TG Therapeutics Publishes Five-Year Comparative Analysis Showing Favorable Long-Term Outcomes for BRIUMVI in Relapsing Multiple Sclerosis
TG Therapeutics, Inc. has announced the publication of results from a five-year matching-adjusted indirect comparison (MAIC) evaluating the long-term efficacy of BRIUMVI® (ublituximab-xiiy) against ocrelizumab and ofatumumab in patients with relapsing multiple sclerosis (RMS). The analysis examined relapse activity and disability progression outcomes, reporting favorable results for BRIUMVI compared with both anti-CD20 therapies across several measures.
The findings were published online in Multiple Sclerosis and Related Disorders in a manuscript titled “Long-Term Comparative Outcomes in Relapse Activity and Disability Progression Among Anti-CD20 Therapies in Relapsing Multiple Sclerosis: An Unanchored Matching-Adjusted Indirect Comparison.”
The analysis used individual patient-level data from 545 participants treated with BRIUMVI in the Phase 3 ULTIMATE I and ULTIMATE II trials and their open-label extension. These data were reweighted to align baseline patient characteristics with published aggregate data from the Phase 3 OPERA I and II trials evaluating ocrelizumab and the ASCLEPIOS I and II trials evaluating ofatumumab.
The results indicated that BRIUMVI was associated with a lower relative hazard of 24-week confirmed disability progression compared with both ocrelizumab and ofatumumab over the five-year evaluation period. The analysis also reported lower estimated cumulative incidence rates of confirmed disability progression and consistently low annualized relapse rates through Year 5.
TG Therapeutics stated that the findings add to the growing body of evidence supporting the long-term efficacy profile of BRIUMVI. However, the company noted that the results are exploratory and require confirmation through direct comparative studies. Because the analysis relied on data from separate clinical trial programmes rather than a head-to-head trial, the findings should be interpreted with appropriate caution.
Five-Year Analysis Compares Three Anti-CD20 Therapies
BRIUMVI, ocrelizumab and ofatumumab are anti-CD20 therapies used in the treatment of relapsing forms of multiple sclerosis. These treatments target CD20-expressing B cells, which play a role in the immune processes involved in MS disease activity.
Although several anti-CD20 therapies are available, comparing their long-term outcomes can be challenging because clinical trials may differ in patient characteristics, study designs, follow-up periods and outcome assessments. Direct head-to-head studies can help address these questions, but when such trials are unavailable, researchers may use statistical methods to compare data across separate studies.
The TG Therapeutics analysis applied an unanchored matching-adjusted indirect comparison to evaluate long-term outcomes with BRIUMVI against ocrelizumab and ofatumumab.
The researchers used individual patient-level data from 545 BRIUMVI-treated participants enrolled in the Phase 3 ULTIMATE I and II trials and their open-label extension. These data were compared with published aggregate results from the OPERA I and II trials of ocrelizumab and the ASCLEPIOS I and II trials of ofatumumab.
In a MAIC analysis, patient-level data from one treatment group are statistically reweighted to match selected baseline characteristics reported for another clinical trial population. The objective is to improve comparability between groups and reduce the potential influence of differences in measured patient characteristics on the estimated treatment outcomes.
For this publication, BRIUMVI patient data were reweighted separately to align with the populations evaluated in the comparator programmes.
An unanchored MAIC differs from an anchored indirect comparison because it does not rely on a shared comparator arm to connect the treatments statistically. Consequently, its validity depends heavily on the availability and appropriate adjustment of relevant baseline characteristics and on assumptions about factors that may influence treatment outcomes.
Although the methodology can provide useful comparative insights when direct trial data are unavailable, it cannot eliminate all uncertainty arising from differences between separate studies. Unmeasured patient characteristics, variations in trial conduct and other potential confounding factors may affect the results.
The investigators therefore characterised the findings as exploratory, emphasising the need for confirmation in direct comparative research.
