MOA of Voxelotor and the Effect of Oxygen on Brain Tissue

Peter Salgo, MD: Now, let’s take the other drug I think you were referring to, which is going to be voxelotor. There’s a HOPE trial. It’s in phase 3. What is that drug? What does it do? What’s its mechanism of action?

Elliot Vichinsky, MD: Well, this is a drug that was built on 40 years of other drug attempts. In other words, one of the first drugs that was used in sickle cell was cyanate. That was another drug that at the time in the 1970s we’d say we’ve cured sickle cell disease with cyanate. And these drugs are in a category, or what they do is they increase the oxygen within the cell by shifting oxygen affinity, so that the sickle molecules don’t sickle inside, and they stay.

And so, 1 of the problems is the protein inside the cell really starts sickling when the oxygen goes down. What this drug particularly does is it increases the oxygen to stay in the cell by altering oxygen affinity. And therefore, there’s less sickling in the cell and therefore, the cells don’t fall apart as early and the downstream effects. And the data they’ve done with this drug is 1) the hemoglobin, the anemia gets significantly elevated in the majority of patients, and the markers of hemolysis go down, including reticulocyte count, bilirubin, LDH [lactate dehydrogenase], and even erythropoietin. They’re definitely making healthier cells, so when you look at it under the microscope, the deformability and other factors are much better. It clearly will raise the hemoglobin and make healthier cells.

Peter Salgo, MD: Allow me to play devil’s advocate. I can make cells never sickle if they never offload oxygen ever. They hold on to every molecule. They never give it to where it has to go, to the brain, to the heart, to the kidney, but that’s not doing the body any good.

Jane Hankins, MD, MS: Yes. I think this drug, what it does, it modifies about 30% of the hemoglobin.

Peter Salgo, MD: It shifts the curve.

Jane Hankins, MD, MS: It shifts the curve in about 30%, and then it doesn’t on 70%. So, you have a mix. You end up delivering enough oxygen to the tissues. I think you’re alluding to if I shift every single hemoglobin in the body to the left, then there’s no oxygen delivery, right?

Peter Salgo, MD: Right. I was being deliberately provocative.

Elliot Vichinsky, MD: Well, a lot of the drugs are coming out using this model, and some of the other drugs coming out really alter, PK [pyruvate kinase] stimulators, a whole bunch of other drugs do these things, too. But basically, the way hemoglobin F [fetal hemoglobin] works is by altering the oxygen affinity. It’s the same mechanism.

I was part of these trials in terms of involvement, they have been piloting and looking at changes in the transcranial Doppler to see if that flow gets better. And recently they’ve had a pilot abstract on looking at brain perfusion, as well as histologically in the murine sickle mouse model. So far, the data are quite supportive of the fact that clearly there is not decreased brain oxygenation on imaging.

Peter Salgo, MD: Because that would concern me.

So, if you had to put voxelotor into some sort of clinical model, how would you anticipate using this? Clinically? Do you add it to hydroxyurea? You don’t take away hydroxyurea? And when do you add it? Does everybody get it? How do you this?

Jane Hankins, MD, MS: A college fund. I would say, if I can save more money, if I can keep those bricks, by the time you’re 45, I’ll go for it. I would never, at this point, there are not enough data to say you should substitute crizanlizumab or voxelotor for hydroxyurea. I don’t think that is the case.

Elliot Vichinsky, MD: I agree with you. The exciting thing from a clinician scientist is, and someone who does oncology, you have multiple drugs that are somewhat complementary to each other. And so, 1 is raising the hemoglobin of healthy cells significantly, and the other 1 is lowering pain events. And if you had AML [acute myeloid leukemia] or leukemia, the cancer groups would target them with chronic medications and with periodic medications aiming at different cell cycles. So frankly, sickle cell is a complex disease. My gut feeling is it would benefit from intelligent trials that look at synergistic use of multi medications.

Jane Hankins, MD, MS: It works in HIV, right? HIV is a chronic disease today. Why? Polytherapy, right? Different mechanisms of action.

Biree Andemariam, MD: Getting to your question about the second silo, which is chronic organ damage, I think, for me, the mechanism of action of voxelotor suggests that there could be a long-term effect on protection of organ function, just based on its antihemolytic property.

But when you ask who I would start it on, and forward thinking, I think for me as an adult hematologist, I see a lot of profound anemia, probably due to a number of things—marrow burnout, kidney disease. And for me, I have a sizable population, I think a lot of adult practitioners do, of severely anemic patients who you don’t want to transfuse or already aren’t overloaded with lots of antibodies. And so that’s a natural starting point. Again, I agree on top of hydroxyurea.

Transcript edited for clarity.