Leqvio (Inclisiran) and Autoimmune Disease: What Clinicians Need to Know

Does the Leqvio label mention autoimmune disease?

The current label covers adults with hypercholesterolemia, patients 12 years and older with heterozygous familial hypercholesterolemia (HeFH), and patients 12 years and older with homozygous familial hypercholesterolemia (HoFH) [1]. Inclisiran is a small interfering RNA conjugated to GalNAc that directs breakdown of PCSK9 messenger RNA in hepatocytes; it is not a monoclonal antibody and not a statin [1]. The Contraindications section names only a prior serious hypersensitivity reaction to inclisiran or an excipient, and the label has no boxed warning [1]. The only Warning and Precaution is hypersensitivity [1].

Is there any evidence in people with autoimmune disease?

The trials described on this page enrolled people with hypercholesterolemia, atherosclerotic cardiovascular disease (ASCVD), or familial hypercholesterolemia. The label and the cited ORION trials report no autoimmune-specific data [1][3][4]. The safety figures on this page therefore come from that general treated population, and there are no separate figures for people taking methotrexate, biologics, or corticosteroids.

What does immunogenicity show?

The label reports that 2% of adults had anti-inclisiran antibodies before treatment and 5% had them during 18 months [1]. It says no clinically significant effect on pharmacodynamics, safety, or effectiveness was identified, but the long-term consequences of continued treatment with antibodies present are unknown [1].

Which adverse reactions matter?

In pooled adult placebo-controlled trials, 1,833 patients received Leqvio and 1,822 received placebo [1]. Injection site reaction occurred in 8% vs 2%, arthralgia in 5% vs 4%, and bronchitis in 4% vs 3% [1]. Adverse reactions led to discontinuation in 2.5% vs 1.9%; injection site reactions were the most common cause, 0.2% vs 0% [1]. Postmarketing reports include anaphylaxis, angioedema, rash, pruritus, and urticaria [1]. In 141 children 12 and older with HeFH, safety was consistent with adults except headache, 13% on Leqvio vs 6% on placebo [1].

Do immunosuppressants interact with inclisiran?

No formal clinical drug interaction studies were done, so interactions with methotrexate, biologics, or other immunosuppressants were not tested [1]. The label says inclisiran is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes or transporters, and a population pharmacokinetic analysis found it did not clinically significantly change atorvastatin or rosuvastatin concentrations [1]. The label lists no specific interacting drug [1].

What about kidney or liver disease?

The label recommends no dose adjustment for mild, moderate, or severe renal impairment, and says inclisiran was not studied in end-stage renal disease [1]. In patients with renal impairment, Cmax rose 2.3- to 3.3-fold and AUC 1.6- to 2.3-fold in mild, moderate, or severe impairment, while LDL-C reductions were similar across groups [1]. No adjustment is recommended for mild to moderate hepatic impairment; severe hepatic impairment was not studied [1]. In moderate hepatic impairment, baseline PCSK9 was lower and LDL-C reductions were smaller than with normal liver function [1].

What did the ORION trials show?

ORION-10 randomized 1,561 adults with ASCVD, and ORION-11 randomized 1,617 adults with ASCVD or an ASCVD risk equivalent, all on maximally tolerated statins; baseline LDL-C was about 105 mg/dL [3]. At day 510, the placebo-corrected LDL-C reduction was 52.3% in ORION-10 and 49.9% in ORION-11 [3]. Neither trial was designed to show a reduction in cardiovascular events [3]. The label says cardiovascular outcomes trials have shown that lowering LDL-C reduces major adverse cardiovascular events with statins or PCSK9 monoclonal antibodies added to a statin, and it does not report a cardiovascular outcomes result for inclisiran itself [1].

In ORION-9, 482 adults with HeFH received inclisiran sodium 300 mg (equivalent to the label's 284 mg of inclisiran) or placebo [4]. At day 510, LDL-C fell 39.7% with inclisiran and rose 8.2% with placebo, a difference of -47.9 percentage points [4].

How is it given and monitored?

A healthcare professional gives 284 mg subcutaneously at day 1, 3 months, then every 6 months [1]. The label says LDL-C can be measured as early as 30 days after the first dose and anytime thereafter without regard to dose timing [1]. It lists the abdomen, upper arm, or thigh as injection sites and says not to inject into areas of active skin disease or injury, such as sunburn, rash, inflammation, or skin infection [1]. The label also says patients should be advised on the signs and symptoms of hypersensitivity and to seek prompt medical attention if they occur [1].

Bottom line

The Leqvio label's safety concerns are hypersensitivity reactions including anaphylaxis and angioedema, plus injection-site reactions, arthralgia, and bronchitis in trials [1]. Anti-inclisiran antibodies were found in 2% of adults before treatment and 5% during 18 months, and the long-term effect of continued treatment with antibodies present is unknown [1].