R. Scott Wright, MD: ORION-10 Findings

New ORION-10 findings presented at the American Heart Association (AHA) 2019 Scientific Sessions in Philadelphia this weekend show investigative therapy inclisiran can significantly reduce LDL cholesterol in high-risk patients with atherosclerotic cardiovascular disease.

The findings, which also highlight the simplistic administration schedule and adherence expectation for patients, play a role in introducing a novel drug class to cardiovascular care. In an interview with MD Magazine® while at AHA 2019, study author R. Scott Wright, MD, professor of Medicine & Cardiology at the Mayo Clinic, detailed the team’s findings, and the mechanism of inclisiran.

MD Mag: What were the findings of the ORION-10 study?

White: The ORION-10 trial evaluated inclisiran, a new and novel way to lower cholesterol in patients who had atherosclerotic cardiovascular disease. These are the high-risk patients that primary care physicians often see, who were already on a statin, or statin with ezetimibe, and despite that had elevated LDL cholesterol.

So these were patients—not at-goal patients, still at-risk—patients who frequently have further events. So, we randomized them to placebo or inclisiran and followed them for 18 months.

Inclisiran is a new and novel way to lower cholesterol. It actually is a drug that is taken up by the body to the liver, where it inhibits production of the PCSK9 protein in the cell itself. So, it actually lowers PCSK9 in the body dramatically, and by doing that, it lowers LDL cholesterol.

What we saw in the trial was that at day 510, there was a 58% reduction in LDL cholesterol in the inclisiran group compared to placebo. And when we average the reduction in cholesterol over days 90 to 540 in the trial, there was a 56% average reduction, and this reduction is already on top of what statins had done in this population.

So, the patients started with a median cholesterol of 105. So a 58% reduction puts them really well below 50 milligrams per deciliter.

MD Mag: How does inclisiran function in patients?

White: So, inclisiran is a drug which harnesses the body's natural ability to silence message RNA translation. A few years ago, a Nobel Prize was awarded for a scientist who discovered how RNA can inhibit the translation of RNA. So it's a small RNA inhibitor, and it works by going into the apadosite, where it turns off the transcription of message RNA for PCSK9 through a complex called RSC.

It's a new and novel way where drugs are now being developed. So, the monoclonal antibody is actually circulating PCSK9 and reducing plasma levels by binding or sopping it up. Inclisiran stops the production, so the liver doesn't produce it and create those high levels.

Either way, it results in the prolongation of the LDL receptor on the liver cell, which removes cholesterol from the body and lowers cholesterol pretty substantially. And in the inclisiran study, it was 58%. And with monoclonals, it’s about the same degree of lowering.

The difference is that monoclonals are given every 2 weeks, and the patients have to take them on average 26 times a year. Inclisiran, amazingly, can be given every 6 months, which is how we see most patients coming back to us healthcare providers.

So, we believe the drug is something that healthcare providers could either administer in office if it's approved by the FDA, or it's something that they could talk with their patients about at the time they're coming back in. It'll be a small injection if approved—it would be about 1 to 1.5 CCc twice a year, so like taking a GLP-1 drug or something like that, twice a year—a needle delivery system that's a prefilled syringe, and patients would do that.