A Post Hoc Analysis of Immunoglobulin Levels in Patients with Relapsing Multiple Sclerosis Treated with Ozanimod in Phase 3 Trials

Background: Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of adults with relapsing forms of multiple sclerosis (RMS) or moderately to severely active ulcerative colitis. As expected from its mechanism of action, ozanimod decreases absolute lymphocyte count (ALC) and circulating CD19+ B- and CD3+ T-cell subsets in a dose-dependent manner. B and T cells are required for immunoglobulin (Ig) production, but the effect of ozanimod-induced lymphoid tissue sequestration of these cell types on circulating Ig levels is unknown.

Objectives: This exploratory, post hoc analysis evaluated whether ozanimod treatment results in changes in Ig levels (IgA, IgG, and IgM) and assessed the relationship of Ig changes to pharmacodynamic, clinical, and imaging outcomes in RMS patients.

Methods: Serum IgA, IgG, and IgM levels and blood ALC were quantified from samples obtained at baseline and 12-mo intervals from patients with RMS in the phase 3 RADIANCE (NCT02047734; 24-mo duration) and SUNBEAM (NCT02294058; ≥12-mo duration) trials who were randomized to ozanimod 0.46 or 0.92 mg/d or intramuscular interferon (IFN) β-1a 30 µg/wk. Relationships between median proportion of baseline Ig levels at mo 12 (SUNBEAM) or 24 (RADIANCE) and median proportion of baseline ALC, annualized relapse rate (ARR), and mean gadolinium-enhancing (GdE) lesions were analyzed from 1000 bootstrap samples.

Results: Ozanimod-treated patients maintained Ig levels within the normal range; however, dose-dependent decreases from baseline, and relative to IFN β-1a, were observed for all Igs. IFN β-1a‒treated patients showed increases for most of these Igs. At mo 12 in SUNBEAM, ozanimod was associated with dose-dependent median reductions from baseline in both Ig level (proportion of baseline: 0.46 mg=0.906, 0.92 mg=0.877) and ALC (proportion of baseline: 0.46 mg=0.503, 0.92 mg=0.364); similar results were observed at 24 mo in RADIANCE. In both trials, lower IgA, IgG, or IgM levels were associated with lower ARR and fewer GdE lesions in ozanimod-treated patients.

Conclusions: In phase 3 trials, ozanimod treatment resulted in dose-dependent decreases in circulating IgA, IgG, and IgM levels in patients with RMS; however, the Ig levels were maintained within normal ranges. The decreases in Ig levels were associated with lower ARR and fewer GdE lesions. These findings suggest that sequestration of B and T cells in lymphoid tissues by ozanimod does not severely diminish nor abolish circulating Ig levels.