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.
Kenneth I. Ataga
“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.