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Twice-yearly dosing with inclisiran may improve treatment persistence and adherence.
Abstract
Despite the development of new therapies to lower cardiovascular disease (CVD) risk in recent decades, the trend of reductions in CVD mortality has reversed. New therapies are essential for the prevention of first and recurrent CVD. The importance of lowering low-density lipoprotein cholesterol (LDL-C) in the management and prevention of atherosclerotic CVD (ASCVD) is widely reflected in clinical treatment guidelines; however, most patients with established ASCVD do not achieve guideline-recommended LDL-C targets. Common reasons include adherence challenges, public disinformation, statin tolerability issues, access barriers, and clinical inertia. Inclisiran is a novel small interfering ribonucleic acid (RNA) that lowers circulating LDL-C by ∼50% when added to maximally tolerated statins by mimicking the body's natural pathway of RNA interference to specifically prevent proprotein convertase subtilisin/kexin type 9 synthesis. The unique dosing regimen of inclisiran (initial, at 3 months, and then every 6 months) has the advantage of allowing for healthcare provider administration during recommended routine visits for patients with established ASCVD, which can circumvent adherence issues associated with currently available LDL-C-lowering therapies. Inclisiran has demonstrated favorable tolerability and safety for up to 3 years, and evidence from longer-term use is accumulating in ongoing studies. This review discusses the novel mechanism of action of inclisiran and its potential position in the clinical armamentarium.
2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Despite the development of multiple new therapies to prevent ASCVD in recent decades, the disease burden remains high, and initial declines in CVD mortality have now reversed.
New approaches for the management and prevention of ASCVD are therefore paramount and new therapies to lower atherogenic lipids and lipoproteins are much needed. Lipid risk factors that are in the spotlight because of the recent development of novel therapies include low-density lipoprotein (LDL) cholesterol (LDL-C), triglyceride-rich lipoprotein, and lipoprotein(a).
Atherosclerosis precedes all clinical ASCVD, so treatment is directed at interfering with the formation or growth of atherosclerotic plaques. Retention of LDL-C and other apolipoprotein B (apoB)-containing lipoproteins in the arterial wall over time drives the development of atherosclerotic plaques through a process of oxidation, inflammation, necrosis, fibrosis, and calcification.
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Dozens of clinical trials have unequivocally demonstrated that therapies that lower LDL-C by enhancing LDL clearance prevent the development or progression of atherosclerotic plaques and the occurrence of a first or recurrent ASCVD event.
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Moreover, it has been shown that modest reductions in LDL-C conferred by naturally occurring nonsense mutations in the gene encoding for proprotein convertase subtilisin/kexin type 9 (PCSK9) in black and white populations are associated with an 88% and 47% reduction in the risk of coronary heart disease (CHD), respectively.
It has been established that the relationship between LDL-C and ASCVD events is linear, and lowering LDL-C well below currently recommended thresholds (eg, 70 mg/dL) further reduces ASCVD risk, without significant safety concerns.
Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.
Moreover, studies of individuals with genetic variants in genes encoding proteins that regulate LDL-C levels have revealed that the strength of the relationship between LDL-C and cardiovascular risk is time dependent.
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
For example, people with a loss-of-function variant in the gene encoding for PCSK9, such as a nonsense mutation, that results in a reduction in LDL-C have up to an 88% lower risk of CHD (myocardial infarction, fatal CHD, or coronary revascularization) because lower LDL-C is present since birth.
Based on clinical trial evidence, professional society cholesterol guidelines have introduced progressively lower LDL-C thresholds and recommend the use of statin and non-statin LDL-C-lowering therapies in primary and secondary prevention.
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
Inclisiran is a novel LDL-C-lowering, small interfering ribonucleic acid (RNA) [siRNA] with a twice-yearly dosing regimen that has demonstrated safe and effective LDL-C lowering in three phase 3 clinical trials.
