Assessment of Opicinumab in Acute Optic Neuritis Using Multifocal Visual Evoked Potential

Abstract

Background: Multifocal visual evoked potential (MF-VEP) assesses a wider visual field than full-field VEP (FF-VEP) and potentially offers a more precise analysis of optic nerve injury and repair following optic neuritis. MF-VEP may offer advantages over FF-VEP as an endpoint in clinical trials of remyelinating therapies.

Objective: MF-VEP testing was used to study changes in visual pathways in 48% of RENEW [phase II, opicinumab (anti-LINGO-1; BIIB033) vs. placebo after first acute unilateral optic neuritis] participants.

Methods: This exploratory MF-VEP RENEW substudy compared mean outcomes at weeks 24 and 32 among participants in the intent-to-treat (ITT; n = 39; 72% female; mean age: 32.3 years) and per-protocol (PP; n = 31; 71% female; mean age: 32.2 years) populations in affected and fellow eye latency from fellow eye baseline latency and affected and fellow eye amplitude from their own baselines. Treatment differences were evaluated using analysis of covariance (week 24) and a mixed-effect model of repeated measures (week 32). Last observation carried forward was used to impute missing data at week 24.

Results: A trend for improvement in affected eye MF-VEP latency with opicinumab versus placebo was seen in the ITT and PP populations at weeks 24 and 32. Both treatment groups in the ITT population experienced partial recovery of amplitude in the affected eye at week 32. Notably, the mean change in fellow eye amplitude at weeks 24 and 32 was - 17.57 and - 31.41 nanovolts (nV) in placebo but only - 0.59 and 1.93 nV in the opicinumab group [differences at weeks 24 and 32: 16.98 nV (p = 0.050) and 33.33 nV (p < 0.01), respectively].

Conclusion: Results from this substudy showed advantages of MF-VEP over FF-VEP in multicenter studies of central nervous system reparative therapies and provide novel evidence that fellow eye visual pathway amplitude loss occurs after optic neuritis but can potentially be prevented by opicinumab treatment.

Registration: ClinicalTrials.gov identifier NCT01721161.

Conflict of interest statement

Alexander Klistorner has nothing to disclose. Yi Chai was a full-time employee of Biogen during the performance of the clinical trial, data analysis, and initial drafting of the manuscript. Letizia Leocani has received honoraria for consulting and/or speaking activities from Biogen, Merck, Roche, and Teva; research support from Biogen, Merck, and Novartis; and travel support from Almirall, Biogen, Merck, Novartis, and Roche. Philipp Albrecht has received grants from Biogen, the Dr. Robert Pfleger Foundation, Ipsen, Merz, and Novartis; received non-financial support from Bayer HealthCare, Ipsen, Merck, Merz, Novartis, Roche, and Teva; participated in advisory boards for Allergan, Ipsen, and Merz; and received personal fees from Allergan, Bayer HealthCare, Biogen, Ipsen, Novartis, Roche, and Teva, outside of the submitted work. Orhan Aktas has received advisor fees or honoraria from Almirall, Bayer HealthCare, Biogen, MedImmune, Merck, Novartis, and Teva; and research support from Bayer HealthCare, Biogen, Novartis, Roche, and Teva. Helmut Butzkueven has participated in advisory boards for Biogen, Merck, Novartis, and Teva; received consulting fees from Novartis and Oxford Pharmagenesis; lecture fees from Biogen; received payment for development of educational presentations from Biogen, Merck, and Novartis; and research grants from Biogen and Novartis, outside of the submitted work. Tjalf Ziemssen has received consulting fees from Almirall, Bayer HealthCare, Biogen, Genzyme, GlaxoSmithKline, Merck Serono, MSD, Novartis, Sanofi-Aventis, Synthon, and Teva; and research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi-Aventis, and Teva. Focke Ziemssen has received consulting fees from Alimera, Allergan, Bayer HealthCare, Boehringer Ingelheim, Novartis, and Roche; and research support from Novartis. Jette Frederiksen has participated in scientific advisory boards for Almirall, Biogen, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva; received speaker honoraria from Biogen, Merck Serono, Santhera, and Teva; and been an advisor on preclinical development for Takeda, outside of the submitted work. Lei Xu was a full-time employee of Biogen during the performance of the clinical trial, data analysis, and initial drafting of the manuscript. Diego Cadavid was a full-time employee of Biogen during the performance of the clinical trial and a full-time employee of Fulcrum Therapeutics during submission of the manuscript; the work is not related to his employment in Fulcrum Therapeutics. He has patent WO 2016112270 A1: Lingo-1 antagonists and uses for treatment of demyelinating disorders, which is assigned to Biogen.

Figures

Fig. 1

Individual segments assessed using a multifocal visual evoked potential and b reversing black-and-white checks used for monocular stimulation

Fig. 2

Mean change in MF-VEP latency, adjusted for the baseline latency of unaffected fellow eye, at a week 24 and b week 32 in the affected eye compared with the unaffected fellow eye at baseline in the substudy ITT and PP populations. Error bars represent 95% CIs. aAnalyzed by analysis of covariance. bAnalyzed by mixed-effect model of repeated measures. CI confidence interval, ITT intent-to-treat, MF-VEP multifocal visual evoked potential, PP per protocol

Fig. 3

Mean change in multifocal visual evoked potential amplitude by treatment from baseline over 32 weeks in the a affected eye and b unaffected fellow eye in the intent-to-treat population. In the heat map displays, green represents amplitude gains (improvement) and red represents amplitude losses (worsening) from baseline. Results for the per protocol population were not calculated. aCompared with baseline value of the affected eye. bCompared with baseline value of the fellow eye. CI confidence interval, nV nanovolts

Fig. 4

Adjusted mean differences in a MF-VEP latency and b amplitude at week 24 in participants classified with latency recovery using the primary endpoint measure of FF-VEP. FF-VEP latency recovery was defined as affected eye FF-VEP latency at week 24 ≤ 10% worse than the baseline fellow eye; FF-VEP latency was the primary endpoint in RENEW. CI confidence interval, FF-VEP full-field visual evoked potential, MF-VEP multifocal visual evoked potential