Experts review in detail the emerging use of inclisiran as an adjunct therapy for lipid lowering in patients with high cholesterol.
Keith C. Ferdinand, MD: I’ll give you a chance, Manesh, to get a little more detailed about inclisiran. Exactly how does it work, and how is it going to be used if it’s approved by the FDA in clinical practice?
Manesh Patel, MD: Thanks, Keith. I appreciate the opportunity, and the first thing to think about with inclisiran is to recognize that the target of inclisiran is the protein PCSK9, which we know about because there are monoclonal antibodies to that protein that helps break down the LDL [low-density lipoprotein] receptor. So if you can inhibit that protein, you’ll have more LDL receptors, and you’ll lower LDL. We know that’s the target.
Then inclisiran itself; it’s important to recognize that it’s a small RNA molecule that’s interfering with RNA. Some have said what exactly does that mean? It follows a natural pathway of RNA interference. There’s a complex in your cells called the RNA inducing or silencing complex; some people have called that the risk complex. That complex is where 2 RNA molecules are often together. And if you have a small one that enables cleavage of that mRNA [messenger RNA] molecule specifically in coding for PCSK9, you potentially inhibit the production or the translation of the messenger RNA into PCSK9.
Keith C. Ferdinand, MD: You’re not interfering with the DNA in the cell?
Manesh Patel, MD: You’re not interfering with the DNA at all. What you’re doing is you’re putting a small piece of RNA that goes in and interferes with the translation of the mRNA that’s leading the PCSK9. I think that’s an important message because that happens in your liver, and so you can give that shot and inhibit the production or the translation of the PCSK9 molecule, and that prevents that protein.
That’s the first message for people, that it’s an inhibiting RNA molecule.
Keith C. Ferdinand, MD: Now this idea of it lasting for 6 months, why would a drug last for 6 months? That sounds unusual.
Manesh Patel, MD: It’s a great point, because the first thing we always think about is, “The things I’m used to taking are proteins that I take in my body, I break down, and then it inhibits a receptor, or most of the medicines I take, do something to protein.” This is actually an inhibiting RNA molecule, a small molecule that’s going to your liver, inhibiting the translation of that protein. You’re a little upstream, so that if you can have enough of that molecule in your liver, you can prevent enough of that protein from forming so that that machinery slows down, and you may not break down LDL receptors for a period of time. In fact, they studied that, and we’re going to hear about some of the studies about how long that effect might last, which might also give us comfort in understanding this.
But it is important because I think a lot of people are worried, and understandably, that when you do something that has the word RNA or DNA, or something that might get confused for that, that might worry you that you’re going to have some long-lasting effect. We now have at least some longer studies here that have shown us that when we dose this therapy, and the dosing of this is, I think Linda mentioned in one of the prior programs, in the very first ORION study the 300-mg dose was given once or twice, and just with 1 dose the LDL came down, but at about 6 months started going back up. With 2 doses it seemed to last out to a year, getting close to a year, and then that led to a dosing regimen that is about twice a year, to reduce LDL.
Keith C. Ferdinand, MD: Yes, Linda, I think you were making that point earlier because of the pushback that somehow you were changing the very nature of the person’s body by giving this particular compound. You said with time the body returns to baseline unless you give another shot of inclisiran. Is that the point you were making?
Linda Hemphill, MD: Yes. And thinking about this at a simple level, the inclisiran is working out in the cytoplasm. It does not enter the nucleus.
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Transcript Edited for Clarity