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Ophthalmology. 2015 Mar;122(3):545-54. doi: 10.1016/j.ophtha.2014.09.023. Epub 2014 Nov 12.

Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2.

Author information

1
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: pcampo@jhmi.edu.
2
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Center for Retina and Macular Disease, Winter Haven, Florida.
4
Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati School of Medicine, Cincinnati, Ohio.
5
Charlotte Eye, Ear, Nose & Throat Associates, Charlotte, North Carolina.
6
Retina Vitreous Associates Medical Group, Beverly Hills, California.
7
Ophthalmic Consultants of Boston, Boston, Massachusetts.
8
Aerpio Therapeutics, Cincinnati, Ohio.

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 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 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.

PMID:
25439435
DOI:
10.1016/j.ophtha.2014.09.023
[Indexed for MEDLINE]

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