Inflammation represents an important potential treatment target for SCD. Investigational agents target various steps in inflammatory cascades, including nitric oxide and nitric oxide bioavailability, and recent publications describe how agents targeting nitric oxide affect the vascular endothelium pathway. However, targeting the endothelial pathway in vaso-occlusion remains very difficult because it is such a complicated pathway, with multiple components contributing to the adhesion and the inflammation that we see in SCD. Blocking just one branch in that pathway is not going to be sufficient.

The SUSTAIN study proves that blocking P-selectin can decrease vaso-occlusive crisis in individuals with SCD. While highly effective, some patients receiving crizanlizumab still continued to have pain crises, demonstrating that we may need to block multiple pathways at once.

Several agents that are currently under investigation for the treatment of SCD have produced promising results. For example, IMR-687, a novel phosphodiesterase 9 inhibitor, targets cyclic guanosine monophosphate. Data for IMR-687 presented at the 2021 European Hematology Association and American Society of Hematology conferences have shown the pharmacodynamics of IMR-687 as a monotherapy and in combination with hydroxyurea. Further, IMR-687 has demonstrated some signs of favorable effects on fetal hemoglobin and is now in phase 2 and 3 trials that, hopefully, will produce some clinically valuable data.

Arginine therapy also targets the nitric oxide/cyclic guanosine monophosphate pathway and is being evaluated in clinical trials. L-glutamine is also available and is used in SCD, and additional research is warranted. It is not fully understood precisely how L-glutamine works in red blood cells in SCD. The agent is only administered as a powder that has to be mixed in fluid and taken twice daily, which may be inconvenient for some patients. Those treated with L-glutamine have shown improvement, but a better vehicle for delivering the agent would be beneficial.

One of the major hurdles to identifying new treatments is the lack of optimal end points. Clinical trials of agents targeting the vascular endothelium use the number of pain episodes or vaso-occlusive crises as end points because there are very few biomarkers available to us in SCD. However, the vascular endothelium pathway is upstream of vaso-occlusive crises, which is caused by adhesion and occlusion as well as the subsequent ischemia and reperfusion. Thus, there are numerous different inputs that determine/cause pain. Better methods for measuring improvements in endothelial or vascular dysfunction could be truly beneficial. It is important to see the big picture—and that is how I train people to look at it. As trial methodology evolves, it is important to recognize that agents that are currently under investigation may be more efficacious than we realize if we begin to examine alternative end points. We simply need to figure out how to better measure the various impacts of treatment.