Erythropoietin (EPO), shown in early studies to potentially provide neuroprotection for patients with optic neuritis, failed to provide any significant neuroprotection in comparison with placebo in a phase 3 randomized controlled trial.
“EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis as a clinically isolated syndrome,” said first author Wolf A. Lagreze, MD, of the University of Freiburg, Freiburg, Germany, in presenting the results at the virtual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2021.
There are currently no treatments that provide neuroprotection for patients with optic neuritis, which can result in the degeneration of retinal ganglion cells, the axons of which form the optic nerve.
Although methylprednisolone, the standard treatment, can be of benefit, it has no effect in preventing neurodegeneration or subsequent vision impairment.
Importantly, optic neuritis, which can be a first sign of multiple sclerosis (MS), is considered an ideal model for an acute inflammatory attack on the nervous system and resulting neurodegeneration. Therefore, any treatment that provides neuroprotection for patients with optic neuritis could have potentially exciting broader implications.
Preclinical studies have shown that EPO provides a small, potential degree of neuroprotection. To further evaluate EPO in this setting, Lagreze and colleagues conducted the TONE trial (Treatment of Optic Neuritis With Erythropoietin) in Germany between 2014 and 2017, in which they enrolled 108 patients with optic neuritis.
Inclusion criteria were having only unilateral optic neuritis as a clinically isolated syndrome that presented within 10 days of the first symptoms and having moderate to severe loss of visual acuity.
Persons with known MS were excluded; however, patients who were diagnosed with MS at the beginning of the study during the workup evaluation were included. Hence, about 20% of patients did have newly diagnosed MS, Lagreze noted.
The participants were randomly assigned in double-blind 1:1 ratio to receive treatment with either 33,000 IU EPO or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg/d).
The final analysis included 52 patients who received EPO and 51 patients who received placebo. There were no significant differences between the groups in the first primary outcome of retinal nerve fiber layer atrophy, assessed with optic coherence tomography at week 26 (P = .76).
Likewise, no significant difference between groups was observed in the second primary outcome of low-contrast visual acuity at week 26, assessed using the 2.5% Sloan chart score of the affected eye (P = .38).
In addition, there were no significant differences between the groups in the rates of optic neuritis relapse.
In terms of safety measures, one patient in the EPO group developed sinus venous thrombosis, which was treated with anticoagulants and resolved without complications.
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Reduced Conversion to MS?
Interestingly, after 6 months, significantly fewer patients in the EPO arm (36%) had converted from clinically isolated syndrome to MS, compared with 57% in the placebo arm (P = .032). The difference became apparent as early as week 4.
Although those findings suggest that EPO provided some neuroprotection, there are notable caveats, Philippe Albrecht, MD, of the Department of Neurology at the University Hospital Dusseldorf, Germany, and a coauthor on the study, told Medscape Medical News.
“The significant separation of EPO and placebo group regarding MS conversion was observed very early on in the course and did not change thereafter,” Albrecht noted.
“One would expect a true disease-modifying effect of EPO on MS conversion to take longer to develop, and this early separation may very well have been due to an imbalance in the treatment groups, [for example] regarding MRI imaging findings such as gadolinium enhancement at baseline,” he said.
Lagreze said that it was a surprise to see no benefit from the drug, and a closer look at certain subgroups may still be worthwhile. Factors that could have a bearing on results include a shorter time interval for inclusion, having no concomitant use of steroids, and longer duration of treatment with EPO.
“If I could do the study again, I would do the treatment for longer than 3 days ― that was based on experiences in previous EPO trials,” he said. “I would also love to do the trial without the concomitant methylprednisolone, but that is not possible from an ethical point of view.”
Trial Nevertheless Important
Commenting on the study, E. Anne Yeh, MD, of the Division of Neurology at the Hospital for Sick Children, in Toronto, Canada, agreed that a challenge in evaluating therapies for optic neuritis is the potential for confounding from existing therapies that patients need to take.
“This agent could not be evaluated alone for its protective effect in comparison to no treatment at all,” she told Medscape Medical News.
“The development of newer vision-related outcome metrics is important for future studies, and many are hard at work on both structural and functional metrics that may help us to understand the benefits of any protective therapies in a more nuanced manner than we are currently able to,” she said.
However, results of any kind ― negative or positive ― are valuable in improving understanding, Yeh underscored.
“Negative results can be disappointing in any trial, especially one in which alternative therapeutic pathways are being sought,” Yeh said. “I want to emphasize, however, that the fact that we are even considering and completing trials in this area is important.”
Yeh noted that she is currently involved in a trial that is evaluating the diabetes drug metformin for its remyelinating potential. “We hope to have some pilot data on MS in a few years,” she said.
Lagreze, Albrecht, and Yeh have disclosed no relevant financial relationships.
Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2021. Presented February 25, 2021.