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N Engl J Med. 2017 Feb 2;376(5):429-439. doi: 10.1056/NEJMoa1611770. Epub 2016 Dec 3.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.

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From the Division of Hematology-Oncology, University of North Carolina, Chapel Hill (K.I.A.), and the Division of Hematology-Oncology, East Carolina University, Greenville (D.L.) - both in North Carolina; the Sickle Cell Center, Medical College of Georgia, Augusta University, Augusta (A.K.); the Division of Pediatrics, Medical University of South Carolina, Charleston (J.K.); the Department of Hematology-Oncology, Santa Casa Medical School of São Paulo (R.C.), and the Division of Hematology, University of São Paulo (S.G.), São Paulo, the Hematology and Bone Marrow Transplantation Service, Hospital de Clínicas de Porto Alegre, Porto Alegre (J.F.), and the Hematology and Hemotherapy Center, University of Campinas, Campinas (M.P.C.) - all in Brazil; the Baptist Cancer Institute, Baptist Medical Center, Jacksonville, FL (T.H.G.); the Sickle Cell Unit, University of the West Indies, Mona, Jamaica (J.K.-M.); the Division of Pediatric Hematology-Oncology, University of Miami, Miami (O.A.A.); the Department of Medicine, University of Illinois at Chicago, Chicago (V.R.G.); the Division of General Internal Medicine, Virginia Commonwealth University Medical Center, Richmond (W.R.S.); and Selexys Pharmaceuticals, Oklahoma City (S.A.R., J.W.S., R.P.R.).



The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.


In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.


A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.


In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN number, NCT01895361 .).

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