More Trials Needed

For the concept of neuroprotective treatment of glaucoma, independent of intraocular pressure (IOP) reduction, to progress from theory into practice, glaucoma researchers will have to apply the same energy and unity of purpose as researchers do into other neurodegenerative disorders, said Francesca Cordeiro MBBS, PhD, University College London, London, UK. “I think we have to learn from researchers in other areas of neurodegeneration who have gotten together to compare notes and establish consortiums to gain acceptance from the regulatory authorities,” she said, at the 11th European Glaucoma Society Congress in Nice.

There are many potential targets for neuroprotection in glaucoma, although as yet only two agents, memantine and brimonidine, have made it to the clinical trial stage. Allergan has not yet published the results of the memantine trial, but its press release states that patients receiving the treatment did not reach their endpoints.

In contrast, in the Low Tension Glaucoma Treatment Study (LOGTS), progressor analysis of visual field end points indicated a beneficial effect in patients receiving brimonidine compared to patients receiving timolol. That was despite a close similarity between the groups in terms of IOP reduction.

However, the trial has received criticism on multiple grounds. For example, some have suggested that the 20 per cent of patients who dropped out of the brimonidine group, mainly because of side effects, may have had a preponderance of rapid progressors. Alternatively, the poorer results with timolol may actually have been the result of deleterious effect of the agent on the optic nerve.

“Nonetheless, this is the first published study to include the effect on visual fields and I think it gave us a little bit of confidence, especially after the memantine trial,” she said.

Dr Cordeiro noted that the obstacles to bringing neuroprotective approaches in glaucoma from the laboratory to the clinic are the same as those encountered in other neurodegenerative diseases. They include the need for large numbers of patients with long periods of follow-up.

However, unlike glaucoma, and despite previous failures there are numerous phase II and even phase III clinical trials under way in neurodegenerative conditions like stroke and Alzheimer’s disease, but only one trial now under way into neuroprotection in glaucoma. Many of the obstacles to further clinical research could be overcome by the use of more sensitive biomarkers and endpoints and using a more adaptable style in the design of trials, Dr Cordeiro said.

For example, agents could be first tried on patients with a historically high risk of progression to provide proof of concept for the treatment more quickly and with fewer patients. In addition, endpoints and selection criteria could be adjusted on the basis of interim results.

Francesca Cordeiro: M.Cordeiro@ucl.ac.uk