The objective of this review is to discuss the novel mechanism of action of inclisiran, which harnesses the natural pathway of RNA interference (RNAi) and its potential position in the clinical armamentarium to address the unmet need for effective and safe LDL-C-lowering therapies.
Current landscape
Unmet needs
Despite the widespread availability and proven efficacy of statins, ezetimibe, bile acid sequestrants, and PCSK9-inhibiting monoclonal antibodies (mAbs), 83.5% of adults with established ASCVD have LDL-C levels ≥70 mg/dL.
Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011–2012.
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
Effectiveness of adherence to lipid lowering therapy on LDL-cholesterol in patients with very high cardiovascular risk: a real-world evidence study in primary care.
In a US study of adults with clinical ASCVD and LDL-C ≥70 mg/dL identified through electronic medical record data, ∼42% were not receiving any lipid-lowering therapy, and ∼26%, ∼7%, and ∼2% were receiving a high-intensity statin, ezetimibe, or PCSK9-inhibiting mAb, respectively.
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
The importance of ensuring adherence to lipid-lowering therapy is supported by data from another real-world US study demonstrating that statin adherence is inversely associated with mortality in patients with stable ASCVD.
In addition to suboptimal compliance with guidelines and poor adherence to lipid-lowering therapy, poor treatment access or treatment discontinuation due to out-of-pocket expenses, such as with the use of PCSK9-inhibiting mAbs, has also been linked to failure to achieve guideline-recommended LDL-C thresholds and poor treatment outcomes.
All primary therapies for LDL-C lowering with evidence for improvement in major cardiovascular events achieve LDL-C reduction by enhancing hepatic LDL clearance.
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
This can be achieved by direct impact on LDL receptor (LDL-R) expression or indirectly by lowering hepatocyte cholesterol concentration. Hepatocyte cholesterol homeostasis is maintained by multiple redundant mechanisms and pharmacotherapy options. Treatments that reduce hepatocyte cholesterol concentration lead to enhanced LDL-R expression, resulting in improved serum clearance.
Statin drugs and bempedoic acid primarily inhibit cholesterol synthesis. Bempedoic acid is an oral, once-daily pro-drug selectively activated in liver cells that inhibits adenosine triphosphate citrate lyase, which is an early step in the same cholesterol biosynthesis pathway in the liver that is disrupted by statins (Fig. 1).
Ezetimibe inhibits enterocyte sterol absorption, reducing intestinally derived cholesterol. Bile acid resins enhance intestinal bile clearance and hepatic cholesterol catabolism and impair intestinally derived cholesterol absorption. PCSK9 mAbs enable improved LDL-R recycling. While their mechanisms differ, they all result in reduced hepatic cholesterol or up-regulation and expression of the LDL-R and enhanced circulatory LDL clearance (Fig. 1). The most recent lipid-lowering therapy to have received regulatory approval is the siRNA inclisiran. Inclisiran was approved in December 2020 in the EU for use in adults with primary hypercholesterolemia (heterozygous familial [HeFH] and non-familial) or mixed dyslipidemia, and in December 2021 by the US Food and Drug Administration (FDA) as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or ASCVD who require additional lowering of LDL-C.
RNAi was first discovered in 1998 by Fire, Mello, and colleagues, who were awarded a Nobel Prize for their discovery in 2006. RNAi is a physiological defense mechanism for the invasion of viruses and other unwanted RNAs in eukaryotic cells. RNAi molecules, including endogenous micro RNAs (miRNAs) or exogenously introduced siRNAs, silence the expression of specific genes by targeting messenger RNA (mRNA) for degradation in a sequence-specific manner.
This natural mechanism can be utilized as a pharmaceutical treatment. Synthetic double-stranded RNAs (dsRNAs) are designed to incorporate specific modifications to provide stabilization in the blood, target their delivery to specific tissues, and allow them to cross the cell membrane.