Lower Relative Hazard of Confirmed Disability Progression
One of the principal findings was the lower relative hazard of 24-week confirmed disability progression, or CDP24, associated with BRIUMVI compared with both comparator therapies.
CDP24 is a clinical outcome used in multiple sclerosis research to measure disability worsening that remains confirmed over a specified period of 24 weeks. It helps assess whether changes in neurological function represent sustained deterioration rather than temporary fluctuations.
Preventing or delaying confirmed disability progression is an important objective in MS treatment because the disease can lead to cumulative neurological impairment over time.
In the five-year MAIC analysis, BRIUMVI was associated with a 44% lower relative hazard of CDP24 compared with ocrelizumab. The estimated hazard ratio was 0.560, with a 95% confidence interval of 0.380 to 0.826.
Compared with ofatumumab, BRIUMVI was associated with a 49% lower relative hazard of CDP24. The estimated hazard ratio was 0.509, with a 95% confidence interval of 0.350 to 0.741.
Both reported confidence intervals were below a hazard ratio of 1.0, indicating that the adjusted estimates favored BRIUMVI within the statistical model used for the analysis.
However, these relative hazard estimates should not be interpreted as definitive proof that BRIUMVI is superior to either comparator. They represent adjusted comparisons across separate trial populations, and their interpretation depends on the assumptions and limitations of the unanchored MAIC methodology.
The results nevertheless provide additional evidence for evaluating the potential long-term effects of BRIUMVI on disability progression in people with RMS.
Lower Estimated Cumulative Incidence of Disability Progression
The analysis also compared the estimated cumulative incidence of CDP24 at 240 weeks, equivalent to approximately five years.
For BRIUMVI, the estimated cumulative incidence of confirmed disability progression was 9.3% in the comparison with ocrelizumab and 9.4% in the comparison with ofatumumab.
The corresponding estimates for the comparator therapies were 16.1% for ocrelizumab and 17.9% for ofatumumab.
These findings suggest that the BRIUMVI treatment group had lower estimated cumulative rates of confirmed disability progression after statistical adjustment for the measured baseline characteristics.
The results are relevant because the long-term management of RMS involves more than reducing the frequency of relapses. Sustained disability progression can have substantial effects on mobility, independence, employment and quality of life.
Treatments that effectively control inflammatory disease activity while helping delay neurological deterioration may therefore provide important benefits for patients over time.
Nevertheless, the cumulative incidence estimates remain model-based comparisons rather than results from a randomised trial directly comparing all three therapies. Differences in follow-up, study populations and other clinical factors may affect comparisons across programmes.
Further direct comparative evidence would help clarify whether the observed differences reflect meaningful differences between the treatments.
Additional Time Free From Disability Progression
Another measure evaluated in the publication was the estimated additional time patients remained free from confirmed disability progression over the 240-week period.
According to the analysis, BRIUMVI was associated with an average of 8.1 additional weeks free from confirmed disability progression compared with ocrelizumab. The 95% confidence interval ranged from 2.3 to 14.1 weeks.
Compared with ofatumumab, BRIUMVI was associated with an estimated 13.1 additional weeks free from confirmed disability progression, with a 95% confidence interval of 6.7 to 19.3 weeks.
These estimates provide another way to describe the potential clinical implications of differences in disability progression. While hazard ratios and cumulative incidence rates summarise relative and overall event risks, estimates of time free from progression express the findings in terms of the duration over which patients may remain without confirmed worsening.
For people living with a chronic neurological condition, preserving neurological function and delaying sustained disability are important treatment goals. Even modest differences in time without progression may be relevant when considered over extended periods, although the practical significance of these estimates requires careful interpretation.
As with the other findings, the reported additional time is based on a statistical comparison across separate clinical trial programmes. It should not be treated as a confirmed individual benefit for every patient receiving BRIUMVI.
