ADD-ONS / MEDICATION

Inclisiran (LEQVIO)

David Goldemund M.D.
Updated on 21/03/2024, published on 19/03/2024

in recent years, the prevalence of cardiovascular disease (CVD) has been reduced by aggressive management of vascular risk factors in primary and secondary prevention (especially arterial hypertension and dyslipidemia)
statin therapy alone often fails to achieve target serum lipid levels (Bytyci, 2022)
iInclisiran expands the treatment options for dyslipidemia by suppressing the production of proprotein convertase subtilisin/kexin type 9 (PCSK9) through innovative targeted degradation of specific mRNA
- this revolutionary technology allows for long dosing intervals, which increases the patient compliance
because of its highly specific action, it is a safe treatment that is very well tolerated (most AEs are related to mild local reactions to the injection)
- safety and efficacy have been demonstrated in several ORION studies; the ORION-9, 10, and 11 trials are particularly relevant for routine clinical practice

proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulatory protein that binds to and modulates the action of the LDL receptor located on the cell membrane’s surface
when the LDL receptor + LDL particle complex is internalized and fused with the lysosome in the cytoplasm of the hepatocyte, PCSK9 leads to the degradation of the LDL receptor, and it cannot be thus recycled back to the cell surface
in the absence of PCSK9, LDL receptor recycling remains intact, leading to increased clearance of LDL particles and decreased plasma concentration
this can be achieved in 2 ways
- by inhibiting PCSK9 with monoclonal antibodies (such as evolocumab and alirocumab) that bind to the circulating pool of PCSK9 molecules and prevent them from binding to the LDL receptor
- by specifically suppressing the production of PCSK9 directly in the hepatocyte using inclisiran, which belongs to the class of small interfering ribonucleic acids (siRNAs)
therefore, inclisiran, like monoclonal antibodies against PCSK9, is mainly used to lower LDL-cholesterol (LDL-C)

after subcutaneous administration, the drug is absorbed into the bloodstream within a few days
subsequently, inclisiran enters the hepatocyte by endocytosis
- to ensure its transport into the liver, inclisiran is conjugated to N-acetyl-galactosamine (GalNac)
the siRNA is then gradually released into the cytoplasm, where it targets a specific mRNA encoding PCSK9
mRNA is degraded by the endonuclease activity of the complex, resulting in targeted inhibition of PCSK9 synthesis
the prolonged effect is due to the gradual release of inclisiran from endosomes into the cytoplasm of hepatocytes and the formation of a stable ISC complex (induced silencing complex); therefore, inclisiran can be administered at long time intervals

inclisiran is not a substrate for common drug transporters and is not expected to be a substrate for cytochrome P450
inclisiran is neither an inhibitor nor an inducer of cytochrome P450 enzymes or common drug transporters ⇒ inclisiran is not likely to have clinically significant drug interactions, incl. atorvastatin, rosuvastatin, or other statins
common AE (generally mild):
- injection site reaction
- arthralgia, diarrhea, bronchitis
effect of hemodialysis on inclisiran pharmacokinetics has not been studied; inclisiran is excreted by the kidneys; therefore, it is recommended not to perform hemodialysis within 72 hours after inclisiran administration
pregnancy and lactation
- inclisiran is not recommended during pregnancy as its effects on developing fetus are currently unknown
- it is unclear whether inclisiran is excreted in human breast milk; a risk to breastfed infants/children cannot be ruled out
renal or hepatic impairment
- inclisiran can be used in patients with mild to moderate renal or hepatic impairment without dose adjustment
- data are limited for patients with severe renal or hepatic impairment, and caution is advised in these populations

treatment of adults with primary hypercholesterolemia (both familial and nonfamilial) or mixed dyslipidemia
- in combination with a statin or other hypolipidemic drugs in people who do not achieve target LDL-C levels despite taking the maximum tolerated dose of a statin (e.g., with ezetimibe)
- alone or in combination with other lipid-lowering agents for patients who are intolerant to statins or for whom a statin is contraindicated

INCLISIRAN (LEQVIO, 284 mg/1.5 mL solution in prefilled syringe)

recommended dose: 284 mg of inclisiran administered as a single SC injection
the recommended dosing regimen starts with an initial dose, followed by a second dose at 3 months, and subsequent doses every 6 months thereafter
how to proceed with delayed injection:
- scheduled dose delayed < 3 months: administer inclisiran and continue on the original dosing schedule
- scheduled dose delayed > 3 months: start a new dosing regimen (re-administer the initial dose, followed by the next dose after 3 months, and then every 6 months thereafter)
inclisiran can be administered immediately after the last dose of PCSK9 monoclonal antibody
- administer inclisiran within two weeks of the last dose of PCSK9 monoclonal antibody

inclisiran is a first-in-class small interfering RNA (siRNA) therapeutic agent that selectively inhibits the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver
by targeting the PCSK9 mRNA, inclisiran degrades it, preventing the production of PCSK9 protein
this leads to an increase in the number of LDL receptors on the surface of hepatocytes, enhancing the clearance of LDL cholesterol (LDL-C) from the bloodstream

adjunctive treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of LDL cholesterol (LDL-C) alongside diet and maximally tolerated statin therapy

inclisiran is administered via subcutaneous injection
the recommended dosing regimen starts with an initial dose, followed by a second dose at 3 months, and subsequent doses every 6 months thereafter.

the primary contraindication is a history of serious hypersensitivity reaction to the drug
precautions include monitoring for signs and symptoms of hypersensitivity reactions following administration

inclisiran has a low potential for drug-drug interactions
it does not involve cytochrome P450 enzymes in its metabolism, reducing the risk of interactions with commonly used medications

yes, inclisiran provides an alternative or adjunctive treatment option for patients who are intolerant to statins due to its different mechanism of action and route of administration, potentially offering a solution for those with statin-associated muscle symptoms

patients receiving inclisiran should have their LDL-C levels monitored according to clinical guidelines to assess response to therapy
routine monitoring for adverse effects, particularly injection site reactions, is recommended

while the primary effect of inclisiran is the reduction of LDL-C levels, ongoing large-scale cardiovascular outcome trials are investigating its impact on major adverse cardiovascular events (MACE)
preliminary data suggest a promising role in cardiovascular risk reduction