Once in the cytoplasm, dsRNAs are cleaved by an endoribonuclease (Dicer) into siRNAs. siRNAs comprise two complementary RNA strands, an antisense or “guide” strand, which carries the sequence information necessary for target mRNA recognition, and a sense or “passenger” strand, which serves to support the geometry needed for loading the siRNA into the effector RNA-induced silencing complex (RISC). The term RISC describes a multiprotein complex that can facilitate silencing of almost any mRNA. When the siRNA is loaded into the RISC, the passenger strand is separated from the guide strand and then discarded and degraded, while the guide strand remains within the RISC, specifically binding to the Argonaute (Ago) protein in the complex. Recent models suggest that selection of the siRNA guide strand is dependent on binding of the Ago middle domain with a thermodynamically unstable 5’ nucleotide phosphate followed by Ago N-domain binding of the guide strand 3’ end.
The guide strand loaded on the RISC serves as a template to guide RISC to its complementary target mRNA transcripts (through base-pairing interactions) and then selectively and catalytically cleaves the target mRNA, preventing translation of the mRNA (Fig. 2). The loaded RISC complex has a half-life of weeks, with each complex being able to prevent protein synthesis from multiple mRNA copies.
Significant progress has been made in the development of therapeutic siRNAs in recent years. Beyond inclisiran, two additional siRNA-based drugs are currently approved in the United States, both for the treatment of rare inherited disorders (patisiran for polyneuropathy associated with hereditary transthyretin-mediated amyloidosis and givosiran for acute hepatic porphyria).
Inclisiran is a novel synthetic siRNA that inhibits the synthesis of hepatic PCSK9 and results in sustained reductions of LDL-C. Inclisiran is comprised of one 2’-deoxy, 11 2’-fluoro, and 32 2’-O-methyl modified nucleotides (for a total of 44 base pairs) and is conjugated to the ligand triantennary N-acetylgalactosamine (GalNAc) (Fig. 2). The GalNAc ligand binds to asialoglycoprotein receptors (ASGPRs) expressed mainly on hepatocytes (∼500,000 copies/cell), allowing rapid and precise targeted uptake of inclisiran by the liver.
Once GalNAc binds to ASGPR, cellular entry of GalNAc–siRNA is achieved through the naturally existing process of clathrin-mediated endocytosis, enabling the formation of clathrin-coated vesicles and then endosomes.
The targeting of inclisiran to the liver is highly beneficial, as this is where circulating PCSK9 is predominantly produced. First, it reduces the theoretical risk of off-target inhibition, as PCSK9 is also expressed in other tissues including lungs, pancreas, and brain, thus reducing the potential for side effects.
Second, GalNAc-mediated liver specificity allows for the use of much lower cumulative doses compared to the doses that would be required in the absence of this specific delivery. At the relevant clinical plasma concentrations, inclisiran is 87% protein bound in vitro.
As a consequence of the liver specificity of inclisiran, systemic exposure is limited and inclisiran is no longer detectable in the circulation 48 h after administration; this is also true for patients with mild to severe renal impairment, despite the fact that 16% of inclisiran is renally cleared.
Of note is the fact that as an siRNA, inclisiran acts upstream of the PCSK9 protein synthesis to target the PCSK9 gene product specifically in the hepatocytes, leading to a sustained reduction in protein production in the liver. This is in contrast to the PCSK9-inhibiting mAbs, which specifically target circulating PCSK9 protein and, therefore, require more frequent administration to maintain PCSK9 suppression as new PCSK9 protein is rapidly produced.
Moreover, by binding to circulating PCSK9 protein, mAbs against PCSK9 can theoretically also cause systemic effects. Through its ability to mimic the natural process of RNAi in the liver, inclisiran lowers LDL-C levels over time
and, in effect, mimics naturally occurring cardioprotective loss-of-function mutations in PCSK9.
