Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2.
Ophthalmology
; 122(3): 545-54, 2015 Mar.
Article
em En
| MEDLINE
| ID: mdl-25439435
ABSTRACT
PURPOSE:
AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME).DESIGN:
Open-label, dose-escalation clinical trial.PARTICIPANTS:
Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks.METHODS:
Patients were seen weekly during a 4-week treatment period for safety assessments, best-corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral-domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks. MAIN OUTCOMEMEASURES:
Safety assessments, change from baseline BCVA, and change from baseline CST.RESULTS:
All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 µm in 5 patients and by 50 to 100 µm in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA.CONCLUSIONS:
No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Sulfônicos
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Edema Macular
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Receptor TIE-2
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Retinopatia Diabética
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Inibidores Enzimáticos
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Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores
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Compostos de Anilina
Tipo de estudo:
Clinical_trials
/
Guideline
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Ophthalmology
Ano de publicação:
2015
Tipo de documento:
Article