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CHARLOTTE, N.C. — Treatment with the anti-CD20 monoclonal antibody ublituximab for relapsing-remitting multiple sclerosis (RRMS) was associated with significant improvements in patient-reported outcomes across all domains, including safety and tolerability, early results from a phase 4 trial showed. 

Early findings from the observational ENABLE trial — the first real-world study of ublituximab — support results from two pivotal clinical trials that served as the basis for FDA approval in 2022. 

Relative to baseline, improvements in efficacy, convenience, physical scores, psychological scores, and global satisfaction were statistically significant in patients who had received at least 1 dose of ublituximab. 

"Improvements were observed as early as day 15 and were sustained at follow-up assessments at weeks 24 and 48," reported Carrie M. Hersh, DO, an associate professor of neurology at the Cleveland Clinic Lerner College of Medicine in Cleveland.

The findings were presented May 29 at the Consortium of Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting. 

First Real-World Analysis

Ublituximab targets a unique epitope of CD20 and is glycoengineered for enhanced antibody-dependent cellular cytotoxicity and enhanced Fcγ-receptor (FcγR) binding. Pooled results from the identical pivotal phase 3 ULTIMATE I and II trials were published in 2022.

In that analysis of 1000 total patients with RRMS, researchers reported significant improvements on several measures of disability progression for those receiving ublituximab compared to those treated with teriflunomide.

To see if those results would hold in a real-world setting, researchers designed the multicenter, observational ENABLE trial to evaluate the effectiveness, safety, and tolerability of ublituximab. Exploratory objectives include patient-reported outcomes, total infusion time, laboratory assessments, and MS outcomes.

The early analysis of patient-reported outcomes included 658 patients (average age 43 years; 76.1% female; 71.1% White) treated at 87 participating centers who were available by the December 2025 data cutoff. 

Since the data cutoff, enrollment has now topped 1000 patients at more than 100 participating centers. The goal is to enroll 2000 patients with a planned study follow-up of 192 weeks. 

Baseline demographics for ENABLE are broader than those of the pivotal trials. Notably, the phase 4 study includes a higher representation of Black individuals (19.5% vs 1.5%), females (76.1% vs 62.9%), and patients with overweight or obesity (38.3% vs 11.3%), Hersh reported. Participants are also older than in ULTIMATE I and II, which had an average age of 35.4 years.

ENABLE has a similar proportion of patients with gadolinium-enhancing lesions at baseline, and disease duration at entry was slightly longer (8.7 vs 7.4 years). 

Only 38% of ENABLE participants were treatment-naïve at the time of enrollment, compared to nearly 60% in the pivotal trials. Many of those on a prior treatment were transitioning to ublituximab from another high-efficacy monoclonal antibody disease-modifying treatment. The most common of these, representing 19% of those in the ENABLE trial, was ocrelizumab. 

These were followed by another anti-CD20 therapy, ofatumumab, accounting for 8%. Natalizumab was the prior drug in 12%. Patients previously exposed to an S1P inhibitor, a fumarate, and the dihydroorotate dehydrogenase inhibitor teriflunomide represented most of the others transitioning to ublituximab.

Physical and Psychological Benefits

After switching to ublituximab, there was about a 5% improvement from baseline to day 15 for the patient-reported outcome of efficacy (P < .0001). There were further 5% gains in efficacy at weeks 24 and 48 compared to baseline (both P < .0001). 

When queried about the reason for starting ublituximab, efficacy was listed as the primary reason by 82% of those who were treatment-naïve, 59% of those on a prior anti-CD20 therapy, and 74% of those on a non-anti-CD20 therapy. 

Nearly one-third of those on a prior anti-CD20 therapy sought greater convenience and tolerability, but safety was listed by only 17% of those on an anti-CD20 therapy vs 37% of those previously on a non-anti-CD20 therapy.

For the patient-reported outcome of convenience, the improvement was about 10% from baseline at day 15 with no substantial further improvements at weeks 24 and 48 (all P < .0001 vs baseline).

The reduction in side effects from baseline was not significant at day 15. However, the approximate 5% improvement from baseline by week 24 (P = .0042) was sustained at week 48 (P = .038). 

Global satisfaction improved from baseline at day 15 by about 15% (P < .0001) and was sustained at weeks 24 ad 48 (both P < .0001 relative to baseline).

The Multiple Sclerosis Impact Scale (MSIS-19) for physical scores improved by about 4 points at day 15 (P < .0001) and was sustained at weeks 24 (P < .0001) and 48 (P = .0008). Similarly, the MSIS-19 psychological scores improved by about 5.5 points by day 15 (P < .0001) and were sustained at weeks 24 and 48 (both P < .0001 relative to baseline).

Overall, "patients reported significant and durable improvements in all sub-domains of treatment satisfaction," Hersh said. She remarked that the improvements by day 15 for many outcomes reinforce the efficacy and tolerability of ublituximab.

Real-World, Controlled Data Align

The 5-year open-label extension of the ULTIMATE trials was published earlier this year. The principal investigator, Bruce Cree, MD, PhD, clinical research director of the Multiple Sclerosis Center at the University of California, San Francisco, also concluded that this agent offered relatively high rates of both safety and efficacy over extended follow-up.

As the majority of patients enrolled in the initial trials were treatment naïve, the 5-year results support early initiation of high-efficacy therapies for sustained disease control, Cree said in a statement issued when the results were released.

In an expert analysis of the efficacy and safety of ublituximab published by a panel of Italian neurologists in the Journal of Neurology last year, ublituximab was called "a substantial advancement" on the basis of evidence that the promise of its unique characteristics. 

At that time, the only hesitation expressed by the senior author, Massimo Filippi, MD, PhD, a professor of neurology at the San Raffaele Scientific Institute in Milan, was the absence of real-world data.

Real-world evidence, extended follow-ups, and comprehensive biomarker assessment are essential to understanding long-term benefits any drug, he told Medscape Medical News. 

At 5 years, the data are reassuring, but the ongoing phase 4 follow-up will continue to be a major part of the effort to understand the long-term role of this drug in MS control, Hersh reported.

The ENABLE study is funded by TG Therapeutics. Hersh reported financial relationships with TG Therapeutics, Alexion Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Horizon, and Novartis. Cree reported financial relationships with Alexion, Alumis, Avotres, Biogen, Boston Scientific, EMD Serono, Hexal/Sandoz, Horizon, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics. Filippi reported financial relationships with Alexion, Almirall, Bayer, Biogen, Celgene, Chiesi Italia, Eli Lilly, Genzyme, Janssen, Merck, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and Teva. 

The 5-year open-label extension of the ULTIMATE trials was published earlier this year. The principal investigator, Bruce Cree, MD, PhD, clinical research director of the Multiple Sclerosis Center at the University of California, San Francisco, also concluded that this agent offered relatively high rates of both safety and efficacy over extended follow-up.