BACKGROUND: People with MS show abnormal thinning of the retinal layers, which is associated with clinical disability and brain atrophy, and is a potential surrogate marker of neurodegeneration and treatment effects. OBJECTIVE: To evaluate the utility of retinal thickness as a surrogate marker of neurodegeneration and treatment effect in participants with secondary progressive MS (SPMS) from the optical coherence tomography (OCT) substudy of the EXPAND Phase 3 clinical trial (siponimod versus placebo). METHODS: In the OCT substudy population (n = 159), treatment effects on change in the average thickness of the retinal layer, peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (GCIPL) were analyzed by high-definition spectral domain OCT at months 3, 12, and 24. RESULTS: Thinning from baseline was observed across all retinal layers and time points in the placebo group. Siponimod significantly reduced GCIPL thinning versus placebo at month 24 (adjusted mean [SE] [µm]: -0.47 [0.81] vs. -4.29 [1.23]
p = 0.01), and overall retinal thinning at months 12 (+0.66 [0.54] vs. -1.86 [0.75]
p = 0.006) and 24 (-0.05 [0.59] vs. -2.30 [0.88]
p = 0.033). Although not significant, results for pRNFL consistently followed the same trends. CONCLUSION: This exploratory substudy supports further investigation of OCT measurement of retinal atrophy as a non-invasive potential biomarker of treatment effects on neurodegeneration in SPMS.