Treatment Goals and Role of New Therapies for SCD



Alan Anderson, MD: Regarding sickle cell disease [SCD], the goal of therapy is to try to prevent the known end organ damage. SCD causes damage through polymerization of hemoglobin S [Hgb S] that leads to the shape change in the red blood cell. Ultimately, that shape change is going to cause changes in the health of the red blood cell, which causes increased blood viscosity, decreased deformability of the cell, and affect the way the cell carries oxygen. All those things are going to interplay with the other cell types within the system, for example, platelets and white blood cells, and increase the stickiness of the cells as they move through the blood vessels and interact with the receptors on the endothelial lining. As a result, the entire process consisting of the shape change of the red blood cells and the interaction of the multicellular aggregate within the blood cell ultimately leads to the blockade of oxygen in the flow of blood and oxygen to the end organ tissue. Of course, we know that’s what causes all the issues with SCD.

Our ultimate goal in treating individuals who are affected by sickle cell disease is to mitigate that pathway with whatever tools we have available. Over the past 30 years in treating SCD and up until a year ago, the main tool available to us was hydroxyurea. Hydroxyurea is inducing the bone marrow to make more fetal hemoglobin. With an increase in fetal hemoglobin due to hydroxyurea, most patients will have upward of 15% production of fetal hemoglobin. We get a modification of the amount of hemoglobin circulating in the body at any given time that can sickle, which leads to improvements or modification of the disease process. Overall, what’s been shown with hydroxyurea is improvements in fetal hemoglobin in addition to decrease in pain, VOC [vaso-occlusive crisis] events, length of stay, decrease in acute chest syndrome incidents, decrease in the TCD [transcranial Doppler] velocity, and stroke risk.

We know that there are improvements when we modify the number of cells that can sickle at any given time in our patients, which is where I see the introduction of novel therapies able to assist in that process. We’re excited about any therapies that can add to the modification of the disease. We are feeling that hydroxyurea is our foundational therapy. When we have an agent like Oxbryta [voxelotor], which can directly inhibit Hgb S polymerization by binding to hemoglobin, that’s an agent that can be taken by mouth, and can decrease even further, when taken in combination with hydroxyurea, the number of cells circulating that can sickle at any given time. Adakveo [crizanlizumab], which is out in the market right now, doesn’t affect Hgb S, but can mitigate the cascade of the pathophysiology of sickle cell disease by blocking the interaction of sickled red blood cells and other cell types with P-selectin on the endothelial lining. From there, hopefully it can decrease the stickiness of that cellular aggregate and help to promote more blood flow and thereby potentially decrease pain that our patients are experiencing.

Right now, I think we have some very good guidelines that are coming out of the American Society of Hematology and as well as the NHLBI [National Heart, Lung, and Blood Institute] that are promoting the modification of sickle cell disease across the spectrum. Historically, the guidelines have said hydroxyurea is a standard of care therapy for any patients with [hemoglobin] SS disease or S-beta-null [zero] thalassemia, and those with SC or S-beta+ thalassemia that are having significant issues regarding SCD end organ damage. With the novel therapies coming out, particularly Oxbryta, the indication is all types of SCD, so a broad indication for any genotype of individual who could benefit from improvement in the overall hemoglobin and the hemolysis parameters, which have also been shown to improve due to treatment with Oxbryta.

Overall, I think that’s a very broad indication that fits the guidelines we have, which is to try to use preventive health and modification whenever possible to limit the direct disease impact that our patients experience. Regarding Adakveo, the studies have shown direct improvement in pain. Therefore, if we have patients who are having more significant pain-related issues from their SCD, Adakveo is a novel therapy that can potentially benefit that subpopulation of patients.

Transcript Edited for Clarity

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