Safety Profile of Crizanlizumab 5.0 Mg/Kg in Sickle Cell Disease: Pooled Data from Clinical Trials

Abstract

Introduction: Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin and blocks its interaction with its ligands, including P-selectin glycoprotein ligand 1. It is approved to reduce the frequency of or prevent recurrent vaso-occlusive crises (VOCs) in patients aged ≥16 years with sickle cell disease (SCD). This pooled analysis assesses the safety of the recommended dosage of crizanlizumab (5.0 mg/kg monthly) in treated patients. Methods: Safety was assessed based on two clinical program data pools. Pool 1 comprised data from the crizanlizumab-treated groups from 3 Phase 2 studies (SUSTAIN [NCT01895361], SOLACE-adults [NCT03264989], and the pediatric SOLACE-Kids [NCT03474965]) and 1 Phase 3 study (STAND [NCT03814746]) in patients with SCD, with a history of VOCs leading to a healthcare visit. Pool 2 included data from the SUSTAIN and STAND treatment groups and the corresponding placebo group. Adverse events (AEs) were summarized by preferred term /system organ class and seriousness/severity per MedDRA version 23.1, with severity assessed based on CTCAE v5. Based on both its mechanism of action and the fact that crizanlizumab is a mAb, AEs of special interest (AESIs) included infections, infusion-related reactions (IRRs, events typically occurring within 24 hours of the recent crizanlizumab infusion), effects on hemostasis, and immunogenicity (antidrug antibodies [ADAs]). Pooled incidences of treatment-related AEs (TRAEs), suspected to be related to study treatment, were also evaluated. Results: In Pool 1, 245 patients received crizanlizumab 5.0 mg/kg (median age: 24 years [range,12-65]; 54.3% female), with 66.1% having 1 to 4 VOCs and 33.1% having ≥5 VOCs (VOC data were missing for 0.8% patients) at baseline. Pool 2 had 150 patients in the 5.0 mg/kg treatment group (median age: 27 years [range, 12-64]) and 147 patients in the placebo group (median age: 26 years [range, 12-68]). Median crizanlizumab exposure was 87.4 weeks (range, 2-228) in Pool 1, 54.1 weeks (range, 51.9-93.9) in Pool 2 treatment group and 53.3 weeks (range: 50.3-86.0) in the Pool 2 placebo group. The use of crizanlizumab in combination with hydroxyurea/hydroxycarbamide did not result in meaningful differences in safety profile. Most frequently reported AE in Pool 1 were headache (25.7%), pyrexia (22.9%), arthralgia (18.4%), nausea (16.7%), and COVID-19 (15.9%). In Pool 2 (treatment group vs. placebo), the most common AEs were headache (21.3% vs. 17.7%), pyrexia (19.3% vs. 17.7%), and nausea (17.3% vs. 10.2%). Infection events were observed in 62.4% and 56.7% of patients in the Pool 1 and 2 treatment groups, respectively, and in 55.1% in the placebo group (Table 1). The most common infections in Pool 1 were COVID-19 (15.9%), upper respiratory tract infections (12.7%), and urinary tract infections (11.8%). No increased risk or severity of infection was found in patients treated with crizanlizumab. IRRs occurred in 38.8% of Pool 1, 36.7% of the Pool 2 treatment group, and 27.9% of the placebo group. Most common IRRs were headache and nausea (Table 1). IRRs with grade ≥3 occurred in 3.3% of patients in Pool 1, with no grade 4 or 5 events. Bleeding-related events were observed in 16.7% of Pool 1 patients; epistaxis (3.7%) was the most reported. Treatment-induced ADA were reported in 0.8% (n=2) of patients in Pool 1, confirming the low immunogenic potential of crizanlizumab. TRAEs were observed in 31.8% patients in Pool 1, 34.7% in the Pool 2 treatment group, and 24.5% in the placebo group. Among the patients in Pool 1, 10 (4.1%) experienced grade 3 or higher TRAEs. The most reported TRAEs are listed in Table 1. Treatment-related serious AEs occurred in 10 patients (4.1%), with 7 (2.9%) experiencing ≥ grade 3 AEs in Pool 1. Treatment discontinuation due to AEs occurred in 3.3% of patients in Pool 1, 2.7% in the Pool 2 treatment group, and 3.4% in the placebo group. Five on-treatment deaths were reported across the four studies and were considered not related to crizanlizumab by the investigator (myocardial infarction, multiple organ dysfunction, endocarditis, meningitis bacterial, and sepsis [1 patient each]). Conclusion: This pooled analysis of crizanlizumab 5.0 mg/kg in patients with SCD and a history of VOCs showed that crizanlizumab was well tolerated, with a favorable safety profile. Most AEs were mild to moderate, and the discontinuations due to AEs were infrequent. No new safety concerns were identified.