Utility of Potential SCD Biomarkers in SCD Management

Biree Andemariam, MD: Now, Matt, I want to ask you to look into your crystal ball, and we’ve talked a bit about markers of red cell health, right, specifically laboratory markers of red cell health. How do you think in the future we may be able to use those markers to define sickle cell disease severity and possibly be able to correlate those markers with treatment efficacy as new treatments emerge?

Matthew M. Heeney, MD: Well, some of these new biomarkers, again, I hope that at the most basic level that they’ll help us to risk stratify patients and to better understand the heterogeneity of the population as Nirmish and Elna described. I joke with parents that when I have a new baby with me, if I have 100 new SS babies, 10% will go on to have a stroke, historically, by the time they leave my care. Twenty-five percent of them will have a severe acute chest. And 10% or 20% of them will almost never see me because they’re perfectly well. That heterogeneity of clinical phenotype is really challenging. Thus, my hope is that some of those biomarkers will help us discern some of that and risk stratify. And then, depending on what the biomarker is, it may be a target of one of the therapies and demonstrably changed and that will be a good read out, objectively, for providers and patients to monitor the activity of their disease, and of the efficacy of their therapy. That’s really the goal, but it’s been a challenge to identify these biomarkers and to identify ones which are easily obtainable, reproduceable, and widely available that will then change practices like that. I think those are the biggest things.

Biree Andemariam, MD: Thank you, Matt. Now, Nirmish, let’s talk about some of the agents under clinical trial investigation that are focusing on red cell health. What is the unifying mechanism of action, so to speak? How might these treatments be a little bit different? And what does the future hold for us in terms of these agents that are targeting red blood cell health?

Nirmish Shah, MD: We’ve had this conversation about ways to try to help red cell health, and a lot of it’s really coming back and focusing on how do I decrease …? And in the end, how do I correct the oxygen dissociation curve? That can be through upregulating fetal hemoglobin. It can be by modulating the pyruvic highness receptor by activation of that. There are a couple of different medicines or mechanisms that are being evaluated. The one that has a little bit more data and is a little bit further on are those agents focusing on the PKR [pyruvate kinase-R activator]. And in that sense, there are at least 2 companies that are working on this and have data that’s come out in a couple of different conferences. I think they’re pretty exciting at this point. We’re showing that when you decrease the homolysis by shifting the oxygen dissociation curve again back to where hemoglobin A should be, and hopefully that we have an improvement in hemoglobin, we have a direct reduction in homolysis markers, and the key part here is hopefully also having a clinical end point. Also show that this is tied to something that benefits for these trials, pain.

The preliminary data so far is that we’re maybe increasing hemoglobin to about one and a half grams per deciliter in a couple patients. It does seem to be improving red cell health. We have some data coming out at least for … that it’s improving glutathione. It’s improving phosphoserine expression on the surface of the cell and it’s something that actually persists even after the drug stops. All of these things that go wrong is not again eloquently described a very complex pathophysiology. All the things that are going wrong with red cell health seem to be with this preliminary data is to be something that’s being targeted and potentially beneficial for patients.

Biree Andemariam, MD: Thanks, Nirmish. Matt, do you want to piggyback on that and maybe give your opinion on the 2 agents looking at the PKR pathway?

Matthew M. Heeney, MD: Well, much more expertise here in the group than me on these 2 drugs but I do think that they are beginning to potentially show some benefit. I think using the similar sort of mechanism as seen by voxelotor to try and increase the oxygen affinity and therefore increase the overall hemoglobin in patients, but still very early trials. This purported idea of increased red cell health that we’ve been discussing already this morning, the idea of improving the ATP [adenosine triphosphate], or the energy availability to the red cell, may provide some benefit beyond even sickle cell disease but in other hemolytic anemias potentially where these drugs could be released. But also, improvement in other rheologic and sickling features in sickle cell. I think there’s some promise here. I think we still need to learn more about them, the differences between them if there are any, the safety of them in terms of potentially needing to be careful in terms of how you start and stop the medications and then again who the optimal patients are. Is it reserved for those patients who are particularly anemic, if improving hemoglobin is the primary goal, or will they have other benefits in sickle cell disease such as reduction of vaso-occlusion and the consequences of that? Thus, there is still quite a lot to be learned, and there are very early trials but I’m glad that there’s interest in completing these trials and interest in new therapeutics.

Transcript edited for clarity