In addition to its specificity for the liver, inclisiran's sequence was selected for its high specificity to its target mRNA. Once inside the cell there is a low probability of off-target effects because inclisiran is sequestered within RISC and guided to its complementary PCSK9 mRNA sequence, which is highly conserved across diverse ethnic and geographical populations. A comprehensive search against the human transcriptome revealed only 20 potential off-target transcripts, some of which are not normally expressed in the liver.
Subsequent in vitro assays of the remaining transcripts showed a ≥45-fold difference between the “on target” suppression of PCSK9 and the suppression of any of the “off target” transcripts, highlighting the sequence specificity of inclisiran.
After GalNAc-mediated uptake into hepatocytes, inclisiran is slowly released from endosomes into the cytoplasm, where its guide strand binds and stays attached to the RISC protein complex. Once the inclisiran guide strand has bound its target mRNA, the PCSK9-encoding mRNA is cleaved and degraded, thereby preventing the production of the PCSK9 protein (Fig. 2).
The reduced synthesis of PCSK9 protein disables lysosomal degradation of LDL-R, leading to enhanced expression of LDL-R on the surface of hepatocytes. This results in efficient LDL clearance from the circulation and lower LDL-C levels.
The RISC complex has a long half-life and is catalytic: one loaded RISC complex can take out multiple copies of PCSK9 mRNA. As few as 100–200 loaded RISC complexes per cell are enough to eliminate the expression of a targeted gene.
Inclisiran is prepared as a prefilled syringe (containing 300 mg inclisiran sodium, equivalent to 284 mg inclisiran in 1.5 mL water for injection) for subcutaneous [SC] administration. Inclisiran should be stored at controlled room temperature (20–25°C [68–77°F]), with allowable excursions between 15°C and 30°C [59°F and 86°F]), and has a shelf life of 2 years. It is administered as an SC injection initially, again at 3 months, and then every 6 months thereafter.
Inclisiran: efficacy and safety of the novel mechanism
The molecular structure of inclisiran was designed to incorporate chemical modifications including phosphorothioate, 2’-O-methyl nucleotide, and 2’-fluoro nucleotide, which give inclisiran two important features. First, the chemical modifications reduce inclisiran's potential for immunogenicity,
Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1.
and second, they increase inclisiran's molecular stability and thereby the durability of its clinical effect, which is considerably longer compared with that of any other currently available class of lipid-lowering drugs.
A second potential contributing factor to the long duration of effect of inclisiran is the endosome's functioning as a depot that holds inclisiran within the hepatocyte for a prolonged period of time.
These properties confer inclisiran with the advantage of safe and less frequent administration compared with other lipid-lowering therapies. Significantly, although inclisiran's duration of effect is long, it is reversible.
In the phase 2 ORION-1 study, part of the inclisiran clinical development program (Table 1),
LDL-C and PCSK9 returned towards baseline levels in a linear and predictable way following administration of one or two doses (on Day 1 or on Day 1 and Day 90, respectively).
In this trial, after administration of a 300 mg dose of inclisiran sodium on Day 1 and 300 mg again on Day 90, the time-averaged LDL-C reduction over a complete year was 46.4% (Figs. 3 and 4), with administration of the second dose of inclisiran sodium providing an additional ∼10% reduction in LDL-C levels (ie, the reduction in LDL-C was 36.6% after a single dose and 46.4% after two doses). Moreover, with this dosing regimen the mean LDL-C reduction from baseline at 1 year was >30%, and at 1 year, >80% of participants had LDL-C levels that were still ≥20% below their baseline levels. These findings highlight the clinically meaningful long duration of effect of inclisiran but also demonstrate that inclisiran's effect is reversible with time. Of note, the two-dose 300 mg inclisiran sodium regimen maintained a 50% reduction in LDL-C for at least 6 months and also achieved the greatest mean reduction in LDL-C over 1 year (Figs. 3 and 4), providing the rationale for the two-dose inclisiran starting regimen (Day 1 and Day 90) that was subsequently tested in phase 3 trials. In ORION-3, an open-label extension study to ORION-1, inclisiran achieved a 51% (64 mg/dL; p < 0.001) reduction in LDL-C levels from baseline through Day 210 of the extension trial (primary endpoint) (Table 1).
