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Crizanlizumab reduces sickle cell–related pain crises
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SAN DIEGO — The anti–P-selectin antibody crizanlizumab significantly reduced frequency of pain crises compared with placebo in adolescents and adults with sickle cell disease, according to results of the randomized, placebo-controlled phase 2 SUSTAIN study presented at the ASH Annual Meeting and Exposition.
Crizanlizumab (SEG101) — manufactured by Selexys Pharmaceuticals, which Novartis acquired in November — also significantly extended time to first and second sickle cell–related pain crises.
“This study did not look at survival per se, but we know pain crises contribute to decreased quality of life and also contribute to increased morbidity in patients with sickle cell disease,” Kenneth I. Ataga, MD, professor of medicine and director of the comprehensive sickle cell program at University of North Carolina at Chapel Hill, told HemOnc Today. “However, my assumption is ... ultimately we may find a drug like this could actually improve survival.”
Daily hydroxyurea — the only FDA–approved treatment for sickle cell disease complications — can decrease frequency of acute pain crises. However, these episodes — the primary cause for health care encounters in this patient population — still occur.
In addition, there is no alternative for patients who cannot tolerate hydroxyurea, those who are reluctant to take it and those for whom the agent is ineffective.
Upregulation of P-selectin — an adhesion molecule expressed on activated vascular endothelial cells and platelets — contributes to cell–cell interactions involved in the pathogenesis of sickle cell–related pain crises.
In the multicenter, double blind SUSTAIN study, Ataga and colleagues evaluated the safety of crizanlizumab, a first-in-class humanized P-selectin inhibitor administered once monthly via IV. They also assessed whether the agent reduced the frequency of sickle cell–related pain crises.
The analysis included 198 patients aged 16 to 65 years with confirmed diagnosis of sickle cell disease and a history of two to 10 sickle cell–related pain crises in the prior 12 months. Patients who were undergoing treatment with hydroxyurea or erythropoietin were eligible if the agents were prescribed for the preceding 6 months and doses had been stable for at least 3 months.
Ataga and colleagues randomly assigned participants to 14 doses of placebo (n = 65), 2.5 mg/kg crizanlizumab (n = 66), or 5 mg/kg crizanlizumab (n = 67). Patients received an initial dose, followed by another dose 14 days later, then every 4 weeks through week 50.
Demographics were balanced between groups.
Researchers stratified randomization by historical sickle cell–related pain crises in the prior year (two to four vs. five to 10) and concomitant hydroxyurea use.
Annual rate of sickle cell–related pain crises among patients assigned the 5-mg/kg dose vs. those assigned placebo served as the primary efficacy endpoint.
Researchers defined sickle cell–related pain crises as acute sickle cell–related pain that resulted in a visit to a medical facility, and that required an oral or parenteral narcotic or parenteral NSAID. Acute chest syndrome, hepatic and splenic sequestration, and priapism also were included.
A blinded, independent committee adjudicated all pain crises.
Secondary endpoints included annual rate of days hospitalized, time to first and second sickle cell–related pain crises, annual rate of acute chest syndrome and annual rate of uncomplicated pain crises.
The intent-to-treat population included all randomly assigned patients.
Use of crizanlizumab at 5 mg/kg reduced sickle cell–related pain crises by 45.3% compared with placebo (median, 1.63 vs. 2.98; P = .01). Use of crizanlizumab at 2.5 mg/kg reduced sickle cell–related pain crises by 32.6% compared with placebo (median, 2.01 vs. 2.98), although the difference was not statistically significant.
Twenty-four patients assigned the 5-mg/kg dose of crizanlizumab had a sickle cell–related pain crisis rate of 0 at the end of the study, compared with 12 patients assigned the 2.5-mg/kg dose and 11 patients assigned placebo.
The 5-mg/kg dose significantly extended median time to first pain crisis (4.07 months vs. 1.38 months; P = .001) and median time to second pain crisis (10.32 months vs. 5.09 months; P = .022). The 2.5-mg/kg dose also extended median time to first and second crises, but the differences were not statistically significant.
The 5-mg/kg dose significantly reduced the annual rate of uncomplicated sickle cell–related pain crises compared with placebo (median, 1.1 vs. 2.9; P = .015). The higher dose also was associated with a lower annual rate of days hospitalized compared with placebo (median, 4 vs. 6.9), but the difference was not statistically significant.
Overall, crizanlizumab appeared well tolerated, Ataga said.
Researchers reported a low rate of acute chest syndrome incidence during the study period.
Adverse events that occurred in at least 5% of patients assigned an active dose and occurred at rates at least twice as high in a treatment group compared with the placebo group included arthralgia, vomiting, pruritus, chest pain, fatigue, diarrhea, myalgia, musculoskeletal chest pain, abdominal pain, influenza and oropharyngeal pain.
Crizanlizumab treatment did not appear to increase infection incidence.
