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DRUG:

Briumvi (ublituximab-xiiy)

i
Other names: TG-1101, LFB R603, LFBR 603, LFBR-603, EMAB-6, R603, TG20, TGTX-1101, LFB-R603
Company:
Ildong, LFB SA, Neuraxpharm, TG Therap
Drug class:
CD20 inhibitor
Related drugs:
16d
Acalabrutinib, Umbralisib and Ublituximab Regimen (AU2) Demonstrates High Response Rate and Undetectable Molecular Minimal Residual Disease (MRD) in Patients (pts) with De Novo Mantle Cell Lymphoma (MCL) (ASH 2024)
Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.
Clinical • IO biomarker • Minimal residual disease
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TP53 (Tumor protein P53)
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TP53 mutation
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clonoSEQ
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Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
18d
Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (clinicaltrials.gov)
P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Dec 2023 --> Dec 2026
Trial primary completion date
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
1m
Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (clinicaltrials.gov)
P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Jan 2025 --> Dec 2023
Trial primary completion date
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
1m
New P1 trial
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Briumvi (ublituximab-xiiy)
4ms
DELIVER-MS: Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (clinicaltrials.gov)
P4, N=800, Active, not recruiting, The Cleveland Clinic | Trial primary completion date: Apr 2030 --> Jul 2027
Trial primary completion date
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Rituxan (rituximab) • Briumvi (ublituximab-xiiy) • fingolimod • Lemtrada (alemtuzumab) • Ocrevus (ocrelizumab) • Tysabri (natalizumab)
4ms
Enrollment open • Real-world evidence • Real-world
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Briumvi (ublituximab-xiiy)
4ms
Study of TG-1801 Alone or in Combination With Ublituximab in Subjects With B-Cell Lymphoma or Chronic Lymphocytic Leukemia (clinicaltrials.gov)
P1, N=21, Terminated, TG Therapeutics, Inc. | N=60 --> 21 | Trial completion date: Dec 2024 --> Jun 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jun 2024; Strategic/Business Decision
Enrollment change • Trial completion date • Trial termination • Trial primary completion date • Combination therapy
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Briumvi (ublituximab-xiiy) • TG-1801
5ms
A Study Evaluating the Effect of BRIUMVI® (Ublituximab) on Pregnancy and Infant Outcomes in Participants With Multiple Sclerosis (MS) (clinicaltrials.gov)
P=N/A, N=728, Recruiting, TG Therapeutics, Inc. | Not yet recruiting --> Recruiting | Trial completion date: Jan 2030 --> Jun 2025 | Trial primary completion date: Jan 2030 --> Jun 2025
Enrollment open • Trial completion date • Trial primary completion date
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Briumvi (ublituximab-xiiy)
5ms
TG-1701-101: Study of TG-1701, an Irreversible Bruton's Tyrosine Kinase Inhibitor, in Patients With B-Cell Malignancies (clinicaltrials.gov)
P1, N=172, Terminated, TG Therapeutics, Inc. | Active, not recruiting --> Terminated; Strategic/Business Decision
Trial termination
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • edralbrutinib (TG-1701)
6ms
New trial • Real-world evidence • Real-world
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Briumvi (ublituximab-xiiy)
6ms
New trial
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Briumvi (ublituximab-xiiy)
7ms
Trial termination • Combination therapy
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Gazyva (obinutuzumab) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • Leukeran (chlorambucil)
7ms
DELIVER-MS: Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (clinicaltrials.gov)
P4, N=800, Active, not recruiting, The Cleveland Clinic | Recruiting --> Active, not recruiting
Enrollment closed
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Rituxan (rituximab) • Briumvi (ublituximab-xiiy) • fingolimod • Lemtrada (alemtuzumab) • Ocrevus (ocrelizumab) • Tysabri (natalizumab)
7ms
PROVIDE: A Study Evaluating the Presence and Concentration of BRIUMVI™ (Ublituximab) in Breast Milk (clinicaltrials.gov)
P=N/A, N=16, Recruiting, TG Therapeutics, Inc. | Not yet recruiting --> Recruiting
Enrollment open
