期刊
OPHTHALMOLOGY
卷 122, 期 3, 页码 545-554出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ophtha.2014.09.023
关键词
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资金
- Aerpio
- Genentech
- Regeneron
- Allergan
- GlaxoSmithKline
- Genzyme
- Oxford Biomedica
- Novartis
- Alcon
- Pfizer
- Alimera
- Lpath
- Valeant
- Bausch Lomb
- Bayer
- Ophthotech
- Pan Optica
- Alcon/Novartis
- Ohr Pharmaceuticals
- Equity owner - Allegro
- Acucela
- Fovea
- Neovista
- Neurotech
- Notal Vision
- Paloma
- Aerpio Therapeutics
- Cincinnati
- Ohio
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 Outcome Measures: 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 mu m in 5 patients and by 50 to 100 mu m 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. (C) 2015 by the American Academy of Ophthalmology.
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