Kausik “Kosh” Ray, MBChB, MD, MPhil

The principal finding from a 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)—was a potential sustained reduction of more than 45% in LDL-C, with twice-yearly injections, according to a presentation at the 2022 American Heart Association Scientific Sessions. Phase 2 trial data were presented from the ORION-3 trial by Kausik “Kosh” Ray, MBChB, MD, MPhil, professor of public health and consultant cardiologist at Imperial College London, UK.1

In ORION-3, an open-label extension of the phase 2 ORION-1 trial, LDL-C level reduction was sustained during the 4-year study: patients treated with inclisiran achieved an average 47.5% reduction in LDL-C from baseline (Day 1 of ORION-1) to Day 210 (95% Cl, -50.7 to -44.3) and a time-averaged reduction in LDL-C of 44.2% during the 4 years via twice-yearly dosing.

Physician’s Weekly spoke with Dr. Ray.

PW: Can you please place these new data into context?

Dr. Ray: The big New England Journal of Medicine papers2-4 previously published were lipid-lowering studies, and they obviously allowed inclisiran to be launched around the world with a license and a label for LDL-lowering. The cardiovascular outcome trials are ongoing. From those initial 3,600 patients, we have safety data reporting, and the first signal that LDL-lowering is effective over 18 months, with a relatively small number of events (about 300) showed a preliminary reduction in cardiovascular events by about 25%. That bodes well for those two big ongoing trials, but we will have to wait for that data.

What ORION-3 attempted to answer the question “Over an additional 4 years, is the twice a year dosing regimen viable?” And “Does the effect wear off—do I get a similar reduction in LDL?” And also “Are there any new safety signals?”

There is also a second arm, in which patients switch with evolocumab, but that is not a head-to-head comparison. We basically switched people sequentially (ie, 21 days after their last dose) or just gave people the same injections at the same time. The results showed that it did not make any difference in terms of safety or efficacy; that manuscript is in revision and re-review, so it was not presented at the AHA Scientific Sessions. Numerically, a monoclonal antibody is more powerful, because it binds all of the PCSK9, entirely shutting down hepatic PCSK9, which accounts for 70% of what is in blood. We are now seeing that you could, for example, over 4 years, use 106 injections of a monoclonal antibody dosed every 2 weeks to maintain 60% lowering, or you could use 9 half-yearly injections of inclisiran to maintain about 47% lowering.

A couple years ago, we presented and published the ORION-9, 10, and 11 trials, studying patients with established cardiovascular disease or high-risk primary prevention, which some called risk equivalent and heterozygous familial hypercholesterolemia. These were people with elevated cholesterol despite maximally tolerated statins, and so you would believe that they might benefit from further LDL-lowering. Those earlier trials tested additional lipid-lowering therapies in this patient population with a high unmet need.

Inclisiran is the first of a class of drugs called small interfering RNAs. These drugs shut off translation, meaning they target the messager RNA, so there is no protein to be made. In this case, reducing the levels of PCSK9 helps the LDL receptor function better, even with a statin backbone therapy. The rationale of all the ORION trials with inclisiran is that if we have combinations of statin to make more LDL receptors in combination with something that lowers PCSK9, then you have a really good way of achieving really low cholesterol levels.”

PW: What did ORION-3 teach us?

Dr. Ray: We know that monoclonal antibodies are effective at lipid-lowering, but they have to be dosed every 2 weeks to maintain a 60% LDL reduction. That means that in a year, 26 injections will be needed, and we are reliant on patient adherence. This being the background, we tested inclisiran in 3,655 patients, with an injection on day 1, day 90, and thereafter to a 6-monthly dosing schedule. In these previous studies, the primary outcome was at 18 months, and the treatment stopped at that point. We knew inclisiran was safe up to that time point, and that it provided placebo-corrected 50% LDL reduction. No patient in those studies received more than four doses, so we did not know, for example, if repeat dosing over another 4 years would be associated with any differences in safety, or if the effect of inclisiran would wear off after repeated dosing. Furthermore, there may be patients, for example, who were on a monoclonal antibody, but there may be an opportunity for the patient and physician to switch to a more convenient regimen.

