FDA Approves Novel PCSK9 Inhibitor Inclisiran (Leqvio)

By Jessica Pyhtila, PharmD, BCGP, BCPS

The FDA recently approved inclisiran (Leqvio), a first-in-class small interfering RNA (siRNA) PCSK9 inhibitor. The drug is indicated for LDL-C lowering in heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease in conjunction with maximally tolerated statin therapy.

In contrast to other PCSK9 inhibitors, inclisiran is administered only twice a year when given on a chronic basis. The drug is administered as a 284 mg subcutaneous injection once, with a follow-up injection at 3 months, and then every 6 months thereafter. Unlike other agents which can be self-administered, inclisiran should be administered by a healthcare professional. It comes in a prefilled syringe and may be injected into the abdomen, upper arm, or thigh.

Inclisiran is a double-stranded siRNA formulated to facilitate uptake by the liver. In hepatocytes, inclisiran causes the breakdown of mRNA for PCSK9. As such, the medication increases both LDL-C receptor recycling and receptor expression on hepatocyte cell surfaces. In turn, LDL-C uptake is increased and serum LDL-C levels decrease.

Common side effects of inclisiran include injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremities, and dyspnea. LDL-C levels can be monitored as clinically indicated and may be drawn as early as 30 days after the initial injection to assess LDL-lowering.

In the ORION clinical trials, inclisiran was shown to reduce LDL-C by up to 52% when added to statin therapy. This effect was sustained over the 17-month follow-up period. However, the ultimate effect of the agent on cardiovascular morbidity and mortality remains unclear at this time, although further clinical trials are ongoing.

Although inclisiran does not have any contraindications, it should be discontinued if the patient becomes pregnant. No data on adverse fetal or maternal outcomes is available at this time. However, it is possible that a patient may be able to breastfeed despite inclisiran therapy due to poor oral bioavailability of the agent and no evidence of systemic absorption during lactation in animal studies.

References:

Food and Drug Administration. “Leqvio.” December 2021. Retrieved from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214012lbl.pdf