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Is there a future for neuroprotection in the treatment of glaucoma?
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New study design, emerging technologies may shorten trial duration
The clinical trial design to test neuroprotection has improved dramatically recently, and we now have convincing clinical evidence that neuroprotection can be the next exciting step into the future of glaucoma treatment and early prevention.
With the development of OCT algorithms, we now have the ability to detect damage and progression as much as 2 years before visual field changes occur. We believe the FDA will consider OCT as a surrogate biomarker of visual field progression as the use of trend analysis can now shorten the duration of trials. By incorporating these new approaches in visual fields, the United Kingdom Glaucoma Treatment Study enabled significant differences in vision to be assessed in a relatively short observation period of 18 months.
A further decisive improvement is coming from new technologies including swept-source OCT, adaptive optics and DARC, short for detection of apoptosing retinal cells, a test that has just completed phase 2 studies. We are planning to perform a phase 3 multicenter glaucoma trial hopefully at the end of 2019. DARC identifies sick cells within the retina, which in glaucoma is the ganglion cells, the target organ of the disease. Sick cells can be visualized after staining with a fluorescent dye, allowing us to monitor disease activity. We have shown experimentally that this technology can provide us with a quick answer on whether specific treatments, including neuroprotective agents, are efficacious or not. Even the most advanced OCT and visual field analysis require at least 18 months before providing useful information on the effects of medications. That is why clinical trials go on for so long. With DARC, we can look at patients even 2 weeks after starting treatment to see if there is a reduction in apoptosing cells, as an indication of treatment efficacy. DARC has already been approved as an exploratory marker by both the FDA in the U.S. and the Medicines and Healthcare Products Regulatory Agency in the U.K.
M. Francesca Cordeiro, MD, PhD, is chair of ophthalmology at Imperial College London, U.K. Disclosure: Cordeiro reports she is an inventor on patents for DARC and receives support from Heidelberg Engineering.
Neuroprotection treats cells disconnected from the brain
While it is clear that glaucoma is a multifactorial disease, a preponderance of evidence suggests that the initial site of axonal injury is at the level of the lamina cribrosa, with a variety of vascular, mechanical, cellular and other interrelated factors creating a pathologic milieu within this region. Salvaging the retinal ganglion cell soma within the retina is a sound and viable treatment. However, without addressing the fundamental pathology that disconnects the retinal ganglion cell axons from the rest of the brain, ultimately this therapy may not prove successful. Neuroprotective agents aim at salvaging the retinal ganglion cells, but if their axons are cut off at the lamina cribrosa, these cells will not be able to communicate with the brain and will continue to require supplementation from neurotrophic factors.
While there are many promising studies with agents in animal models for neuroprotection, no clinical trial has definitively proven that neuroprotection strategies are working in glaucoma. This may be due to the different nature of injury seen in animal models vs. human disease or the complex nature of the disease process. Classic neuroprotective strategies have been focused on preserving the retinal ganglion cell soma. These approaches need to be combined with approaches to restore a healthy milieu for their axons as they exit the eye and ultimately with efforts to regenerate retinal ganglion cell axons and incorporate accurately to their central projections.
Christopher A. Girkin, MD, MSPH, is the chairman, Department of Ophthalmology, University of Alabama at Birmingham. Disclosure: Girkin reports his research support is from the National Eye Institute, the EyeSight Foundation of Alabama and Heidelberg Engineering.