We started with a phase 2 dose-finding study: ORION-1. In ORION-1, approximately 180 people got three single doses of inclisiran and 60 got matched placebo.2 Then we had another 180 participants who received three different doses of inclisiran, but only two times, on days 1 and 90. Another 60 people got two injections of placebo, and we followed those people up to 1 year. At the end of that 1-year period, people were invited to enter an open-label extension study; ORION-3 then followed those individuals for another 4 years.

If an individual had any dose of inclisiran in the prior year, there was still some response, reducing the lipids more than 20%. Therefore, we could not establish a baseline reading after 1 year. For ORION-3, we had to use the treatment-naïve starting point of ORION-1 as the baseline.

The patients who were randomized to inclisiran in ORION-1 went onto 300 milligrams of inclisiran sodium every 6 months without a loading dose and just continued for another 4 years. However, the people randomized to placebo in ORION-1 had of course never been exposed to inclisiran or any other PCSK9-lowering therapy. Their last cholesterol measurement at that point, around 210 days into ORION-1, was taken as the baseline for that group. They were then invited to in an open-label study, to start with evolocumab 140 milligrams every 2 weeks, self-administered for 1 year. We then tested two forms of switching for years 2-4. Some of these patients were given their last dose of evolocumab about 2.5 weeks before the first dose of inclisiran, so that is called a sequential switch. Another small group of patients had both inclisiran and evolocumab on the same day, called a concurrent switch. This is not a head-to-head comparison because they are not randomized to be matched in ORION-3. ORION-3 is an open-label extension, meaning that every arm is reported separately.

In patients who had received inclisiran all the way through ORION-1 and then continued onto that 300 milligrams of inclisiran every 6 months, 9 months into the open label extension studies at day 210, they achieved 47% lowering from that starting level. You might look at that and say, “Oh, but that looks to be less effective than monoclonal antibody treatment.” But remember, these data are not placebo-corrected. Importantly, that amount of lowering is exactly what we have seen in the inclisiran-treated patients from ORION-9, -10, and -11 when you look at their individual change from baseline. What is more important, I think, is that when you then look at the next 4 years, the same amount of reduction in LDL is maintained year to year to year.

If you look at the entirety of that 4-year extension period, roughly 44% lowering of LDL cholesterol is being maintained with two injections per year. That is really a quite clinically meaningful reduction.

In terms of safety signals, we did not see anything new. The commonest events were transient injection site adverse events (these are mild to moderate in severity), the same as we had witnessed in around ORION-9, 10, and 11. We do not see any attenuation effect. We also observed no safety signals with either concurrent or sequential switching.

PW: What is the take-home message?

Dr. Ray: The vast majority of patients taking inclisiran will achieve at least 50% lipid lowering, and those reductions are maintained over 4 years. That is great news for doctors and patients, because we have two really good, effective options now. With ORION-3, we have addressed the previously unanswered questions about whether the durability of the effect can last, and whether we can achieve long-term effects with twice-a-year dosing. Remember that in ORION-9, -10, -11, there was only a 1-year window in which we tested the twice-yearly regimen, because the studies were stopped at 1 year; that is important. We also have some preliminary data from ORION-9, -10, -11, from the pooled safety data, showing a 25% lower risk of major cardiovascular events, and that has just been published in the European Heart Journal.5 I hope this kind of answers many of these questions that physicians may have around what we have presented, what it adds, and how we can look forward to the ongoing cardiovascular outcome trials.

PW: What is next on the horizon?

Dr. Ray: These outcomes for cardiovascular outcomes are expected to report in 2026 or 2027, so they are a long way away. I think some real-world studies will be next to report on such things as implementation data. There will also be some populations who have not been studied before, like the Japanese patient population, and some other people who we did not recruit into those earlier studies. We are doing a number of modeling exercises to determine what large-scale implementation of inclisiran could mean to a population’s health. I think the key thing coming up is that there will be some real-world studies about, for example, adherence of the medication versus other types of therapies.