Briumvi (ublituximab-xiiy)

P3, N=603, Terminated, TG Therapeutics, Inc. | Completed --> Terminated; Strategic/Business decision

P4, N=800, Active, not recruiting, The Cleveland Clinic | Recruiting --> Active, not recruiting

P=N/A, N=16, Recruiting, TG Therapeutics, Inc. | Not yet recruiting --> Recruiting

P1, N=50, Completed, TG Therapeutics, Inc. | Active, not recruiting --> Completed

P3, N=1100, Active, not recruiting, TG Therapeutics, Inc. | Enrolling by invitation --> Active, not recruiting

P1, N=50, Active, not recruiting, TG Therapeutics, Inc. | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

P1, N=60, Active, not recruiting, TG Therapeutics, Inc. | Recruiting --> Active, not recruiting

P3, N=1100, Enrolling by invitation, TG Therapeutics, Inc.

P1, N=60, Recruiting, TG Therapeutics, Inc.

P1, N=50, Active, not recruiting, TG Therapeutics, Inc.

P1, N=172, Active, not recruiting, TG Therapeutics, Inc.

P=N/A, N=16, Not yet recruiting, TG Therapeutics, Inc.

P2, N=12, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2023 --> Sep 2025

P1, N=60, Recruiting, TG Therapeutics, Inc. | Phase classification: P1b --> P1

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.

P1b, N=60, Recruiting, TG Therapeutics, Inc. | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

• 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).

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

P1, N=172, Active, not recruiting, TG Therapeutics, Inc. | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P2, N=1, Terminated, Weill Medical College of Cornell University | N=24 --> 1 | Recruiting --> Terminated; Terminated due to low accrual

P1/2, N=0, Withdrawn, City of Hope Medical Center | N=48 --> 0 | Not yet recruiting --> Withdrawn

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.

P2, N=4, Completed, University of Colorado, Denver | Suspended --> Completed | N=24 --> 4 | Trial completion date: Dec 2023 --> Jun 2022

P2, N=24, Suspended, University of Colorado, Denver | Trial primary completion date: Jul 2023 --> Jul 2022

P2, N=12, Active, not recruiting, City of Hope Medical Center | Suspended --> Active, not recruiting | N=27 --> 12

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.

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.

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.

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

P2, N=27, Suspended, City of Hope Medical Center | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Sep 2022 --> Sep 2023

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.

P2; Recruiting --> Active, not recruiting

P2, N=27, Suspended, City of Hope Medical Center | Recruiting --> Suspended | Trial primary completion date: Mar 2023 --> Sep 2022

P2, N=24, Recruiting, Weill Medical College of Cornell University | Trial completion date: Nov 2024 --> Dec 2023 | Trial primary completion date: May 2022 --> Apr 2023

P2, N=24, Suspended, University of Colorado, Denver | Recruiting --> Suspended

In a short time, the US Food and Drug Administration (FDA) has approved five agents for the treatment of MCL: lenalidomide, an immunomodulatory agent; bortezomib, a proteasome inhibitor; and ibrutinib, acalabrutinib, and zanubrutinib, all Bruton kinase inhibitors. Epigenetic agents (e.g. cladribine and vorinostat), mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus and everolimus), and monoclonal antibodies and/or antibody-drug conjugates (e.g. obinutuzumab, polatuzumab, and ublituximab) are promising therapeutic agents currently under clinical trial investigation...However, due to its intricate pathology nature and high relapse incidence, there are still unmet needs in developing optimal therapeutic strategies for both frontline and relapsed/refractory settings. The ultimate goal is to develop innovative personalized combination therapy approaches for the purpose of delivering precision medicine to cure this disease.

This novel patient care approach of "add-on" combination therapy was well tolerated and effective, with achievement of uMRD in 71% of evaluable patients allowing for tailored, time-limited therapy and sustained treatment-free observation. This approach may assist nurses with patient care challenges such as management of adverse events due to indefinite ibrutinib therapy.

Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy. Patients with BTKi risk factors attained durable clinical benefit from U2. In this population with BTKi risk factors, the baseline disease characteristics aligned with the overall population treated with U2, and efficacy and safety outcomes did not appear to be negatively impacted by the presence of comorbidities or the use of concomitant medications. These data suggest that U2 can be a valuable treatment option for patients with these conditions.

Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy...Among 14 patients previously treated with ibrutinib, the ORR was 57%... At data cut-off date of May 1, 2020, U2-treated patients had a median follow-up of 35.27 months. Of the 210 patients treated with U2, 119 were TN and 91 were PT. TN patients had a median age of 68 years (39 – 88 years) and 63% were male.

Treatment with a more selective BTK inhibitor could result in improved efficacy and safety outcomes compared with ibrutinib (ALPINE study, EHA 2021), and we hypothesized that dual blockade of the B-cell receptor (BCR) pathway through combination of TG-1701 with U2 may confer greater depth of response compared to either regimen alone. TG-1701 exhibits an encouraging safety and efficacy profile as monotherapy in patients with CLL and additionally shows promising activity and a manageable tolerability profile in combination with U2. Future registration trials are being planned in CLL with TG-1701. Recruitment to this study (NCT03671590) continues.

In the DLBCL cohort of UNITY-NHL, the U2+benda triplet regimen was active and well tolerated in patients with R/R DLBCL who were unsuitable for transplant or who had relapsed following ASCT. Umbra monotherapy and U2 were also well tolerated but resulted in lower ORR than in the U2+benda cohort.