Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of MS (RMS). Ozanimod 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 MS is unknown but may involve reduction of lymphocyte migration into the central nervous system. In healthy volunteers (HV) and patients with RMS, ozanimod induces differential reductions in lymphocyte subset counts.
To evaluate the recovery of lymphocyte subsets to pre-treatment levels following discontinuation of ozanimod in HV.
In a phase 1, randomized, double-blind, placebo-controlled study (NCT03694119) in HV (25–55 y), oral ozanimod 1.84 mg/d (2 x the approved dose, n=27) was administered for 28 days, which included a 10-day dose escalation (0.23 mg/d x 4 d, 0.46 mg/d x 3 d, and 0.92 mg/d x 3 d). Lymphocyte subset counts were evaluated at baseline and at 7±2 and 75±10 days after cessation of ozanimod. Lymphocyte subsets were measured using an epigenetic platform and are summarized descriptively as mean (standard deviation [SD]) percentage change from baseline.
At 7±2 days after cessation of ozanimod, total lymphocyte counts were reduced by 52.4% (23.0) from baseline and CD3+ T cells were reduced by 49.7% (20.1). Within the T-cell population, CD4+ (−56.1% [22.5]), CD8+ (−39.3% [24.5]), regulatory T cells (−31.6% [30.3]), and Th17 cells (−36.5% [27.2]) were reduced from baseline. Total B cells (−56.3% [25.3]) and memory B cells (−46.6% [16.5]) were also reduced. At 75±10 days after cessation of ozanimod, total lymphocytes and all subsets had recovered to near baseline values, although at different rates. Total lymphocytes (−18.3% [26.1]) had less recovery than CD3+ (−4.8% [28.0]), CD4+ (−14.5% [27.5]), and CD8+ (−11.0% [26.0]) T cells. Th17 cells (3.8% [33.5]) recovered faster than regulatory T cells (−15.4% [28.8]). Total B cells (−18.6% [25.1]) and memory B cells (−18.9% [24.7]) had recovered less than T cells.
Ozanimod induced differential declines in T and B cell subsets in HV. By the final assessment at 65‒85 days after cessation of ozanimod, all cell populations evaluated showed gradual and variable rates of recovery to near baseline levels, indicative of a return of circulating lymphocytes toward pre-treatment levels.