Leqvio (Inclisiran) Long-Term Cardiovascular Benefits

What does inclisiran do?

Inclisiran is a double-stranded small interfering RNA conjugated to GalNAc, which helps hepatocytes take it up. In the liver it directs catalytic breakdown of PCSK9 messenger RNA, increasing LDL receptor recycling and expression on the hepatocyte surface, so more LDL-C is taken up from the circulation [1]. It is not a monoclonal antibody and not a statin [1].

After a single 284 mg subcutaneous dose, LDL-C reduction was apparent within 14 days. After doses on day 1 and day 90, mean serum PCSK9 fell about 75% at day 120 and 69% at day 180 [1]. The label schedule is 284 mg initially, again at 3 months, then every 6 months, administered by a healthcare professional [1].

How much does inclisiran lower LDL-C?

The two pivotal adult trials, ORION-10 and ORION-11, enrolled adults with established ASCVD or an ASCVD risk equivalent who had elevated LDL-C despite maximally tolerated statin therapy [2].

• ORION-10: 1,561 patients. At day 510, inclisiran lowered LDL-C by 52.3% versus placebo (95% CI 48.8 to 55.7) [2].
• ORION-11: 1,617 patients. At day 510, the placebo-corrected reduction was 49.9% (95% CI 46.6 to 53.1) [2].

Mean baseline LDL-C was about 105 mg/dL in both trials [2]. Neither trial was designed to show a reduction in cardiovascular events [2]. The Leqvio label gives the day 510 difference from placebo as -52% in ORION-10 and -50% in ORION-11 [1].

In adults with heterozygous familial hypercholesterolemia, ORION-9 randomized 482 patients with a mean baseline LDL-C of 153 mg/dL to inclisiran sodium 300 mg (equivalent to the 284 mg of inclisiran in the label) or placebo on days 1, 90, 270 and 450. At day 510, LDL-C fell 39.7% with inclisiran and rose 8.2% with placebo, a between-group difference of -47.9 percentage points (95% CI -53.5 to -42.3) [5].

Does inclisiran reduce heart attacks and strokes?

Published results do not show that inclisiran itself reduces major adverse cardiovascular events. The label's cardiovascular outcomes statement says that lowering LDL-C reduces major adverse cardiovascular events in adults at increased risk when treated with statins or PCSK9 monoclonal antibodies added to a statin; it does not report a cardiovascular outcomes result for inclisiran [1].

The largest published safety analysis pooled seven trials: 3,576 patients treated with inclisiran for up to 6 years and 1,968 placebo-treated patients for up to 1.5 years. Serious treatment-emergent adverse events, hepatic, muscle and kidney events, incident diabetes, and elevations of creatine kinase or creatinine accrued at comparable rates between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond that period. Numerically fewer major cardiovascular events reported as treatment-emergent adverse events occurred with inclisiran [3]. That was a post hoc safety analysis, not a trial designed to measure cardiovascular outcomes [3].

For context, two PCSK9 monoclonal antibodies do have published outcomes results. In FOURIER, evolocumab 140 mg every 2 weeks or 420 mg monthly lowered LDL-C by 59% at 48 weeks and reduced the primary composite endpoint from 11.3% to 9.8% (hazard ratio 0.85; 95% CI 0.79 to 0.92) in 27,564 patients with ASCVD on statin therapy [6]. In ODYSSEY OUTCOMES, alirocumab reduced the primary composite endpoint from 11.1% to 9.5% (hazard ratio 0.85; 95% CI 0.78 to 0.93) in 18,924 patients after acute coronary syndrome [7]. Those results belong to those drugs, not to inclisiran.

What does the label say to watch for?

The only Warning and Precaution in the Leqvio label is hypersensitivity. Anaphylaxis and angioedema have been reported, and the label tells patients to seek medical attention promptly for signs and symptoms of hypersensitivity [1]. Inclisiran is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any excipient; such reactions have included anaphylaxis and angioedema [1].

In pooled placebo-controlled adult trials, injection site reactions occurred in 8% of inclisiran-treated patients versus 2% of placebo-treated patients. Arthralgia occurred in 5% versus 4%, and bronchitis in 4% versus 3%. Adverse reactions led to discontinuation in 2.5% versus 1.9%; injection site reactions were the most common cause of discontinuation (0.2% versus 0%) [1].

Who is inclisiran approved for?

The current label covers inclisiran as an adjunct to diet and exercise to reduce LDL-C in adults with hypercholesterolemia, in adults and children 12 years and older with heterozygous familial hypercholesterolemia, and in children 12 years and older with homozygous familial hypercholesterolemia [1]. The pivotal adult trials were run on top of maximally tolerated statin therapy [2]. The label says inclisiran is administered by a healthcare professional [1].