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Briumvi (ublituximab-xiiy)
8ms
Study of TG-1801 in Subjects With B-Cell Lymphoma (clinicaltrials.gov)
P1, N=50, Completed, TG Therapeutics, Inc. | Active, not recruiting --> Completed
Trial completion
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Briumvi (ublituximab-xiiy) • TG-1801
8ms
An Extension Study of Ublituximab in Participants With Relapsing Multiple Sclerosis (clinicaltrials.gov)
P3, N=1100, Active, not recruiting, TG Therapeutics, Inc. | Enrolling by invitation --> Active, not recruiting
Enrollment closed
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Briumvi (ublituximab-xiiy)
9ms
Study of TG-1801 in Subjects With B-Cell Lymphoma (clinicaltrials.gov)
P1, N=50, Active, not recruiting, TG Therapeutics, Inc. | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024
Trial completion date • Trial primary completion date
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Briumvi (ublituximab-xiiy) • TG-1801
9ms
Study of TG-1801 Alone or in Combination With Ublituximab in Subjects With B-Cell Lymphoma or Chronic Lymphocytic Leukemia (clinicaltrials.gov)
P1, N=60, Active, not recruiting, TG Therapeutics, Inc. | Recruiting --> Active, not recruiting
Enrollment closed
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Briumvi (ublituximab-xiiy) • TG-1801
11ms
Trial completion date • Trial primary completion date
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Briumvi (ublituximab-xiiy)
11ms
Trial completion date • Trial primary completion date • Combination therapy
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Briumvi (ublituximab-xiiy) • TG-1801
11ms
Study of TG-1801 in Subjects With B-Cell Lymphoma (clinicaltrials.gov)
P1, N=50, Active, not recruiting, TG Therapeutics, Inc.
Trial completion date • Trial primary completion date
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Briumvi (ublituximab-xiiy) • TG-1801
11ms
Trial completion date • Trial primary completion date
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • edralbrutinib (TG-1701)
almost1year
New trial
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Briumvi (ublituximab-xiiy)
1year
Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov)
P2, N=12, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2023 --> Sep 2025
Trial completion date • Combination therapy
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CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1)
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Chr t(11;14) • CCND1 overexpression • Chr t(11;14)(q13;q32)
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
1year
Phase classification • Combination therapy
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Briumvi (ublituximab-xiiy) • TG-1801
1year
A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (ASH 2023)
Immune-related adverse events were frequently observed and required dose reduction of umbralisib in 38% of the patients but most were then able to stay on therapy. Longer follow-up is required to determine durability of remission off therapy.
P2 data • IO biomarker
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TP53 (Tumor protein P53) • ATM (ATM serine/threonine kinase) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • IGH (Immunoglobulin Heavy Locus) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
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TP53 mutation • ATM mutation • NOTCH1 mutation • SF3B1 mutation • ATM deletion • TS 12
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
1year
Study of TG-1801 Alone or in Combination With Ublituximab in Subjects With B-Cell Lymphoma or Chronic Lymphocytic Leukemia (clinicaltrials.gov)
P1b, N=60, Recruiting, TG Therapeutics, Inc. | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
Trial completion date • Trial primary completion date • Combination therapy
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Briumvi (ublituximab-xiiy) • TG-1801
over1year
LI-RADS threshold growth based on tumor growth rate can improve the diagnosis of hepatocellular carcinoma ≤ 3.0 cm. (PubMed, Eur Radiol)
• The diagnostic accuracy of Liver Imaging Reporting and Data System (LI-RADS) v2018 was not significantly affected by the time interval between prior and index assessments of threshold growth. • In the 334 hepatocellular carcinomas, the frequency of threshold growth was significantly higher using tumor growth rate ≥ 10%/month (TG-10%) than original threshold growth (53.3% vs. 18.0%, p  .999).
