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180 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 114. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Therapeutic Advances in Sickle Cell Disease
Hematology Disease Topics & Pathways:
Clinical trials, Research, Sickle Cell Disease, Clinical Research, Hemoglobinopathies, Pediatric, Diseases, Adverse Events, Study Population, Human
Saturday, December 7, 2024: 3:15 PM

Matthew M. Heeney, MD1, David C Rees2, Slimane Allali3*, Isaac Odame, MBBCh4, Rodolfo D Cançado5*, Adlette Inati, MD6, Elena Cela, MD, PhD7*, Deborah Keefe8*, Evgeniya Reshetnyak8*, Velusamy Shanmuganathan Muthusamy9*, Lidiya Bebrevska10*, Michele L Nassin8 and Julie Kanter, MD11

1Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA
2Department of Paediatric Haematology, King's College London, London, United Kingdom
3Department of Pediatrics and Sickle Cell Center APHP, Centre-Université Paris Cité, Necker Hospital for Sick Children, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, Institut Imagine, Paris, France
4The Hospital for Sick Children (SickKids) and the University of Toronto, Toronto, ON, Canada
5Department of Oncology and Hematology, Hospital Samaritano de Sao Paulo, São Paulo, Brazil
6Lebanese American University Gilbert and Rose-Marie Chagoury School of Medicine, Byblos and NINI Hospital, Tripoli, Lebanon
7Pediatric Hematology and Oncology, Hospital Gregorio Marañón. Universidad Complutense de Madrid, Madrid, Spain
8Novartis Pharmaceuticals Corporation, East Hanover, NJ
9Novartis Healthcare Pvt. Ltd., Hyderabad, India
10Novartis Pharma AG, Basel, Switzerland
11University of Alabama at Birmingham, Birmingham, AL

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.

Disclosures: 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.

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