A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal of Edoxaban-Induced Anticoagulation in Healthy Subjects By Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors
Notice bibliographique
Résumé
Abstract Background: Direct fXa inhibitors appear to have similar or superior anticoagulant efficacy and safety relative to warfarin (and in some cases low molecular weight heparin) in the management of venous thromboembolism and stroke prevention in atrial fibrillation. However, they are limited by the lack of a specific antidote to reverse anticoagulation in cases of major bleeding episodes or prior to urgent/emergency surgery. Andexanet alfa (AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct and indirect fXa inhibitors, therefore acting as a decoy to bind and sequester fXa inhibitors. We previously reported Phase 2 data with apixaban, rivaroxaban and enoxaparin in healthy subjects and demonstrated that AnXa was able to rapidly and extensively reverse pharmacodynamic (PD) markers of anticoagulation. Here we report new clinical data demonstrating that AnXa rapidly reverses the PD markers of edoxaban-mediated anticoagulation – anti-fXa activity and inhibition of thrombin generation. Methods: This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of edoxaban (edox, the most recent fXa inhibitor for which an NDA/MAA was submitted) as well as its pharmacokinetics (PK) and safety profile in healthy subjects. Reversal of edox anticoagulation is being studied with up to 3 different dose cohorts/regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Edox is administered at an oral dose of 60 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last edox dose. PD and safety data are collected through Day 48 with PK data through Day 10. Results and Conclusions: We report here available data from the first 2 AnXa dose cohorts (600 mg bolus, n=9; 800 mg bolus followed by 8 mg/min infusion for 1 hr, n=9). Immediately after completion of the 600 mg or 800 mg bolus, anti-fXa activity decreased dose-dependently by 52% and 73%, respectively, from the pre-AnXa level, remained constant during the infusion, and returned to placebo levels by approximately 2 hours after treatment. In addition, edox-induced inhibition of thrombin generation and prolongation of clotting times were also reversed by AnXa in a dose-dependent manner. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. One subject was discontinued on Day 5 prior to AnXa dosing due to a vasovagal reaction. These data are consistent with previously reported results for other fXa inhibitors in that AnXa rapidly reverses PD markers of anticoagulation, restores normal thrombin generation, and is well tolerated. Disclosures Crowther: CSL Behring: Honoraria; Shire: Honoraria; Celgene: Honoraria; Bayer: Honoraria; AKP America: Consultancy; Leo Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Portola Pharmaceuticals, Inc.: Consultancy; The Heart and Stroke Foundation of Ontario: Career Investigator Award, Career Investigator Award Other. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Lu:Portola Pharmaceuticals Inc: Employment. Leeds:Portola Pharmaceuticals, Inc: Employment. Lin:Portola Pharmaceuticals, Inc.: Employment. Pratikhya:Portola Pharmaceuticals, Inc.: Employment. Conley:Portola Pharmaceuticals Inc: Employment; Portola Pharmaceuticals Inc: Equity Ownership. Connolly:Portola Pharmaceuticals Inc: Consultancy. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 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 ».