Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

Abstract

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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 ClinicalTrials.gov number, NCT01895361.)

Sickle Cell Disease

“…In addition, a New Drug Application has been submitted to the Food and Drug Administration for an oral, pharmaceutical-grade l-glutamine treatment to reduce the frequency of acute pain and hospitalizations among patients with sickle cell disease. Also, a recent report on a multicenter, phase 2, randomized, placebo-controlled, double-blind study showed that a monoclonal antibody inhibiting P-selectin 92 reduced the frequency of acute pain in adults with sickle cell disease. This is an exciting result, given that hydroxyurea is still the only drug with established efficacy for this indication.…”

Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review

“…[56][57][58][59][60][61][62][63] Three studies did not use a placebo intervention for their control group. 43,54,56 A majority of studies were performed in North America (n 5 10), 33,46,47,51,61,62,[64][65][66][67][68] Africa (n 5 9), 38,42,52,55,56,59,[69][70][71] and Latin America (n 5 8).…”

“…40,44,48,49,53,54,57,72 Four studies were performed on multiple continents. 58,60,63,73 The number of patients per study ranged from 9 to 341. A majority of studies were limited to patients with the HbSS or HbSb 0 genotype (n 5 26).…”

“…Only 7 of the 35 studies scored an overall low risk of bias on all items in the quality assessment. [58][59][60]66,69,72,73 Fourteen studies scored a high risk of bias on at least 1 of the items of the quality assessment, in particular on incomplete outcome data (n 5 8) and blinding of participants (n 5 6) and personnel for intervention (n 5 6). 37,[43][44][45]48,49,51,54,56,63,64,70,71,74 Anticoagulation.…”

“…Ataga et al 58 performed an international trial assessing the effects of the monthly IV administration of high-dose and low-dose crizanlizumab (N 5 198), a monoclonal antibody binding the adhesion molecule P-selectin. 58 In this study, high-dose crizanlizumab compared with placebo resulted in a decrease in the annual rate of VOCs and uncomplicated VOCs and a longer time until first VOC (Table 1; supplemental Table 3). There was no significant reduction in the annual rate of hospital admission days.…”