Five patients died during the study period — two assigned the 5-mg/kg dose, one assigned the 2.5-mg/kg dose, and two assigned placebo — but no deaths were considered related to crizanlizumab treatment.
Ataga said he believes crizanlizumab “will make a significant difference in patients’ lives.”
Additional studies are needed to assess the agent in younger children with sickle cell disease.
“Children younger than 16 years of age also have painful crises but the pathophysiology is the same, so there is no reason in my mind to think it would not work,” Ataga told HemOnc Today. – by Mark Leiser
Reference: Ataga KI, et al. Abstract 1. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: The researchers report research funding from and consultant roles with Novartis, as well as equity ownership in and previous employment with Selexys Pharmaceuticals.
Perspective
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Gregory M. Vercellotti, MD, FACP
The basis of the SUSTAIN study is that inflammation plays a critical role in vaso-occlusion in sickle cell disease. Proinflammatory molecules increase the adhesion of sickle red blood cells, white cells and platelets to vascular endothelium, leading to occlusion of blood vessels. The occlusion of blood vessels is the basis of vaso-occlusion and pain crises. Targeting specific molecules that enhance the adhesion of these blood cells is the primary focus of this trial.Researchers targeted the P-selectin molecule, which is rapidly upregulated on endothelial cells, as well as on platelets. A variety of basic science studies throughout the years have focused on how P-selectin upregulation can promote the adherence of red cells, white cells and platelets. Now we have a drug that can target P-selectin selectively, and hopefully minimize vascular occlusion in sickle cell disease.
Hydroxyurea is the only FDA–approved drug for sickle cell disease to minimize crises, minimize stroke and prolong life. Hydroxyurea — an absolutely wonderful discovery — increases hemoglobin F and other effects on the inflammation of vasculature. It clearly has had such an impact on the quality of life of sickle cell patients. However, we need to do something more; it’s not just enough to use hydroxyurea, because we still have the unrelenting hemolysis and oxidative stress that is leading to inflammation in the blood vessels.
An antibody to P-selectin was given monthly to sickle cell patients for approximately 1 year. At the end of that year, the investigators examined how frequently patients were admitted to the hospital, the duration between crises, and whether overall patients had fewer crises and complications. Remarkably, the changes were significant.
This is important because it verifies the basic research that has been done to try to understand the path of physiology, which is now coming to fruition with agents that can alter patients’ lives. I’m not sure if the cost of this drug will be so prohibitive that we won’t be able to utilize it; however, hopefully that won’t be true. This is the first study using a very specific selectin inhibitor that shows an impressive decrease in painful crises and improvement in quality of life. This research could change the lives of thousands of patients with sickle cell anemia.
Perspective
Back to TopKim Smith-Whitley, MD
Hydroxyurea is a great medication. It is wonderful that we have an agent that can reduce pain, reduce acute chest syndrome and reduce the need for transfusion therapy. One of the big challenges with hydroxyurea is, even though we had great FDA–supported trials for adults, we really had to grandfather its use for pediatrics, and also for those without hemoglobin SS or hemoglobin S beta plus, which is 25% to 30% of the patient population.
We understand more about the underlying pathophysiology of sickle cell disease now than we did 40 years ago. We understand it’s not just the red cells that play a role. We know the endothelium plays a role, there is platelet involvement and there is white cell involvement. If you take the red cell as the target, hydroxyurea increases fetal hemoglobin within the erythrocyte. If you add another approach that targets the endothelium or the white cells, then you are giving multidrug therapy for those with sickle cell disease, which is wonderful.
Individuals who receive hydroxyurea are primarily those with SS and S beta 0 types of sickle cell disease. This study included those individuals regardless of whether they were on hydroxyurea, as long as they were on a consistent dose. That is important because, despite the fact their pain may be decreased on hydroxyurea, it is not nonexistent.
The second plus of the study design was that it included patients with hemoglobin SC and hemoglobin S beta plus right from the start. They looked at the role of this agent in individuals with sickle cell disease who have not had an FDA–approved targeted therapy. To tease down the results of pain reduction in those individuals will be very important going forward. Hydroxyurea in patients with the SC type of sickle cell disease has been shown in some cases to increase pain episodes, and in some pediatric studies, it showed has shown some reduction but it has not been sustained over time. We really are looking at a subpopulation that does not have a targeted therapy, so this is really exciting to see.
The other thing that will be interesting to see is that adherence to hydroxyurea therapy is a challenge. It has to be taken once a day. To have an agent that can be administered once a month is promising. Based on the safety profile, if it is feasible, imagine what it could mean for those who live long distances from the hospital. If this medication can be administered by a home care agency or someone goes to another local medical setting to get this drug once a month, that means they are touching base with a health care provider frequently. With a chronic illness, that is a plus. You’re also getting improved adherence because it’s not something they have to receive on a daily basis.
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