Twice-yearly inclisiran injections halve LDL-cholesterol levels

The safety and durability of the LDL-cholesterol (LDL-C)-lowering effects of inclisiran, a small interfering RNA that inhibits the synthesis of PCSK9 in the liver, have now been confirmed in three phase III clinical trials. The ORION-10 and ORION-11 trials show that inclisiran therapy administered every 6 months reduces LDL-C levels by 50% in patients with atherosclerotic cardiovascular disease who had elevated LDL-C levels despite receiving maximally tolerated statin therapy. A similar LDL-C-lowering effect with inclisiran was seen in the ORION-9 trial in patients with familial hypercholesterolaemia (FH). “Importantly, compliance is guaranteed given that, with only two injections of inclisiran per year, the LDL-C level can be halved,” says Frederick Raal, lead investigator of ORION-9. “This should reduce the risk of premature atherosclerotic cardiovascular disease.”

“The phase II ORION-1 trial suggested that after dosing on day 1 and day 90, the interval could be extended to 6-monthly doses,” says Kausik Ray, lead investigator of ORION-10 and ORION-11. Therefore, the ORION programme investigators conducted three trials to assess the efficacy and safety of inclisiran over 18 months. Two trials included patients who had high LDL-C levels despite receiving statin therapy at the maximum tolerated dose and either atherosclerotic cardiovascular disease (ORION-10; n = 1,561) or atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11; n = 1,617). The ORION-9 trial included 482 adult patients with heterozygous FH.

Credit: Sebastian Kaulitzki/Science Photo Library/Getty

In all three trials, patients were randomly assigned to receive either inclisiran 284 mg or placebo by subcutaneous injection on day 1, day 90 and every 6 months thereafter over 540 days. At day 510, the between-group difference in the change in LDL-C level from baseline with inclisiran therapy versus placebo was −52.3 percentage points in the ORION-10 trial, −49.9 percentage points in the ORION-11 trial and −47.9 percentage points in the ORION-9 trial (all P < 0.001). Of note, the large reductions in LDL-C levels occurred regardless of FH genotype. In all three trials, the adverse event profile of inclisiran was similar to that of placebo, except for a higher frequency of injection-site adverse events with inclisiran.

In addition to the advantages of this therapy to overcome non-adherence and non-compliance issues, Raal and Ray highlight the potential of inclisiran in early prevention approaches. “We could offer treatments earlier, and these might be more acceptable than taking 365 tablets a year,” comments Ray. “This approach lends itself to population-level reductions in exposure to LDL-C at a scale that current therapies cannot achieve,” he adds. Raal and Ray explain that several ORION trials are ongoing, including ORION-8 (involving participants with FH from ORION-9) to evaluate the longer-term efficacy and safety of inclisiran in this patient population, the cardiovascular outcomes trial ORION-4 and the primary prevention trial ORION-17.


Original articles

  1. Ray, K. K. et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1912387 (2020)

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  2. Raal, F. J. et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1913805 (2020)

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Related article

  1. Nordestgaard, B. G. et al. Advances in lipid-lowering therapy through gene-silencing technologies. Nat. Rev. Cardiol. 15, 261–272 (2018)

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Correspondence to Irene Fernández-Ruiz.

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Fernández-Ruiz, I. Twice-yearly inclisiran injections halve LDL-cholesterol levels. Nat Rev Cardiol 17, 321 (2020). https://doi.org/10.1038/s41569-020-0373-0

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