Inclisiran − a new addition to the arsenal of dyslipidemia treatment

Mechanism of action of inclisiran

Inclisiran belongs to the group of small interfering RNA (siRNA) molecules for therapeutic use. The molecule utilizes the natural RNA interference pathway by binding intracellularly in hepatocytes to the RNA-induced silencing complex (RISC), which then specifically cleaves mRNA molecules encoding proprotein convertase subtilisin/kexin type 9 (PCSK9).

The cleaved mRNA is thus degraded and not available as a template for the translation of the PCSK9 protein, thereby suppressing PCSK9 synthesis. The reduced availability of PCSK9 for LDL receptors on the surface of hepatocytes leads to their reduced degradation in lysosomes, increased renewal of LDL receptors, and thus increased absorption of LDL-c from circulation.

The targeted transport of siRNA to hepatocytes is facilitated by conjugation with triantenary N-acetylgalactosamine, which binds to asialoglycoprotein receptors (ASPGR) abundantly present on the surface of hepatocytes. The advantage of the drug is specific and long-lasting action in hepatocytes, as the RISC complex acts relatively long and repeatedly in hepatocytes. Specificity reduces the number of side effects and drug interactions.

Inclisiran is indicated for adult patients with primary hypercholesterolemia (heterozygous familial and non-familial form) or mixed dyslipidemia in combination with statin or statin in combination with another lipid-lowering therapy in patients who fail to achieve target LDL-c levels at the maximum tolerated statin dose. Inclisiran monotherapy or combination therapy with another lipid-lowering drug is possible in cases of intolerance or contraindication to statin therapy.

Insights from clinical trials

The efficacy and safety of inclisiran were confirmed in a series of phase III clinical trials ORION-9, -10, and -11. In them, compared to placebo, effective reduction of LDL cholesterol levels was achieved along with a reduction in total cholesterol, non-HDL cholesterol, apolipoprotein B, and lipoprotein (a) levels.

From the results of available clinical studies, it appears that the only side effect associated with inclisiran administration is an injection site reaction. The recommended initial dose is 284 mg, administered as a single subcutaneous injection by a healthcare professional into the abdominal area, with the next dose recommended after 3 months and then every 6 months.

No dose adjustment is needed for elderly individuals, patients with mild or moderate hepatic impairment, or patients with renal impairment, including those in the end stage of their disease.

Cases from real Czech practice

In addition to general information about this treatment, which was conveyed to the audience by the head of the Center for Diabetes IKEM, prof. MUDr. Martin Haluzík, DrSc., a case-oriented presentation by prof. MUDr. Hana Rosolová, DrSc., from the 2nd Internal Clinic of the Medical Faculty, UK and FN Plzeň, was also presented during the symposium. Inclisiran therapy was administered to a total of 25 patients at her workplace, most often due to intolerance of conventional hypolipidemic therapy. Due to the short period of inclisiran use, only short-term therapy results over 6 months (a total of 2 doses of inclisiran) could be evaluated.

Case study 1

The first selected case study was the case of a 70-year-old woman referred by an angiologist for the setup of secondary prevention because unsatisfactory cholesterol spectrum values were observed despite therapy with atorvastatin at a daily dose of 40 mg (the patient could not tolerate a higher dose due to muscle pain). Due to a complicated social situation, inability to administer injections at home, and regular commuting to the clinical center, she was indicated for inclisiran therapy instead of PCSK9 inhibitors.

After just 3 months (with the administration of the 2nd dose of inclisiran), a 48.5% drop in LDL cholesterol was observed, from an initial level of 4.55 mmol/l to 2.34 mmol/l. After 6 months, the LDL-c value was 1.82 mmol/l, and the patient tolerated the combined therapy with atorvastatin very well. If she could also tolerate the maximum dose of statin or ezetimibe, it would most likely achieve the target LDL-c level of < 1.4 mmol/l.

Case study 2

The second presented case involved a 66-year-old patient with high cardiovascular risk (chronic ischemic heart disease, status post triple aortocoronary bypass) referred by a cardiologist due to unsatisfactory cholesterol levels with statin intolerance and suspected familial hypercholesterolemia. In the context of hypolipidemic therapy, it was possible to titrate a tolerable chronic medication in the form of a fixed combination of ezetimibe/atorvastatin 10/10 mg.

However, this therapy did not achieve satisfactory lipid spectrum values, so the patient was indicated for PCSK9i therapy. He was first treated with alirocumab, but after the 4th dose, he developed skin efflorescences, which disappeared after discontinuation. Subsequently, inclisiran therapy was initiated, with LDL-c levels dropping from an initial 4.31 mmol/l to 2.25 mmol/l after 3 months, and to 1.26 mmol/l after 6 months.

Case study 3

The protagonist of the third case study was a 65-year-old patient with mixed dyslipidemia with high cardiovascular risk and a rich cardiovascular history (CVA, status post brainstem ischemia, status post stenting of the superior mesenteric artery for significant stenosis, status post PTA of the renal artery, ischemic lower limb disease with a history of PTA of lower limb arteries) intolerant to statins (myopathy), ezetimibe (GI issues), and PCSK9i evolocumab.

The man was indicated for inclisiran therapy, and after 3 months of therapy, his LDL-c levels dropped from an initial 5.30 mmol/l to 2.58 mmol/l, and after 6 months, to 2.11 mmol/l.

Summary

Although not all patients achieved target LDL cholesterol levels (mainly due to intolerance of statins or ezetimibe), the LDL-c level significantly decreased in all cases, thanks in part to the administration of inclisiran. It is important to consider that in such high-risk patients, any decrease in LDL-c is positive news and reduces overall risks. Furthermore, the treatment was free of any side effects.

(holi)

Sources:
1. Haluzík M. Leqvio: soon in the internist's arsenal for dyslipidemia treatment. XXIX Congress of the Czech Society of Internal Medicine ČLS JEP, Prague, 8. 11. 2022.
2. Rosolová H. Case studies − inclisiran. XXIX Congress of the Czech Society of Internal Medicine ČLS JEP, Prague, 8. 11. 2022.
3. SPC Leqvio. Available at: www.ema.europa.eu/en/documents/product-information/leqvio-epar-product-information_cs.pdf