Mechanism of Action of Inclisiran in Lipid Lowering

Keith C. Ferdinand, MD: Manesh, there’s an emerging therapy that’s not approved, it’s still investigation: inclisiran. Tell us a little about this particular molecule, how it works, how you administer, and what type of results we have seen thus far.

Manesh Patel, MD: Thanks, Keith. It’s a very exciting time for us. All of us in the last few years have seen that there are new pathways or potentially new ways to treat our patients with high cholesterol. We’ve heard a little about PCSK9, the protein—just to remind everyone, that’s a protein that’s a protease in your liver. It actually helps break down the LDL [low-density-lipoprotein] receptor. So, if you inhibit PCSK9, you prevent that LDL receptor on the cells from taking in LDL, and you allow them to be on the cell receptor, so they can take in more LDL and reduce your circulating LDL level by up to 50%, 60%.

Inclisiran is a newer molecule that’s interestingly different. We’ll talk about PCSK9 inhibitors in a second, the first range of the more antibodies to that protein. Inclisiran is a small interfering RNA molecule. Before the pandemic, people probably didn’t think as much about RNA and ways that that all works, but a small interfering RNA molecule is a strand of that molecule that actually goes to your liver after an injection and inhibits the translation of that PCSK9 protein, so potentially a longer-acting way of inhibiting the production of that PCSK9 protein or inhibiting that function.

How have we dosed it, and why are we so excited about it? I’ll talk about the dosing, and then we’re going to talk about some of the ORION trials that are coming out about it. The original studies looked to dose it day 1, at 90 days, and see people at 1 year to just see the effect. And it was really surprising that if you could give an injection at once and then out to 90 days or 6 months, you could get a reduction up to about 50%. The dosing schedule of this therapy, once you get started on it, is every 6 months. You would potentially inject this as this therapy, and it would inhibit the production of that protein at your liver. That certainly is a very innovative and potentially disruptive way to improve how we take care of our patients with high cholesterol.

Keith C. Ferdinand, MD: Norm, we have some data from the ORION studies. Manesh talked about that 50% to 60% reduction. We have some evidence from clinical trials—peer reviewed, publicly available. What did it show?

Norman Lepor, MD, FACC, FAHA, FSCAI: I was an investigator on a number of the ORION trials, including ORION-2, ORION-10, and ORION-8, and I’m an investigator on the ORION-4 cardiovascular outcome trial. But what the pooled analysis showed, No. 1, was that you’re able to achieve a very consistent level of LDL lowering in the 55% range with this twice-a-year or every-6-month subcutaneous injection of inclisiran, a 30-mg dose of inclisiran.

The area under the curve is very consistent. The levels of LDL reduction are consistent at a variety of end points, so what we were able to see in terms of efficacy—the definition of efficacy we’re talking about, pending the results of the cardiovascular outcome trial ORION-4, which hopefully we’ll have in a couple of years—was significant LDL reduction, similar to what we see with the currently available higher doses of PCSK9 inhibition, but certainly those we know are given on an every-2-week schedule vs the inclisiran, which is given only twice a year, every 6 months.

We know from an efficacy point of view; we’re getting LDL reductions of about 55%. This is on top of patients who are receiving statin therapy. A minority of patients were also receiving treatment at baseline and continuing through the trial with ezetimibe. We found that to be consistent.

In the safety analysis, we found that the drug, certainly in terms of treatments, emerged in adverse events. They were consistent with by far most of these events being placebo-like. I am talking about, for instance, the development of diabetes was placebo-like. Hypertension, arthralgias—most of these adverse events were placebo-like, including the development of liver function abnormalities, muscle adverse events, and abnormalities of liver function.

What we have been able to find in these particular trials is certainly efficacy as well as safety.

Keith C. Ferdinand, MD: If you enjoyed watching this HCPLive® Peer Exchange, if you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. Thank you very much for listening to this program.

Transcript Edited for Clarity