Voxelotor and Crizanlizumab: Safety and Tolerability



Alan Anderson, MD: The initial 24-week data coming out of the phase 3 HOPE trial were what the accelerated approval of voxelotor was based upon. The data showed that 51% of the patients had greater than 1 g/dL rise in their hemoglobin from baseline to week 24 of therapy. At the same time, not only in those studies was the hemoglobin rising in those patients who were taking voxelotor, but there was also definite health improvement in the red blood cells. What the studies further showed is a decline in the indirect bilirubin and percent reticulocyte count as surrogate markers of the fact that the mechanism of action of the agent being inhibition of hemoglobin S polymerization was actually resulting in less sickling and therefore less destruction of red blood cells. This was manifested in both of those surrogate markers of hemolysis declining significantly compared to the placebo arm.

Regarding recent data from ASH [the American Society of Hematology annual meeting], there was a concern within the clinical realm of those of us taking care of individuals with sickle cell disease, that if the hemoglobin rises too high, there could be an issue related to increasing viscosity or decrease in the delivery of oxygen to the tissues. So it was exciting to see in the data presented at ASH that not only are there data from the HOPE trial that show improved oxygen affinity in response to voxelotor, but there were also data presented that show both improvements in blood viscosity and improvements in deformability of the cell in response to voxelotor. Additionally, there were 72-week data that look at the VOC [vaso-occlusive crises] incidence when compared with the rise in hemoglobin. That presented data showed that the higher the hemoglobin goes in response to voxelotor, the lower the overall VOC incidences that can occur in the patient.

Of course, that goes a long way to discourage any concern that as the hemoglobin rises that there would be a decrease in flow of blood to the microvasculature or end organ. You would expect the inverse to happen, where pain would increase as the hemoglobin rises if there was any issue with oxygen delivery. The studies showed that when you went from greater than 10, 10 to 12, and greater than 12 g/dL rises in hemoglobin, the VOC incidence continues to decline the higher the hemoglobin goes. Overall, I think those are very exciting follow-up data as presented at the ASH conference regarding voxelotor.

When we look at the new information coming out for crizanlizumab, we see that there are continued findings of improvement in overall pain, whether that pain is regarding time in the hospital or time of the first VOC in response to the infusion. We have seen in clinical practice that there are some patients who do have some joint-related issues related to the crizanlizumab infusion, with joint pain typically following relatively soon after infusion. That was updated by Novartis [AG]. There are some clinicians who are utilizing preventive therapies such as fluids and/or Tylenol and Benadryl around the infusion of crizanlizumab to mitigate those findings of joint pain. Overall, I believe the data reported at ASH seem to correlate with what had already been seen in the phase 3 trials regarding crizanlizumab and improvement in pain. I was very pleased with that.

Transcript Edited for Clarity

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