Hypercholesterolemia is well-established major risk factor for atherosclerotic cardiovascular disease (ASCVD), along with others including hypertension, diabetes mellitus, chronic kidney disease, obesity and metabolic syndrome.
While statin therapy remains the cornerstone for primary and secondary prevention of ASCVD, studies have suggested >70% patients with established ASCVD do not reach target low-density lipoprotein cholesterol (LDL-C) levels, with poor adherence associated with increased risks for CVD. There have also been observations of an unmet clinical need in local patients who are not achieving target lipid goals despite effective statin therapy, with hypotheses of varied responses of Asian patients to statin therapy as compared to their Western counterparts.
These developing insights have paved the way for new technologies to enter the market, with the discovery of a new biological target: the proprotein convertase subtilisin-kexin type 9 (PCSK9) and its role in familial hypercholesterolemia.
While the seat for novel hypercholesterolemia treatment has barely been warmed by evolocumab and alirocumab –both PCSK9 inhibitors, marketed as Repatha and Praluent, respectively – there now appears a new kid on the block, inclisiran. Inclisiran is marketed as Leqvio® and manufactured by Swiss pharmaceutical firm Novartis.
How inclisiran works
Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) therapy. It reduces LDL-C levels by binding to the messenger RNA of PCSK9, thereby preventing its protein translation. PCSK9 is a serine protease that regulates LDL-C. The decreased concentration of PCSK9 results in upregulation of the LDL receptor (LDL-R) on hepatocytes, which in turn increases uptake of and ultimately lowers plasma concentrations of LDL-C.
Therapeutic indications
The Health Sciences Authority has approved Leqvio® for the treatment of primary hypercholesterolemia in adults. The drug is currently still under review by the US Food and Drug Administration (FDA), but has been approved for use in the European Union (EU) by the European Medicines Agency (EMA).
Leqvio® is indicated in adults with both heterozygous familial and non-familial hypercholesterolemia or mixed dyslipidemia as an adjunct to diet:
- In combination with a statin or with a statin and 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, or for whom a statin is contraindicated.
How it is administered
With its long half-life, Leqvio® is administered as a single subcutaneous injection of 284mg initially, again at 3 months and then once every 6 months. The infrequent dosing of Leqvio® is expected to facilitate long-term adherence, adding to its overall attraction.
Efficacy data
The bulk of the evidence base for Leqvio® arises from the ORION Phase III LDL-C-lowering Studies. The studies and their key findings are summarised in the table below:
| Study | Treatment arms | Summary of primary and secondary efficacy endpoints |
| ORION 9
N=482, patients with heterozygous familial hypercholesterolemia (FH) with elevated cholesterol levels despite maximum tolerated statin dose from 46 sites in eight countries. |
Inclisiran 284mg
VS Placebo Administered on days 1, 90, 270 and 450 over a period of 540 days. |
|
| ORION 10
N=1561, patients with cardiovascular disease (CVD) with elevated cholesterol levels despite maximum tolerated statin dose from 145 sites in United States. |
|
|
| ORION 11
N= 1617, patients with CVD or risk-equivalent disease (Type 2 diabetes, heterozygous FH, or 10-year 20% risk in Framingham risk score) with elevated cholesterol levels despite maximum tolerated statin dose from 70 sites in seven countries. |
|
Additionally, pooled post-hoc analysis of the ORION trials has likewise demonstrated similar effective and sustained LDL-C reductions in smaller ASCVD subpopulations – namely established cerebrovascular disease (CeVD) and polyvascular disease (PVD)
It should be noted that efficacy evidence for inclisiran is currently unaccompanied by real-world data. A larger study, ORION 4, is ongoing to assess the effects of inclisiran on clinical outcomes among patients with pre-existing ASCVD over a planned median duration of 5 years.
Safety data
Inclisiran was generally well-tolerated in the Phase III clinical trials, with the most common adverse events reported to be injection site reactions, arthralgia, urinary tract infection, diarrhoea, bronchitis, pain in extremity and dyspnea. AEs occurred in ≥3% of patients treated with inclisiran and more frequently than placebo. Reported AEs were generally mild and none were severe or persistent.
Final thoughts
Inclisiran may benefit patients who are unable to achieve their LDL-C targets despite maximally tolerated statin therapy or who are intolerant to statin therapy. However, more data is required to confirm cardiovascular outcome benefits, as well as long term safety to compel its use. Furthermore, as seen from the underwhelming utility of PCSK9 inhibitors in clinical practice owing to their prohibitive cost and more frequent injection schedule, inclisiran should be priced appropriately to facilitate access and provide the technology with an edge above its comparators.
