Understanding Relapsing Multiple Sclerosis

Relapsing multiple sclerosis (RMS), also known as relapsing-remitting multiple sclerosis (RRMS) in its early stages, is the most common form of multiple sclerosis (MS). Multiple sclerosis is a chronic autoimmune disease where the immune system mistakenly attacks the protective myelin sheath covering nerve fibers in the central nervous system, leading to inflammation, demyelination, and eventual axonal damage. This disrupts nerve signal transmission, resulting in a wide array of symptoms that can significantly impair quality of life.

Symptoms of RMS typically include episodes of new or worsening neurological deficits, called relapses or flares, followed by periods of partial or complete recovery. Common manifestations encompass fatigue, numbness or tingling in limbs, muscle weakness, vision problems such as optic neuritis, balance and coordination issues, bladder or bowel dysfunction, cognitive difficulties, and pain. Over time, repeated relapses can lead to cumulative disability, transitioning some patients to secondary progressive MS (SPMS), where disability steadily worsens without clear relapses.

The impact on patients is profound: RMS affects over 85% of the 2.8 million people worldwide living with MS, predominantly young adults aged 20-40 at onset, with women twice as likely to be diagnosed as men. Early and effective treatment is crucial to minimize relapses, slow disability progression, and preserve brain health. Disease-modifying therapies (DMTs) form the cornerstone of management, aiming to reduce inflammation, prevent relapses, and protect against neurodegeneration.

For individuals navigating RMS, accessing reliable research on long-term treatment outcomes is essential for informed decision-making alongside healthcare providers. Academic institutions play a key role in advancing such knowledge through clinical trials and neurology research programs.

Introduction to BRIUMVI (Ublituximab-xiiy)

BRIUMVI, or ublituximab-xiiy, represents a targeted therapy designed specifically for adults with relapsing forms of multiple sclerosis, including clinically isolated syndrome (CIS), RRMS, and active SPMS. As a monoclonal antibody targeting CD20 on B cells, BRIUMVI works by depleting these immune cells implicated in MS pathogenesis. B cells contribute to MS by producing autoantibodies, acting as antigen-presenting cells to activate T cells, and releasing pro-inflammatory cytokines.

What sets BRIUMVI apart is its glycoengineered design, which enhances antibody-dependent cellular cytotoxicity (ADCC) for more rapid and profound B-cell depletion compared to earlier anti-CD20 therapies. Administered intravenously, the dosing regimen includes a 150 mg initial infusion on day 1, followed by 450 mg at week 3 (approximately 1-hour infusion), and then 450 mg every 24 weeks thereafter—making it the only 1-hour, twice-yearly maintenance infusion for RMS.

This convenient schedule reduces treatment burden, potentially improving adherence. Approved by the FDA in December 2022 based on phase 3 data, BRIUMVI has since accumulated extensive real-world and extension study evidence supporting its role in RMS management.

Overview of the ULTIMATE I and II Trials

The foundation for BRIUMVI's long-term data stems from the pivotal phase 3 ULTIMATE I (NCT03277261) and ULTIMATE II (NCT03277248) trials. These identical, multicenter, randomized, double-blind, active-controlled studies enrolled 1,094 adults with RMS, aged 18-55, with an Expanded Disability Status Scale (EDSS) score of 0-5.5, indicating mild to moderate disability.

Participants received either BRIUMVI or teriflunomide (Aubagio, 14 mg oral daily, a pyrimidine synthesis inhibitor) for 96 weeks. Baseline characteristics were balanced: mean age around 36-38 years, approximately 65-70% female, mean disease duration 6-7 years, and about 20-25% with gadolinium-enhancing (Gd+) lesions on MRI. Primary endpoint was annualized relapse rate (ARR), with secondary measures including MRI lesions, confirmed disability progression (CDP), and no evidence of disease activity (NEDA).

BRIUMVI demonstrated superior efficacy over teriflunomide, reducing ARR by 48-59%, suppressing Gd+ lesions by 97%, and achieving higher NEDA-3 rates. Following the double-blind period (DBP), participants could enter the open-label extension (OLE; NCT04130997), receiving continuous BRIUMVI (UBL-UBL group) or switching from teriflunomide (TER-UBL). Of 985 DBP completers, 851 (86%) enrolled in OLE, with data cutoff January 1, 2024, providing over 3,600 patient-years of exposure.

At OLE year 3 (total study year 5), over 70% remained on treatment: 297/422 UBL-UBL and 327/429 TER-UBL, reflecting good tolerability.

📊 Key Efficacy Findings from Five-Year Data

Recently published in JAMA Neurology, the five-year analysis confirms BRIUMVI's sustained efficacy in RMS. Continuous treatment yielded progressively lower relapse rates and favorable disability outcomes compared to switchers.