Furthermore, inclisiran demonstrated a time-averaged absolute reduction in LDL-C levels of ∼60 mg/dL over 22 months, and a consistent and durable >50% LDL-C-lowering effect over the long term (∼3 years).
Table 1Key clinical trials of inclisiran for MoA, efficacy, and safety.
Study name and identifier
Phase
Patient population
Primary endpoint
Other key results
Completed MoA supportive trials
Phase 1, NCT0231444226
1
Healthy volunteers (n = 70)
Safety; no serious AEs observed Pharmacodynamics; doses of ≥300 mg reduced PCSK9 (up to 75% from baseline) and LDL-C (up to 51% from baseline) for at least 6 months
Significant reductions from baseline to Day 84 in TC, non-HDL-C, and apoB after single dose ≥250 mg (all p < 0.05)
ORION-1, NCT0259712728
2
ASCVD or ASCVD risk equivalents and elevated LDL-C (n = 501)
Mean percentage change from baseline in LDL-C on Day 180: 38.4% with single dose of inclisiran
Doses of inclisiran differ from those used in the pivotal trials. Abbreviations: AE, adverse event; apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MoA, mechanism of action; PCSK9, proprotein convertase subtilisin/kexin type 9; TC, total cholesterol.
; 52.6% with two-dose starting regimen of inclisiran
Time-averaged reduction in LDL-C over 1 year: 29.5–38.7% with single dose of inclisiran; 29.9–46.4% with two-dose starting regimen of inclisiran
Completed pivotal trials
ORION-9, NCT033971218
3
HeFH and elevated LDL-C (n = 482)
Placebo-corrected percentage change in LDL-C from baseline on Day 510: −47.9%, p < 0.001 (ORION-9); −52.3%, p < 0.001 (ORION-10); −49.9%, p < 0.001 (ORION-11)Time-averaged percentage change in LDL-C from baseline between Day 90 and Day 540: −44.3%, p < 0.001 (ORION-9); −53.8%, p < 0.001 (ORION-10); −49.2%, p < 0.001 (ORION-11)
No differences in LDL-C reductions between different HeFH genotypes
ORION-10, NCT033993709
3
ASCVD and elevated LDL-C (n = 1561)
Inclisiran significantly lowered TC, non-HDL-C, and apoB versus placebo at Day 510 (all p < 0.001)
ORION-11, NCT034008009
3
ASCVD or ASCVD risk equivalents and elevated LDL-C (n = 1617)
Ongoing extension trials
ORION-3, NCT0306057729
2
ASCVD or ASCVD risk equivalents and elevated LDL-C (n = 290)
Mean percentage change from baseline in LDL-C on Day 210: 51% (64 mg/dL; p < 0.001)
Time-averaged reduction in LDL-C over 22 months: ∼60 mg/dL
ORION-8, NCT03814187
3
ASCVD, ASCVD risk equivalents, HeFH or HoFH and elevated LDL-C (n = 2991)
Trial is ongoing
Doses of inclisiran differ from those used in the pivotal trials. Abbreviations: AE, adverse event; apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MoA, mechanism of action; PCSK9, proprotein convertase subtilisin/kexin type 9; TC, total cholesterol.
Fig. 3Time courses of percentage change in LDL-C with single-dose (Panel A) and two-dose (Panel B) inclisiran. Abbreviation: LDL-C, low-density lipoprotein cholesterol.
Fig. 4Waterfall plots of individual percentage changes in LDL-C at Day 360 after a single-dose (Panels A–C) or two-dose (Panels D–F) starting regimen for those who had not returned to within 20% of their change from baseline at Day 330 and thus returned for a final visit. Abbreviation: LDL-C, low-density lipoprotein cholesterol.
