At Week 24, most participants in both groups (placebo, 74% [26/35]; opicinumab, 69% [22/32]) had a clinically meaningful improvement of ≥4 points from baseline in NEI-VFQ-25 composite score, whereas no participants in the placebo group and 6% (2/32) of the opicinumab group experienced a ≥4-point decline (see Supplemental Digital Content, Figure E1, http://links.lww.com/WNO/A330). Similarly, at Week 32, 71% (25/35) and 74% (23/31) of the placebo and opicinumab groups, respectively, had a ≥4-point improvement in NEI-VFQ-25 composite score, whereas 1 participant in each group experienced a ≥4-point decline. Neither of the 2 participants who experienced the 4-point decline developed new or recurrent AON during the RENEW study.
High-Contrast Visual Acuity Outcomes: Per-Protocol Population
The mean baseline HCVA letter score of the affected eyes was lower than that of the fellow eyes in both the placebo (affected eye, 44.4 letters; fellow eye, 58.3 letters) and opicinumab groups (affected eye, 43.0 letters; fellow eye, 60.4 letters; see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A324). Both groups experienced partial recovery in HCVA during the study. No differences in recovery between treatment groups were observed for the ANCOVA or MMRM analyses. The adjusted mean recovery from baseline in the HCVA letter score at Week 24 for the affected eyes by ANCOVA was 11.8 letters for the placebo group and 8.7 letters for the opicinumab group (difference for the adjusted mean [95% CI]: −3.2 [–8.0 to 1.7] letters; P = 0.202). Adjusted mean changes in HVCA over time, analyzed using the MMRM, showed similar improvements in the affected eye in both treatment groups over 24 weeks (Fig. 2). In the fellow eyes, small improvements from baseline in the HCVA letter score were observed in both treatment groups (Fig. 2).
Mean LCLA outcomes at baseline and Weeks 24 and 32 for participants in the PP population of RENEW were calculated (see Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A325). As previously described, no treatment differences were observed between placebo and opicinumab (10).
Pairwise Correlation Analyses
Results of pairwise correlation analyses are provided (see Supplemental Digital Content, Tables E4, http://links.lww.com/WNO/A326, E5, http://links.lww.com/WNO/A327, and E6, http://links.lww.com/WNO/A328). Change in FF-VEP, RNFL thickness, HCVA, and LCLA for each time point is the change for the affected eye at that time point from the baseline of the unaffected fellow eye. Overall, in the RENEW PP population, correlations between change from baseline in the mean NEI-VFQ-25 composite score and mean RNFL thickness and mean FF-VEP amplitude were negative and mild in both treatment groups for both time points (see Supplemental Digital Content, Table E4, http://links.lww.com/WNO/A326). Correlations between change from baseline in the mean NEI-VFQ-25 composite score and mean FF-VEP latency were positive and mild in both treatment groups for both time points (see Supplemental Digital Content, Table E4, http://links.lww.com/WNO/A326). Correlations of change from baseline were largely absent between the NOS-10 composite score and RNFL thickness, FF-VEP amplitude, and FF-VEP latency for both time points and both treatment groups.
Moderate correlations were observed between recovery of HCVA and LCLA and recovery of mean FF-VEP latency in the placebo arm; this correlation was lost in the 100 mg/kg opicinumab group. RNFL thinning showed the best overall correlation with changes in LCLA in both treatment groups (see Supplemental Digital Content, Tables E5, http://links.lww.com/WNO/A327, and E6, http://links.lww.com/WNO/A328). Recovery of patient-reported visual function showed absent or mild correlation with changes in VA. The strongest correlation of change from baseline was observed between the 1.25% and 2.5% LCLA endpoints. HCVA was more highly correlated with 2.5% LCLA vs 1.25% LCLA.
