Newly Launched Phase 4 ENABLE Trial to Test Real-World Efficacy of Ublituximab in Relapsing Multiple Sclerosis

Investigators have shared the study design of ENABLE, the first phase 4, post-marketing observational trial (NCT06433752) assessing ublituximab (Briumvi; TG Therapeutics), one of the more newly approved medications for relapsing multiple sclerosis that came into market in 2022. The study, which aims to collect data on effectiveness, safety, and tolerability of the therapy, is expected to enroll at least 500 patients with relapsing MS across 100 centers in the United States.¹

Expected to span a total of 96 weeks, this phase 4 study will use annualized relapse rates (ARRs) as the primary end point, with secondary end points that include proportion of patients experiencing adverse events (AEs), as well as incidence, severity, and type of infusion-related reactions (IRRs) at each infusion. Intended to collect data on a wide range of geographic and racial/ethnic populations, enrollment for the study is expected to take up to 24 months, with several sites already beginning enrollment back in mid-2024.

Presented at the 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5-9 in San Diego, California, the post-marketing study includes several exploratory end points as well. These include patient-reported outcomes such as the Treatment Satisfaction Questionnaire for Medication (TSQM) 1.4 and Multiple Sclerosis Impact Scale (MSIS-29), infusion time data (including premedication and post-infusion observation, and changes in immunoglobulins, B cell counts, MRI activity, Expanded Disability Status Scale, Symbol Digit Modalities Test, Timed 25-foot Walk, and Nine-Hole Peg Test.

Among the study investigators includes senior author Carrie Hersh, DO, MSc, FAAN, an associate professor of neurology at the Cleveland Clinic Lerner College of Medicine. For the study, Hersh and colleagues have put minimal restrictions on who can and can’t be included in the study. For inclusion, patients must have a confirmed MS diagnosis who were prescribed ublituximab but have not yet received their first infusion on day 1 of 150 mg. Patients are excluded if they received live or live-attenuated vaccines within 4 weeks, non-live vaccines within 2 weeks before the first ublituximab dose, had an active infection, or were participating in other interventional MS trials or planned to use other MS disease-modifying therapies in the study.

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Approved in 2022, ublituximab is an anti-CD20 monoclonal antibody that works by selectively targeting and depleting CD20-expressing B cells, which play a key role in MS-related neuroinflammation. Unlike other anti-CD20 therapies like ocrelizumab and rituximab, ublituximab is uniquely engineered with glycoengineering technology to enhance antibody-dependent cellular cytotoxicity, leading to more efficient B-cell depletion at lower doses and with shorter infusion times.²

Approved based on data from the phase 3 ULTIMATE 1 and 2 trials (NCT03277261; NCT03277248), ublituximab is administered in a 1-hour infusion, twice yearly following the starting dose. To be eligible, patients must be screening for hepatitis B virus (HBV) before starting treatment. In addition, ublituximab remains contraindicated in patients with a history of life-threatening reactions to the drug. In terms of safety, the most common adverse events, including fever, chills, and hypotension, typically occur with the first dose. Patients on the drug may also see an increased risk of serious infections, including upper respiratory infections, urinary tract infections, and reactivation of HBV.

At the 2024 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, investigators presented a new post-marketing study on ublituximab called PROVIDE (NCT06143514), that will evaluate the presence and concentration of the medication in breastmilk of patients with MS. This multicenter, prospective study aims to enroll 16 breastfeeding women with relapsing MS to obtain 10 completed mother-infant dyads. Based in the US, the primary objective of the study is to characterize the presence and concentration of ublituximab in breast milk using area under the concentration-time curve, concentration at the end of dosing interval, maximum observed concentration, and time of first occurrence of maximum concentration.

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REFERENCES
1. Fox E, Parker J, Bodhinathan K, Sportelli P, Miskin H, Hersh C. ENABLE: The First Phase 4 Observational Study for Patients with Relapsing MS Treated with Ublituximab in Real World Clinical Setting. Presented at: 2025 AAN Annual Meeting; April 5-9; San Diego, CA. ABSTRACT 004773
2. TG Therapeutics Announces FDA Approval of BRIUMVI™ (ublituximab-xiiy). News release. TG Therapeutics. December 28, 2022. Accessed April 4, 2025. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-fda-approval-briumvitm-ublituximab
3. 1. Bove R, Parker J, Gocke A, et al. A post-marketing study evaluating the presence and concentration of BRIUMVI (ublituximab-xiiy) in breastmilk (PROVIDE). Presented at: 2024 CMSC Annual Meeting; May 29-June 2; Nashville, TN. ABSTRACT DMT46