PHILADELPHIA – A third phase 3 trial with the novel lipid-lowering drug inclisiran (The Medicines Company), which is given just once every 6 months, has shown impressive results in reducing in low-density lipoprotein (LDL) levels, consistent with the previous two studies, but this time in patients with familial hypercholesterolemia (FH).
The third study ― ORION-9 ― yielded a 50% reduction in LDL over an 18-month period in FH patients who were already taking maximum tolerated doses of statins; half of those patients were also taking ezetimibe.
ORION-9 was presented here today at the American Heart Association (AHA) Scientific Sessions 2019.
The results are in line with results from ORION-10, presented earlier at the meeting, which showed a 58% reduction in LDL in patients with established atherosclerotic cardiovascular disease; and the ORION-11 study, presented at the recent European Society of Cardiology meeting, which showed a 54% reduction in LDL in a mix of patients with atherosclerotic cardiovascular disease and those at high risk for cardiovascular disease but with higher baseline LDL levels.
Inclisiran is the first of a new class of cholesterol-lowering agents known as small interfering RNA. It is a double-stranded RNA molecule that harnesses a natural process called RNA interference. It has the ability to switch off specific genes — in this case, the gene for PCSK9.
Chemical modification has allowed inclisiran to be selectively taken up by the liver and inhibit the synthesis of the PCSK9 protein, which interferes with the clearance of LDL. Through this mechanism, it has a very long duration of action, such that dosing is required just twice a year.
Presenting the ORION-9 data, Frederick Raal, MBBCh, noted that FH is a genetic disorder affecting around 1 in every 250 people. It results in highly elevated LDL levels over a person’s lifetime and drives early-onset atherosclerotic cardiovascular disease.
Raal, who is professor and head of the Division of Endocrinology and Metabolism at the University of the Witwatersrand, Johannesburg, South Africa, concluded, “Inclisiran shows potential to address the unmet need of high-risk FH patients.”
The ORION-9 study enrolled 482 patients with heterozygous FH and LDL levels higher than 100 mg/dL (mean, 150 mg/dL) who were already taking maximum tolerated doses of statins with or without ezetimibe. Baseline data showed that 90% of patients were taking statins; 80% were taking high-intensity doses, and 50% were also taking ezetimibe.
The patients were randomly assigned to receive inclisiran 300 mg or placebo given by subcutaneous injection at day 1 and day 30, then every 6 months thereafter for 18 months.
Results showed that at the end of the study (day 510), LDL was reduced in the inclisiran group by 50% vs placebo. The time-averaged reduction in LDL from day 90 to day 540 was 45% (for both endpoints, P < .0001).
The absolute reduction in LDL in the inclisiran group was 71 mg/dL at day 510 and 63 mg/dL over the time average period.
Genetic testing showed that about half of the enrolled patients had genetic variants of the LDL receptor, 5% had ApoB variants, one patient had a PCSK9 gain-of-function variant, and 7% had two different gene variants. In 24%, no variant was detected.
For all of these different genotypes, patients responded in a similar way to inclisiran treatment, including those patients with two gene variants, Raal reported.
The patient with the gain-of-function PCSK9 variant showed an exaggerated effect with a 90% reduction in LDL on inclisiran, which Raal said was consistent with the its mechanism of action.
As in the other two phase 3 trials, adverse events did not differ between the inclisiran group and the placebo group apart from injection site reactions, which occurred in 13.7% of inclisiran patients vs 0.4% of those taking placebo. “But these reactions were mostly mild, and all were transient,” Raal reported.
Laboratory test results were also similar between the active-treatment group and the placebo group, with no evidence of liver, kidney, muscle, or platelet toxicity, he noted. There was also no difference in all-cause death, cardiovascular or cancer deaths, or new or worsening malignancy between the two groups.
A prospective exploratory cardiovascular endpoint (MedDRA-defined cardiovascular nonadjudicated terms, including cardiac death, and any signs or symptoms of cardiac arrest, nonfatal myocardial infarction, and/or stroke) occurred in 4.2% of each group.
The discussant of the study, Daniel Radar, MD, noted that inclisiran is the first of a new crop of RNA therapeutics, small interfering RNA, which have been designed to specifically target individual genes.
He said the 50% reduction in LDL seen in ORION-9 showed the drug to be “very effective,” and “the 18-month safety appears good.
“This is a new platform, and the safety data generated by the inclisiran program is helping to de-risk this entire platform,” he commented.
However, Radar added that he still had some questions regarding the effect of inclisiran on Lp(a) and its efficacy in homozygous FH.
He also pointed out that it would be important to establish safety in children with FH.
“Starting LDL-lowering therapy in children with FH is of utmost importance. With a twice-yearly dosing schedule, this could be a great approach to ensure adherence in teenagers and young adults,” he suggested.
The ORION-9 trial was funded by The Medicines Company. Raal reports receiving honoraria from the company.
American Heart Association (AHA) Scientific Sessions 2019: Presented November 18, 2019.