RNA (Cm-sp-Um-sp-Am-Gm-Am–Cm-(2′-deoxy-2′-fluoro)C-Um-(2′-deoxy-2′-fluoro)G-Um-dT-Um-Um-Gm-Cm-Um-Um–Um-Um-Gm-Um) 3′-(((2S,4R)-1-(29-((2-(acetylamino)-2-deoxy-beta-D-galactopyranosyl)oxy)-14,14-bis((3-((3-((5-((2-(acetylamino)-2-deoxy-beta-D-galactopyranosyl)oxy)-1-oxopentyl)amino)propyl)amino)-3-oxopropoxy)methyl)-1,12,19,25-tetraoxo-16-oxa-13,20,24-triazanonacos-1-yl)-4-hydroxy-2-pyrrolidinyl)methyl hydrogen phosphate) (1:1) |
2.3 Therapeutic Trials
Inclisiran effectively reduced LDL-C levels in patients with ASCVD or an ASCVD risk equivalent (type 2 diabetes, familial hypercholesterolaemia, or a ≥ 20% 10-year risk of a cardiovascular event as assessed by Framingham Risk Score for Cardiovascular Disease or equivalent) in the randomized, double-blind, placebo-controlled, multinational phase III ORION-11 trial (NCT03400800) [
7]. ORION-11 was conducted in the Czech Republic, Germany, Hungary, Poland, South Africa, Ukraine and the United Kingdom. The trial enrolled patients with elevated LDL-C levels despite receiving maximally tolerated statin therapy with or without additional lipid-lowering treatment. Enrolled patients were randomized to inclisiran free acid 284 mg (corresponding to inclisiran sodium 300 mg;
n = 810) or placebo (
n = 807) administered as a 1.5 mL subcutaneous injection on day 1, day 90 and every 6 months thereafter over a total of 540 days. The percentage change in LDL-C level from baseline to day 510 was − 45.8% in the inclisiran group versus 4.0% in the placebo group [between-group difference (BGD) − 49.9%; 95% CI − 53.1 to − 46.6;
p < 0.001], while the time-adjusted change in LDL-C level from baseline after day 90 and up to day 540 was − 45.8% in the inclisiran group versus 3.4% in the placebo group (BGD − 49.2%; 95% CI − 51.6 to − 46.8;
p < 0.001) [co-primary endpoints]. With respect to key secondary endpoints, inclisiran significantly (
p < 0.001 vs placebo) improved both absolute change in LDL-C level at day 510 and time-adjusted absolute change in LDL-C level from day 90 to day 540 [
7]. Benefits of inclisiran over placebo for LDL-C change were observed irrespective of background lipid lowering therapy or PCSK9 levels [
13]. In an prespecified exploratory analysis, cardiovascular events (cardiac death or any signs/symptoms of cardiac arrest, non-fatal myocardial infarction and/or stroke) occurred in 7.8% of inclisiran recipients versus 10.3% of placebo recipients (risk ratio 0.8; 95% CI 0.6–1.0) [
14]; cardiovascular outcomes will be definitively assessed in the ORION-4 trial (NCT03705234).
Inclisiran was also effective in reducing LDL-C levels in patients with ASCVD in the randomized, double-blind, placebo-controlled, phase III ORION-10 trial (NCT03399370) conducted in the USA [
7]. Patients eligible for enrolment had elevated LDL-C levels despite receiving maximally tolerated statin therapy with or without additional lipid-lowering treatment. They were randomized to inclisiran 284 mg (
n = 781) or placebo (
n = 780) administered as a 1.5 mL subcutaneous injection on day 1, day 90 and every 6 months thereafter over a total of 540 days. Inclisiran significantly improved percentage change in LDL-C level from baseline to day 510 relative to placebo (− 51.3% vs 1.0%; BGD − 52.3%; 95% CI − 55.7 to − 48.8;
p < 0.001) and the time-adjusted change in LDL-C level from baseline after day 90 and up to day 540 relative to placebo (− 51.3% vs 2.5%; BGD − 53.8%; 95% CI − 56.2 to − 51.3;
p < 0.001) [co-primary endpoints]. Absolute change in LDL-C level at day 510 and time-adjusted absolute change in LDL-C level from day 90 to day 540 were also significantly improved (
p < 0.001) with inclisiran versus placebo (key secondary endpoints) [
7]. Benefits of inclisiran over placebo for LDL-C lowering were observed across subgroups of patients with type 2 diabetes, metabolic syndrome and neither (
p < 0.001 vs placebo in each subgroup) [
15].
