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Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphate

Mohamed A Ibrahim1, Diana V Do16, Yasir J Sepah1, Syed M Shah1, Elizabeth Van Anden1, Gulnar Hafiz1, J Kevin Donahue23, Richard Rivers4, Jai Balkissoon5, James T Handa1, Peter A Campochiaro1 and Quan Dong Nguyen16*

Author Affiliations

1 Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 745, Baltimore, MD 21287, USA

2 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3 Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA

4 Department of Anesthesia, Johns Hopkins University School of Medicine, Baltimore, MD, USA

5 OxiGene, Inc., South San Francisco, California, CA, USA

6 Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA

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BMC Pharmacology and Toxicology 2013, 14:7  doi:10.1186/2050-6511-14-7

Published: 14 January 2013



This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).


Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).


The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (pā€‰=ā€‰0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods.


The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy.

Trial registration NCT01570790.

Angiogenesis; Neovascularization; Ocular pharmacology; Retinal degeneration; Combretastatin A-4 Phosphate; CA4P; Vascular disrupting agents; VDA