TG Therapeutics Completes Enrollment in Phase 3 ENHANCE Trial of Simplified Dosing for BRIUMVI in Multiple Sclerosis
Breakthrough Clinical Results
TG Therapeutics announced the completion of enrollment in the Phase 3 ENHANCE trial, which is evaluating a simplified dosing schedule for BRIUMVI (ublituximab-xiiy) in patients with relapsing forms of multiple sclerosis (RMS). The trial assesses the non-inferiority of a consolidated Day 1 and Day 15 dosing schedule compared to the existing approved regimen. BRIUMVI is currently approved in the United States and other countries as a twice-yearly one-hour intravenous infusion for adults with RMS. The company anticipates a potential launch of the new dosing regimen in 2027 if the data are positive.
Key Highlights
- Enrollment completed in Phase 3 ENHANCE trial evaluating a simplified dosing schedule for BRIUMVI.
- The trial assesses a consolidated Day 1 and Day 15 dosing schedule for IV BRIUMVI in RMS patients.
- BRIUMVI is a novel, glycoengineered, anti-CD20 monoclonal antibody.
- The primary endpoint is non-inferior exposure with respect to area under the curve (AUC) at week 16.
Recent Studies
Recent Multiple Sclerosis Clinical Trials: Interventions, Safety, and Efficacy
Self-GEN Trial (2019)
- Intervention: Self-generation learning program with metacognitive strategies
- Efficacy: Significantly improved learning and memory, self-regulation, and metacognition compared to placebo; similar improvements in depression, functional status, and quality of life
- Evidence Level: Provides Class I evidence for efficacy of this behavioral intervention
Project: EVO™ (2020)
- Intervention: In-home, tablet-based, videogame-like digital treatment (25 minutes daily, 5 days weekly, for 4 weeks)
- Efficacy: Significant improvements in processing speed and psychomotor function; mean increase in SDMT of 3.6 points
- Adherence: 78% of participants completed 75% of prescribed sessions
4-Aminopyridine Study (2019)
- Intervention: 4-aminopyridine for relapsing-remitting multiple sclerosis
- Efficacy: Significantly higher scores in attention span, verbal fluency, planning and graphics and constructive motion
- Safety: Drug doses were safe with mild to moderate adverse events
BrainHQ (2020)
- Intervention: 12-week at-home restorative cognitive training program
- Efficacy: Significant improvement with mean SDMT improving from 49.6±14.7 to 52.6±15.6
- Success Predictors: Better outcomes with relapsing-remitting course, higher trait Conscientiousness-Orderliness, and higher baseline gray matter volume
REHACOP (2018)
- Intervention: Integrative group-based cognitive rehabilitation (3 one-hour-sessions per week for three months)
- Efficacy: Significant improvements in processing speed, working memory, verbal memory, and executive functioning with medium-large effect sizes
EvolutionRMS1 and EvolutionRMS2 (2023)
- Intervention: Evobrutinib (45 mg twice per day) vs. teriflunomide
- Efficacy: Annualized relapse rates were comparable between treatments
- Safety: Evobrutinib had more liver-related safety concerns
FENopta (2024)
- Intervention: Fenebrutinib (200 mg twice daily)
- Efficacy: 69% relative reduction in new T1 gadolinium-enhancing lesions; during extension, annualized relapse rate was 0.04 with 96% of patients relapse-free
- Safety: Well tolerated with hepatic enzyme elevations, headache, and nasopharyngitis as common adverse events
PLP10 trial (2013)
- Intervention: Combination of Ω-3 and Ω-6 polyunsaturated fatty acids with γ-tocopherol
- Efficacy: Reduced annualized relapse rate by 64% compared to placebo; significantly reduced risk of disability progression
- Safety: No adverse events reported during the 30-month study period
Mesenchymal Stem Cell Therapy (2022)
- Intervention: Mesenchymal stem cell (MSC) therapy
- Efficacy: No detectable effect on cognition in the short-term
- Safety: Some cognitive decline noted at Week 24, but temporary with performance returning to baseline levels at Week 48
Study Design Parameters
Study Design Parameters and Endpoints in Key MS Trials
Study Designs
Randomized controlled trials (RCTs) are the gold standard for establishing efficacy in MS treatments. Other important designs include:
- Observational studies (valuable for discoveries but limited by confounding by indication)
- Phase 4 observational studies (evaluate treatment effectiveness in daily practice)
- Adaptive designs (allow modification based on interim results)
- RCT-extension studies (free from confounding by indication)
- Patient registries (collect uniform data on disease-defined populations)
Recent examples include: - CELLO trial (2023): Phase 4, multicenter, randomized, double-blind, placebo-controlled study evaluating ocrelizumab in patients with radiologically isolated syndrome (RIS), enrolling 100 participants across ≥15 sites with 1:1 randomization to receive 3 courses of ocrelizumab or placebo, following patients for ≥3 years - Cognitive therapy trial (2022): Randomized-controlled trial comparing cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT) - Levidex trial: Included 421 adult participants (mean age: 47.5, 78.1% women) randomized to intervention (n=195) or control (n=226)
Primary Endpoints
Primary endpoints vary by trial phase and MS type: - Phase III trials: Clinical relapses (to reduce study size and duration) - Phase II studies: Lesion counts based on MRI (more sensitive than clinical measures) - CELLO trial: Time to development of new radiological or clinical evidence of MS - FLUOX-PMS trial: Time to confirmed disease progression (20% increase in timed 25-Foot Walk or 9-Hole Peg Test) - ACTiMuS trial: Global evoked potential from multimodal evoked potentials - Rolipram trial: Change in contrast-enhanced lesions - BZA trial: Change in Myelin Water Fraction (MWF) on MRI - RESTORE trial: Improvement in Versional Dysconjugacy Index-area
Secondary Endpoints
Common secondary endpoints include: - Adverse event reporting - Clinical rating scales (EDSS and MSFC) - Self-assessment scales (MSIS-29) - Optical coherence tomography (OCT) - Brain and spine MRI - Patient-reported outcomes: Anxiety, fatigue, cognitive functioning, quality of life, problem-solving skills, social support, mastery, satisfaction, and compliance
Advanced Outcome Measures
- CombiWISE (combinatorial weight-adjusted disability score) integrates four clinical scales and outperformed all clinical scales (Δ = 9.10%; p = 0.0003)
- Salient central lesion volume (SCLV) serves as a robust proxy for T2-lesion volume with strong correlation (r = .90, P < .001)
Landmark Trials
- Rituximab phase II study: Showed 74% of post-treatment MRI scans free of gadolinium-enhanced lesions
- Ocrelizumab OPERA I and II: Decreased annualized relapse rates (46-47%) and gadolinium-enhanced lesions (94-95%)
- Ocrelizumab ORATORIO trial: First drug to lower progression rates in primary progressive MS (PPMS) with significantly lower 12-week confirmed disability progression (32.9% vs 39.3%)
- MIST trial: Showed autologous haematopoietic stem cell transplantation resulted in prolonged time to disability progression
- StarMS trial: Currently assessing efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs
