Fingolimod after a first unilateral episode of acute optic neuritis (MOVING) – preliminary results from a randomized, rater-blind, active-controlled, phase 2 trial

Abstract

Background: Neuroprotection and promotion of remyelination represent important therapeutic gaps in multiple sclerosis (MS). Acute optic neuritis (ON) is a frequent MS manifestation. Based on the presence and properties of sphingosine-1-phosphate receptors (S1PR) on astrocytes and oligodendrocytes, we hypothesized that remyelination can be enhanced by treatment with fingolimod, a S1PR modulator currently licensed for relapsing-remitting MS. Methods: MOVING was an investigator-driven, rater-blind, randomized clinical trial. Patients with acute unilateral ON, occurring as a clinically isolated syndrome or MS relapse, were randomized to 6 months of treatment with 0.5 mg oral fingolimod or subcutaneous IFN-β 1b 250 μg every other day. The change in multifocal visual evoked potential (mfVEP) latency of the qualifying eye was examined as the primary (month 6 vs. baseline) and secondary (months 3, 6 and 12 vs. baseline) outcome. In addition, full field visual evoked potentials, visual acuity, optical coherence tomography as well as clinical relapses and measures of disability, cerebral MRI, and self-reported visual quality of life were obtained for follow-up. The study was halted due to insufficient recruitment (n = 15), and available results are reported.Results: Per protocol analysis of the primary endpoint revealed a significantly larger reduction of mfVEP latency at 6 months compared to baseline with fingolimod treatment (n = 5; median decrease, 15.7 ms) than with IFN-β 1b treatment (n = 4; median increase, 8.15 ms) (p < 0.001 for interaction). Statistical significance was maintained in the secondary endpoint analysis. Descriptive results are reported for other endpoints. Conclusion: Preliminary results of the MOVING trial argue in support of a beneficial effect of fingolimod on optic nerve remyelination when compared to IFN-β treatment. Interpretation is limited by the small number of complete observations, an unexpected deterioration of the control group and a difference in baseline mfVEP latencies. The findings need to be confirmed in larger studies.Trial registration: The trial was registered as EUDRA-

Early predictors of visual and axonal outcomes after acute optic neuritis

“…Acute ON remains a common phase II clinical trial model for neuroprotective and/or remyelinating therapies in patients at risk of, or with MS ( 4 – 8 ). These clinical trials studied varying primary and secondary outcomes, concentrating on either visual loss, or axonal loss, but have not used early assessments as a selection strategy to identify participants who would have poorer outcomes after acute ON.…”

“…Predicting patients who will have poor recovery in the long term is of utmost importance in selecting patients early in their disease course who will benefit from these treatment trials. Due to its close association with multiple sclerosis (MS), intervention after acute and/or chronic ON is now an established clinical trial model for phase studies of potential neuroprotective and remyelinating treatments ( 4 – 8 ), However, the current literature is conflicting and incomplete for choosing a reliable predictor.…”

Teriflunomide treatment is associated with optic nerve recovery in early multiple sclerosis

“…Similar combinations of the abovementioned effects were also observed for fingolimod, which had beneficial effects following ON in a smaller study, and, besides its profound anti-inflammatory effects, exerts a plethora of direct effects on CNS cells by S1P receptor modulation. 17,18 Furthermore, preclinical data also suggested protective effects for 4-aminopyridine in ON, which was potentiated by a combination of immunomodulation and explained by direct effects on the optic nerve. 19 Several substances have demonstrated subtle or borderline significant beneficial effects on structural or functional outcomes in controlled clinical trials on acute ON or chronic optic nerve demyelination.…”

Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis

“…Neuroprotective effects of such drugs as erythropoietin [ 33 ], simvastatin [ 34 ], phenytoin [ 35 ], and anti-LINGO-1 antibody opicinumab [ 36 ] were evaluated with this technique. In another recent study of patients with acute unilateral optic neuritis, a significant shortening of VEP latency after six months of fingolimod treatment was reported [ 37 ].…”