Brian Goff: Yes, and Chris, I mean, that last point is the one that I would just emphasize, is that I know folks are trying to make comparisons, but in so many ways, they’re incomparable because of the profound difference in the mechanisms. And you’ll hear a lot from us because we continue to be emboldened by this, by the data that we see very consistently that the benefits of the of PYRUKYND kinase activation really do go beyond hemoglobin. So we’ll await the data. Fortunately, we don’t have to wait that long. ENERGIZE-T is coming mid-year. But I think above oral and the other dimensions, hemoglobin and the like, that’s really the big headline for this mechanism is, it’s ultimately about red blood cell health.
Operator: Our next question comes from the line of Danielle Brill with Raymond James.
Danielle Brill: Hi guys, good morning. Thanks so much for the questions. I also have a question on powering assumptions for ENERGIZE-T. Like Chris said, we know it’s not apples-to-apples. But when you look at Luspatercept, their mean hemoglobin increase is about 1.5 grams. And they achieved, I think, around a 40% response rate on your primary endpoint. With this context, what are your internal expectations for how mitapivat will perform? And I also have a follow-up.
Sarah Gheuens: Thanks for the question. So in regards to powering assumptions, we haven’t spoken about these, but we have, of course, studied all of the programs in front of us, which includes our own internal programs in which we took a very similar development approach for thalassemia as we have for PKD. In regards to the hemoglobin increase that you mentioned, so we don’t, from a transfusion dependent perspective, we don’t believe you necessarily need to increase hemoglobin on top of making people reduce their transfusions. This is truly a different approach because people, when they get transfused, their hemoglobin goes down over time. So what we are trying to do here is basically avoiding that people, their hemoglobin decreases back to a transfusion trigger, which then would trigger a transfusion.
And it comes down again to that different mechanism of action. If you are like stimulating out red blood cells, ultimately, you’re going to increase the hemoglobin versus what we’re trying to do about keeping the red blood cells happier and healthier, thereby reducing hemolysis. It’s a completely different way of actually trying to avoid transfusions.
Danielle Brill: Thanks, Sarah. That’s helpful. And that actually is a perfect segway for my follow-up. Do you have data on the potential of mitapivat for extending the half -life of healthy red blood cells?
Sarah Gheuens: So we, in the context of, you mean, healthy volunteers red blood cells?
Danielle Brill: Or like, yes, extending the lifespan of transfused blood.
Sarah Gheuens: So, yes, so this is something that is extremely difficult to measure in the context of a transfusion setting as everything is kind of mixed. So it would require a very, very unique experiment to be able to tease apart those types of red blood cells that are available, so we’re not planning on doing that right now for transfusion-dependent patients.
Operator: And our next question comes from the line of Gregory Renza with RBC Capital Markets.
Gregory Renza: Hey, good morning, Brian and team. Congrats on all the progress, and thanks for taking my questions. Brian, you certainly speak to the multibillion dollar opportunity available with PK activation and your portfolio. I’m just curious if you could maybe just elaborate a little bit on that, maybe provide some of the inputs or assumptions that you’re using to get to that characteristic, whether it’s with respect to mitapivat and the ramp of indications or the broader portfolio. And maybe I’ll just layer in my second question, which with respect to the landscape in PK activation, perhaps if you and Sarah can just riff a little bit about maybe the differences with mitapivat versus others, especially etavopivat. Certainly you’ve mentioned the lead. You have the body of data, but when you think about some of the nuances on pan-PK activation or even selectivity, maybe just help us understand the differences between mitapivat and the landscape. Thanks so much.
Brian Goff: Yes, thanks, Greg. So I’ll get started on your first question about the multibillion dollar opportunities that I referenced in my prepared comments. That really comes from the fact that we’re rapidly progressing in our pipeline, moving from clear ultra-rare with PKD into successively larger prevalent diseases. Some of those diseases, I think are well characterized in terms of opportunity, sickle cell for sure, where there’s been lot of interest and a lot of therapeutic development focus. And here we’re talking about moving from 3, 000 to 8, 000 patients across the US in EU5 in the case of PKD, jumping to just in the US alone 100, 000 patients with sickle cell disease. But it’s more than that. I mean, as we’ve already discussed this morning, we had this really exciting opportunity relatively near term with a potential launch next year in thalassemia which is a prevalent step up in the case of the US from PKD.
Sickle cell, I just mentioned. And then even after that with our other PK activator, AG-946, moving into low risk MDS. The great news about all this is we’re moving in the right direction in terms of prevalence. And that is allowing us to enter into very compelling commercial opportunities. And it also allows us to navigate through the appropriate pricing dynamics as we go forward. But we are very excited, most importantly, with the fact that as we advance our pipeline and as we’ve already noted, we have two back-to-back launch potentials with thalassemia next year followed by sickle cell disease in 2026. And then, Sarah, you want to pick up with the next question?
