Inclisiran Injection (Leqvio)
January 30, 2022 3 minutes read
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first small interfering RNA (siRNA) to lower low-density lipoprotein cholesterol (LDL-C). Inclisiran acts by inhibiting the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9). Inhibition of PCSK9 increases LDL-C receptors, lowering LDL-C levels. It is distributed as Leqvio.
INDICATIONS
Inclisiran can be prescribed as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) who required additional LDL-C lowering.1
DOSAGE
The recommended dose is a single injection given subcutaneously into the abdomen, upper arm, or thigh initially, then again in three months, and then every six months. Inclisiran should be administered by a healthcare professional.1 It is available as a single-dose prefilled syringe containing 284 mg/1.5 mL.1
POTENTIAL ADVANTAGES
Inclisiran provides another option that targets PCSK9 via inhibiting its synthesis as opposed to monoclonal antibodies that bind directly to PCSK9. Its long pharmacological action permits dosing every six months after the first two doses.2 Inclisiran was reported to be well-tolerated, with a safety profile comparable to placebo.3,4
POTENTIAL DISADVANTAGES
The use of a siRNA is a new therapeutic approach. Long-term safety has not been established. In contrast to monoclonal antibodies, the effect of inclisiran on cardiovascular morbidity and mortality has not been established. Adverse reactions were primarily injection site reactions (8.2% vs. 1.8% for placebo).1
COMMENTS
Inclisiran lowers LDL-C levels by inhibiting the synthesis of liver-derived PCSK9. The siRNA, once taken up by hepatocytes, inhibits PCSK9 mRNA translation. The efficacy of inclisiran was demonstrated in three randomized, 18-month, double-blind, placebo-controlled trials — two in subjects with ASCVD and one in subjects with HeFH.1-4 Both subject groups were on maximally tolerated statin therapy. Users of PCSK9 inhibitors were excluded. In the two studies in patients with ASCVD, subjects were randomized to inclisiran (n = 781) or placebo (n = 780) in study 1 and n = 712 and n = 702, respectively, in study 2. Baseline LDL-C levels were 105 mg/dL and 101 mg/dL, respectively. The primary efficacy endpoint was change in LDL-C from baseline to day 510. Changes were -52% vs. +1% in study 1 and -46% vs. +4% in study 2. Total cholesterol, non-HDL cholesterol, and ApoB values also were lower, ranging from a difference from placebo of -30% to -47%. Results were similar across subgroups, including age, sex, race, and disease characteristics. In a similarly designed study of subjects with HeFH (74% on high-intensity statin therapy), inclisiran reduced LDL-C by 40% vs. an increase of 8% for placebo.
CLINICAL IMPLICATIONS
Inclisiran takes a different approach to targeting PCSK9 in contrast to monoclonal antibodies that bind to extracellular PCSK9. The magnitude of LDL-C reduction is roughly similar to that produced by alirocumab and evolocumab. In a systematic review and network meta-analysis, PCSK9 inhibitors added to medium- to high-intensity statin therapy lowered LDL-C by 54% to 74% vs. placebo.5 There are no head-to-head comparisons between inclisiran with a PCSK9 inhibitor. In contrast to alirocumab and evolocumab, inclisiran is not FDA-approved for reducing CV risk (e.g., myocardial infarction, stroke) in patients with homozygous familial hypercholesterolemia. Numerous studies are registered in ClinicalTrial.gov to address these indications: VICTORION-2P (NCT05030428), testing whether inclisiran plus high-intensity statin therapy can cut the risk of three-point major adverse cardiovascular events (CV death, non-fatal myocardial infarction, and non-fatal ischemic stroke); and ORION-4 (NCT03705234) as secondary prevention of myocardial infarction or stroke. Inclisiran may offer significant out-of-pocket cost advantages for patients, as it is administered by a healthcare provider vs. an anti-PCSK9 monoclonal antibody, which is administered by the patient or caregiver. The cost of inclisiran is $3,250 per dose, resulting in the first year of treatment costing $9,750 and $6,500 for subsequent years.
REFERENCES
- Novartis. Leqvio prescribing information. December 2021.
- Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41-51.
- Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507-1519.
- Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med 2020;382:1520-1530.
- Toth PP, Worthy G, Gandra SR, et al. Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia. J Am Heart Assoc 2017;6:e005367.
Inclisiran can be prescribed as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who required additional low-density lipoprotein cholesterol lowering.
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