BRIUMVI Demonstrates Consistently Low Annualized Relapse Rates
The publication also examined annualized relapse rates (ARR), a measure of the average number of relapses per patient-year. Relapse activity is a key indicator of inflammatory disease activity in RMS and is commonly used to assess treatment response.
The MAIC-adjusted results showed consistently low annualized relapse rates with BRIUMVI across the five-year assessment period.
In the comparison with ocrelizumab, the adjusted ARR for BRIUMVI declined from 0.118 in Year 1 to 0.032 in Year 5.
In the comparison with ofatumumab, the corresponding adjusted ARR declined from 0.116 in Year 1 to 0.030 in Year 5.
These results indicate a low estimated annual relapse frequency in the BRIUMVI-treated population during the later years of the analysis.
Reducing relapses is an important component of RMS treatment because episodes of inflammatory disease activity can cause new or worsening neurological symptoms and may contribute to long-term disability in some patients.
However, relapse rates represent only one aspect of disease control. Comprehensive evaluation of treatment effectiveness also considers disability progression, magnetic resonance imaging findings, safety, tolerability, treatment persistence and patients’ individual clinical circumstances.
The declining adjusted relapse rates reported in the analysis therefore complement the findings on disability progression, providing a broader picture of the long-term outcomes assessed in the publication.
The data do not establish that every patient will experience a similar reduction in relapse activity, and comparisons with other therapies remain subject to the limitations of indirect statistical methods.
TG Therapeutics Highlights the Need for Comparative Evidence
Michael S. Weiss, chairman and chief executive officer of TG Therapeutics, highlighted the importance of comparative evidence as physicians and patients consider available anti-CD20 treatments for RMS.
“In an era where physicians and patients are fortunate to have multiple anti-CD20 treatment options available for relapsing MS, the lack of comparative data makes choosing the right one challenging. This is particularly important for people living with a chronic disease like MS, where preventing the accumulation of disability over time is an important treatment goal,” Weiss said.
He noted that MAIC provides a statistical approach to evaluating comparative outcomes when direct head-to-head clinical trials are not available.
Weiss added that the analysis showed lower relapse activity with BRIUMVI compared with ocrelizumab and a lower risk of confirmed disability progression compared with both ocrelizumab and ofatumumab over five years.
“We believe these findings add to the growing body of evidence supporting the durable efficacy profile of BRIUMVI and its potential to provide meaningful long-term benefit for people living with MS,” he said.
The company’s comments reflect the importance of generating additional information about long-term outcomes as the treatment landscape for RMS expands.
While randomised head-to-head trials remain an important way to establish comparative efficacy, analyses such as MAIC can provide supplementary evidence to inform further research and clinical discussion.
Publication Adds to the Evidence Base for BRIUMVI
The manuscript, titled “Long-Term Comparative Outcomes in Relapse Activity and Disability Progression Among Anti-CD20 Therapies in Relapsing Multiple Sclerosis: An Unanchored Matching-Adjusted Indirect Comparison,” is available online through Multiple Sclerosis and Related Disorders.
The publication can be accessed through ScienceDirect or the publications section of the TG Therapeutics corporate website.
The five-year analysis contributes to the growing body of evidence concerning BRIUMVI’s long-term clinical profile. Its findings include lower adjusted hazards of confirmed disability progression compared with ocrelizumab and ofatumumab, lower estimated cumulative incidence rates of progression, additional estimated time free from disability progression and consistently low adjusted annualised relapse rates.
At the same time, the authors’ exploratory findings must be interpreted in the context of the study design. The use of separate clinical trial populations and published aggregate comparator data introduces limitations that statistical adjustment cannot fully eliminate.
Further research, particularly direct comparative studies, will be important to confirm the findings and establish how the observed differences translate into clinical practice.
For TG Therapeutics, the publication provides additional information on the long-term outcomes associated with BRIUMVI and contributes to ongoing discussions about treatment selection in RMS. As clinicians continue to assess available therapies, evidence addressing both relapse control and disability progression remains central to the goal of improving long-term outcomes for people living with multiple sclerosis.
