Phase 3 ORION Trials for Inclisiran 

Keith C. Ferdinand, MD: Norm, you’ve been an investigator for ORION. You introduced it earlier in our first segment when we were talking about some novel agents, but I’ll give you a little more time. Talk about the efficacy in terms of the LDL [low-density lipoprotein] reductions and revisit the safety. I’m not convinced. Is it safe?

Norman Lepor, MD, FACC, FAHA, FSCAI: That was an important series of trials, and the data, you had ORION-9, which looked at the heterozygotes, and you had ORION-10 and 11, which looked at variety of patients either with ASCVD [atherosclerotic cardiovascular disease], or ASCVD with high-risk features including diabetics and heterozygotes. When they put all the data together from these phase 3 trials, which represented somewhere around 3700 patients, what they found was the type of LDL reduction that I had mentioned, LDL reduction in excess of 50%, closer to 55%. If you want to look at how this worked with a heterozygote versus the other populations, the heterozygotes seem to have an effect that was closer to about 50% LDL reduction. In the secondary, the other trials, it was closer to 53%, 55% reduction, versus with placebo subtraction. So definitely robust LDL reduction.

I think what was also interesting, and again, we don’t know exactly, it will be interesting to see what Manesh, Dean, and Linda feel, there was also some reduction of lipoprotein(a), in about the 20% range. The question is similar to what we see with the PCSK9 inhibitors, do we think that’s kind of a “pleiotropic effect” that perhaps contributed to what we saw with the PCSK9 inhibitors, and perhaps what we will see when the ORION-4 CV [cardiovascular] outcomes trial comes about? I think that’s what we’re looking at in terms of efficacy.

In terms of safety, we’re not seeing really any safety issues. I know that Linda, Dean, and Manesh commented about the fact that the RNA plays its role in the cytoplasm and doesn’t affect the nucleus. We’ll see what the longer term shows, the outcomes trial will give us perhaps more comfort with longer-term data, but the development of renal, of hepatic, hematologic adverse events was basically placebo-like. And again, just like the PCSK9 inhibitors, you generally will see some small increase in terms of injection site reactions.

Keith C. Ferdinand, MD: If you enjoyed watching this HCPLive® Peer Exchange, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox.

Thank you very much for listening to this program.

Transcript Edited for Clarity