Inclisiran for hypercholesterolaemia

Approved indication: as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with heterozygous familial hypercholesterolaemia, atherosclerotic cardiovascular disease, or a high risk of a cardiovascular event: in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin; or alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant.
Leqvio (Novartis)
prefilled syringe containing inclisiran 284 mg/1.5 mL (equivalent to 300 mg inclisiran sodium) solution for injection

Small interfering ribonucleic acids (siRNAs) are a class of gene-based therapeutics used for a number of indications, including more recently in the treatment of hypercholesterolaemia.¹ Inclisiran is a double-stranded siRNA used to lower low-density lipoprotein cholesterol (LDL‑C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. It exerts its effect through the RNA interference mechanism, hindering the translation of PCSK9. This in turn increases LDL-C receptor recycling and expression on hepatocytes, which increases LDL-C uptake and lowers LDL-C concentration in the circulation.² Inclisiran is approved for use to reduce LDL-C in adults with heterozygous familial hypercholesterolaemia or atherosclerotic cardiovascular disease (ASCVD), or adults with a high risk of a cardiovascular event when standard lipid-lowering therapies are inadequate or not tolerated.³

The pre-registration studies informing the efficacy and safety profile of inclisiran were 3 randomised, placebo-controlled, double-blind, phase 3 trials: ORION-9, ORION-10 and ORION-11.² ORION-9 included participants with heterozygous familial hypercholesterolaemia, ORION-10 included participants with ASCVD, and ORION-11 included participants with ASCVD or ASCVD-risk equivalents (type 2 diabetes, familial hypercholesterolaemia, or a 10-year cardiovascular risk of 20% or higher). All participants had elevated LDL-C concentrations despite being on a maximally tolerated dose of a statin with or without other lipid-lowering drugs, or were intolerant of statins.

The pooled efficacy population from the 3 trials consisted of 3660 individuals who were treated with inclisiran sodium 300 mg administered subcutaneously on day 1, day 90, and every 6 months thereafter, or placebo, for a duration of 18 months. The studies had similar coprimary endpoints which included the placebo-adjusted percentage change in LDL-C from baseline to day 510, and the time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540, compared with placebo.² A pooled analysis of ORION-9, -10 and -11 showed that the participants who received inclisiran demonstrated a mean reduction in LDL-C from baseline of approximately 50% when corrected for placebo and time (calculated as the average of all LDL-C measurements between day 90 and day 540).⁴ The proportion of participants who achieved global lipid targets for their level of ASCVD risk (i.e. LDL-C less than 1.8 mmol/L for ASCVD, or less than 2.6 mmol/L for ASCVD-risk equivalent, at day 510) was 82% for inclisiran versus 16% for placebo in those with ASCVD, and 70% for inclisiran versus 17% for placebo in those with ASCVD-risk equivalents.² Additionally, inclisiran was associated with a mean reduction in total cholesterol of approximately 30%, non–high-density lipoprotein cholesterol 43%, and apolipoprotein B 40%.⁴

Two network meta-analyses indirectly compared the efficacy of inclisiran and non-statin lipid-lowering therapies in reducing LDL-C, using data from placebo-controlled trials.^5,6 One study found inclisiran had similar efficacy to the monoclonal antibody PCSK9 inhibitors alirocumab and evolocumab,⁵ while the other study found alirocumab and evolocumab were more efficacious than inclisiran, but inclisiran was more efficacious than ezetimibe.⁶ However, given there are no head-to-head trials, these comparisons are limited by inherent differences between the trials.

The most frequently reported adverse drug reactions with inclisiran in pooled data from the phase 3 trials were injection-site reactions (inclisiran 8.2% versus placebo 1.8%). These were mild to moderate in severity. Patients who received inclisiran had a higher incidence of lower respiratory tract infections compared with patients who received placebo (inclisiran 8.1% versus placebo 6.0%).³

A pooled safety analysis of data from 3576 people who received inclisiran and 1968 people who received placebo over a 6-year follow-up period reiterated that injection-site reactions were more frequent with inclisiran than placebo, and that they were more common in women. Other treatment-emergent adverse events were comparable in the inclisiran and placebo groups.⁷

Data on cardiovascular outcomes with inclisiran are currently limited. At the time of writing, multiple trials are underway to evaluate cardiovascular outcomes and longer-term safety.^8,9

The dose of inclisiran is 284 mg (equivalent to inclisiran sodium 300 mg) administered as a single subcutaneous injection initially, repeated at 3 months, and then subsequently every 6 months. The drug is intended for administration by a healthcare professional. Dose adjustment is not required for patients with mild to moderate renal or hepatic impairment. Inclisiran is not recommended in severe renal or hepatic impairment because of a lack of data. It is categorised as Pregnancy Category B1.³

Inclisiran may serve as an alternative treatment option to PCSK9 monoclonal antibodies to reduce LDL-C in selected patients, in combination with other lipid-lowering drugs, dietary modification and exercise. Studies demonstrated a long-lasting effect in lowering LDL-C in individuals with familial hypercholesterolaemia, ASCVD or high cardiovascular risk, most of whom were already receiving maximally tolerated doses of standard lipid-lowering drugs. The twice-yearly dosing regimen may offer a convenient advantage for some patients.

This new drug comment was finalised on 27 May 2024.

🅃 🅃 manufacturer provided additional useful information. The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, the European Medicines Agency and the Therapeutic Goods Administration.

 

References

1. Hu B, Zhong L, Weng Y, Peng L, Huang Y, Zhao Y, et al. Therapeutic siRNA: state of the art. Signal Transduct Target Ther 2020;5:101.
2. Therapeutic Goods Administration. Australian Public Assessment Report for Inclisiran. Department of Health and Aged Care; 2022. [cited 2024 Apr 29]
3. Therapeutic Goods Administration. Australian Product Information – Leqvio (inclisiran) solution for injection. Department of Health and Aged Care; 2022. [cited 2024 Apr 29]
4. Wright RS, Ray KK, Raal FJ, Kallend DG, Jaros M, Koenig W, et al. Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis. J Am Coll Cardiol 2021;77:1182-93.
5. Burnett H, Fahrbach K, Cichewicz A, Jindal R, Tarpey J, Durand A, et al. Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis. Curr Med Res Opin 2022;38:777-84.
6. Toth PP, Bray S, Villa G, Palagashvili T, Sattar N, Stroes ESG, et al. Network Meta-Analysis of Randomized Trials Evaluating the Comparative Efficacy of Lipid-Lowering Therapies Added to Maximally Tolerated Statins for the Reduction of Low-Density Lipoprotein Cholesterol. J Am Heart Assoc 2022;11:e025551.
7. Wright RS, Koenig W, Landmesser U, Leiter LA, Raal FJ, Schwartz GG, et al. Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials. J Am Coll Cardiol 2023;82:2251-61.
8. ClinicalTrials.gov. A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION-4). Identifier NCT03705234. National Library of Medicine (US); 2023. [cited 2024 May 21]
9. Novartis. Media & Investor Release: New Novartis data show early addition of twice-yearly Leqvio (inclisiran) following maximally tolerated statin therapy significantly reduces LDL-C in ASCVD patients in real-world setting. 2024. [cited 2024 Apr 30]

 

The new drug commentaries in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Advisory Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.