FO080APABETALONE, AN INHIBITOR OF BET PROTEINS, IMPROVES CARDIOVASCULAR RISK AND REDUCES ALKALINE PHOSPHATASE IN BOTH CVD PATIENTS AND PRIMARY HUMAN CELL CULTURE SYSTEMS
Notice bibliographique
Résumé
INTRODUCTION: Apabetalone is an orally active inhibitor of bromodomain and extraterminal (BET) proteins - epigenetic readers modulating gene expression by bridging acetylated histones or transcription factors with transcriptional machinery. In phase 2 clinical trials, apabetalone reduced major adverse cardiac events (MACE) in patients with cardiovascular disease (CVD), resulting in 44% relative risk reduction on top of standard of care. Chronic kidney disease (CKD) is frequently accompanied by cardiovascular complications, which remain resistant to current therapies. Elevated serum alkaline phosphatase (ALP) contributes to vascular calcification (VC) and endothelial dysfunction. Accordingly, serum ALP is emerging as an independent and novel predictor of MACE and of all-cause mortality. METHODS: Serum ALP levels were examined post-hoc in CVD patients receiving apabetalone in the 3 month (ASSERT) and 6 month (SUSTAIN & ASSURE) phase 2 trials, including a subset with impaired renal function (eGFR<60 mL/min/1.73m2). Effects of BET inhibitors (BETi) on expression of tissue-nonspecific ALP (TNAP; gene symbol ALPL) was determined in cultured primary human hepatocytes (PHH), the HepaRG cell line, primary human vascular smooth muscle cells (VSMCs) during trans-differentiation to calcifying cells, and vascular endothelial cells. ALP enzyme activity was measured in enzymatic assays. RESULTS: In phase 2 trials, baseline serum ALP independently predicted MACE (hazard ratio [HR] per SD 1.6, 95% CI 1.2-2.2, p=0.001). In ASSERT, apabetalone dose dependently reduced serum ALP (n=74-76/group; p<0.001 median change vs. placebo). Patients in phase 2 on apabetalone (n=553) had greater reductions in ALP than placebo (n=242; p<0.001). ALP reduction by apabetalone was associated with reduction in MACE (HR 0.58 per SD, 95% CI 0.44-0.77, p<0.001). In the subgroup with eGFR<60, patients on apabetalone (n=69) also had lower on-treatment serum ALP (p=0.008) vs. placebo (n=22). Liver-derived TNAP accounts for ≍50% of ALP enzyme activity in serum. In PHH & HepaRG cells, apabetalone suppressed ALPL expression by 60-80%. Vascular expression of ALPL also contributes to VC & cardiovascular risk. Compared to basal conditions, trans-differentiation of VSMCs to calcifying cells resulted in 2.5x increase in ALPL expression. Apabetalone or JQ1 (BETi with different chemical scaffolds) countered extracellular calcium deposition and suppressed ALPL gene expression, TNAP protein levels, and enzyme activity. Apabetalone downregulated ALPL expression in human aortic endothelial cells, umbilical vein endothelial cells, and brain microvascular endothelial cells by 50-70%. CONCLUSIONS: Apabetalone dose dependently lowers serum ALP in patients, which is associated with reduction in cardiovascular events. Decreased ALPL expression in cultured hepatocytes with apabetalone is consistent with reduced serum ALP in patients. In addition, apabetalone downregulates ALPL expression in vascular cell types including VSMCs and endothelial cells, while reducing VSMC calcification. Involvement of BET proteins in VSMC calcification is a novel discovery. Our data indicate apabetalone has potential to decrease progression of pathological VC and contribute to positive cardiovascular outcomes in CVD patients. The impact of apabetalone treatment on biomarkers, renal function, and CVD outcomes is being evaluated in the phase 3 BETonMACE trial (NCT02586155).
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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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 ».