Voxelotor for Sickle Cell Disease

Ify Osunkwo, MD, MPH: The next drug that has been recently FDA approved is voxelotor. I want to start with Dr Shah, or Nirmish. What is voxelotor? Talk about the HOPE study that got it approved by the FDA. How does it work? What does it do?

Nirmish Shah, MD: This is a drug that’s a hemoglobin modifier. It actually binds to the hemoglobin, actually to alpha-globin. Also it increases the oxygen affinity. Again, speaking to what we were talking about in regard to hydroxyurea, in a very similar fashion, if you have hemoglobin that’s holding on to oxygen, you’re preventing that sickling polymerization that you have.

It’s a very interesting drug in the sense that it is taken up directly by the red blood cells. It doesn’t have to go and trick the bone marrow into making more fetal hemoglobin, so it has this pan-cellular effect, it has this effect across all the hemoglobin within the red blood cell. The interesting part of what this product is trying to do is focus on preventing sickling and increasing the hemoglobin. The trial was again, randomized, double-blind, placebo-controlled trial looking at 2 different doses—1500 mg, 900 mg—and placebo, and trying to compare that, a primary outcome, did it increase the hemoglobin by 1 g/dL in those patients who were treated.

Ify Osunkwo, MD, MPH: Biree, with this study, what was the toxicity profile like for the patients who participated in it? What should we expect to see when we start prescribing this medicine for sickle cell disease?

Biree Andemariam, MD: It was generally well tolerated. I think common complications or adverse events included headache, maybe 10%, rash, which is a little bit surprising, but generally well tolerated. And it’s oral, which is different from crizanlizumab. I think we didn’t touch on that, crizanlizumab is IV [intravenous]. Voxelotor is an oral drug.

Ify Osunkwo, MD, MPH: The dose approved was the 1500 mg or the 900 mg?

Biree Andemariam, MD: Fifteen hundred mg.

Ify Osunkwo, MD, MPH: Fifteen hundred mg. What are the clinical implications? Who would be the ideal patient to offer this drug to?

Biree Andemariam, MD: I think that’s the million dollar question.

Julie Kanter, MD: We forgot to mention or didn’t mention up front, what we saw was an increase in hemoglobin by at least a gram per deciliter, which was their primary end point. But we didn’t see any other changes. We didn’t see any significant reductions in pain or vaso-occlusive crises. I think that that’s what makes this a little bit harder in determining optimal treatments for optimal people. Certainly, I would think we all probably agree that we have some individuals who cannot be transfused for various reasons.

Biree Andemariam, MD: People with kidney disease, low EPO [erythropoietin] who have very low hemoglobin.

Ify Osunkwo, MD, MPH: People with…phenotype.

Biree Andemariam, MD: There are populations for which a rise in the hemoglobin would be beneficial. But I think getting back to what Nirmish was saying about the mechanism of action, it’s just not simply raising the hemoglobin but decreasing hemolysis, which we know leads to a lot of complications in sickle cell disease, including pulmonary hypertension.

Ify Osunkwo, MD, MPH: Can you speak about that a little bit? Because I think a lot of providers are unaware that in sickle cell disease you don’t just have vaso-occlusion, which is one very well-known pathophysiology mechanism, but also the hemolysis has its own separate set of short- and long-term consequences. Talk about that a little bit.

Biree Andemariam, MD: I think we began to understand maybe a decade, a decade-and-a-half ago, more and more the impact of hemolysis and release of free hemoglobin, which scavenges nitric oxide, and causes a relative depletion of nitric oxide, which further enhances vasoconstriction. The hemolytic effects of having sickle cell disease are profound and do contribute to vasculopathy. We’re understanding that, and I think that for people to better understand voxelotor, where it plays a role is not just in raising the hemoglobin, which we know just a simple transfusion getting a patient’s hemoglobin up by 1 g/dL doesn’t really do much. But if you’re decreasing hemolysis, I think that’s really where you get the clinical benefit.

Nirmish Shah, MD: I think going back to that number, this magic number 1 g/dL, that’s been the debate. I think that many times now we’re referencing Dr Kenneth Ataga’s talk from ASH [American Society of Hematology 2018 annual meeting], where he had a meta-analysis looking at what are subgroups of patients who have other complications. They have pulmonary hypertension, you have acute chest syndrome, you have more mortality. The difference in hemoglobin, again, this is in a retrospective fashion, showed that the difference was between 0.4 and 1.1 g/dL, so really a very small amount of hemoglobin did make a difference.

Julie Kanter, MD: It did, but it didn’t prove that changing that hemoglobin would change that outcome.

Nirmish Shah, MD: You literally answered my next sentence there.

Ify Osunkwo, MD, MPH: Patience, dear Watson.

Nirmish Shah, MD: The next thought process is, give me time to say that can I prospectively make that difference? The data so far have not clearly shown any clinical benefit. There are some separations that occur for pain, so that maybe down the line we may have some more data to show that. But pathophysiologically, as you were saying, the 2 main buckets, the 2 main issues in sickle cell disease are hyperhemolysis and anemia, and the vaso-occlusion. So now we have 2 drugs that really address both.

Julie Kanter, MD: But they can overlap.

Nirmish Shah, MD: Absolutely, they can overlap, yes.

Transcript edited for clarity.