ORION-10 and ORION-11: Pooled Analysis of Two Phase 3 Trials Showed Sustained LDL Cholesterol Reduction with Inclisiran in Patients with ASCVD or ASCVD Risk Equivalent

Fahad Alkhalfan, M.D.
By Fahad Alkhalfan, M.D. on

The results of a pooled analysis of the ORION-10 and ORION-11 trials were recently presented at the American College of Cardiology 2020 Conference. The combined results published in the New England Journal of Medicine, demonstrated that inclisiran, a drug that inhibits hepatic synthesis of proprotein convertase subtilisin–kexin type 9, reduced low-density lipoprotein (LDL) cholesterol by 50% over 510 days.

Atherosclerotic cardiovascular disease continues to be the leading cause of death worldwide. Lowering LDL-cholesterol has been shown to be one of the most effective interventions to improve outcomes. Despite aggressive treatments with currently available medication, including statins, LDL cholesterol continues to carry a risk of increased cardiovascular events. There is a need to further lower LDL cholesterol in order to continue improving outcomes. Inclisiran is a small interfering double-stranded RNA agent that inhibits the production of proprotein convertase subtilisin/kexin type 9 (PCSK-9). Previous trials suggest that Inclsiran could potentially lead to a sustained reduction of LDL-cholesterol over at least one year. The investigators aimed to determine whether Inclisiran would lead to a sustained reduction in LDL-cholesterol over a longer period. ORION-10 and 11 had similar protocols but enrolled different patient populations.

ORION-10 was carried out in the United States and enrolled patients with atherosclerotic cardiovascular disease (ASCVD). ORION-11 was conducted in Europe and South Africa and enrolled patients with either atherosclerotic cardiovascular disease or an ASCD equivalent. ASCVD equivalents included type 2 diabetes, familial hypercholesterolemia, or a 10-year risk of a cardiovascular event of ≥20% as determined by a scoring system. Patients were randomized in a 1:1 ratio to either Inclisiran or a placebo. Each patient received four injections of either inclisiran or placebo over the first year and a half. The study had two primary endpoints: (1) placebo-corrected percentage change in LDL cholesterol level from baseline to day 510; (2) Time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.

ORION-10 and ORION-11 randomized 1,561 patients (781 to Inclisiran and 780 to placebo) and 1,617 patients (810 to Inclisiran and 807 to placebo) respectively. The mean age and gender distribution were similar between the two trials. However, ORION-10 enrolled fewer white patients but had a higher proportion of patients with diabetes, hypertension and familial heterozygous familial hypercholesterolemia. The mean LDL cholesterol was 104.7 mg/dl in ORION-10 and 105.5 mg/dl in ORION-11. Most patients in both trials were already on a stable dose of a statin, with the majority on a high-intensity statin.

In both trials, the percent change in LDL was greater in the Inclisiran group as compared to placebo by Day 510 (ORION-10: 1.0% (Placebo) vs −51.3% (Inclisiran); ORION-11: 4.0% (Placebo) vs −45.8% (Inclisiran), p <0.001 for both). Additionally, the time-adjusted change from Day 90 up to Day 540 was greater for the Inclisiran group in both studies (ORION-10: 2.5% (Placebo) vs −53.8% (Inclisiran); ORION-11: 3.4% (Placebo) vs −45.8% (Inclisiran)).

In an interview with Dr. C. Michael Gibson, Dr. R. Scott Wright, one of the presenters at ACC 2020 and author of the study, discussed some of the implications of the study. He noted, “I think the reality is going to be that everyone is going to be on a statin who has high-risk disease (ASCVDFH risk equivalent). Most people are not going to get to an LDL threshold that we feel is truly appropriate, like 70 or 50 or even lower. There will need to be an extra therapy. I think at that point, clinicians and patients will decide if they want to prescribe a drug that is given 26 times a year, and cost around 6 grand a year, or a drug that is given twice a year, we don’t know about pricing, but the sponsors have said that it’s going to come out with value pricing. Let’s presume that it will be a better value than current monoclonals and if that is the case, I think it will be attractive to clinicians:”

Click here to view the discussion between Dr. Gibson and Dr. Wright.

Click here to view the study slides.

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