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 (C_max) and area under the curve (AUC), respectively, from time zero to the last measurable concentration after the first infusion (AUC_d15), while the 8.5 mg/kg dose achieved 52% and 40% increase in C_max and AUC_d15, respectively, confirming its use for Group 2 patients.

Mean AUC_d15 and AUC after multiple doses at steady state (AUC_tau) 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 C_max 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 (T_1/2) 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.

Heeney:Novartis: Consultancy, Current equity holder in publicly-traded company; Beam Therapeutics: Consultancy, Current equity holder in publicly-traded company; Pfizer: Consultancy, Current equity holder in publicly-traded company; Bluebird Bio: Consultancy; Blueprint Medicines: Consultancy; MiNA Therapeutics: Consultancy; Omeros: Consultancy; Abbott Labs: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; CRISPER Therapeutics: Current equity holder in publicly-traded company; Dianthus Therapeutics: Current equity holder in publicly-traded company; GE Healthcare: Current equity holder in publicly-traded company; Praxis: Current equity holder in publicly-traded company. Odame:Novartis: Research Funding; Pfizer: Other: Data Safety Monitoring Board; Novo Nordisk: Honoraria; Vertex: Other: Adboard. Cançado:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Aztrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Inati:Pharmacosmos: Research Funding; Agios: Research Funding; Vifor: Consultancy, Research Funding; Bausch Health: Research Funding; Novo Nordisk: Consultancy, Research Funding; Roche: Consultancy, Research Funding; GBT/Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cela:Vertex: Consultancy, Speakers Bureau; Pfizer: Consultancy. Keefe:Novartis: Current Employment. Reshetnyak:Novartis: Current Employment. Muthusamy:Novartis: Current Employment. Bebrevska:Novartis: Current Employment. Nassin:Novartis: Current Employment. Kanter:GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; CDC: Other: Federal Funding; Fulcrum: Consultancy; Optum United Health: Consultancy; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; GLG Pharma: Consultancy; Guidepoint Global: Consultancy; Affimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy; NIH/NHLBI: Other: Federal Funding; Merck: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam Tx: Consultancy, Research Funding; EcoR1: Consultancy; Chiesi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Research Funding; Takeda: Research Funding; Novartis: Consultancy; Bioline Rx: Consultancy; Bausch: Consultancy; Emerging Therapy Solutions: Honoraria; Health Resources and Services Administration: Other: Federal Funding; Watkins, Lourie, Roll & Chance: Consultancy.