RENEW was the first study of its kind to evaluate patient-reported visual functioning in patients with an AON episode treated with a candidate optic nerve reparative treatment in addition to the standard-of-care treatment with high-dose steroids. Randomization was balanced except that more severe cases of AON were randomized to the opicinumab group vs the placebo group, as previously discussed (10). Lower baseline NEI-VFQ-25 composite scores, NOS-10 composite scores, and lower HCVA in the affected eye (vs the fellow eye) show that most participants had some impairment in visual functioning at the start of the study. Regardless of treatment group, participants demonstrated notable improvements in patient-reported vision-related functioning scores from baseline to Week 24. In fact, most participants in both treatment groups (∼70%) demonstrated a clinically meaningful improvement of ≥4 points in the NEI-VFQ-25 composite score from baseline to Week 24. Although mean NEI-VFQ-25 composite scores had substantial improvements by Week 24, they were still lower than those observed in a healthy eye disease-free reference population (3,6). These findings suggest that the participants had clinically meaningful recovery of their self-reported visual functioning but with some residual impairment resulting from persistent injury to the optic nerve and retinal ganglion cells.
Improvements in the HCVA letter score from baseline to Week 24 in the affected eye were also similar between the 2 treatment groups. Most improvements in HCVA from baseline occurred by Week 12 for both treatment groups. This observation is consistent with the natural recovery of AON, during which HCVA improves for most patients within the first 2 months after the onset of symptoms (13). Improvements from baseline in LCLA (1.25% and 2.5% Sloan chart) in the affected eye were also similar between the placebo and opicinumab groups; no between-treatment differences were observed (10). Compared with the fellow eye, deficits in LCLA were evident in the affected eye in both treatment groups at Weeks 24 and 32.
The small improvements seen in the HCVA of the fellow eyes may be due to practice effects and familiarity with standardized testing conditions, as the tests were repeated frequently over 24 weeks. However, subtle involvement of the fellow eye in cases of unilateral AON has been suggested as another possible mechanism. An analysis of fellow eyes in patients from the Optic Neuritis Treatment Trial (ONTT) reported that visual deficits observed in the fellow eye of some patients at the onset of unilateral AON recovered to normal after 6 months and may not have been related to preexisting demyelination (14).
Changes in RFNL thickness, P100 latency, and P100 amplitude were found to be weakly correlated with change in patient-reported visual function as measured with the NEI-VFQ-25, but no correlations were observed with the NOS-10. Changes in VA outcomes demonstrated no correlations with changes in the NEI-VFQ-25 and mild to absent correlations with changes in the NOS-10. The strongest correlations between change in VA and biomarkers were seen for P100 latency and LCLA in the placebo arm. By contrast, a mild correlation was seen for change in VA with change in P100 amplitude in the opicinumab group but not in the placebo group. Change in RNFL thickness showed a consistent correlation with the change from baseline in all LCLA outcomes in both the placebo and opicinumab groups, linking RNFL thickness to LCLA. Treatment with opicinumab improved the latency without corresponding improvements in measures of VA.
Despite the marked improvements from baseline in the affected eyes, the HCVA of the affected eyes remained below that of the fellow eyes in both treatment groups. Previous studies have shown that patient-reported vision-related functioning is reduced in patients with a history of AON even with “good” recovery of HCVA. An analysis of patients from the ONTT found that NEI-VFQ-25 scores were lower in study patients compared with an independent healthy reference group 5–8 years after study entry, despite the majority of patients (61%) having VA 20/20 or better (1). A cross-sectional observational cohort study by Sabadia et al (3) that examined patient-reported vision-related functioning in patients with history of AON with VA recovery of 20/40 or better also found that NEI-VFQ-25 and NOS-10 scores were significantly reduced compared with disease-free controls.
The residual impairment in patient-reported visual functioning, HCVA, and LCLA seen in some participants is consistent with the SD-OCT–observed retinal ganglion cell layer neuronal thinning that occurred early after the AON onset and was completed to a large extent before study randomization (10). This limited the ability to study whether treatment with opicinumab may be neuroprotective when given within 28 days of the onset of AON, suggesting a shorter enrollment window than that used in the RENEW study may be needed in future studies of neuroprotective therapies.
The marked and natural recovery of patient-reported visual functioning scores and HCVA in the placebo group of patients with AON further limited the potential to demonstrate the clinical benefit of opicinumab in the RENEW study. The simple activities assessed with these measures may not adequately capture the complex multidimensional activities used by subjects in this population affected by AON and at risk of AON episodes. Presently, the only therapy available for the treatment of AON is a short course of high-dose IV steroids, such as methylprednisolone, which may accelerate recovery of vision but does not significantly improve long-term visual function (13). It is possible that administration of methylprednisolone played some role in the clinical recovery observed in both arms of this study (13).
