edralbrutinib (TG-1701)

P1, N=172, Terminated, TG Therapeutics, Inc. | Active, not recruiting --> Terminated; Strategic/Business Decision

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

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

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.

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.

These data validate phosphoproteomic as a valuable tool for the early detection of response to BTK inhibition in the clinic, and for the determination of drug mechanism of action.

P2, N=102, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

Here we show that, when compared to irreversible and reversible BTKis including ibrutinib, acalabrutinib, and ARQ-531, TG-1701 showed similar cytotoxic activity either in ibrutinib-sensitive or in ibrutinib-resistant MCL cells. We then evaluated the activity of TG-1701 and ibrutinib on anti-CD20 antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), as ibrutinib has previously been show to block rituximab-mediated ADCC due to off-target inhibition of ITK (Kohrt et al., Blood 2014)...In accordance with in vitro data, the antitumor activity of the drug combination was associated with increased production of IL-2, IL-6 and TNFα, and with an increased infiltration of mouse macrophages and NK cells. Altogether, these data warrant further clinical investigation of TG-1701-mediated engagement of TME-related anti-tumor effect, and clinical evaluation of the triple combination of TG-1701, ublituximab, and umbralisib, is ongoing.