Inclisiran reduced LDL-C levels to a greater degree than placebo in adults with heterozygous familial hypercholesterolemia in the randomized, double-blind, placebo-controlled, multinational phase III ORION-9 trial (NCT03397121) [
6]. For enrolment in ORION-9, patients had elevated LDL-C levels despite receiving the maximally tolerated dose of a statin with or without ezetimibe. They were randomized to receive inclisiran 284 mg (
n = 242) or placebo (
n = 240) administered as a 1.5 mL subcutaneous injection on day 1, day 90 and every 6 months thereafter over a total of 540 days. Inclisiran significantly improved percentage change in LDL-C level from baseline to day 510 (− 39.7% vs 8.2% with placebo; BGD − 47.9%; 95% CI − 53.5 to − 42.3;
p < 0.001) and the time-averaged percentage change in LDL-C level between day 90 and day 540 (− 38.1% vs 6.2%; BGD − 44.3%; 95% CI − 48.5 to − 40.1;
p < 0.001) [primary endpoints]. Mean absolute change from baseline in LDL-C level at day 510, time-averaged observed difference in LDL-C levels between day 90 and day 540, percentage change in PCSK9 level at day 510, mean absolute change in PCSK9 level at day 510, and time-averaged observed difference in PCSK9 levels between day 90 and day 540 were also significantly improved (
p < 0.001) with inclisiran versus placebo (key secondary endpoints). Reductions in LDL-C levels with inclisiran versus placebo were observed across all familial hypercholesterolemia genotypes [
6].
Inclisiran was associated with reductions in LDL-C and PCSK9 levels in adults with homozygous familial hypercholesterolaemia in the open-label, single-arm, multicenter phase II ORION-2 study (NCT02963311) [
16]. This proof-of-concept pilot study enrolled patients with homozygous familial hypercholesterolaemia receiving maximally tolerated lipid-lowering therapy. Patients were administered inclisiran 284 mg (
n = 4) as a 1.5 mL subcutaneous injection on day 1 and either day 90 or 104 if mean PCSK9 levels were not reduced from baseline by > 70% on day 60 or 90. Three patients achieved durable LDL-C reductions [− 11.7% to − 33.1% at day 90 (primary endpoint) and − 17.5% to − 37.0% at day 180], while the remaining patient showed no reduction. All patients showed robust, durable reductions in PCSK9 levels. These data were considered sufficient to justify a long-term phase III trial in patients with homozygous familial hypercholesterolaemia (ORION-5; NCT03851705) [
16].
Inclisiran produced durable LDL-C reductions in patients with high cardiovascular risk and elevated LDL-C levels in the randomized, double-blind, placebo-controlled, multicentre phase II ORION-1 study (NCT02597127) [
17]. This dose-finding study enrolled patients who had elevated LDL-C levels despite receiving the maximal possible dose of a statin with or without additional lipid-lowering therapy (
n = 501 randomized). Patients received a single dose of inclisiran 200 mg, 300 mg, 500 mg or placebo, or two doses (days 1 and 90) of inclisiran 100 mg, 200 mg, 300 mg or placebo. Inclisiran was associated with dose-dependent reductions in LDL-C and PCSK9 levels. Least-squares mean reductions in LDL-C from baseline to day 180 were 28–42% after a single dose of inclisiran, while reductions of 36–53% were observed after two doses (
p < 0.001 for all doses vs placebo) [primary endpoint] [
17]. At days 180, 240 and 360, the greatest LDL-C reductions were observed in patients who received two doses of inclisiran 300 mg (53%, 47% and 31%, respectively) [
17,
18]. In an interim analysis of data from ORION-3 (NCT03060577;
n = 382), the open-label extension of ORION-1, patients treated with twice-a-year inclisiran sodium 300 mg achieved a 51% reduction in LDL-C levels through day 210 (
p < 0.001; primary endpoint) and a time-averaged absolute LDL-C reduction of 59.4 mg/dL (
p < 0.001); effects were independent of group assignment in ORION-1 [
19].