It is unclear whether any of the 49 items included in the NEI-VFQ-25 and NOS-10 are specifically sensitive to demyelination/remyelination in the optic nerve, as these instruments are not specific to AON. The NOS-10, which was developed for neuro-ophthalmologic disorders (6), seems to be more sensitive than the NEI-VFQ-25 based on the nature of its items and the lower baseline and end of study scores. In this study, it showed more impairment at baseline and had more sensitivity to change over time than the NEI-VFQ-25. However, the change in NEI-VFQ-25 scores showed some correlation with changes by OCT and VEP, whereas the NOS-10 did not. In addition, neither item sets are specific to the sudden loss of vision because of AON or the complex daily visual activities in an otherwise healthy, working-age population.
It is important to understand the mechanisms underlying the observed recovery in vision-related PROs in the placebo group from baseline to Week 24. The mandatory use of high-dose steroids likely contributed to the speed of visual recovery (13). The fact that participants similarly recovered on VA scores regardless of VEP latency recovery is a critical issue to examine in the context of the clinical development of CNS remyelinating therapies and the observed benefit of opicinumab on VEP latency recovery in the PP population (10). VEP latency recovery was selected as the primary efficacy endpoint in the RENEW study because it was predicted to be the most sensitive to a CNS remyelinating therapy and because CNS remyelination had the strongest evidence of efficacy in preclinical rodent models. At present, there is no clarity on which clinical measures, if any, are sensitive to CNS remyelination, as this is a new therapeutic field.
Despite good recovery of HCVA and LCLA in the RENEW study, complete recovery of patient-reported visual function did not occur in many patients, likely due to the initial neuroaxonal loss as a result of AON and the persistence of demyelination for surviving optic nerve axons (4,15). The marked clinical improvement that follows AON despite residual damage to the retina and optic nerve as demonstrated by OCT and VEP may be potentially due to adaptive neuroplasticity, defined as the reorganization of the structure and function of the brain in response to injury (16). Adaptive neuroplasticity has been proposed as a potential key contributor to the recovery of visual function in AON cases (17–19) and evidence of it in AON has been demonstrated in several studies (18–20).
Limitations of this study include the small sample size (10) and, as previously discussed, the rapid onset of injury to the retina after AON, which limited the therapeutic window for potential neuroprotection with high-dose opicinumab. Another potential limitation is that it is unclear whether the visual function endpoints selected correlate with VEP latency improvement, the prespecified primary endpoint of the RENEW study (21). Furthermore, it is possible that the current patient-reported assessments of visual functioning are mistargeted in terms of complexity and may not address important visual function items in this digitally engaged population. No qualitative or conceptual framework evidence exists to support the use of these measures in AON. Detection of movement is one example of an important visual function that is not properly captured with the existing instruments (22).
Overall, this study found that the majority of RENEW participants demonstrated improved, albeit incomplete, recovery in patient-reported visual functioning and HCVA regardless of treatment group. Despite the lack of between-treatment differences between high-dose opicinumab and placebo, these results provide important information on the course and extent of recovery of clinical visual function in patients with AON and how they relate to the structural changes that take place in the retina and optic nerve.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: L. Balcer, S. Galetta, Y. Chai, L. Xu, and D. Cadavid; b. Acquisition of data: Y. Chai, L. Xu, and D. Cadavid; c. Analysis and interpretation of data: J. Petrillo, L. Balcer, S. Galetta, Y. Chai, L. Xu, and D. Cadavid. Category 2: a. Drafting the manuscript: J. Petrillo, L. Balcer, S. Galetta, and D. Cadavid; b. Revising it for intellectual content: J. Petrillo, L. Balcer, S. Galetta, Y. Chai, L. Xu, and D. Cadavid. Category 3: a. Final approval of the completed manuscript: J. Petrillo, L. Balcer, S. Galetta, Y. Chai, L. Xu, and D. Cadavid.
The authors thank all the participants and investigators in the RENEW trial. Biogen provided funding for medical writing support in the development of this manuscript. Rebecca A. Jarvis from Excel Scientific Solutions wrote the first draft of the manuscript based on input from the authors, and Elizabeth Cassell from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the paper to the authors. The authors had full editorial control of the paper and provided their final approval of all content.
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Supplemental Digital Content
© 2019 by North American Neuro-Ophthalmology Society