Long-term follow-up demonstrates durable clinical benefits of exagamglogene autotemcel for sickle cell disease with recurrent vaso-occlusive crises: Final results of climb SCD-121
Notice bibliographique
Résumé
Abstract Background: Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo CRISPR/Cas9 gene-edited, autologous cell therapy approved for patients ≥12 years old with severe sickle cell disease (SCD). We report results for durable, long-term efficacy and safety for the completed phase 3 CLIMB SCD-121 and ongoing CLIMB-131 trials. Methods: CLIMB SCD-121 is a 2-year, phase 3 trial of a single-infusion of exa-cel in participants (pts) aged 12-35 years with SCD and a history of ≥2 vaso-occlusive crises (VOCs)/year in the 2 years before screening. The primary efficacy endpoint is the proportion of pts free of severe VOCs for ≥12 consecutive months (VF12); the key secondary efficacy endpoint is the proportion of pts free from inpatient hospitalization for severe VOCs for ≥12 consecutive months (HF12). Secondary endpoints include VOC-free duration, total hemoglobin (Hb), hemoglobin F (HbF), allelic editing, hemolysis measures, and patient-reported outcomes (PROs). Following completion of CLIMB SCD-121, pts enroll in the long-term follow-up trial CLIMB-131 for up to 15 years after exa-cel. Data are from April 10, 2025; data will be updated to reflect the final analysis of the completed CLIMB SCD-121 trial. Results:46 pts (12 adolescents, 34 adults [≥18 years]; mean age: 21.4 years, range: 12, 34) with mean 4.2 VOCs/year at baseline received exa-cel. The median number of mobilization/apheresis cycles was 2 (range: 1, 6); 92% of adolescents underwent 1-2 cycles. 42 pts completed 2 years of follow-up in CLIMB SCD-121 and enrolled in the ongoing CLIMB-131 trial. The median follow-up was 41.3 months (range: 8.9, 70.3). After exa-cel infusion, all pts engrafted neutrophils and platelets at a median of 27 days (range: 15, 40) and 35 days (range: 23, 126), respectively. 45 pts were evaluable for the primary and key secondary endpoints in CLIMB SCD-121; 41/45 (91.1%) achieved VF12 (95% CI: 78.8%, 97.5%) and 44/45 (97.8%) achieved HF12 (95% CI: 88.2%, 99.9%). In CLIMB SCD-121 and CLIMB-131 combined, 45/45 (100%) of pts achieved VF12 and HF12 with a mean VOC-free duration of 35.3 months (range: 12.9, 67.7). All evaluable pts had durable increases in mean HbF of ≥40% from Month 6 onward with pancellular distribution (~95% RBCs expressing HbF) resulting in normal or near normal total Hb levels. Allelic editing was stable over time in both bone marrow and peripheral blood cells. Clinically meaningful improvements in hemolysis markers (lactate dehydrogenase, haptoglobin, reticulocyte count, indirect bilirubin) and quality of life (QOL) measures were observed compared to baseline and were maintained over time. Exa-cel safety profile was consistent with myeloablative conditioning and autologous hematopoietic stem cell transplant. Efficacy and safety were consistent in adults and adolescents and across genotypes. There was one death which occurred 8.9 months after exa-cel infusion, which was previously reported, from respiratory failure due to COVID-19 infection not related to exa-cel; no malignancies occurred.Conclusion: The completedCLIMB SCD-121 trial demonstrates elimination of VOCs after exa-cel in 91.1% of evaluable pts. 100% of pts achieved VOC free in CLIMB SCD-121 and CLIMB-131 combined, which was maintained long-term for up to 5.6 years. All pts had durable increases in Hb and HbF levels and stable allelic editing; clinically meaningful improvements were also seen in hemolysis markers and QOL measures. These results confirm the potential for exa-cel to provide a one-time functional cure for severe SCD.
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.
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 | 0,001 | 0,001 |
| 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 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».