Key clinical trials of inclisiran
Drug(s) | Indication | Phase | Status | Location(s) | Identifier | Sponsor |
Inclisiran, PL | Adolescents with HeFH and elevated LDL-C | III | Not yet recruiting | Multinational | ORION-16; NCT04652726 | Novartis Pharmaceuticals |
Inclisiran, PL | Adolescents with HoFH and elevated LDL-C | III | Not yet recruiting | Multinational | ORION-13; NCT04659863 | Novartis Pharmaceuticals |
Inclisiran, PL | ASCVD or ASCVD risk equivalents and elevated LDL-C | III | Completed | Multinational | ORION-11; NCT03400800; MDCO-PCS-17-08 | The Medicines Company |
Inclisiran, PL | ASCVD and elevated LDL-C | III | Completed | USA | ORION-10; NCT03399370; MDCO-PCS-17-04 | The Medicines Company |
Inclisiran, PL | HeFH and elevated LDL-C | III | Completed | Multinational | ORION-9; NCT03397121; MDCO-PCS-17-03 | The Medicines Company |
Inclisiran | ASCVD, ASCVD risk equivalents, HeFH or HoFH and elevated LDL-C | III | Active, not recruiting | Multinational | ORION-8; NCT03814187; MDCO-PCS-17-05 | Novartis Pharmaceuticals |
Inclisiran, PL | HoFH and elevated LDL-C | III | Active, not recruiting | Multinational | ORION-5; NCT03851705; MDCO-PCS-17-02 | Novartis Pharmaceuticals |
Inclisiran, PL | ASCVD | III | Recruiting | United Kingdom | ORION-4; NCT03705234 | University of Oxford |
Inclisiran, PL | High cardiovascular risk and elevated LDL-C | II | Not yet recruiting | Japan | NCT04666298 | Novartis Pharmaceuticals |
Inclisiran, evolocumab | ASCVD or ASCVD risk equivalents and elevated LDL-C | II | Active, not recruiting | Multinational | ORION-3; NCT03060577; MDCO-PCS-16-01 | Novartis Pharmaceuticals |
Inclisiran, SOC | HoFH and elevated LDL-C | II | Completed | Multinational | ORION-2; NCT02963311; MDCO-PCS-16-02 | The Medicines Company |
Inclisiran, placebo | ASCVD or ASCVD risk equivalents and elevated LDL-C | II | Completed | Multinational | ORION-1; NCT02597127; MDCO-PCS-15-01 | The Medicines Company |
2.4 Adverse Events
Inclisiran administered as a subcutaneous injection was generally safe and well tolerated as a lipid lowering therapy in clinical trials, showing a safety profile comparable to that of placebo [
6,
7,
12,
16,
17,
20,
21]. In the pivotal phase III clinical trials (ORION-9, ORION-10 and ORION-11), adverse reactions at the injection site were the only adverse reactions associated with inclisiran (occurring in 8.2% of inclisiran recipients versus 1.8% of placebo recipients) [
3]. In inclisiran recipients, the most frequently reported adverse reactions at the injection site were injection site reaction (3.1% of patients), injection site pain (2.2%), injection site erythema (1.6%) and injection site rash (0.7%). Adverse reactions at the injection site led to treatment discontinuation in 0.2% of inclisiran recipients (vs 0.0% of placebo recipients). All adverse reactions at the injection site were of mild or moderate severity and transient, resolving without sequelae [
3].
Aside from injection site adverse events, the adverse event profile of inclisiran was well documented [
22]. Serious adverse events occurred in 20.4% of inclisiran recipients compared with 23.0% placebo recipients in phase III trials, and there was no evidence of kidney, liver, muscle or platelet toxicity. Treatment-emergent adverse events led to treatment discontinuation in 2.5% of inclisiran recipients compared with 1.9% of placebo recipients [
22]. There were no overall differences in safety between younger patients and older patients ≥ 65 or ≥ 75 years of age [
3]. The safety profile of inclisiran in patients with impaired renal function was similar to that in patients with normal renal function in an analysis of data from ORION-1 and the phase I ORION-7 renal study (NCT03159416) [
23].
During the pivotal clinical trials, 1.8% of patients tested positive for anti-inclisiran antibodies prior to dosing and 4.9% of patients tested positive over 18 months of inclisiran treatment; neither safety nor efficacy differed in any clinically significant manner based on the presence of anti-inclisiran antibodies [
3].
2.5 Ongoing Clinical Trials
Ongoing phase III clinical trials evaluating inclisiran include the ORION-4 cardiovascular outcomes trial (NCT03705234; currently recruiting) in adults with ASCVD and the ORION-5 trial (NCT03851705) in adults with homozygous familial hypercholesterolaemia. ORION-8 (NCT03814187), an ongoing open-label extension study of the phase III lipid-lowering trials (ORION-5, ORION-9, ORION-10 and ORION-11), is currently assessing the long-term use of inclisiran in adults with high cardiovascular risk and elevated LDL-C. ORION-3 (NCT03060577), the open-label, active-comparator extension study of the phase II ORION-1 trial, is similarly assessing the long-term use of inclisiran in this patient population.
The placebo-controlled, multinational, phase III ORION-13 (NCT04659863) and ORION-16 (NCT04652726) trials, which are not yet recruiting, will evaluate inclisiran in adolescents aged 12 to 17 years with homozygous familial hypercholesterolaemia and heterozygous familial hypercholesterolaemia, respectively, and elevated LDL-C on stable, standard of care background lipid-lowering therapy. Also yet to begin recruiting is a phase II trial (NCT04666298) that will compare inclisiran and placebo in Japanese patients with high cardiovascular risk and elevated LDL-C and a phase III trial that will evaluate the efficacy and safety of inclisiran in Asian patients with ASCVD or ASCVD high risk and elevated LDL-C (as an adjunct to diet and maximally tolerated statins with or without additional lipid-lowering therapy).