Article

Neuroprotective drug need not be an impossible dream

By Cheryl Guttman Krader

The idea that a neuroprotective agent for glaucoma will be available within the next decade is wishful thinking, but not unrealistic, according to Robert N. Weinreb, MD.

Dr. Weinreb said that with selection of an appropriate drug and implementation of new testing paradigms, there is a high likelihood that a trial of a neuroprotective agent could achieve its clinical endpoints within a reasonable time period and at a reasonable cost.

Robert Weinreb, MD, is optimistic that a neuroproctective agent will be available in five to 10 years.

“I am optimistic that within five to 10 years, we will have a neuroprotective agent that would slow the rate of glaucoma damage,” said Dr. Weinreb, distinguished professor and chairman, Department of Ophthalmology, and director of the Shiley Eye Institute, University of California, San Diego.

Outlining the pathway to developing a commercially available neuroprotective agent, Dr. Weinreb explained that an “appropriate drug” could be one that has been shown to have neuroprotective activity in an experimental model and that has demonstrated safety and perhaps some efficacy in a pilot clinical study.

Study population defined

The study population would have to be tightly defined, which would allow for a trial with adequate power to detect what may be a moderate treatment effect with a smaller sample size. Dr. Weinreb suggested proper candidates would be patients whose glaucoma is rapidly progressing on standard therapy or who have significant risk factors for progression, such as exfoliation, disc hemorrhage, or family history of glaucoma.

 

“Using these inclusion criteria would reduce the ability to generalize the results and would also make recruitment more difficult,” Dr. Weinreb added. “However, since change is more likely in these patients, the likelihood of detecting benefit with a neuroprotective agent would be improved.”

The sample size will depend on the rate of worsening of the outcome measures in untreated patients and the desired level of improvement to be provided by the treatment. Dr. Weinreb pointed out it might be possible to design trials enrolling just a few hundred patients treated for less than 1 year, and perhaps even just 6 months.

However, endpoint selection is critical.

“The detection of progressive glaucomatous injury and the definition of study endpoints have been problematic,” Dr. Weinreb said. “Regulatory agencies equate glaucoma progression with standard achromatic visual field loss and have not embraced structural alterations in optic nerve as primary endpoints.”

He acknowledged that preservation of visual function and vision-related quality of life is the ultimate goal in the clinical management of glaucoma patients. However, these are subjective endpoints.

Visual field thoughts

Speaking specifically about visual field loss, Dr. Weinreb said it is an insensitive measure early in the disease, variable (particularly late in disease), and not patient-friendly. He suggested that the ability to detect change with standard perimetry could be improved by increasing the frequency of testing, i.e., performing a cluster of tests at baseline and the end of the trial. Otherwise, demonstrating preservation of visual function would depend on the development of a more objective test.

Use of a structure-related endpoint is more attractive for assessing efficacy in glaucoma neuroprotection studies–since structural change is an objective measure and often occurs before functional change. Furthermore, with current spectral-domain optical coherence tomography (SD-OCT) systems, the imaging is patient-friendly.

“OCT imaging is done through an undilated pupil and data acquisition is very fast, which enables repeat testing,” Dr. Weinreb said. “The ability to easily collect a sufficient number of endpoints would allow a study that has a smaller sample size, shorter duration, and lower cost.”

Using an endpoint that combines structure and function testing is another approach that is promising. The combined structure-function index (CSFI), developed by Felipe A. Medeiros, MD, PhD, and colleagues at the Hamilton Glaucoma Center and Shiley Eye Institute, estimates retinal ganglion cell loss using data from SD-OCT imaging of the retinal nerve fiber layer, functional results from standard perimetry, and takes into account age-related change.

 

The CSFI is considerably more sensitive than mean deviation, visual field index, and OCT average thickness for detecting progressive glaucomatous damage [Am J Ophthalmol. 2012;154:814-24].

Looking to the future, Dr. Weinreb proposed two indications for a neuroprotective drug for glaucoma. One use would serve as complementary therapy, where the agent is added to medical treatment or used after surgery in patients who achieve IOP-lowering, but are still experiencing progressive loss of visual function. The second would serve as an alternative therapy for patients in whom IOP-lowering agents are not tolerated or ineffective.

“I am optimistic that we have a pathway forward and there is an opportunity to bring neuroprotection therapy to glaucoma management,” Dr. Weinreb said.

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