P1522: LONG-TERM EFFICACY AND SAFETY OF THE ORAL PYRUVATE KINASE ACTIVATOR MITAPIVAT IN ADULTS WITH NON–TRANSFUSION-DEPENDENT ALPHA- OR BETA-THALASSEMIA
Notice bibliographique
Résumé
Background: Thalassemia is characterized by ineffective erythropoiesis and hemolysis that occur due to imbalanced production and precipitation of globin chains. Thalassemic red blood cells (RBCs) have insufficient levels of adenosine triphosphate (ATP) to meet increased energy demands associated with globin chain imbalance, protein degradation, and cellular oxidative stress responses. Mitapivat is a first-in-class, small molecule, oral activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme regulating ATP production. In a phase 2, open-label trial of mitapivat in adults with α- or β-non–transfusion-dependent (NTD) thalassemia (NCT03692052), 80% (16/20) of patients (pts) met the primary endpoint of a hemoglobin (Hb) response (≥1.0 g/dL increase from baseline [BL] at ≥1 assessments between Weeks (Wks) 4–12, inclusive). Improvements in markers of hemolysis and ineffective erythropoiesis were also observed and mitapivat was generally well tolerated. Aims: To report data from the ongoing long-term extension (LTE) period (≤Wk 72; data cutoff 27Mar2021). Methods: Pts aged ≥18 years (yrs) with a known medical history of α- or β-thalassemia, Hb concentration ≤10.0 g/dL, and ≤5 RBC units transfused in prior 24 wks and none in 8 wks prior to study drug were eligible. All pts started mitapivat 50 mg twice daily (BID), escalating to 100 mg BID based on individual safety and Hb assessments. After completion of the 24-wk core period, pts with a Hb response or a delayed Hb response (after Wk 12), with no ongoing study drug-related grade ≥3 treatment-emergent adverse events (AE), continued on mitapivat in the LTE at the same dose as the Wk 24 visit. Study visits occur every 12 wks for ≤10 yrs. Results: Of 19 pts who completed the core period, 17 entered the LTE (mitapivat 100 mg BID, n=16; 50 mg BID, n=1). As of the data cutoff, 1 pt discontinued (pt decision). Median duration of treatment for pts in the LTE was 70.9 wks (range 54.7, 105.6); 8 pts received ≥72 wks of treatment as of data cutoff. Median pt age in the LTE was 44 yrs (range 29, 67). Mean (standard deviation [SD]) BL Hb, total bilirubin and lactate dehydrogenase (LDH) were 8.1 (1.2) g/dL, 40.1 (26.2) μmol/L, and 272.4 (121.7) U/L, respectively. Median BL erythropoietin (EPO) was 70.5 (range 15, 11191) IU/L. Hb improvements achieved in the core period were sustained in the LTE (Figure). Mean (SD) Hb increase from BL to Wk 60 (α-thalassemia, n=4; β-thalassemia, n=9) and Wk 72 (β-thalassemia, n=8) were 1.5 (0.4) and 1.7 (0.5) g/dL, respectively. Improvements in markers of hemolysis and ineffective erythropoiesis observed in the core period were maintained in the LTE up to Wk 72 (mean [SD] bilirubin and LDH, –15.8 [16.6] μmol/L and –63.6 [216.0] U/L, respectively; median [range] EPO, –33.0 [–72.0, –16.0] IU/L). The safety profile was consistent with that observed in the core period. AEs in ≥15% of pts were headache (5/17) and back pain (3/17), none were grade ≥3. No trends for decreases in bone mineral density were observed. No treatment-related serious AEs occurred. Image:Summary/Conclusion: In pts with either α- or β-thalassemia, a favorable efficacy-safety profile was observed with long-term treatment with mitapivat. Data show sustained improvements in Hb, hemolysis, and ineffective erythropoiesis despite globin genotypic heterogeneity, and no new safety findings. Mitapivat, through its unique mechanism of action, may represent a novel therapeutic approach for this condition. Two phase 3 trials of mitapivat in α- and β-thalassemia for both NTD (ENERGIZE, 2021-000211-23) and transfusion-dependent (ENERGIZE-T, 2021-000212-34) pts are enrolling.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 tête enseignante, 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 ».