• Annualized relapse rate (ARR) declined over time, reaching 0.020 in year 5 for UBL-UBL (one relapse per 50 patient-years).
• 97.7% relapse-free in year 5 (UBL-UBL), 95.0% (TER-UBL).
• Cumulative relapse-free from baseline to year 5: 83.6% UBL-UBL vs. 68.9% TER-UBL (p<0.001).
• 24-week confirmed disability progression (CDP24) at year 5: 8.0% UBL-UBL vs. 14.3% TER-UBL (HR 0.61, p=0.01).
• 24-week confirmed disability improvement (CDI24): 17.0% UBL-UBL vs. 12.2% TER-UBL (HR 1.47, p=0.02).

These results underscore the value of early high-efficacy therapy initiation.

Diving Deeper into Relapse Reduction

Relapses represent acute inflammatory events in RMS, often requiring steroids and risking permanent damage. The ULTIMATE OLE tracked adjudicated relapses, defined as new/worsening symptoms lasting >24 hours.

For TER-UBL switchers, ARR dropped 58.4% in OLE year 1 (0.182 to 0.076, rate ratio 0.42, p<0.001), stabilizing at 0.048 (year 4) and 0.045 (year 5). Continuous UBL-UBL patients saw ARR of 0.053 (year 3), 0.032 (year 4), and 0.020 (year 5), with 91.7% relapse-free from years 2-5 vs. 86.7% switchers (p=0.02).

This trajectory suggests ongoing disease control, potentially due to sustained B-cell depletion preventing immune reactivation.

Disability Progression and Improvement Outcomes

Disability is assessed via EDSS (0-10 scale: 0 normal, 10 death) and Multiple Sclerosis Functional Composite (MSFC) for leg/arm function, cognition. CDP24 requires sustained ≥1.0-point EDSS increase (baseline ≤5.5) or ≥0.5-point (>5.5).

At year 5, 92% UBL-UBL remained CDP24-free, vs. lower in switchers. CDI24, indicating meaningful improvement, favored continuous therapy. MSFC z-scores remained stable, supporting functional preservation. These metrics highlight BRIUMVI's neuroprotective potential over extended periods.

Safety Profile Across Five Years

Safety data from pooled DBP/OLE (exposure-adjusted incidence rates per 100 patient-years) show consistency. Serious infections (excluding COVID): 2.10 UBL-UBL, 2.58 TER-UBL. Treatment-emergent adverse events (TEAEs): 205 overall, infusion-related reactions (IRRs) 26.69 (mostly mild, reduced from DBP).

Immunoglobulins (IgG, IgM) averaged above lower normal limits; no association with infection rates regardless of levels. No progressive multifocal leukoencephalopathy (PML) cases. Discontinuations due to AEs: <2/100 PY. As with anti-CD20s, monitor for infections, HBV reactivation, IRRs; pre-treat with corticosteroids/antihistamines.

Details available on the BRIUMVI HCP site.

BRIUMVI in Context with Other RMS Treatments

BRIUMVI joins anti-CD20 peers like ocrelizumab (Ocrevus, 2-hour q6m), ofatumumab (Kesimpta, subcutaneous q4w). Phase 3 data show comparable ARR reductions vs. active controls, but BRIUMVI's shorter infusions appeal for convenience. Long-term OLE data now affirm durability, with no new signals.

Compared to oral DMTs like teriflunomide, BRIUMVI offers superior efficacy. Selection depends on patient factors: infusion tolerance, monitoring needs, PML risk (low across class).

Implications for Patients and Healthcare Providers

These findings reinforce early high-efficacy DMT use to alter RMS trajectory, potentially delaying progression. Patients should discuss switching/starting BRIUMVI with neurologists, considering comorbidities, lifestyle, fertility plans (contraception advised).

Lifestyle complements therapy: exercise, vitamin D, smoking cessation, cognitive rehab. For academics and researchers driving MS innovations, opportunities abound in clinical research jobs and research jobs within higher education.

Future Directions and Ongoing Research

Beyond ULTIMATE, real-world ENABLE study (NCT06433752) tracks BRIUMVI outcomes. Six-year ECTRIMS 2025 data showed 89.9% progression-free. Head-to-head trials vs. other anti-CD20s could clarify differentiators. Advances in biomarkers may personalize therapy.

Explore academic career advice for those entering neurology research fields.

Photo by Leo Talabardon on Unsplash

Wrapping Up: A Promising Outlook for RMS Management

The JAMA Neurology publication solidifies BRIUMVI as a durable RMS option, with ultra-low year-5 ARR and 92% CDP-free rate. Press release from TG Therapeutics emphasizes clinician value.

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