Pharmacokinetics/Pharmacodynamics, Safety, and Efficacy of Crizanlizumab in Patients with Sickle Cell Disease Aged 6 to <12 Years: 2-Year Data from the Phase 2 Solace-Kids Study

Introduction: SOLACE-Kids is an ongoing phase 2, open-label study to assess dosing and evaluate the safety and efficacy of crizanlizumab in pediatric patients with sickle cell disease (SCD) (ClinicalTrials.gov: NCT03474965; EudraCT: 2017-001747-12). The initial data from the 2-year analysis of 50 patients with SCD aged 12 to <18 years showed that crizanlizumab 5.0 mg/kg was safe and well tolerated with clinically relevant reduction in the median annualized rate of vaso-occlusive crises (VOCs) compared with baseline (Heeney M et al. Hemasphere. 2023; S267). Here we report the first pharmacokinetic (PK), pharmacodynamic and safety data from 53 patients with SCD aged 6 to <12 years who received crizanlizumab 5.0 mg/kg (n=13) or 8.5 mg/kg (n=40) after all enrolled participants had completed or discontinued treatment at least in the first 26 weeks. Methods: Children with SCD (any genotype) and history of ≥1 VOC leading to a healthcare visit within 12 months before screening were enrolled and stratified by age: Group 1 (12 to <18 years), Group 2 (6 to <12 years), and Group 3 (2 to <6 years). Patients received crizanlizumab with or without hydroxyurea on Day 1, Day 15, and every 4 weeks up to 2 years. Results: As of March 02, 2023, 53 patients aged 6 to <12 years received crizanlizumab 5.0 mg/kg (n=13) or 8.5 mg/kg (n=40). In the 5.0 mg/kg group, 76.9% of patients completed treatment, while in the 8.5 mg/kg group, 27.5% completed and 62.5% were still undergoing treatment. Median exposures times in the 5.0 mg/kg and 8.5 mg/kg groups were 105.9 weeks and 34.8 weeks, respectively (difference due to sequential enrolment). Dose confirmation analyses showed that crizanlizumab 5.0 mg/kg resulted in 45% and 40% lower maximum serum concentrations (Cmax) and area under the curve (AUC), respectively, from time zero to the last measurable concentration after the first infusion (AUCd15), while the 8.5 mg/kg dose achieved 52% and 40% increase in Cmax and AUCd15, respectively, confirming its use for Group 2 patients. Mean AUCd15 and AUC after multiple doses at steady state (AUCtau) were 8180 and 14800 hr*μg/mL, respectively, in the 5.0 mg/kg group and 20600 and 35900 hr*μg/mL, respectively, in the 8.5 mg/kg group. Both groups exhibited minimal crizanlizumab accumulation, as indicated by the mean Cmax after the first infusion and at steady state (5.0 mg/kg: 65.9 and 77.5 μg/mL; 8.5 mg/kg: 175 and 171 μg/mL, respectively). Mean elimination half-life (T1/2) at steady state was 11.1 days for 5.0 mg/kg group and 12.1 days for 8.5 mg/kg group. The arithmetic mean pre-dose P-selectin inhibition ranged from 82.3% to 98.9% for 5.0 mg/kg and 93.4% to 99.7% for 8.5 mg/kg groups, from weeks 3 to 51. The median absolute change in the annualized rate of VOCs from baseline was −0.55 in overall, −1.00 in 5.0 mg/kg and −0.53 in 8.5 mg/kg group. Five patients (38.5%) in the 5.0 mg/kg group and 11 (27.5%) in 8.5 mg/kg group were VOC free until the data cut-off. Overall, 46 patients (86.8%) reported ≥1 adverse event (AE); 13 patients (100%) in the 5.0 mg/kg and 33 (82.5%) in 8.5 mg/kg group reported ≥1 AE. Most common AEs were pyrexia, abdominal pain and headache. Treatment-related AEs (TEAEs) occurred in 5 patients (38.5%) in 5.0 mg/kg and 12 patients (30.0%) in 8.5 mg/kg group; the most common TEAEs were infusion-related reactions (15.4% in 5.0 mg/kg and 7.5% in 8.5 mg/kg) and back pain (10% in 8.5mg/kg). Grade ≥3 AEs occurred in 6 patients (46.2%) in 5.0 mg/kg and 15 patients (37.5%) in 8.5 mg/kg group, of which anemia in 1 patient (1.9%) treated with the 8.5 mg/kg dose was reported to be related to crizanlizumab. AEs leading to dose reduction/interruption were reported in 12 patients (22.6%), of whom 4 (2 each in 5.0 and 8.5 mg/kg groups) had Grade ≥3 AEs leading to dose reduction/interruption. No AE-related treatment discontinuation or deaths were reported. Two participants (1 each in 5.0 and 8.5 mg/kg groups) developed transient antibodies against crizanlizumab, reported at the Week-27 visit. No additional antibodies against crizanlizumab were detected. Conclusions: In this interim analysis, crizanlizumab 8.5 mg/kg dose was confirmed for patients aged 6 to <12 years with SCD based on adult population PK model. Both 5.0 and 8.5 mg/kg doses showed a reduction in VOCs, resulting in decreased healthcare visits per year. Crizanlizumab was safe and well tolerated with no new/unexpected safety concerns in this patient group, consistent with the established profile of crizanlizumab in adults.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.