S267: PHARMACOKINETICS/PHARMACODYNAMICS, SAFETY AND EFFICACY OF CRIZANLIZUMAB IN PATIENTS WITH SICKLE CELL DISEASE AGED 12 TO <18 YEARS: 2-YEAR DATA FROM THE PHASE 2 SOLACE-KIDS STUDY
Notice bibliographique
Résumé
Background: Vaso-occlusive crises (VOCs) are a key characteristic of sickle cell disease (SCD). Safety and efficacy of crizanlizumab from 26-week analysis of SOLACE-kids study in 50 children with SCD aged 12 to <18 years were reported at ASH 2021. Safety and tolerability of the confirmed dose (5 mg/kg) of crizanlizumab in these children were consistent with the established profile in adults from the SUSTAIN study. Crizanlizumab also showed a reduction in the median annualized rate of VOCs compared to baseline. Aims: To confirm and establish appropriate dosing for different pediatric age groups (Part A), and to evaluate the safety and efficacy of the confirmed dose of crizanlizumab (Part B), in additional pediatric patients with SCD (ClinicalTrials.gov: NCT03474965; EudraCT: 2017-001747-12). Methods: SOLACE-kids is an ongoing Phase 2 study conducted in children with SCD (any genotype) and a history of ≥1 VOC leading to a healthcare visit within 12 months prior to screening. Eligible patients are grouped by age: Group 1 (12 to <18 years), Group 2 (6 to <12 years), and Group 3 (6 months to <6 years). Patients received crizanlizumab on Day 1, Day 15, then every 4 weeks (up to 2 years), with or without hydroxyurea (HU)/Hydroxycarbamide (HC). This analysis reports updated pharmacokinetics (PK)/pharmacodynamics (PD; ex vivo P-selectin inhibition), safety, and efficacy results for patients in Group 1 who received crizanlizumab 5 mg/kg IV for 2 years. Results: As of 05 May 2022, of 50 patients enrolled in Group 1 (median [range] age 14.9 [12.0–17.9] years; 58% female; 88% HbSS genotype; 64% Black/African American; 84% receiving HU), 33 (66%) completed treatment with crizanlizumab. Median (Q1-Q3) duration of crizanlizumab exposure was 106.1 (94.9–107) weeks; 86% and 56% of patients received treatment for ≥54 and ≥106 weeks, respectively. Eleven patients’ data were evaluated for PK/PD analysis. The mean area under the curve from time zero to the last measurable concentration after the first infusion (AUCd15) and after multiple doses at steady state (AUCtau) was 10500 and 15800 hr*μg/mL, respectively. The mean maximum serum concentrations (Cmax) after the first infusion (80.5 μg/ml) and at steady state (95.6 μg/mL), indicated no significant accumulation of crizanlizumab. At steady state, the mean apparent elimination half-life (T1/2) was 10.3 days. The mean P-selectin inhibition ranged from 98.7% to 100% at a first dose and from 88.6% to 97.6% at the steady-state dose. Overall, 47 (94%) patients reported ≥1 adverse event (AEs), most commonly with headache (38%). Treatment-related AEs occurred in 15 (30%) patients, of which infusion-related reaction (10%) and nausea (6%) were most common. Grade ≥3 AEs occurred in 24 (48%), of which back pain and pain in extremity in 1 patient and increased bilirubin in 1 patient were related to crizanlizumab. None of the serious AEs or AEs leading to discontinuation (including one death due to bacterial meningitis), dose change, and/or interruption were deemed related to crizanlizumab per the investigator. None of these patients developed antibodies against crizanlizumab. The impact of crizanlizumab on annualized rate of VOCs is summarized in Table. Summary/Conclusion: In this 2-year analysis, crizanlizumab 5 mg/kg with or without concomitant HU/HC has shown a reduction in VOCs resulting in decreased healthcare visits per year, consistent with the established profile of crizanlizumab in adults. Crizanlizumab was safe and well tolerated with no new/unexpected safety concerns. These results confirm 5 mg/kg as an adequate dose in pediatrics with SCD aged 12 to <18 years.Keywords: Sickle cell disease, Vasoocclusive crisis, P-selectin, Pediatric
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».