The Food and Drug Administration (FDA) has approved Leqvio® (inclisiran) as an adjunct to diet and maximally tolerated statin therapy for the treatment of heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) in adults who require additional lowering of low-density lipoprotein cholesterol (LDL-C). 

Leqvio is a chemically synthesized small interfering RNA that targets proprotein convertase subtilisin-kexin type 9 (PCSK9) messenger RNA. Leqvio, in combination with maximally tolerated statin therapy, is administered as an initial single subcutaneous injection, a second dose at 3 months, and continued treatment once every 6 months. 

The approval was based on data from the randomized, double-blind, placebo-controlled, ORION-9 (ClinicalTrials.gov Identifier: NCT03397121), ORION-10 (ClinicalTrials.gov Identifier: NCT03399370), and ORION-11 (ClinicalTrials.gov Identifier: NCT03400800) trials which evaluated the efficacy and safety of Leqvio in 3457 patients 18 years of age and older with HeFH or clinical ASCVD and who had elevated LDL-C despite maximally tolerated doses of LDL-C lowering therapies (eg, statin and/or ezetimibe). 

ORION-9 included 482 patients with HeFH, ORION-10 included 1561 patients with ASCVD, and ORION-11 included 1414 patients with ASCVD or ASCVD-risk equivalents. Patients were randomly assigned to receive Leqvio 284mg or placebo subcutaneously on days 1, 90, 270, and 450. The primary endpoint was the percentage change in LDL-C reductions from baseline to day 510. 

Results from these trials showed that treatment with Leqvio achieved the following average decreases in LDL-C at day 510 compared with the average increases in LDL-C for placebo, respectively:

  • ORION-9: -40% vs 8% (difference from placebo, -48%; 95% CI, -54 to -42; P <.0001);
  • ORION-10: -51% vs 1% (difference from placebo, -52%; 95% CI, -56 to -49; P <.0001);
  • ORION-11: -46% vs 4% (difference from placebo, -51%; 95% CI, -54 to -47; P <.0001).

Additionally, patients treated with Leqvio achieved consistent reductions in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B across all trials. 

As for safety, the most common adverse reactions (incidence of at least 3%) for Leqvio were injection site reactions, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity, and dyspnea. The effect of Leqvio on cardiovascular morbidity and mortality has not been determined and is currently being investigated in clinical trials.

“People with ASCVD have most likely experienced a heart attack or stroke from high cholesterol, causing a burden on the family and having a negative impact on lives,” said Andrea Baer, Executive Director of The Mended Hearts, Inc. “One of the first steps to improving patients’ health is to manage high cholesterol and we’re encouraged that this new twice-a-year treatment offers a new option.” 

Leqvio is supplied as a 284mg/1.5mL (189mg/mL) injection in single-dose prefilled syringes, and is expected to be available in early January 2022. 

References

  1. FDA approves add-on therapy to lower cholesterol among certain high-risk adults. News release. US Food and Drug Administration. December 22, 2021. Accessed December 27, 2021. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-lower-cholesterol-among-certain-high-risk-adults?utm_medium=email&utm_source=govdelivery 
  2. FDA approves Novartis Leqvio® (inclisiran), first-in-class siRNA to lower cholesterol and keep it low with two doses a year. News release. Novartis Pharma AG. December 22, 2021. Accessed December 27, 2021. https://www.globenewswire.com/news-release/2021/12/22/2357041/0/en/FDA-approves-Novartis-Leqvio-inclisiran-first-in-class-siRNA-to-lower-cholesterol-and-keep-it-low-with-two-doses-a-year.html
  3. Leqvio. Package Insert. Novartis Pharmaceuticals Corp; 2021. Accessed December 27, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214012lbl.pdf