Derick Raal, MMed, PhD: ORION-9 Findings

New findings from the ORION-9 trial, presented at the American Heart Association (AHA) 2019 Scientific Sessions in Philadelphia this morning, show investigative therapy inclisiran reduced LDL cholesterol by about 45% in patients with familial hypercholesterolemia.

The findings present a promising development of care for the fairly common cardiovascular condition, but also raise questions about the twice-annual therapy’s future role among monoclonal antibodies and statins.

In an interview with MD Magazine® while at AHA 2019, presenting author Derick Raal, MMed, PhD, head of the Division of Endocrinology & Metabolism at Johannesburg Hospital, discussed the details of the ORION-9 trial, and the potential of inclisiran.

MD Mag: What were the findings of the ORION-9 trial?

Raal: I’m at the AHA this year to present the results of the ORION-9 study. So, the ORION-9 study was a study in subjects with familial hypercholesterolemia. Now, most people don't know familial hypercholesterolemia is one of the commonest inherited diseases in the world.

It affects about 1 in every 250 people, and worldwide there is about 30 million people that have familial hypercholesterolemia. In the United States, for example, we estimate there’s probably about 1.3 million people with familial hypercholesterolemia. They are at high risk for premature atherosclerotic vascular disease, because they have a lifetime high LDL cholesterol level, which is usually about twice the normal level. When they're the age of 20, their arteries have been exposed to twice as much cholesterol as somebody with a normal level.

So, we thought this was an important group to study with this new drug called inclisiran. Inclisiran is a small interfering RNA drug that works in the liver to inhibit the production of PCSK9. There are monoclonal antibodies against PCSK9, but monoclonal antibodies are cleaning up the PCSK9s produced by the liver. This is turning of the cap—so it's actually stopping the liver from producing cholesterol.

It was a big study. There were over 600 patients screened, we enrolled 482 patients, and they were randomized 1:1 to either inclisiran given at day 1, day 90, and then six-monthly until the end of the study. It was an 18-month study.

And the results were very impressive. Inclisiran, compared to placebo, reduced cholesterol LDL cholesterol by about 50%. That was at the end of the study. But there was also a time-average reduction. So, over the duration of the study, LDL cholesterol was reduced by about 45%, and this was on top of background therapy. So 90% of the patients were on statin therapy, the vast majority on high-intensity statins. Over 50% were also on ezetimibe. So, they were quite a well-treated group of patients. But despite that, they had an LDL of about 150 milligrams per deciliter.

The introduction of inclisiran allowed a big proportion of these patients to lower their cholesterol to

better targets—LDL below 100 or even 70 milligrams per deciliter and. That's only with an injection twice a year.

I think: where will this drug have a place? I mean, you've got 100% compliance. If the dose is administered, you're guaranteed a reduction in your LDL in the region of 45% over a six-month period. So, how will the drug be administered? Will it be the general physician that sees the patient twice a year, much like a flu vaccine? Just gives them the drug, and there's a 100% compliance?

Because one of the problems is, I mean, statin is still first-line. But you've got to take your tablets every day, and monoclonal antibodies against PCSK9s are also good drugs, but that requires that we add twice-weekly days. That's about 26 injections per year, as opposed to this medication, which is only twice a year.

Is there a price to pay—what about side effects? So, some patients do get an injection site reactions at the site of the injection. In the ORION study, it was slightly more than in other trials—it was about 13%. But all of these were mild or transient. None of them persisted.

So, there doesn't seem to be any major side effects of this medication. We are going to need a big outcome study, and that is in process. That's called the ORION-4 study, to show that inclisiran will reduce cardiovascular events. But at least in proof of concept for these high-risk patients that have a very high cholesterol level, this is a very worthwhile drug, and I think it has a great future.