Results from the Phase 2 SUSTAIN clinical trial demonstrated that crizanlizumab (SEG101, Selexys Pharmaceuticals, Novartis), an anti-P-selectin antibody, reduced by 45.3% the median annual rate of sickle cell-related pain crises (SCPC), compared to placebo in patients with or without hydroxyurea therapy, a drug used to reduce the rate of painful attacks in sickle-cell disease (SCD). Crizanlizumab also significantly extended time to first and second SCPC, the researchers reported.
“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 the University of North Carolina at Chapel Hill, said in a press release. “However, my assumption is … ultimately we may find a drug like this could actually improve survival.”
SUSTAIN was a multicenter, multinational, randomized, placebo-controlled, double-blind, 12-month clinical trial (NCT01895361) that evaluated the safety and efficacy of crizanlizumab administrated once monthly with or without hydroxyurea therapy in 198 SCD patients with history of 2 to 10 sickle cell-related pain crises in the previous 12 months.
Patients under treatment with hydroxyurea or erythropoietin were qualified to participate in the trial if these agents were prescribed 6 months before the trial and if the doses had been stable for at least 3 months.
All patients were randomised to either 14 doses of placebo (65 patients), 2.5 mg/kg crizanlizumab (66 patients), or 5 mg/kg crizanlizumab (67 patients). Patients received an initial dose, followed by another dose 14 days later, then every four weeks through week 50.
The primary endpoint was the annual rate of sickle cell-related pain crises among patients assigned the 5-mg/kg dose compared to placebo. Secondary endpoints included the 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 results showed that treatment with crizanlizumab (5 mg/kg) reduced by 45.3% SCPC, compared to placebo. Patients treated with crizanlizumab at 2.5 mg/kg experienced a 32.6 reduction in SCPC, compared to those that received the placebo, however, this result was not statistically significant, the researchers reported.
At the end of the study, 24 patients taking crizanlizumab at 5-mg/kg had a rate of SCPC of 0, compared with 12 patients taking the 2.5-mg/kg dose and 11 patients taking the placebo drug.
Crizanlizumab at 5-mg/kg dose extended by 2.9 times the median time to first SCPC versus placebo (medians of 4.07 versus 1.38 months), and time to second SCPC was 2.0 times longer than placebo (medians of 10.32 versus 5.09 months). Patients taking that 2.5-mg/kg dose also had an extended median time to first and second crises, but again the differences were not statistically significant.
The 5-mg/kg dose significantly reduced the annual rate of uncomplicated SCPC compared with placebo (1.1 versus 2.9). The higher dose also was associated with a lower annual rate of days hospitalized compared with placebo (4 versus 6.9), but this difference was not statistically significant.
Overall, crizanlizumab was well-tolerated, with a low rate of acute chest syndrome incidence observed.
Adverse events that occurred in 5% or more of patients in an active dose group and were elevated over placebo by at least twofold included arthralgia, pruritus, vomiting, chest pain, diarrhea, road traffic accident, fatigue, myalgia, musculoskeletal chest pain, abdominal pain, influenza and oropharyngeal pain. Treatment with crizanlizumab did not increase the incidence of infections.
Five deaths occurred during the study period. However, these were considered not related with the treatment.
While more studies are necessary to evaluate crizanlizumab in younger children with SCD, Ataga predicts the agent “will make a significant difference in patients’ lives.”
“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,” he said.