Prevention of Acute Sickle Cell Crisis: Review of the NEJM Report
A recent article in the New England Journal of Medicine, presented the results of a phase 2 clinical trial that found positive results for the efficacy and safety of crizanlizumab, a novel pharmaceutical agent currently in pipeline development by Selexys Pharmaceuticals.
The drug, designed to block the underlying mechanism of acute painful crisis in patients suffering from sickle-cell disease, could be one of the first and most effective medications of its kind. For all the details on the Phase 2 research, read the original Practical Pain Management report.
In this commentary, Leonard B. Goldstein, DDS, PhD, and colleagues review the research and provide their own opinion on the prospect of a novel pharmaceutical agents for patients suffering from sickle cell disease.
Sickle-Cell Disease: Painful Crisis
Acute painful crisis (APC) in sickle cell disease (SCD) is an abrupt onset of pain, which in severe cases requires hospitalization and treatment with opioid analgesics. APC is thought to be a “clinical consequence of sickle hemoglobin containing red blood cells becoming trapped in the microcirculation, leading sequentially to ischemia, infarction, reperfusion, and inflammation.”1
The vaso-occlusive crisis, which is a major cause of morbidity and mortality in SCD patients, could eventually lead to multiorgan damage in the long term.2 Endothelial cell P-selectin, a member of the selectin family of cell adhesion molecules, plays a key role in leukocyte recruitment, as well as the adhesion of sickle red blood cells (RBCs) to the endothelium.3-5 During inflammatory processes, the release of P-selectin is thought to be what initiates leukocyte adhesion to the endothelium and starts the progression of further adhesion involving sickle erythrocytes and platelets.6
Expression levels of P-selectin are elevated in patients with SCD.7 The interactions between P-selectin and its ligands are likely to contribute to cell adhesion between multiple types of cells, which results in the impairment of microvascular circulation involved in the development of painful vaso-occlusive episodes.8 In studies involving sickle cell diseased transgenic mice who were either deficient in P-selectin (and E-selectin) or where the secretion of P-selectin was inhibited, there were fewer vaso-occlusive events.
Crizanlizumab’s mechanism of action blocks P-selectin from its ligand.6 In this recent Phase 2 trial of crizanlizumab, the study resulted in a “significantly lower rate of sickle-cell related pain crises than placebo, and was associated with a lower incidence of adverse effects,” according to the authors.6
This published multi-center, randomized double-blind, placebo-controlled study shows great promise for the use of crizanlizumab with or without the use of hydroxyurea therapy for SCD. Participants in the trial received at least 12 of the 14 doses of IV crizanlizumab or placebo over the course of 52 weeks. The study results presented a 45.3% lower rate of sickle cell-related pain crises in the group receiving high-dose crizanlizumab versus placebo (and 32.6% lower rate in the low-dose group versus placebo).
Additionally, the time to first and second crisis was longer in the high-dose group (with results apparent within 2 weeks of starting treatment). In regards to safety, 55 patients experienced serious adverse events (17/67 receiving high-dose, 21/66 low-dose, and 17/65 placebo). Five patients died, with 2 in the high-dose group due to acute chest syndrome and endocarditis with sepsis.6
Research trials must continue to evaluate the long term use of crizanlizumab, and its possible resultant development of antibodies in SCD patients which could limit the long term effectiveness. This study has shown the short-term effectiveness and safety in the use of crizanlizumab for use against the adhesion molecule P-selectin and for a decrease in sickle-cell related pain crisis.