Thalamic Volume Loss Reduced in Relapsing, Progressive Multiple Sclerosis Treated With Ocrelizumab

Douglas Arnold, MD

Using the phase 3 OPERA I and II (NCT01247324; NCT01412333) and ORATORIO (NCT01194570) studies, investigators found significantly reduced thalamic volume loss in patients with relapsing (RMS) and primary progressive multiple sclerosis (PPMS) treated with ocrelizumab (Ocrevus; Genentech) compared with those on interferon beta-1a or placebo.¹

Led by Douglas Arnold, MD, neurologist, Montreal Neurological Institute and Hospital, and Department of Neurology and Neurosurgery, McGill University, the study showed that ocrelizumab had the greatest effect on thalamic volume compared with whole brain, and white or cortical gray matter. “This could be explained from the perspective that thalamic injury may reflect much of the MS-related damage that occurs throughout the whole CNS and may not be specific to the thalamus only,” Arnold et al wrote.

Thalamic loss, typically occurring early in patients with MS, has been associated with loss in disability progression, measured by changes in Expanded Disability Status Scale (EDSS) and cognitive impairment. The aims of the study included evaluating the efficacy of ocrelizumab during the double-blind periods (DBPs); effectiveness of switching to or maintaining ocrelizumab in the open-label extensions (OLEs); the similarities and differences in thalamic atrophy based on MS subtype; and the relationship between thalamic volume, clinical outcomes, and disability progression.

Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model. At baseline, the normalized thalamic volume was 15.14 cm3 (±1.93) in patients with RMS and 14.41 cm3 (±1.80) in patients with PPMS. At the end of the DBPs (ORATORIO: 120 weeks; OPERA: 96 weeks), ocrelizumab progressively reduced thalamic volume loss by 43% and 35% in patients with RMS and PPMS, respectively. In comparison to whole brain, cortical gray matter, and white matter volume, treatment effect on the thalamus showed the largest effect size (respective Cohen d: RMS: 0.320, 0.383, 0.159, vs 0.561 for the thalamus; PPMS: 0.158, 0.126, 0.08 vs 0.427 for the thalamus).

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The study investigators wrote that "these findings, together with the association between thalamic volume and disability, suggest that measurement of thalamic volume loss may be a particularly useful biomarker for assessing treatment effects on the prevention of tissue damage."

After 7 years of treatment, those on ocrelizumab still showed 16% less thalamic volume loss compared with those on interferon beta-1a then ocrelizumab in OPERA and 25% less compared with those on placebo then ocrelizumab in ORATORIO. In PPMS, those who switched from placebo to ocrelizumab had a slightly lower rate of volume loss than ocrelizumab, but it was not significant (P = .071). When considering time points after OLE day 1, estimated yearly percentage changes for placebo to ocrelizumab and ocrelizumab were –0.42% per year (95% CI, –0.48% to –0.37%) and –0.53% per year (95% CI, –0.57% to –0.49%), respectively.

On clinical outcomes, lower thalamic volume at baseline was associated with the 9-Hole Peg Test (9HPT), Timed 25-Foot Walk, and EDSS scores in both RMS and PPMS. During the DBP for patients with RMS, the interaction between baseline thalamic volume and treatment was significant for composite 12- and 24-week confirmed disability progression (P = .019 and P = .024), as well as 12- and 24- week confirmed disability progression on 9HPT (P = .004 and P = .007). Across treatment groups, higher thalamic volume at baseline was associated with a decrease in progression events in the interferon beta-1a arm, but not in the ocrelizumab arm.

For the other disability progression measures, there were no evidence of an association between baseline thalamic volume and treatment effect on disability progression occurring during the DRP (P >.05 for all models). In PPMS, baseline thalamic volume was not significantly associated with any progression measure (P >.05 for all models).

REFERENCE
1. Arnold DL, Sprenger T, Bar-Or A, et al. Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS. Mult Scler J. Published online June 7, 2022. doi:10.1177/13524585221097561