Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator that blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
To characterize the phenotype of circulating leukocytes in relapsing multiple sclerosis (RMS) in participants treated with ozanimod.
In a phase 1, open-label, pharmacokinetic/pharmacodynamic study, 24 participants with RMS were randomized to oral ozanimod 0.46 (n=13) or 0.92 mg/d (n=11) [equivalent to ozanimod HCl 0.5 or 1 mg] for ~12 weeks, including an initial 7-d dose escalation (0.23 mg/d x 4d + 0.46 mg/d x 3d). Key exclusion criteria were active infection, history of chronic infections or immunodeficiency, recent live vaccination, previous lymphocyte-depleting or immunosuppressant therapy, and absolute lymphocyte count <1.0 × 109/L. Exploratory analyses used flow cytometry to characterize proportional changes from baseline in leukocyte subsets on days 28, 56, and 85 in total peripheral blood mononuclear cells (PBMC) and total T cells. Proportional change from baseline is reported using descriptive statistics.
Ozanimod was associated with dose-dependent decreases in absolute numbers of CD4+ and CD8+ T cells. Within the PBMC population, ozanimod was associated with a minimal increase in the proportion of CD8+ TEMRA cells (ozanimod 0.92 mg only) and no change in CD8+ effector memory T (TEM) cells. A decrease in the proportion of CD4+ and CD8+ naive and central memory T (TCM) cells and CD4+ TEM cells was evident. Within the total T cell population, ozanimod was associated with an increase in the proportion of CD4+ TEM cells (ozanimod 0.92 mg only) and CD8+ TEM and TEMRA cells. A decrease in the proportion of CD4+ naive (ozanimod 0.92 mg only) and CD8+ naive cells was observed; CD4+ and CD8+ TCM cells were minimally affected. Changes from baseline were more pronounced with ozanimod 0.92 mg than with ozanimod 0.46 mg.
During ozanimod treatment, the relative frequencies of circulating cell types within total PBMCs and within the remaining T cell population were altered. These shifts in circulating leukocyte proportions support the hypothesis that although ozanimod inhibits trafficking of some subsets of lymphocytes, the remaining circulating cells are still poised to provide immune surveillance.