RENEW Trial: Promising Results for Optic Neuritis Treatment

The human monoclonal antibody opicinumab may potentially enhance spontaneous remyelination after acute optic neuritis (AON), according to prespecified per protocol population results, but not intent-to-treat (ITT) results, of a study published in the Lancet.¹

Opicinumab inhibits leucine-rich repeat and immunoglobulin domain-containing neurite outgrowth inhibitor receptor interacting protein-1 (LINGO-1), a mechanism that has previously demonstrated remyelination properties in vitro and in rat and mice studies of demyelination of the central nervous system.^2-4

A multinational team of investigators enrolled a total of 82 patients (41 opicinumab, 41 placebo) into the Safety and Efficacy of Opicinumab in Acute Optic Neuritis (RENEW) phase 2 trial and followed them for 32 weeks. The results showed slightly shorter latency of optic nerve conduction velocity of the affected eye (measured by full-field visual-evoked potentials) at 24 weeks, with no significant difference compared with placebo in the ITT group (adjusted mean of treatment difference: −3.5 ms [17.3 (SE, 2.5) vs 20.8 (SE, 2.5); 95% CI, −10.6 to 3.7; P =.33], 17% improvement). A significant difference was observed, however, at week 32 in the per protocol treatment group compared with placebo (−9.1 ms [13.2 vs 22.4; 95% CI, −16.1 to −2.1; P =.011], 41% improvement).

Researcher Diego Cadavid, MD, lead author of the study, offered 2 possible explanations for this finding, the first of which was that the drug was actually no better than placebo. He discounted this theory, however, telling Neurology Advisor, “we believe that is unlikely because both the per protocol population analysis at 24 and 32 weeks and the prespecified responder analysis in both the ITT and per protocol population showed better recovery of [visual evoked potential] latency with opicinumab than placebo.” A more likely explanation, he said, was that the study was not powered to show statistical significance in the ITT population. “I believe this is indeed the case,” he added, “because the RENEW study was not designed to be powered for statistical significance on the primary endpoint ([visual evoked potential] latency recovery).”

Acute optic neuritis is often the first clinical sign of multiple sclerosis, and is associated with inflammation and retinal nerve fiber layer thinning that occurs in the first 6 months of onset and may continue for up to 1 year.^5,6 Remyelination begins after the acute inflammation resolves, but is often incomplete, as structural and functional damage often persists.^7,8

Measurement of axonal injury and retinal thinning by spectral-domain optical coherence tomography are prevented by initial inflammation caused by AON, although studies have shown that the retinal ganglion cell layer appears to be less affected by edema and can provide measurement of the timing of thinning. Recent studies suggest that thinning of the retinal ganglion cell layer starts within several weeks after an episode of ON and may precede retinal nerve fiber layer thinning.^9,10

Dr Cadavid reported that findings of the RENEW trial were consistent with the general knowledge that demyelination occurs rapidly after onset of AON symptoms, as about 90% of the patients showed delay on full-field visual-evoked potentials in the affected eye before treatment. “What is novel in RENEW was the learning that the loss of retinal ganglion cell neurons occurs very rapidly following AON, within days rather than weeks,” he said.

These combined results pointed to the potential for opicinumab to enhance remyelination after AON, and that intervention needs to begin within the first days after onset.

References

1. Cadavid D, Balcer L, Galetta S, et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16:189-199. doi: 10.1016/S1474-4422(16)30377-5
2. Mi S, Miller RH, Lee X, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005;8:745-751. doi: 10.1038/nn1460
3. Mi S, Miller RH, Tang W, et al. Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Ann Neurol. 2009;65:304-315. doi: 10.1002/ana.21581
4. Mi S, Hu B, Hahm K, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med. 2007;13:1228-1233. doi: 10.1038/nm1664
5. Petzold A, de Boer JF, Schippling S, et al. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2010;9:921-932. doi: 10.1016/S1474-4422(10)70168-X
6. Costello F, Hodge W, Pan YI, Eggenberger E, Coupland S, Kardon RH. Tracking retinal nerve fiber layer loss after optic neuritis: a prospective study using optical coherence tomography. Mult Scler. 2008;14:893-905. doi: 10.1177/1352458508091367
7. Galetta SL, Villoslada P, Levin N, et al. Acute optic neuritis: unmet clinical needs and model for new therapies. Neurol Neuroimmunol Neuroinflamm. 2015;2:e135. doi: 10.1212/NXI.0000000000000135
8. Moro SI, Rodriguez-Carmona ML, Frost EC, Plant GT, Barbur JL. Recovery of vision and pupil responses in optic neuritis and multiple sclerosis. Ophthalmic Physiol Opt. 2007;27:451-460. doi: 10.1111/j.1475-1313.2007.00501.x
9. Gabilondo I, Martínez-Lapiscina EH, Fraga-Pumar E, et al. Dynamics of retinal injury after acute optic neuritis. Ann Neurol. 2015;77:517-528. doi: 10.1002/ana.24351
10. Huang-Link Y-M, Al-Hawasi A, Lindehammar H. Acute optic neuritis: retinal ganglion cell loss precedes retinal nerve fiber thinning. Neurol Sci. 2015;36:617-620. doi: 10.1007/s10072-014-2011-2