ORION: Inclisiran Phase 3 Trials Published

March 18, 2020

Three phase 3 trials of the novel small-interfering RNA (siRNA) agent inclisiran (The Medicines Company) have been published, all showing an approximate halving of LDL cholesterol levels with the drug, which is given just twice a year by subcutaneous injection.

The ORION-9, ORION-10, and ORION-11 trials were all published online in the New England Journal of Medicine on March 11.

The ORION-9 trial, in patients with familial hypercholesterolemia (FH), is the subject of its own paper, while the ORION-10 and ORION-11 studies, in patients with or at risk for atherosclerotic cardiovascular disease, are reported together in one publication.

Preliminary results from all three trials have been presented at recent major cardiovascular medical meetings and were reported at the time by Medscape Medical News. The ORION-11 trial was presented at the European Society of Cardiology meeting last September and the ORION-9 and ORION-10 trials were presented at the American Heart Association meeting last November.

ORION-9

The ORION-9 trial randomized 482 heterozygous FH patients to receive subcutaneous injections of inclisiran (300 mg) or placebo on days 1, 90, 270, and 450. The mean baseline LDL level was 153 mg/dL. Statins were being taken by 90% of patients, including 75% on high-intensity statins, and more than 50% were also on ezetimibe.

Final results show that at day 510 the mean change in LDL levels from baseline was a reduction of 39.7% in the inclisiran group and an increase of 8.2% in the placebo group, giving a between-group difference of -44.3%. There were robust reductions in LDL in all genotypes of FH.

Inclisiran was also associated with lower levels of total cholesterol, non-HDL cholesterol, lipoprotein(a), apolipoprotein B, and triglycerides than placebo, and higher levels of HDL.

The agent, which acts by switching off the PCSK9 gene, led to a reduction in PCSK9 levels of 60.7% compared with an increase of 17.7% in the placebo group, a between-group difference of -78%. 

Adverse events were reported in 76.8% of the inclisiran group and in 71.7% of the placebo group, but these were mild or moderate in 94.6% and 91.9% of patients, respectively. Injection-site reactions were reported in more inclisiran patients (17% vs 1.7%), but 90% of these were mild and none classed as severe or persistent.

Serious adverse events were reported in 7.5% of inclisiran patients and 13.8% of those on placebo. Laboratory-defined adverse events were also similar between the groups.

The ORION-9 authors, led by Frederick Raal, MD, University of the Witwatersrand, Johannesburg, South Africa, note that the significant reduction in Lp(a) with inclisiran has also been seen with the PCSK9 antibodies but is not seen with other cholesterol drugs such as the statins. 

"Since an elevated Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease. This activity may be an additional benefit of inclisiran therapy," they say. 

Because inclisiran acts predominantly in the liver, which is the main site of PCSK9 production, the reduction in LDL levels with inclisiran in patients with heterozygous FH is similar to that achieved with PCSK9 antibodies, the researchers state.

"The reduction in LDL cholesterol of almost 50% with twice yearly administration of inclisiran in patients with heterozygous FH who had been receiving maximally accepted background statin therapy has the potential to improve their adherence to treatment regimens," they add.

ORION-10 and ORION-11

The ORION-10 and ORION-11 trials had similar designs. ORION-10 enrolled 1561 patients with atherosclerotic cardiovascular disease with a mean LDL level of 104 mg/dL. The ORION-11 trial enrolled 1414 patients with atherosclerotic cardiovascular disease and 203 risk-equivalent patients (with diabetes, familial hypercholesterolemia, or 10-year risk for cardiovascular disease of 20% or greater) with a mean LDL level of 105 mg/dL. 

Statin use was high — 89% in ORION-10 and 95% in ORION-11 — with the majority receiving high-intensity statins (68% and 78%, respectively).

Patients in both trials were randomized to receive inclisiran (284 mg) or placebo by subcutaneous injection on days 1 and 90 and every 6 months thereafter, over a period of 540 days.

Results showed that at day 510 inclisiran reduced LDL by 52.3% in ORION-10 and by 49.9% in ORION-11.   

As in ORION-9, both trials showed reductions in total cholesterol, non-HDL cholesterol, Lp(a), apolipoprotein B, and triglycerides with inclisiran, and increased levels of HDL. 

The prespecified composite cardiovascular endpoint (cardiac death, cardiac arrest, myocardial infarction, stroke) occurred in 7.4% of inclisiran patients vs 10.2% in the placebo group in ORION-10, and in 7.8% of inclisiran patients vs 10.3% in the placebo group in ORION-11. 

The authors of the paper, led by Kausik Ray, MD, Imperial College, London, United Kingdom, caution that "the total number of non-adjudicated cardiovascular events observed was too small to draw meaningful conclusions about any potential benefits of inclisiran on cardiovascular outcomes, a question that is being tested in an ongoing cardiovascular outcome trial." 

Adverse events were similar between the inclisiran and placebo groups in both trials. Serious adverse events were reported in 22.4% of inclisiran patients and 26.3% of those on placebo in ORION -10, and in 22.3% of inclisiran and 22.5% of placebo patients in ORION-11.

Injection-site reactions were more common with inclisiran (2.6% vs 0.9% in ORION-10 and 4.7% vs 0.5% in ORION-11). These were reported to be "generally mild and none were severe or persistent."

The researchers note that a theoretical concern for therapies with a long duration of action is for the potential of irreversible adverse effects.  

They report that without further injections the LDL-lowering effects of inclisiran are reversed at the rate of approximately 2% per month, which means that the effects can persist for up to 2 years.

"It is therefore reassuring that in the present trials (ORION-10 and 11) with 6075 injections of inclisiran and 2166 person years of exposure, the adverse event profile of inclisiran was similar to placebo," they state. Ongoing label extension studies will provide longer-term safety follow-up information, they add.

"The potential for siRNA-based therapeutics has already reached fruition in rare-disease area such as transthyretin amyloidosis and porphyria. … The results of our trials have the potential to move RNA-based therapies from the realm of rare to common disease," Ray and colleagues say.

Noting that poor adherence to prescribed medication attenuates the benefit of LDL reduction that could be achievable, they suggest that complete adherence to inclisiran therapy with its twice-yearly dosing may be possible if administered by a healthcare professional, "thus potentially helping address an existing challenge to contemporary prevention strategies — namely, how to maintain reductions to adverse exposures such as LDL cholesterol over the long term."

All three studies were funded by The Medicines Company. Raal and Ray report grants from The Medicines Company during the conduct of the study.

N Engl J Med. Published online March 18. ORION-9 (Abstract), ORION-10 and ORION-11 (Abstract).

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