Dr Kausik Ray: ORION-3 Data Show Inclisiran Produces Durable Sustained LDL-C Reduction

At this year’s American Heart Association’s Scientific Sessions in Chicago, trial data were presented from the ORION-3 4-year open-label extension study of inclisiran, a small interfering RNA that targets proprotein convertase subtilisin kexin type 9 (PCSK9) to lower low-density lipoprotein cholesterol (LDL-C). The principal finding was a potential sustained reduction of 45% in LDL-C, with twice-yearly injections.

Kausik K. Ray, MB ChB, MD, MPhil, professor of public health and a consultant cardiologist at Imperial College London in the United Kingdom presented these data in, “Efficacy and Safety of Twice-Yearly Subcutaneous Inclisiran in Patients With High Cardiovascular Risk and Elevated Low-Density Lipoprotein Cholesterol up to 4 Years-The ORION-3 Trial,” during the The Present and Future of Lipid Lowering session today on the last day of the American Heart Association’s Scientific Sessions in Chicago.

Transcript

Can you tell us about the ORION-3 study you presented and how these findings build upon ORION-1 clinical data?

I think that's a really important question. And for context, I need to give you some background, in particular, that’s relevant because of the mode of action of the drug. So, this has a unique mode of action. This is the first treatment that works through targeting the messenger RNA for a given protein in the liver. When we basically did ORION-9, 10, and 11—and these were the phase 3 studies in 3600 individuals, a placebo-controlled trial—we tested dosing regimens at day 1, day 90, and 6 monthly thereafter, buy the total follow up was 1.5 years. So that basically means that no patient has actually received more than 4 doses.

So what you don't know, because the effect of the drug is so long is, one, what happens with repeat exposures. And therefore, you have to go out further, because you don't know if efficacy, for example, is lost because we're targeting something called the risk complex. And that's how the drug works. Nobody's ever tested, what happens with repeat exposure to that with a drug? Do you lose efficacy? Are there any new things that you haven't seen in terms of adverse events? And, importantly, we could actually study that twice-a-year dosing regimen that we all know, and this kind of proves that if we are able to show this, that that twice-yearly dosing is achievable chronically. So that was really the background.

So, how do you do it? How do you do all of this? Well, we had done a trial called ORION-1, and that was around 500 patients. And we had in that study roughly 184 patients who had received at least 1 dose of inclisiran; some had received 2 doses, about half had received a single dose—3 different doses—and about half of those had received 2 different doses. And there were 120, roughly, placebo patients. So because the effect of the drug is so long, what we did is, those patients that had been treated with any dose of inclisiran, we invited them into a 4-year open-label extension study. For those patients, what we tested is, in that second year of the open-label extension—we didn't give any boost doses or anything—we just went straight to 6 monthly, is when we do that, what is the peak effect, ie into that second year, roughly nine months (day 210), what is the peak effect?

And the answer to that question is, with 2 doses, the peak effect of that second dose is 47.5% lowering of LDL. So what we’d seen in that first year, when nobody had got any PCSK9 therapy, through to that almost end of second year, is that maintenance of that effect when this is not placebo corrected. More importantly than that, though, is you can for a drug like this with twice-a-year dosing, you can look at those 4 years in bite-sized chunks—year 1, year 2, year 3, year 4—and essentially what you see is you're getting roughly 45% lower in each year, and it's maintained. That's the key thing. Put it another way, in a 4-year window, with 8 to 9 injections, you can maintain a time average reduction in LDL cholesterol of 44%.

We didn't see any extra safety features that we hadn't seen before. Remember, you’re following people up for longer, so the usual things that we see, a mild to moderate injection-site adverse event, the percentage will be higher because you're following people up for longer—but they're all transient. We've seen this with all injectable therapy.

So the key things to summarize are: There's a durable sustained reduction in LDL cholesterol, with no new adverse event profiles that we've seen before, and what we can actually really reassuringly, say, to conceptualize ways of managing patients, you can do the sums. Imagine being able to say to a patient, “Over the next 10 years of your life, with 20 injections, I can maintain coverage of 45%. That's what you're talking about. And I can do so safely.”