Leqvio (inclisiran) and Cancer: What the Label and Trials Report

Does the Leqvio label name cancer as a risk?

No. Leqvio (inclisiran) injection, 284 mg/1.5 mL, was approved on 22 December 2021 under NDA 214012 [3], and the current label carries no boxed warning [1]. Its single Warning and Precaution is hypersensitivity: anaphylaxis and angioedema have been reported after approval, along with rash, pruritus and urticaria. The label says to advise patients on the signs and symptoms of hypersensitivity reactions and to instruct them to seek medical attention promptly [1]. Malignancy is not addressed in that section.

What the label's adverse reactions section lists

The adult safety data pool placebo-controlled trials: 1,833 patients on Leqvio (1,682 exposed for 18 months, median treatment duration 77 weeks) and 1,822 on placebo [1]. Reactions reported in at least 3% of Leqvio patients and more often than with placebo were injection site reaction (8% vs 2%, including pain, erythema and rash), arthralgia (5% vs 4%) and bronchitis (4% vs 3%) [1]. Treatment discontinuation for adverse reactions was 2.5% vs 1.9%, with injection site reactions the most common cause (0.2% vs 0%) [1]. The postmarketing reactions the label lists are all hypersensitivity reactions [1]. In the 141-patient pediatric HeFH trial (ages 12 and older), the profile matched adults except for headache, 13% on Leqvio vs 6% on placebo [1].

What the ORION trials reported

ORION-10 randomized 1,561 adults with atherosclerotic cardiovascular disease; ORION-11 randomized 1,617 adults with ASCVD or an ASCVD risk equivalent. All were on maximally tolerated statins and received 284 mg or placebo on day 1, day 90, then every 6 months, over 540 days [2]. The placebo-corrected LDL-C reduction at day 510 was 52.3% in ORION-10 and 49.9% in ORION-11 [2]. Adverse events were generally similar to placebo apart from more injection-site events, and neither trial was designed to show a reduction in cardiovascular events [2].

ORION-9 enrolled 482 adults with heterozygous familial hypercholesterolemia and gave inclisiran sodium 300 mg (equivalent to the 284 mg of inclisiran in the label) or placebo on days 1, 90, 270 and 450 [4]. LDL-C fell 39.7% at day 510 against a rise of 8.2% on placebo, a between-group difference of -47.9 percentage points [4].

Where inclisiran acts

Inclisiran is a double-stranded small interfering RNA conjugated to GalNAc, which helps liver cells take it up. In the liver it directs catalytic breakdown of PCSK9 messenger RNA; more LDL receptors then recycle to the cell surface and circulating LDL-C falls [1]. The label describes high uptake into, and selectivity for, the liver, the target organ. Plasma concentrations peak about 4 hours after a 284 mg dose and are undetectable by 24 to 48 hours, with a terminal half-life of about 9 hours, while LDL-C lowering persists for months [1].