Study Describes Ozanimod’s Mechanism of Action in Relapsing MS

Ozanimod reduces B and T cells in patients with relapsing multiple sclerosis (RMS) at levels dependent on dosing, and has differential effects on naive and memory CD4+ and CD8+ T cells and CD19+ B cells, according to a new investigation of the drug’s mechanism of action.

Ozanimod is a sphingosine-1-phosphate (S1P) receptor 1 and 5 modulator and is FDA-approved for the treatment of relapsing forms of MS. In Europe, it is approved for relapsing-remitting MS (RRMS).

Writing in the journal Neurology Neuroimmunology & Neuroinflammation, corresponding author Sarah Harris, PhD, of Bristol Myers Squibb, and colleagues explained their findings from an exploratory analysis of a phase 1 trial of ozanimod. Their goal was to better understand how the drug affects circulating leukocyte subsets in patients with RMS. Bristol Myers Squibb markets ozanimod under the trade name Ziposia.

The phase 1 study referenced in the new report randomized patients to ozanimod hydrochloride in 2 dosage groups, 0.5 mg/d (13 patients) or 1 mg/d (11 patients). All patients were treated for 12 weeks, including a 7-day dosing escalation. The investigators counted circulating leukocyte subsets using flow cytometry on days 28, 56, and 85 and epigenetic cell counting on days 2, 5, 28, 56, and 85.

The authors found that absolute lymphocyte counts dropped in correlation with dosage. At day 85, CD19+ B-cell counts and CD3+ T-cell counts were reduced by >50% in patients receiving the lower dose and >75% in patients with the higher dose. The flow cytometry analysis also showed the higher dosage had the following effects:

• Reductions in CD4+ were greater than reductions in CD8+ T cells
• Reductions in CD4+ and CD8+ central memory T cells were greater than the reductions in effector memory T cells
• Reductions in mean CD4+ and CD8+ naive T cells were ≥90%
• Changes in monocytes, natural killer, and natural killer T cells were minimal
• Epigenetic cell counting further showed that Th17 cells were reduced at a greater rate than T regulatory cells.

Harris and colleagues said their findings were largely in line with earlier research. As for the lack of an impact on natural killer and natural killer T cells, the authors said the findings could raise the concern that the therapy increases the risk of infection and malignancy in patients taking the therapy.

“However, phase 3 clinical trials of ozanimod showed infection rates that were comparable with patients treated with IM interferon beta-1a, and infrequent serious infections, no serious opportunistic infections, and low (<1%) rates of malignancy among patients with RMS receiving ozanimod,” the authors wrote.

Another important finding of the study was simply that the higher dosage led to meaningful increased effects.

The authors cautioned, however, that their primary goal was to describe the mechanism of action of ozanimod, and thus the study should be seen as exploratory. They said the novel approach of using epigenetic cell-counting in addition to flow cytometry helped to bolster their overall analysis, but said a cross-validation study of epigenetic cell-counting and flow cytometry methods would be worth pursuing.

Reference

Harris S, Tran JQ, Southworth H, Spencer CM, Cree BAC, Zamvil SS. Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e839. Published July 31, 2020. doi:10.1212/NXI.0000000000000839