Inclisiran has been evaluated in three pivotal, randomized, double-blind phase 3 studies, ORION-9, ORION-10, and ORION-11. The results of these studies confirm that twice-yearly dosing with inclisiran achieves marked and sustained LDL-C reductions compared with placebo in patients with elevated LDL-C despite maximally tolerated statin therapy (with or without additional lipid-lowering therapy). ORION-9 enrolled patients with clinical or genetic evidence of HeFH and LDL-C ≥100 mg/dL,
Additionally, the ORION-11 study also included patients with an ASCVD risk equivalent (type 2 diabetes, HeFH, or a 10-year risk of a cardiovascular event of ≥20% as assessed by the Framingham Risk Score for CVD or equivalent) and LDL-C ≥100 mg/dL.
In all three studies, patients were randomly assigned to receive either inclisiran 300 mg or placebo, administered by SC injection on Day 1, Day 90, and every 6 months thereafter over a period of 540 days. The primary endpoints in each trial were the placebo-corrected percentage change in LDL-C level from baseline to Day 510 and the time-adjusted percentage change in LDL-C level from baseline after Day 90 and up to Day 540.
A total of 482 patients were included in the ORION-9 study, with a mean baseline LDL-C level of 153.1 mg/dL.
The placebo-corrected percentage change in LDL-C from baseline to Day 510 was −47.9% (95% confidence interval [CI] −53.5 to −42.3; p < 0.001). Similar findings were reported for the time-averaged percentage change from baseline in LDL-C between Day 90 and Day 540, with a placebo-corrected change of −44.3% (95% CI −48.5 to −40.1; p < 0.001). Robust reductions in LDL-C were achieved in all genotypes of HeFH in the study (Table 1).
A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively.
Stable doses of statin were used in 89.2% and 94.7% of patients in the ORION-10 and ORION-11 trials, respectively, with 68.0% and 78.6% of patients receiving high-intensity statins. Ezetimibe was used in 9.9% (ORION-10 trial) and 7.1% (ORION-11 trial) of patients. Mean LDL-C levels at baseline were 104.7 mg/dL and 105.5 mg/dL, respectively. At Day 510, the placebo-adjusted change in LDL-C from baseline was –52.3% (95% CI –55.7 to –48.8) in ORION-10 and –49.9% (95% CI –53.1 to –46.6) in ORION-11. The corresponding time-adjusted changes from baseline in LDL-C between Day 90 and Day 540 were –53.8% (95% CI –56.2 to –51.3) and–49.2% (95% CI –51.6 to –46.8), respectively (p < 0.001 for all comparisons versus placebo). In both studies, inclisiran also resulted in a significant improvement in other lipid parameters at Day 510, including lower levels of total cholesterol, apoB, and non-high-density lipoprotein cholesterol compared with placebo (Table 1). In a pooled analysis of ORION-10 and ORION-11, an LDL-C reduction ≥50% was reached by 1359 (86.6%) patients treated with inclisiran versus 97 (6.2%) patients treated with placebo at any visit. An LDL-C reduction ≥30% was reached by 1523 (97.0%) patients treated with inclisiran versus 371 (23.7%) patients treated with placebo.
LDL-C lowering leads to a reduction in the risk of future cardiovascular events when achieved by a variety of different approaches. This provides a strong rationale for the phase 3 ORION-4 trial (NCT03705234), a long-term cardiovascular outcomes study designed to follow ∼15,000 patients with pre-existing CVD for a median of 5 years. The primary outcome of ORION-4 is the time to the first occurrence of death from CHD, MI, fatal or non-fatal ischemic stroke, or urgent coronary revascularization procedure. Secondary outcomes include the number of patients with a composite of CHD death or MI and the number of patients with cardiovascular death. ORION-4 was initiated in October 2018, with completion of the primary outcome expected in December 2024. However, due to enrollment challenges related to the global COVID-19 pandemic, primary completion is now estimated to be in July 2026. Additionally, the phase 3 VICTORION-2P trial (NCT05030428) evaluating inclisiran sodium for patients with established ASCVD is also currently ongoing. This study is designed to determine whether treatment with inclisiran sodium in addition to well-tolerated, high-intensity statin therapy will reduce the risk of 3-Point-Major Adverse Cardiovascular Events, defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke.
