Ublituximab’s Therapeutic Benefit Revealed in ULTIMATE Trials Analyses

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by Lindsey Shapiro, PhD |

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Ublituximab, an investigational antibody-based treatment for multiple sclerosis (MS), was efficacious across most patient subgroups, and led to marked improvements in disability and quality of life over nearly two years.

This is according to new exploratory analyses from the identical Phase 3 ULTIMATE I and II trials, which evaluated the safety and efficacy of TG Therapeutics’ ublituximab in adults with relapsing forms of MS.

The findings were presented in three poster presentations at the 2022 Congress of the European Academy of Neurology, held June 25–28 in Vienna and virtually.

“We are encouraged by the findings from these additional exploratory analyses of the ULTIMATE I & II Phase 3 trials, which reinforces our belief in the potential of ublituximab in the treatment of relapsing forms of multiple sclerosis,” Michael S. Weiss, chairman and CEO of TG Therapeutics, said in a press release.

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Ublituximab works by targeting the CD20 protein found on the surface of B-cells — immune cells that play a central role in driving the autoimmune attacks characteristic of MS. In binding to CD20, ublituximab is thought to lower the number of B-cells and lessen inflammation.

ULTIMATE I (NCT03277261) and ULTIMATE II (NCT03277248) collectively enrolled 1,094 people with active, relapsing forms of MS to test ublituximab against Sanofi Genzyme’s approved oral MS treatment Aubagio (teriflunomide).

Ublituximab was delivered as a four-hour 150 mg infusion directly into the bloodstream on the first day of treatment followed by a one-hour 450 mg infusion on day 15 and then 450 mg infusions once every six months. The trials ran for 96 weeks, or nearly two years.

Trial results showed that ublituximab significantly outperformed Aubagio in its ability to lower relapse rates and reduce the number of brain lesions. Also, a significantly higher proportion of patients on ublituximab achieved no evidence of disease activity — meaning no relapses, no confirmed disability progression, and no new or enlarging brain lesions — over the 96 weeks.

The recently presented posters now encompass a number of post hoc analyses from the ULTIMATE trials, which were designed and carried out after the trials were over.

In one poster, “Ublituximab Efficacy Outcomes in Relapsing Multiple Sclerosis Patient Subgroups in the ULTIMATE I and II Studies,” researchers assessed whether ublituximab showed similar efficacy among key patient subgroups.

The analysis evaluated ublituximab’s effectiveness when patients were divided by sex, age, disability, number of relapses prior to treatment, previous treatment with disease-modifying therapies (DMTs), or presence of inflammatory lesions at the study’s start.

Findings revealed that ublituximab outperformed Aubagio in its ability to reduce the number of active inflammatory and new or enlarging brain lesions, and increase the proportion of patients with no evidence of disease activity across all subgroups.

It also was significantly better than Aubagio at lowering relapse rates in most groups, with the exception of patients who were 38 years or older, and of those who had three or more relapses before starting treatment.

Earlier results from the ULTIMATE trials had shown that more patients receiving ublituximab (12% vs. 6% for Aubagio) experienced a confirmed disability improvement — meaning a reduction in their expanded disability status scale (EDSS) scores (indicating less disability) that were sustained for at least 12 weeks.

For most patients, these improvements were sustained through the end of the trials, according to results presented in the poster “Disability Improvements With Ublituximab in Relapsing Multiple Sclerosis: Pooled Post Hoc Analyses of the ULTIMATE I & II Studies.”

Overall, out of the 65 patients on ublituximab who experienced a confirmed disability improvement, 62 (95.4%) maintained that improvement through the end of the 96 weeks. Participants taking ublituximab also saw improvements significantly sooner than those on Aubagio, regardless of whether they had taken prior DMTs or had never received treatment.

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The third presentation, “Improved Quality of Life With Ublituximab in the ULTIMATE I and II Studies in Relapsing Multiple Sclerosis,” showed ublituximab’s ability to improve various aspects of quality of life in ULTIMATE participants.

Quality of life was tracked with the Multiple Sclerosis Quality of Life-54 (MSQOL-54), a self-reported questionnaire that combines both generic and MS-specific items into a single instrument, and the Short Form-36 (SF-36), a more generic measure of quality of life.

Ublituximab led to significant improvements in overall MSQOL-54, as well as in several subscores of that measure, including physical health, mental health, role limitations, changes in health, and energy, compared with the Aubagio group. It similarly outperformed Aubagio in improving scores for various physical components of the SF-36.

The U.S. Food and Drug Administration (FDA) is now reviewing ublituximab as a potential treatment for relapsing forms of MS. A decision is expected late this year. TG Therapeutics has plans to seek a similar approval in Europe.

“As a company, our primary focus remains on obtaining FDA approval of ublituximab by December 28, 2022,” Weiss said.

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