Clinical Implications of Using Voxelotor To Treat Sickle Cell Disease

Peter Salgo, MD: We’re talking about 3 drugs. We have hydroxyurea, crizanlizumab, and voxelotor. Are all 3 working on different sites? Different mechanisms? Would you start somebody on all 3?

Biree Andemariam, MD: Well, and different toxicities.

Peter Salgo, MD: Right.

Biree Andemariam, MD: Different—they’re not overlapping, which is important, sorry.

Elliot Vichinsky, MD: Well those are important. That’s why people say: What we don’t have, unfortunately in many drug trials, is long-term data on organ failure. I agree completely that, if we know that severe anemia is a risk factor for multiple morbid complications, wouldn’t we want to take that subgroup who have predictively really low and start that population on it? And it makes total sense to me.

But what was pointed out, and what’s plagued sickle cell for a long time, is really the lack of very detailed, prospective long-term outcome organ failure. But we know that doesn’t mean you don’t do things to make them better.

Peter Salgo, MD: I’m afraid to ask this question because I think I know the answer I’m going to get. But if we just take these 2 newer drugs—crizanlizumab and voxelotorcan—we compare their effect on end-organ damage, hemolysis, and death?

Biree Andemariam, MD: To each other? No.

Jane Hankins, MD, MS: No.

Peter Salgo, MD: All right, let me go somewhere else. If you take a look at the rheology of blood, the higher the hematocrit, the thicker the blood, the more difficult it is to pump. And in fact, there’s a sweet spot which is well below the hematocrit of 30, where you have less myocardial oxygen consumption for adequate oxygen delivery, right? So why don’t we aim for a hematocrit lower than 30 with sickle cell? I’m asking this for my benefit.

Elliot Vichinsky, MD: In terms of what?

Jane Hankins, MD, MS: I‘m not sure we need it because the voxelotor data showed that if you increase the hemoglobin, you’re not increasing the amount of pain, which is a concern, right? Because would higher hematocrit have more vaso-occlusive crisis? It depends. If you increase the hemoglobin but didn’t increase the osmolarity of the blood, then you’re fine.

Biree Andemariam, MD: And in the trial they thought, we think of hemoglobin we think of hematocrit, so let’s translate a 30 to a 10.There was a significant number of patients on trial, I don’t remember exactly how many, who achieved hemoglobin of 11, 12, one-half. And, again, as Jane said, there didn’t seem to be any adverse effects.

Sophie Lanzkron, MD, MHS: But let’s keep in mind also that the study was done in people who were homozygous for hemoglobin SS disease. And so, we have no idea, right? And probably none of us would think about using this in someone who had SC [sickle cell] disease, right?

Elliot Vichinsky, MD: There are some patients with S-beta-thals [sickle beta thalassemia], but patients with SC were not in that. But I actually have a paper here at this meeting on the data you’re talking about. We did an ad hoc analysis of the group, and then we broke the patients, with this drug, into stratified, then into hemoglobin levels after 24 weeks and looked at the groups going from those. Hemoglobin groups were at 12, down to those who only got 8, as well as occupancy on the drug. And as we were referring to in this post-analysis data, what it showed was the higher the hemoglobin you went, actually the lower the pain rate in that trial.

Peter Salgo, MD: That’s what I was talking about.

Elliot Vichinsky, MD: And the occupancy rate went in the same direction.

Jane Hankins, MD, MS: That’s correct.

Elliot Vichinsky, MD: So, there were encouraging results, and clearly what you could take away from that data is that raising the hemoglobin didn’t increase the pain. That you could definitely say from the drug.

Peter Salgo, MD: But you’re telling me it actually might have decreased the pain.

Elliot Vichinsky, MD: Yes. I think because there was more drug; in that study it clearly demonstrated it doesn’t cause more pain, and it suggests that pain rates would down. But you need a long term study.

Peter Salgo, MD: But that’s the answer I was looking for. Because if you look at this from a cardiologic perspective in patients without sickle cell, hemoglobins at 8 are great. We’re not transfusing until hemoglobin is a 7. All comers, without red cell pathology.

Elliot Vichinsky, MD: They’re not the same disease as when you look at hemoglobinopathies. For instance, in thalassemia, it really isn’t the number, it’s what the body has to do to maintain that number. If you have a hypermetabolic, basil metabolic rate, or you have ineffective erythropoiesis, so your bones are becoming it, or other issues. So, it isn’t just anemia that is the motivating factor.

Sophie Lanzkron, MD, MHS: And the data you’re talking about is sort of in the acute setting, right, not just choosing people over 7? This is chronic anemia.

Peter Salgo, MD: Let’s put a cap on this. If I saw somebody coming in with a hemoglobin of 8, I would look for the cause, and I wouldn’t automatically transfuse. This is a different problem, is what you’re saying. You’ve got data that showed if you get a better hematocrit, there’s less pain, and probably hemolysis.

Elliot Vichinsky, MD: It’s because the cells break apart and the hemolytic proteins and breakdown products actually upregulate everything else.

Peter Salgo, MD: Got it.

Elliot Vichinsky, MD: So, it isn’t just that your tank is at 8.

Sophie Lanzkron, MD, MHS: It’s not the numbers.

Elliot Vichinsky, MD: The downside is that those cells are falling apart.

Peter Salgo, MD: I love what you just said about this, it’s not the numbers.

Jane Hankins, MD, MS: It’s not the number. It’s what makes the number, right? It’s the quality of the hemoglobin that is making the number higher.

Peter Salgo, MD: Let me understand that are you actually telling me you have to look at your patient?

Jane Hankins, MD, MS: Yes.

Peter Salgo, MD: And globally estimate what your patient is doing?

Jane Hankins, MD, MS: Yes, we do.

Sophie Lanzkron, MD, MHS: Time to decrease the free hemoglobin, right? It’s one of the key things that we want to try and do, which is decreasing the hemolysis.

Biree Andemariam, MD: I agree. And I think as more people start to use voxelotor, I think it’s incumbent among all of us as experts to remind everyone what we’ve been saying here, is that this is not a drug to be used solely for the purpose to raise the hemoglobin but to decrease hemolysis.

Peter Salgo, MD: Got it.

Biree Andemariam, MD: And if you understand that, then you’ll understand the utility.

Transcript edited for clarity.