FP330APABETALONE, A SELECTIVE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR, REDUCES SERUM FGF23 IN CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE PATIENTS
Notice bibliographique
Résumé
INTRODUCTION: Fibroblast growth factor-23 (FGF23) is an osteocytic phosphaturic hormone known to increase renal phosphorus excretion and reduce calcitriol synthesis via the alpha-klotho obligate co-receptor. FGF23 has been identified as an independent marker for cardiovascular (CV) risk in various patient populations, including chronic kidney disease (CKD). Research has linked elevated levels of FGF23 to mortality, left-ventricular dysfunction, cardiac hypertrophy, vascular and endothelial dysfunction, and progression of CKD. Apabetalone is a first-in-class orally active bromodomain and extra-terminal (BET) inhibitor associated with the reduction of major adverse cardiac events (MACE) in patients with cardiovascular disease (CVD) in phase II clinical trials, now undergoing confirmatory phase III testing (BETonMACE trial). Apabetalone has previously been shown to downregulate markers of atherosclerosis, vascular calcification, and vascular inflammation. Here we demonstrate the effects of apabetalone on FGF23 in high risk patient populations, especially CKD. METHODS: In the phase II clinical studies, ASSERT & ASSURE, high risk CVD patients were treated with 100 mg b.i.d. apabetalone vs. placebo. In a phase I renal impairment study, CS-016, stage 4/5 CKD patients not on dialysis were matched with control subjects without renal impairment, both groups receiving a single 100 mg oral dose of apabetalone. Plasma samples were collected from patients for proteomic analysis using the SOMAScan™ 1.3K platform to assess relative fluorescent units (RFUs) of ~1,300 analytes. Changes in protein levels were measured following 12 weeks (ASSERT) and 26 weeks (ASSURE) of treatment, and at 12 hours post dose in CS-016. RESULTS: In the ASSURE trial, patients treated with apabetalone (n=47) saw a greater reduction of serum FGF23 (median change and percent change relative to baseline) of -17.3 RFUs, -3.7% vs. placebo patients (n=47), -8.6 RFUs, -1.7% (ANCOVA p-values vs. placebo: change = 0.01; percent change = 0.02). In patients that had baseline FGF23 levels greater than the median value, those that were treated with apabetalone (n=23) demonstrated an even greater reduction of FGF23 vs. placebo (n=23): -82.5 RFUs and -12.5% vs. -15.5 RFUs and -3.0% (ANCOVA p-value vs. placebo: change = 0.05; percent change = 0.1). CKD patients from both ASSERT and ASSURE trials treated with apabetalone (n=5) showed a decrease in levels of FGF23 (-31.1 RFUs, -6.6%) vs. placebo (n=5), who saw an increase (+264.2 RFUs, +49.3%) (Mann-Whitney p-value vs. placebo = 0.06 for both change and percent change). In the renal impairment study CS-016, stage 4/5 CKD patients treated apabetalone (n=8) showed a significant reduction in median serum FGF23 at 12 hours (-151.7 RFUs, -18.4%) vs. matched controls treated with apabetalone (n=8) (-24.6 RFUs, -5.8%) (ANCOVA p-value CKD patients vs. matched controls: change = 0.08; percent change = 0.03). CONCLUSIONS: In CVD and renally impaired CKD patients, BET inhibition and apabetalone demonstrates consistent reduction of circulating FGF23, a marker of CV risk and progression of CKD. This effect appears to be more pronounced in patients that are at higher risk, including those with elevated levels of FGF23 above the median baseline level, and patients with CKD. The potential impact of chronic treatment with apabetalone on biomarkers, renal function, and CVD outcomes is currently being evaluated in the phase III BETonMACE CVD outcomes trial.
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 | 0,000 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».