Journal
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Briumvi (ublituximab-xiiy)
over1year
UNITY-CLL: Ublituximab + TGR-1202 Compared to Obinutuzumab + Chlorambucil in Patients With Untreated and Previously Treated Chronic Lymphocytic Leukemia (clinicaltrials.gov)
P3, N=603, Completed, TG Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Jan 2024 --> Feb 2023 | Trial primary completion date: Nov 2023 --> Feb 2023
Trial completion • Trial completion date • Trial primary completion date
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Gazyva (obinutuzumab) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • Leukeran (chlorambucil)
over1year
TG-1701-101: Study of TG-1701, an Irreversible Bruton's Tyrosine Kinase Inhibitor, in Patients With B-Cell Malignancies (clinicaltrials.gov)
P1, N=172, Active, not recruiting, TG Therapeutics, Inc. | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024
Trial completion date • Trial primary completion date
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • edralbrutinib (TG-1701)
over1year
Umbralisib Plus Ublituximab (U2) in Progressive CLL After Novel Therapy (clinicaltrials.gov)
P2, N=1, Terminated, Weill Medical College of Cornell University | N=24 --> 1 | Recruiting --> Terminated; Terminated due to low accrual
Enrollment change • Trial termination
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BCL2 (B-cell CLL/lymphoma 2)
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over1year
Tazemetostat in Combination With Umbralisib and Ublituximab for the Treatment Relapsed or Refractory Follicular Lymphoma (clinicaltrials.gov)
P1/2, N=0, Withdrawn, City of Hope Medical Center | N=48 --> 0 | Not yet recruiting --> Withdrawn
Enrollment change • Trial withdrawal • Combination therapy
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Tazverik (tazemetostat) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over1year
G protein-coupled receptor 183 mediates the sensitization of Burkitt lymphoma tumors to CD47 immune checkpoint blockade by anti-CD20/PI3Kδi dual therapy. (PubMed, Front Immunol)
Cell response to TG-1801 alone or combined with the U2 regimen associating ublituximab to the PI3Kδ inhibitor umbralisib, was analyzed by proliferation assay, western blot, transcriptomic analysis (qPCR array and RNA sequencing followed by gene set enrichment analysis) and/or quantification of antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP). Genetic depletion and pharmacological inhibition of GPR183 impaired ADCP initiation, cytoskeleton remodeling and cell migration in 2D and 3D spheroid B-NHL co-cultures, and disrupted macrophage-mediated control of tumor growth in B-NHL CAM xenografts. Altogether, our results support a crucial role for GPR183 in the recognition and elimination of malignant B cells upon concomitant targeting of CD20, CD47 and PI3Kδ, and warrant further clinical evaluation of this triplet regimen in B-NHL.
Journal • Checkpoint inhibition • IO biomarker • Checkpoint block
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CD19 (CD19 Molecule) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • GPR183 (G Protein-Coupled Receptor 183) • SIRPA (Signal Regulatory Protein Alpha)
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • TG-1801
over1year
Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma (clinicaltrials.gov)
P2, N=4, Completed, University of Colorado, Denver | Suspended --> Completed | N=24 --> 4 | Trial completion date: Dec 2023 --> Jun 2022
Trial completion • Enrollment change • Trial completion date
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CD20 (Membrane Spanning 4-Domains A1)
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over1year
Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma (clinicaltrials.gov)
P2, N=24, Suspended, University of Colorado, Denver | Trial primary completion date: Jul 2023 --> Jul 2022
Trial primary completion date
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CD20 (Membrane Spanning 4-Domains A1)
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over1year
Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov)
P2, N=12, Active, not recruiting, City of Hope Medical Center | Suspended --> Active, not recruiting | N=27 --> 12
Enrollment closed • Enrollment change • Combination therapy
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CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1)
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Chr t(11;14) • CCND1 overexpression • Chr t(11;14)(q13;q32)
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
2years
First-in-Human (FIH) Study of the Fully-Human Kappa-Lambda CD19/CD47 Bispecific Antibody TG-1801 in Patients (pts) with B-Cell Lymphoma (ASH 2022)
Combination of CD47 blockade with the anti-CD20 antibody rituximab has resulted in encouraging clinical activity (Advani 2018), and CD19 is also an established target of multiple B-NHL therapies...A 3+3 design was also utilized to evaluate two dose levels of TG-1801 (300 mg and 400 mg) with a standard dose of ublituximab (900 mg)... TG-1801 monotherapy and combination therapy demonstrates clinical activity, particularly in relapsed and refractory DLBCL, with an acceptable preliminary safety profile. This study (NCT03804996) has completed enrollment.
