Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

Abstract

The cell adhesion molecule P‐selectin plays a key role in the pathogenesis of a vaso‐occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double‐blind, placebo‐controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti‐P‐selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2‐4/5‐10), SCD genotype (HbSS/non‐HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event‐free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5‐10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time‐to‐first VOC vs placebo in these subgroups. The rates of treatment‐emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event‐free and delays time‐to‐first VOC.

Antibodies to watch in 2020

“…FDA's approval was based on Phase 2 results from the SUSTAIN study (NCT01895361), which demonstrated that crizanlizumab provided significant benefit over placebo, such as: 1) the percentage of crizanlizumab-treated patients (5 mg/kg) who did not experience any vaso-occlusive crisis (VOC) was higher compared to those treated with placebo (36% vs 17%, P = .010); 2) 45% reduction in the median annual rate of VOCs leading to health care visits in patients with or without hydroxyurea therapy compared to placebo (1.63 vs 2.98, P = .010); 3) 42% reduction in median annual rate of days hospitalized versus placebo (4.00 vs 6.87 P = .45), and 4) a 3-fold longer median time to first VOC vs placebo (4.07 vs 1.38 months, P < .001). 27,28 Antibody therapeutics approved outside the US or EU in 2019…”

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

“…The SENTRY clinical trials program funded by Novartis Pharmaceuticals includes the SUSTAIN trial, one of several studies assessing the use of crizanlizumab in persons with SCD. There are seven planned or active trials; major active trials currently include SUSTAIN, SOLACE‐adults, SOLACE‐kids, STAND, and SUCCESSOR . A phase II trial (NCT01895361), known as the SUSTAIN trial (198 subjects), was conducted in 2016 to determine the safety and efficacy of crizanlizumab for the prevention of pain crises in SCD over 52 weeks.…”

“…The authors concluded that crizanlizumab resulted in a significant reduction in sickle cell pain crisis with a low incidence of adverse events when compared with placebo. A post hoc analysis of three subgroups (VOC in the year before study entry; stratification based on SCD genotype; and concomitant hydroxyurea) in SUSTAIN patients who had not experienced VOC during the initial 52‐week study period found that the annual rate of VOC was lower in the crizanlizumab treatment group compared with placebo (1.04 vs 2.18, respectively; p=0.02) …”

“…There are seven planned or active trials; major active trials currently include SUSTAIN, SOLACE-adults, SOLACE-kids, STAND, and SUCCESSOR. [21][22][23][24][25] A phase II trial 22 (NCT01895361), known as the SUSTAIN trial (198 subjects), was conducted in 2016 to determine the safety and efficacy of crizanlizumab for the prevention of pain crises in SCD over 52 weeks. The median rate of VOC in patients receiving crizanlizumab 5 mg/kg was 1.6 compared with 3.0 in the placebo group (p=0.010).…”

“…A post hoc analysis of three subgroups (VOC in the year before study entry; stratification based on SCD genotype; and concomitant hydroxyurea) in SUSTAIN patients who had not experienced VOC during the initial 52-week study period found that the annual rate of VOC was lower in the crizanlizumab treatment group compared with placebo (1.04 vs 2.18, respectively; p=0.02). 21 SOLACE-kids is currently recruiting pediatric patients with SCD (NCT03474965) to assess the appropriate dose and safety of crizanlizumab. 23 This is a phase II interventional multicenter open-label study that was estimated to have primary results by April 2019.…”