About the MAIC Analysis
In the absence of randomized head-to-head trials directly comparing anti-CD20 therapies in RMS, investigators conducted an unanchored MAIC to explore comparative outcomes over five years. Individual patient data from the pivotal Phase 3 ULTIMATE I and II studies were reweighted to match published baseline characteristics from the pivotal Phase 3 studies for ocrelizumab (OPERA I/II) and ofatumumab (ASCLEPIOS I/II), including age, sex, baseline Expanded Disability Status Scale (EDSS) score, gadolinium-enhancing lesion prevalence, T2 lesion volume, prior relapse activity and time since diagnosis, where corresponding data were available. Following weighting, baseline characteristics were closely aligned with both comparator populations.
The authors note that the findings should be interpreted within the inherent limitations of an unanchored MAIC. Notably, the methodology cannot adjust for unmeasured differences between trials, and residual confounding cannot be excluded. Accordingly, the analysis is exploratory and the findings require confirmation through direct comparative studies or robust real-world evidence.
The study was funded by Neuraxpharm, TG Therapeutics’ European commercialization partner for BRIUMVI.
ABOUT THE ULTIMATE I & II PHASE 3 TRIALS
ULTIMATE I & II are two randomized, double-blind, double-dummy, parallel group, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks. Patients were randomized to receive either BRIUMVI, given as an IV infusion of 150 mg administered in four hours, 450 mg two weeks after the first infusion administered in one hour, and 450 mg every 24 weeks administered in one hour, with oral placebo administered daily; or teriflunomide, the active comparator, given orally as a 14 mg daily dose with IV placebo administered on the same schedule as BRIUMVI.
Both studies enrolled patients who had experienced at least one relapse in the previous year, two relapses in the previous two years, or had the presence of a T1 gadolinium (Gd)-enhancing lesion in the previous year. Patients were also required to have an Expanded Disability Status Scale (EDSS) score from 0 to 5.5 at baseline. The ULTIMATE I & II trials enrolled a total of 1,094 patients with RMS across 10 countries. These trials were led by Lawrence Steinman, MD, Zimmermann Professor of Neurology & Neurological Sciences, and Pediatrics at Stanford University. Additional information on these clinical trials can be found at www.clinicaltrials.gov (NCT03277261; NCT03277248).
ABOUT TG THERAPEUTICS
TG Therapeutics is a fully integrated, commercial stage, biotechnology company focused on the acquisition, development and commercialization of novel treatments for B-cell diseases. In addition to a research pipeline, TG Therapeutics has received approval from the U.S. Food and Drug Administration (FDA) for BRIUMVI® (ublituximab-xiiy) to treat adult patients with relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, as well as approval from several regulatory agencies outside of the U.S. for BRIUMVI to treat adult patients with RMS who have active disease defined by clinical or imaging features. For more information, visit www.tgtherapeutics.com, and follow us on X (formerly Twitter) @TGTherapeutics and on LinkedIn.
BRIUMVI® is a registered trademark of TG Therapeutics, Inc.
ABOUT BRIUMVI® (ublituximab-xiiy) 150 mg/6 mL Injection for IV
BRIUMVI is a novel monoclonal antibody that targets a unique epitope on CD20-expressing B-cells. Targeting CD20 using monoclonal antibodies has proven to be an important therapeutic approach for the management of autoimmune disorders, such as RMS. BRIUMVI is uniquely designed to lack certain sugar molecules normally expressed on the antibody. Removal of these sugar molecules, a process called glycoengineering, allows for efficient B-cell depletion at low doses.
BRIUMVI is indicated in the U.S. for the treatment of adults with RMS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease and in several countries outside of the U.S. for the treatment of adult patients with RMS with active disease defined by clinical or imaging features.