Clinical • P1 data
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CD19 (CD19 Molecule) • CD47 (CD47 Molecule) • SIRPA (Signal Regulatory Protein Alpha)
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CD47 expression
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Rituxan (rituximab) • Briumvi (ublituximab-xiiy) • TG-1801
2years
Rapid Tumor Debulking of Relapsed/Refractory CLL Patients By PI3Kδ Inhibition and Anti-CD20 Monoclonal Antibody Treatment (ASH 2022)
The combination of a novel highly-specific phosphoinositide 3-kinase delta (PI3Kδ) inhibitor and casein kinase 1 epsilon (CSK1ε) inhibitor, umbralisib (UMB), and a glycoengineered chimeric monoclonal antibody (mAb) targeting a unique epitope on CD20, ublituximab (UBL), with the BCL2 inhibitor venetoclax (VEN) may decrease drug resistance, reduce risk of tumor lysis syndrome (TLS) and achieve higher levels of undetectable minimal residual disease (MRD). In conclusion, our initial data show that treatment with a selective PI3Kδ and CSK1ε inhibitor (UMB) combined with an anti-CD20 mAb (UBL) is effective in decreasing CLL cell counts in all patients assessed in the U2-VEN clinical trial. However, treatment efficacy could be limited by large decreases in the CLL surface CD20 levels.
Clinical
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CD19 (CD19 Molecule) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • CD5 (CD5 Molecule)
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Venclexta (venetoclax) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
2years
A Phase II Trial of Acalabrutinib in Combination with PI3Kδ Inhibitor Umbralisib and the Anti-CD20 Antibody Ublituximab (AU2) in Patients with Previously Untreated Mantle Cell Lymphoma (MCL) (ASH 2022)
Thus, AU2 is a highly effective regimen in patients with previously untreated MCL, including those with high-risk genetics (100% CR rate). While a combination of continuous umbralisib and acalabrutinib was associated with liver function test abnormalities, intermittent dosing of umbralisib was well tolerated.
Clinical • P2 data • Combination therapy
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TP53 (Tumor protein P53) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
2years
CHOP U2: Clinical Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL) (clinicaltrials.gov)
P1/2, N=1, Terminated, University of Alabama at Birmingham | N=35 --> 1 | Trial completion date: Jun 2025 --> Jun 2022 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Jun 2022; FDA hold
Enrollment change • Trial completion date • Trial termination • Trial primary completion date
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CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • CD5 (CD5 Molecule)
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Chr t(11;14)
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doxorubicin hydrochloride • cyclophosphamide • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
2years
Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov)
P2, N=27, Suspended, City of Hope Medical Center | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Sep 2022 --> Sep 2023
Trial completion date • Trial primary completion date • Combination therapy
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CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1)
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Chr t(11;14) • CCND1 overexpression • Chr t(11;14)(q13;q32)
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
2years
Extended Abstract: New BTKi (SOHO 2022)
It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo and in vitro screening studies, with safety and activity seen in early studies23,24...This resistance mechanism appears shared among available irreversible BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib26...Three such inhibitors have completed phase 1 studies in CLL: vecabrutinib, nemtabrutinib, and pirtobrutinib with another currently in phase 1, luxeptinib...Subsequently, pirtobrutinib is being further studied as both a monotherapy and in combination with venetoclax-rituximab in phase 3 trials in both the frontline and relapsed/refractory settings in CLL in addition to MCL...These non-C481 BTK mutations conferred resistance across multiple non-covalent BTKi’s (in addition to pirtobrutinib, vecabrutinib, nemtabrutinib and fenebrutinib were tested) in addition to variable levels of resistance to covalent BTKi’s36...This is being accomplished by improved tolerability, allowing for patients to stay on drug for longer, and potentially improved effi cacy, including activity despite acquisition of C481 resistance mutations, in the case of the non-covalent inhibitors. The non-covalent inhibitors would help fi ll a major area of unmet need for CLL patients progressing on covalent BTK inhibitors who are not candidates for or progress following venetoclax therapy.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • PLCG2 (Phospholipase C Gamma 2) • IL2 (Interleukin 2) • ITK (IL2 Inducible T Cell Kinase)
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Chr del(11q) • BTK C481S • PLCG2 mutation • BTK mutation • BTK C481
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Zydelig (idelalisib) • Yinuokai (orelabrutinib) • entospletinib (GS-9973) • pomalidomide • Jaypirca (pirtobrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • edralbrutinib (TG-1701) • luxeptinib (CG-806) • vecabrutinib (SNS-062) • DTRM-555 • DTRMWXHS-12 • Velexbru (tirabrutinib) • fenebrutinib (RG7845) • nemtabrutinib (MK-1026)