Clinical Implications of Voxelotor in SCD Treatment


John J. Strouse, MD, PhD, and Sophie M. Lanzkron, MD, MHS, discuss the real-world significance of voxelotor for the treatment of sickle cell disease.


John J. Strouse, MD, PhD: Dr Lebensburger talked about the results of the HOPE trial, the study that led to the approval of voxelotor. We also have some real-world experience with voxelotor. [Nirmish] Shah, [MD,] in his 2 abstracts they presented in 2020 at the American Society of Hematology meeting, did go over some of this real-world evidence. In the first abstract, they included a total of 60 patients from 5 centers who had been started on voxelotor. Of these 60 patients, 27 patients had longer-term follow-up data, including a hemoglobin level before and at least a month after starting the medication. They were all on the medication for at least a month with a mean duration of treatment of 6 months. In these patients who had a mean age of 33 years, most of the patients could tolerate the 1500-mg dose, but 15% of them required dose reduction to 1000 mg a day, and that was mostly for GI [gastrointestinal] symptoms. In these 27 patients, the hemoglobin increased by 1 g/dL deciliter or greater at 1 month in 52% of the patients, and in 44% at 3 months. Three patients discontinued the medication because of adverse effects. This tells us that in general clinical practice, people can take this medication. A small but significant number do require some dose reduction because of the adverse effects. We see similar increases in hemoglobin in this group as we saw in the clinical trials.

Dr Shah and colleagues also looked at a Symphony Health claims database, where they identified 1275 people treated with voxelotor, of which 56% had received hydroxyurea in the past year, 10% had received L-glutamine, and 13% had at least 1 transfusion in the last year. That just tells you that the people being started on voxelotor have received other disease-modifying therapies. We know from the clinical trials that a large proportion of patients who are on voxelotor are also receiving hydroxyurea at the same time. Of those 1275 people, 52 had available pre- and post-hemoglobin values, with a mean hemoglobin increase, the average of values while on voxelotor, of 1.1 g/dL, and 55% had a mean hemoglobin increase of 1 g/dL or greater while on voxelotor. We’re seeing similar changes in people’s hemoglobin. They were able to look at the transfusion rate before and after starting on voxelotor, and they showed a small, but statistically significant decrease in transfusion rate from an average of 0.45 per person per year to 0.31 per person per year in the entire group of 1275 people. In the clinical trial, which was a shorter duration with fewer people, they did not show a decrease in transfusion, but you would hope that an agent that we know increases hemoglobin well would be able to decrease the need for transfusion. They did show us a definite decrease in transfusions, though it was a little more modest than I expected, with that reduction being about 20%. They also showed a modest decreased frequency of vaso-occlusive events that required medical attention, from 3.86 to 3.64 a year. But this change was not statistically significant. Much like they showed in the clinical trial, they weren’t able to show a significant decrease in acute vaso-occlusive events in people with sickle cell disease.

A question that I think remains to be completely answered is, what’s the effect of hemolysis and anemia on these complications? These 2 abstracts support that by decreasing anemia in people with sickle cell disease, we may be able to decrease their need for transfusion. This is important because some people with sickle cell disease are very difficult to transfuse. They may have alloimmunization to minor blood groups and minor red blood cell antigens to make it hard to find compatible blood. They may have had transfusion reactions, such as delayed hemolytic transfusion reactions that can trigger sickle-cell pain and worsening anemia and be life-threatening, or they may have a religious objection to blood transfusions. It’s good to be able to have other therapies that can raise people’s hemoglobin and decrease their need for transfusion. As far as the effects of hemolysis on acute vaso-occlusion and acute sickle-cell events, I think that these 2 abstracts show small reductions but not statistically significant reductions in the frequency of acute vaso-occlusion in people with sickle cell disease. We cannot say that voxelotor decreases acute vaso-occlusive events, but it is having an impact on anemia and has an effect on the need for red blood cell transfusion.

Sophie M. Lanzkron, MD, MHS: The paper by [Paul] Telfer, [MD,] that looked at markers of hemolysis demonstrated that those markers decreased for people who are on voxelotor. Binding or increasing the oxygen affinity and decreasing the risk of sickling makes sense that you would therefore have a decrease in markers of hemolysis.

The presumed mechanism of the drug was that if the hemoglobin is holding onto oxygen longer, you’ll have less hemolysis, and hemolysis is measured by bilirubin and an increase in hemoglobin and a decrease in reticulocyte count. If you can decrease hemolysis, then the downstream effects of having all that hemolysis should go away. The less hemolysis you’re having, the less free hemoglobin that you have present in the vascular space, the less nitric oxide consumption you end up having. Lots of the downstream effects that we think we see with sickle cell disease, like potentially pulmonary hypertension or renal disease, which we think are potentially driven by the presence of free hemoglobin in the circulation, should decrease with the use of voxelotor because it decreases hemolysis.

Transcript edited for clarity.

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