Predictors of response to opicinumab in acute optic neuritis

Abstract

ObjectiveThe objective of this study was to evaluate prespecified and post hoc analyses in RENEW subgroups to identify participants more likely to benefit from opicinumab.Methods RENEW assessed the efficacy/safety of opicinumab versus placebo in participants with a first unilateral acute optic neuritis (AON) episode. Difference in visual evoked potential (VEP) latency of the affected eye at 24 weeks versus the fellow eye at baseline was the primary endpoint. Interactions between the primary endpoint and prespecified baseline variables (including age, timing of treatment initiation, and visual impairment) using the median as cut‐off were evaluated in the per protocol population using analysis of covariance (ANCOVA); subgroups based on preexisting brain T2 lesion volume were also analyzed. Interactions between the primary endpoint and retinal ganglion cell layer/inner plexiform layer (RGCL/IPL) and retinal nerve fiber layer (RNFL) thickness were assessed post hoc as was weight gain by treatment.ResultsTreatment benefit of opicinumab (n = 33) over placebo (n = 36) on the primary endpoint was greatest in participants older than the median age at baseline (≥33 years); the difference versus placebo for baseline age ≥33 years was −14.17 msec [P = 0.01] versus −0.89 msec for baseline age <33 years, [P = 0.87]). Post hoc analysis showed that VEP latency recovery was significantly associated with less RGCL/IPL thinning (P = 0.0164), occurring early on.InterpretationAge was the strongest prespecified baseline characteristic associated with a treatment effect of opicinumab. A strong association between VEP latency recovery at week 24 and early RGCL/IPL preservation was observed.

Relapse recovery

“…At the moment, several such agents are moving along different phases of development and clinical trials. 18,28 Our current analyses, together with our previous observation that a poor early relapse recovery significantly shortens the time to progressive MS onset, 2 raise awareness of the importance of relapse recovery as a predictive factor of long-term outcomes in MS. Abbreviations: Gd+ = presence of gadolinium enhancement; HR = hazard ratio. a Variables included but were not significant or did not maintain significance in the multivariable analyses in either the 6th-month or 1st-year recovery model were sex, new T2 lesion number, T2 lesion volume, Gd+ lesion volume, brain parenchymal fraction, and syndrome at onset.…”

“…As it has been illustrated in the RENEW trial with Opicinumab (anti-LINGO-1) in acute optic neuritis (NCT01721161), where recovery was the actual outcome measure, subclinical recovery assessment exemplified by full-field visual evoked potential latency was found relevant as a potential confounder of outcome. 18 Therefore, we suggest that inclusion of such subclinical metrics of recovery also be considered in a definition of good-versus-poor recovery stratification at enrollment in addition to clinical recovery metrics.…”

“…This lower endogenous recovery potential later in life makes it easier to observe a change with exogenous recovery intervention in older patients in a clinical trial setting. 18 To understand the interaction between relapse recovery and DMT efficacy and given the impact of early relapses on longterm outcome in MS, the best approach would be a placebocontrolled, double-blind trial in CIS with stratification by relapse recovery at enrollment. However, use of DMTs in CIS and early MS is a well-established practice, and the feasibility of a future longitudinal trial could be challenging for recruiting sufficient size of an untreated population with CIS.…”

Monoclonal Antibodies in Multiple Sclerosis: Present and Future

“…However, there was a small improvement of 9.1 milliseconds on full field visual evoked responses in the per protocol analysis that was not significant in the intention to treat analysis [9]. Subgroup analysis showed an improvement for baseline age ≥33 years of −14.17 milliseconds suggesting a greater benefit in older patients [62].…”

“…Opicinumab has been well tolerated, adverse events have been similarly reported among groups treated with opicinumab and placebo [62,63]. However, some mild hypersensitivity reactions have been reported [61].…”