P037 Effect of Ozanimod Treatment and Discontinuation on Absolute Lymphocyte Count in Moderate-to-Severe Ulcerative Colitis: Results from a Phase 3 Trial

BACKGROUND: Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, which reduces migration of lymphocytes involved in adaptive immunity from lymphoid tissues to blood and inflamed tissues while preserving components of the innate immune response. Ozanimod is approved in multiple countries for the treatment of relapsing forms of multiple sclerosis and in the US for the treatment of moderately-to-severely active ulcerative colitis (UC). The reduction of circulating lymphocytes is expected based on the mechanism of action of ozanimod and thought to be an important driver of efficacy. METHODS: We assessed absolute lymphocyte count (ALC) during ozanimod induction and maintenance, and after ozanimod discontinuation, per protocol, in adults with moderately-to-severely active UC to characterize the time course of ALC reduction and recovery. The analysis included patients who received ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo once daily in True North, a phase 3 randomized trial (NCT02435992). During a 10-week induction period, patients were randomized 2:1 to double-blind treatment with ozanimod or placebo (Cohort 1) or received open-label ozanimod (Cohort 2). Patients from either cohort with a clinical response to ozanimod at week 10 were re-randomized 1:1 to double-blind treatment with ozanimod or placebo during maintenance through week 52. Placebo-treated patients with a clinical response at week 10 continued placebo during maintenance. ALC was assessed at baseline and at visits throughout induction and maintenance. RESULTS: A total of 69 patients received continuous placebo treatment, 230 received continuous ozanimod treatment, and 227 received ozanimod during induction and placebo during maintenance. In patients who received continuous placebo, mean ALC remained stable between 1.8‒2.1 x 109/L over time (normal range: 1.02‒3.36 x 109/L). In ozanimod-treated patients, mean ALC was reduced to 43%‒45% of baseline and 70%‒73% of patients had ALC shifts from normal at baseline to low (9/L) at week 10. In patients who continued ozanimod, mean ALC reductions were sustained at approximately the same level and ALC shifts from normal at baseline to low were maintained in 73%‒89% of patients during maintenance. In patients who received ozanimod induction therapy and then were re-randomized to placebo for maintenance, mean ALC recovered within 8 weeks to levels similar to baseline at induction and the proportion of patients with ALC shifts from normal at baseline to low decreased from 73% at week 10 to 6% at week 52. Fewer than 2% of ozanimod-treated patients had ALC 9/L during either induction or maintenance and ALC generally returned to ≥ 0.2 x 109/L while patients remained on ozanimod. Among those who switched from ozanimod induction to placebo maintenance, there were no occurrences of ALC 9/L at the end of maintenance. No patients with a serious/opportunistic infection had concurrent ALC 9/L. CONCLUSION: Consistent with the mechanism of action of ozanimod, ALC reductions occurred during ozanimod induction and were sustained during maintenance. Incidence of ALC 9/L was low. ALC recovered after switching to placebo and most patients did not require treatment discontinuation because of changes in ALC.