SUMMARY: The FDA on November 15, 2019 approved ADAKVEO® (Crizanlizumab-tmca), a treatment to reduce the frequency of vaso-occlusive crisis, for patients age 16 years and older. Vaso-occlusive crisis is a common and painful complication of Sickle Cell Disease (SCD), that occurs when blood circulation is obstructed by sickled red blood cells. Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the United States is approximately 40-60 years.
HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (vaso-occlusive crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 thalassemia (double heterozygote for HbS and b-0 thalassemia) is clinically indistinguishable from HbSS disease.
P-Selectin is a Cell Adhesion Molecule (CAM) expressed on the surfaces of activated vascular endothelial cells and platelets. In unactivated endothelial cells and platelets, it is stored in Weibel-Palade bodies and alpha granules respectively. P-Selectin is released from endothelial cells and platelets when activated by inflammation or trauma and mediates the binding of erythrocytes and leukocytes to the vessel wall. In patients with Sickle Cell Disease (SCD), adherent masses of sickled red cells and leukocytes contribute to vaso-occlusive pain crises. ADAKVEO® is a first-in-class humanized anti-P-Selectin antibody, and the SUSTAIN study evaluated the safety and efficacy of ADAKVEO® on the frequency of Sickle Cell-related Pain Crises (SCPC) in Sickle Cell Disease patients.
The present FDA approval of ADAKVEO® was based on SUSTAIN, a multicenter, randomized, placebo controlled, double-blind clinical trial in which 198 Sickle Cell Disease patients with a history of vaso-occlusive crisis, were randomly assigned to receive ADAKVEO® at doses of 5 mg/kg, 2.5 mg/kg, or placebo, administered intravenously, 14 times over 52 weeks. Treatment groups were well balanced and patients receiving Hydroxyurea or Erythropoietin were included, if prescribed for the preceding 6 months and dose was stable for at least 3 months. The Primary end point was Sickle Cell-related Pain Crises (SCPC), defined as acute sickle cell-related pain that resulted in a visit to a medical facility and required a parenteral or oral narcotic or parenteral NSAID. Acute Chest Syndrome (ACS), priapism, hepatic and splenic sequestration were also included in this definition.
Treatment with ADAKVEO® experienced fewer health care visits for vaso-occlusive crisis annually and significantly lowered the median annual rate of vaso-occlusive crisis by 45% from 2.98 visits to 1.63 visits, compared with placebo. Reductions in the frequency of vaso-occlusive crisis were observed among patients regardless of Sickle Cell Disease genotype and/or Hydroxyurea use. More than one third (36%) of patients who received ADAKVEO® did not experience vaso-occlusive crisis during the study, compared with 17% of placebo-treated patients. ADAKVEO® delayed the time that patients first experienced vaso-occlusive crisis after starting treatment from a median of 1.4 months to 4.1 months. Common side effects associated with ADAKVEO® included back pain, nausea, fever and arthralgia. Patients should be monitored for infusion-related reactions and treatment should be discontinued for severe reactions. Patients should also be monitored for interference with automated platelet counts or platelet clumping and it is advised that CBC be performed using citrate tubes to avoid platelet activation.
It was concluded that ADAKVEO® significantly reduced Sickle Cell-related Pain Crises (SCPC) and increased the time to first and second SCPC. The authors added that chronic inhibition of P-Selectin with once a month IV dosing of ADAKVEO® represents a novel and potentially new disease-modifying, prophylactic treatment option for patients with Sickle Cell Disease. SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises. Ataga KI, Kutlar A, Kanter J, et al. N Engl J Med 2017; 376:429-439