Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease

Abstract

Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of the multiple pathophysiologic mechanisms leading to vaso-occlusion and tissue injury in SCD has now resulted in a burgeoning effort to identify new treatment modalities to prevent or ameliorate the consequences of the disease. Development of new drugs as well as investigation of drugs previously used in other settings have targeted cell adhesion, inflammatory pathways, upregulation of hemoglobin F, hemoglobin polymerization and sickling, coagulation, and platelet activation. Although these efforts have not yet yielded drugs ready for FDA approval, several early studies have been extremely encouraging. Moreover, the marked increase in clinical pharmaceutical research addressing SCD and the new and old drugs in the pipeline make it reasonable to expect that we will soon have new treatments for SCD.

Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli

“…Despite high efficacy, disease activity and mortality remain high in patients taking HU (1), with the life expectancy of SCD patients in the United States still estimated to be 20 years less than that of individuals without the disease (37). It is imperative to identify new treatments to prevent and better manage systemic vaso-occlusive pain crisis, to increase the quality and quantity of life for SCD patients (38). Based on our findings and the recent work of other investigators, targeting adhesion molecules on platelets and/or neutrophils to prevent or disintegrate neutrophil-platelet aggregates can be a promising therapy for SCD patients, particularly for the prevention of acute chest syndrome in high-risk patients presenting with systemic vaso-occlusive pain crisis.…”

Treating sickle cell disease by targeting HbS polymerization

“…100 A recent phase 1B dose-escalation study of 26 HbSS and HbS/b 0 -thalassemia patients found that SCD-101 was well tolerated and, at higher doses, it seemed to relieve chronic pain and fatigue but had no impact on Hb levels or hemolysis. 101 The review by Telen 3 lists only a single antisickling agent undergoing clinical trials that is known to directly modify Hb structure: 5-hydroxymethyl-furfural (Aes-103). This agent is an aldehyde that forms a reversible Schiff base linkage primarily with the N-terminal amino group of a-globin resulting in a dose-dependent increase in oxygen affinity.…”

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

“…In addition, sickle rbc are more adherent to the vascular endothelium than normal rbc (8), which may further contribute to VOC and hemolysis. Adhesive interactions lead to formation of heterocellular aggregates that obstruct blood flow to induce ischemic tissue damage, which leads to the prolonged exposure of rbc to deoxygenated conditions, promoting further HbS polymerization and hemolysis (9).…”