An alternative to these small molecule drugs, inclisiran, has been developed by Alnylam and commercialised in collaboration with Novartis. It is the first small interfering RNA drug to lower LDL-C levels and acts to stop the liver producing proprotein convertase subtilisin-kexin type 9 (PCSK-9), which helps to keep cholesterol levels high.
Unlike statins, which require daily doses, after the first two doses spaced 3 months apart, twice-yearly injections will suffice.
Several studies have been reported. In a Phase I trial, healthy volunteers were given a subcutaneous injection of 25, 100, 300, 500 or 800 mg of inclisiran or a placebo in a single ascending dose phase, or a multiple dose phase with four weekly doses of 125 mg, two fortnightly 250 mg doses or two monthly doses of 300 or 500 mg, either with or without concomitant statins.1
Doses of at least 300 mg (single or multiple) gave significant reductions in PCSK-9 and LDL-C levels for at least 6 months. Adverse events were all mild or moderate, with the most common being cough, musculoskeletal or back pain, headache, nasopharyngitis and diarrhoea, with no discontinuations as a result.
In a Phase II trial, 501 patients with high cholesterol levels were given a placebo or either 200, 300 or 500 mg of the drug as a single dose, or 100, 200 or 300 mg on day 1 and day 90.2 The time-averaged reduction in LDL-C a year after the single dose ranged from 29.5% to 38.7%, whereas for those given two doses it was slightly higher (29.9–46.4%).
In two longer-term Phase III trials, 1561 patients had atherosclerotic cardiovascular disease in one trial and 1617 had an atherosclerotic cardiovascular disease risk equivalent in the other.3 In both cases, they had elevated LDL-C levels despite statin therapy at the maximum tolerated dose.
They were given either 285 mg of inclisiran or a placebo by subcutaneous injection on day 1, day 90 and every 6 months thereafter for 540 days. At the end of the trial period, the first group had an LDL-C reduction of 52.3%, compared with the placebo, and the second group recorded a 49.9% decrease. Injection site reactions were slightly more frequent than with the placebo but, otherwise, adverse events were similar across all patients.
References
- K. Fitzgerald, et al., N. Engl. J. Med. 376, 41 (2017).
- K.K. Ray, et al., JAMA Cardiol. 4, 1067 (2019).
- K.K. Ray, et al., N. Engl. J. Med. 382, 1507 (2020).