Experimental Drug Given Every 6 Months Dramatically Cuts LDL In 3 Studies

Three phase 3 studies of a long-acting cholesterol-lowering drug show it can cut low-density lipoprotein cholesterol levels by half for patients who need treatment beyond statin drugs and spark a similar LDL reduction in adults with heterozygous familial hypercholesterolemia.

The experimental drug, inclisiran, is injected every 6 months. During all three studies, the volunteers continued to receive the maximum tolerable dose of conventional therapy such as a statin.

The findings of the tests, known as ORION-9, ORION-10 and ORION-11, are published online in The New England Journal of Medicine. All were financed by The Medicines Company, which was acquired for nearly $10 billion by Swiss drugmaker Novartis in January. Novartis is seeking approval from the U.S. Food and Drug Administration and the European Medicines Agency.

ORION-10 involved 1,561 US volunteers with established atherosclerotic cardiovascular disease and ORION-11 had 1,617 patients from Europe and South Africa who fell into the same category or had risk factors for cardiovascular disease. All had high LDL levels despite being on a maximum statin dose.

"These are people who need further cholesterol reduction even when you've received the best standard of care," Dr. Kausik Ray of Imperial College London and coauthor of the ORION-9 and ORION-10 results told Reuters Health in a telephone interview.

The volunteers received subcutaneous inclisiran or placebo, followed by another injection 3 months later and then once every 6 months over a period of 540 days.

Mean LDL cholesterol levels started out at 104.7 mg per deciliter in the ORION-10 group and 105.5 mg per deciliter for the ORION-11 patients. At the 17-month mark, the reduction was 51.3% in the first group and 45.8% in the second. Placebo recipients saw their LDL levels rise 1.0% and 4.0% respectively (P<0.001).

There were no clear adverse events aside from a generally mild reaction at the injection site. The reaction appeared in fewer than 2.8% of the inclisiran recipients.

"The day I saw the safety data, I couldn't believe it. It's identical with the placebo and inclisiran groups in the two trials," said Dr. Ray, a professor of public health and consultant cardiologist at Imperial.

In the ORION-9 test, 482 volunteers with heterozygous familial hypercholesterolemia received the drug or a matching placebo on a similar schedule at 46 sites in eight countries.

At 17 months, the mean LDL levels among patients in the inclisiran group, who started out with a mean baseline level of 153 mg per deciliter, were reduced by 39.7%. The mean level increased by 8.2% in the placebo group (P<0.001).

"There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia," said the research team, led by Dr. Johan Raal of the University of the Witwatersrand in Johannesburg. "Adverse events and serious adverse events were similar in the two groups."

Only three of the 241 inclisiran recipients had an adverse event serious enough to halt treatment. Drug recipients were nine times more likely than placebo patients to have a mild reaction at the injection site, but only one in six actually had that reaction. Nasopharyngitis was 40% more likely with the drug, seen in 11.6% of that group. back pain was 70% more common, reported in 7.1% of drug recipients vs 4.2% in placebo.

The LDL-lowering benefit of the drug did not fade over time so "there doesn't seem to be any tolerance to the medication," Dr. Raal, head of the division of endocrinology, told Reuters Health in a telephone interview.

Heterozygous familial hypercholesterolemia affects about 1 in 250 people, or about 30 million worldwide.

"We genuinely believe that lower LDL is a surrogate for reducing cardiovascular events," said Dr. Ray. A study known as ORION 4, which will directly test that, is ongoing in the United States and the United Kingdom. It will look for at least 1,500 cardiovascular events and is expected to be complete in 2024.

Both researchers said a key advantage to inclisiran is the durability of its effect.

"It could be an alternative to statins because you've got guaranteed compliance," said Dr. Raal.

Dr. Ray predicts the payment system will still favor cheap daily oral medication but he said inclisiran will likely cost a lot less than other newer drugs because it is relatively easy to make and not a monoclonal antibody. Such drugs can also drop LDL levels by 50% but have to be taken every 2 to 4 weeks.

"We still want to do that primary prevention trial first," he said.

Inclisiran, whose key component is a small piece of genetic material, accelerates the body's natural process for clearing LDL from the blood by entering liver cells and silencing the expression of a protein known as PCSK9. That puts more LDL-capturing receptors on the surface of the cells.

—Gene Emery

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