The safety and tolerability profile of inclisiran has been established in over 2500 patient-years exposure during the phase 3 pivotal studies (ORION-9, ORION-10, and ORION-11).
Across all three studies, inclisiran was well tolerated, although there was a higher incidence of clinically relevant injection-site reactions with inclisiran than with placebo (inclisiran, 5.0% versus placebo, 0.7%; risk ratio, 7.54). These reactions were generally mild (none of them were severe) and transient.
No effects were observed on liver safety or laboratory parameters. In addition to the safety data reported in these phase 3 studies, data from ORION-3, the long-term extension study of ORION-1, showed consistent tolerability and safety with inclisiran for up to 3 years.
No treatment-related elevations of liver enzymes or changes in renal function were reported in the study, and injection-site reactions were infrequent, mild to moderate, and transient.
Experience with exposure to inclisiran is also increasing rapidly in ongoing studies. For example, the efficacy, safety, and tolerability of long-term administration of inclisiran in patients with ASCVD or ASCVD risk equivalents and elevated LDL-C are currently being evaluated in the open-label, long-term extension study ORION-8, which includes patients who completed ORION-9, ORION-10, or ORION-11; patients enrolled in ORION-8 will receive inclisiran for up to an additional 3 years.
Although long-term efficacy and safety outcomes from ORION-4 are not yet available, all data available to date from the ORION clinical development program support the safety and efficacy of inclisiran in patients with ASCVD. Based on these results, inclisiran was recently approved by the US FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or ASCVD who require additional lowering of LDL-C. Regulatory approval of inclisiran provides physicians with an additional highly effective therapeutic option for the management of elevated LDL-C in patients with ASCVD. The inclisiran twice-yearly dosing regimen may be particularly effective in improving LDL-C levels in patients who struggle to adhere to lipid-lowering therapies that require frequent self-administration.
Conclusions
Inclisiran represents the first LDL-C-lowering therapy in a new class of drugs, siRNAs, with the potential to deliver effective, sustained, and safe reduction of LDL-C levels. Its unique dosing regimen (initial dose, one at 3 months, and then one every 6 months) enables healthcare professional administration, which may circumvent adherence challenges that have prevented us from realizing the full benefits of existing LDL-C-lowering therapies.
Author contributions
All authors contributed to the writing and/or critical review of the manuscript.
Sources of funding
This work was supported by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, in accordance with GPP3 guidelines (http://www.ismpp.org/gpp3).
Declaration of Competing Interest
R.S. is an employee of Novartis Pharmaceuticals Corporation. D.S. is a consultant for Akcea Therapeutics and Novartis Pharmaceuticals Corporation, and a clinical trial investigator for Ionis, Amgen, AstraZeneca, Novartis, Regeneron, and REGENXBIO. R.P. has nothing to disclose.
Acknowledgments
Medical writing support was provided by Reza Sayeed and Rosalba Satta, PhD, of Complete HealthVizion, McCann Health Medical Communications, and was funded by Novartis Pharmaceuticals Corporation. This manuscript was developed in accordance with Good Publication Practice (GPP3) guidelines. Authors had full control of the content and made the final decision on all aspects of this publication.
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Albert MA
et al.
2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.
Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011–2012.
Effectiveness of adherence to lipid lowering therapy on LDL-cholesterol in patients with very high cardiovascular risk: a real-world evidence study in primary care.
Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1.
Doses of inclisiran differ from those used in the pivotal trials. Abbreviations: AE, adverse event; apoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MoA, mechanism of action; PCSK9, proprotein convertase subtilisin/kexin type 9; TC, total cholesterol.
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