Phase 4 Study to Test Switch From Anti-CD20 Therapy to Ozanimod in Stable MS

A recently launched phase 4, open-label, prospective study (NCT06529406) will test the safety and efficacy of ozanimod (Zeposia; BMS), an FDA-approved sphingosine 1-phosphate receptor (S1P) modulator, as a de-escalation therapy in clinically stable patients with relapsing multiple sclerosis (MS) previously treated with anti-CD20 medication. Study site start-up is currently in progress, with the hope that the findings will provide valuable clinical insights on treatment decisions for stable patients living with the disease.¹

An update on the trial was presented as a poster at the 2025 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1 in West Palm Beach, Florida. The study, conducted across several tertiary MS referral centers, is expected to include patients with MS-related symptoms for at least 3 years who’ve had no inflammatory disease activity for at least 2 years and were on anti-CD20 therapy continuously for at least 2 years.

Led by Enrique Alvarez, MD, PhD, an associate professor of neurology at the University of Colorado School of Medicine, the study will use new T2 lesion count and number of serious infections over at least 36 months of follow up as the primary end points. Adverse events (AEs), number of infections, immunoglobulin G and IgM levels, number of relapses, and no evidence of disease activity (NEDA-3) will be used as secondary end points. The study is expected to include at least 500 patients on continuous anti-CD20 therapy who will switch over to ozanimod for an additional 36 months.

For the trial, Ozanimod titration will begin with a dose of 0.23 mg taken orally once daily on days 1-4, followed by 0.46 mg (two 0.23 mg pills) taken once daily on days 5-7. Subjects will receive two bottles, each containing seven 0.23 mg pills, to complete the titration phase. Starting on day 8, maintenance dosing will commence with 0.92 mg taken daily, provided in bottles containing 30 pills of the 0.92 mg dose to ensure sufficient supply.

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Exploratory endpoints of the study include assessments of cognition (4-point/10% change on the Symbol Digit Modalities Test), hand function (20% change on the 9-Hole Peg Test), and walking speed (20% change on the 25-Foot Walk Test). The Multiple Sclerosis Functional Composite (MSFC) will capture changes in any of these criteria. Patient-reported outcomes (PROs) will measure a minimum of 5% change in treatment satisfaction (TSQM), fatigue (Modified Fatigue Impact Scale), and quality of life (MSIS-29). Additionally, changes in employment status and the proportion of participants achieving full employment will be analyzed.

Alvarez and colleagues first announced the design of this study in mid-2024, hypothesizing that a transition to ozanimod may provide some advantages over other treatments after B-cell depletion. Ozanimod, a once-daily oral medication with high tolerability, may provide advantage over fumarates, which are twice daily treatments that have high rates of gastrointestinal intolerability. Additionally, the study authors proposed that ozanimod may have advantages over fingolimod, which was the first S1P partial agonist approved in the treatment of patients with MS, in that it may be safer.²

Due to the decreasing efficacy and increased risks associated with long-term, high-efficacy treatments, de-escalation to safer therapies has become a viable option for MS management. The STRATEGY study (n = 506) evaluated de-escalation from natalizumab (Tysabri; Biogen) to dimethyl fumarate (DMF) across 45 US centers. After one year, the relapse rate was 19.6%, with 8% of patients discontinuing DMF due to adverse events, most commonly gastrointestinal. Limitations included the inclusion of patients with varied disease stability, which may have contributed to continued disease activity.³

Another study evaluated de-escalation from natalizumab to teriflunomide in 51 relapse-free MS patients who had been on natalizumab for an average of 3.4 years. Following a switch to teriflunomide (14 mg daily), patients were monitored for relapse, EDSS, and MRI changes over 12 months. At the end of the study, 29.4% of patients showed new MRI activity, with 14 having contrast-enhancing lesions. Three patients (5.8%) required a change in DMT due to MRI progression, while another 5.8% dropped out due to adverse events or lack of efficacy. The results underscore that while de-escalation to teriflunomide can be effective for relapse-free patients, careful monitoring for disease progression is critical.⁴

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REFERENCES
1. Alvarez E, Honce J, Chaudry B, et al. P111. Trial in Progress: A Multicenter, Open-Label, Prospective Phase 4 Study Evaluating the Safety and Efficacy of Sequencing From Anti-CD20 Therapies to Ozanimod in Clinically Stable Patients With Multiple Sclerosis. Presented at: 2025 ACTRIMS Forum; Feb 27-March 1; West Palm Beach, FL. ABSTRACT P111.
2. Alvarez E, et al. Prospective Evaluation of Sequencing from antiCD-20 Therapies to Ozanimod. Published online July 2, 2024. Accessed February 25, 2025. file:///Users/mmeglio/Desktop/Photo%20screenshots/Prot_SAP_000.pdf
3. Cohan SL, Moses H, Calkwood J, Tornatore C, LaGanke C, Smoot KE, et al. Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: A multicenter retrospective observational study (STRATEGY). Mult Scler Relat Disord. 2018;22:27-34. doi: 10.1016/j.msard.2018.02.028
4. Cohan SL, Edwards K, Lucas L, Gervasi-Follmar T, O'Connor J, Siuta J, et al. Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy. Mult Scler J Exp Transl Clin. 2019;5(1):2055217318824618. doi:10.1177/2055217318824618