BGB-16673

P1/2, N=170, Not yet recruiting, BeiGene

The presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage.

P1/2, N=466, Recruiting, BeiGene | Trial completion date: Sep 2027 --> Mar 2028 | Trial primary completion date: Sep 2024 --> Mar 2025

P1/2, N=127, Recruiting, BeiGene | Phase classification: P1 --> P1/2

P1/2, N=466, Recruiting, BeiGene | N=291 --> 466

Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

P1/2, N=291, Recruiting, BeiGene | Phase classification: P1 --> P1/2

1, 2 Treatment of CLL cells with entospletinib, but not other BCR-signaling inhibitors, led to a disruption of BAFF-BCR cross-talk and downmodulation of MCL1 mRNA and protein, thus implicating SYK in transduction of multiple pro-survival signals emanating from the tumor microenvironment.1 Entospletinib has shown promising clinical activity in CLL, alone or in combination with obinutuzumab, including in patients with high-risk disease such as TP53 aberrant.3, 4 The drug is very well tolerated, however its development in CLL has been halted. Meanwhile, we have shown that luxeptinib, a dual SYK/BTK kinase inhibitor, has activity in BTK inhibitor-resistant lymphoid models in vitro.5 Luxeptinib is now being investigated in lcinical trials in hematologic malignancies...The early results of MS-553, a selective PKC-β inhibitor, indicates that this agent is tolerable and effective both as single agent and in combination with venetoclax.8 Proteolysis-targeting chimeras (PROTACs) are a new class of small molecules with two covalently-linked ligands recruiting target protein and E3 ubiquitin ligase together to trigger and enable proteasomal degradation of the target protein.9 “BTK degraders”, such as NRX- 2127 (Nurix Therapeutics) and BGB-16673 (Beigene), have entered clinical trials in patients with lymphoid malignancies...Additionally, NX-2127 has shown preclinical activity similar to immunomodulatory drugs (IMiDs) by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in increased T-cell activation.10 Early results of an ongoing clinical trial of NX-2127 demonstrate an ORR of 33% in heavily pre-treated patients with CLL, and overall good tolerability 11...The preclinical activity of AZD5991 has shown that selective targeting of MCL1 induced metabolic dysfunction and abrogated survival of diffuse large B cell lymphoma and ibrutinib-resistant mantle cell lymphoma cell lines in vivo and in vitro.13 Other BH3-mimetics targeting MCL1 include AMG176 and S63845.14-16 In an experimental design testing the effects of AMG-176 on CLL and normal hematopoietic cell death it was demonstrated that AMG-176 is an active agent in inducing CLL cell death while sparing normal blood cells...Anti-CD20 monoclonal antibodies – rituximab, obinutuzumab and ofatumumab – have significantly improved the survival outcomes. The B cell activating factor receptor (BAFF-R) is one of the main pro-survival receptors in B cells.18 In a preclinical study, ianalumab (VAY-736), a humanized defucosylated engineered antibody directed against BAFF-R, antagonized pro-survival effects of BAFF in CLL cells and showed promising activity both as a single agent and in combination with ibrutinib.19 A phase 1 study of dose escalation and dose expansion investigated the combination of ianalumab with ibrutinib in 32 patients with CLL with median one prior line of therapy (range, 0-4)...This study showed promising results not expected with ibrutinib alone.20 Tafasitamab – a Fc-enhanced, humanized, monoclonal antibody to CD19 – in combination with idelalisib or venetoclax in 24 patients has been associated with an ORR of 77% and 91%, respectively...In a phase 1 study involving 26 patients with R/R CLL, cirmtuzumab administered at four biweekly infusions was shown to have a long plasma half-life and did not have dose-limiting toxicity, potentially providing another treatment opportunity for patients with CLL.22 Immune Cell Enabling Therapies...A recent report of a phase 1/2 study of lisocabtagene maraleucel, an autologous CD19-directed CAR T-cell therapy (TRANSCEND CLL 004), confirmed efficacy in patients with R/R CLL.23 In this study, 23 patients with median 4 prior lines of therapy (range 2-11) were enrolled, 10 of whom were considered double exposed/refractory...In total, 65% of patients required administration of tocilizumab and/or corticosteroids.23 In addition to the ongoing phase 2 portion of this study, efforts now focus on innovative CAR T-cell designs as well as combination strategies...A phase 1b/2 ongoing trial is currently examining the safety and tolerability of the product in patients with R/R CLL. The early results suggest that epcoritamab administered subcutaneously is well tolerated in a heavily pretreated patient population with multiple high-risk features and shows clinical activity.25 Furthermore, an ongoing study is demonstrating preliminary efficacy of epcoritamab in patients with Richters transformation, a notoriously difficult-to-treat complication of CLL.26

Inhibition of BTK by covalent BTK inhibitors (BTKi), such as ibrutinib, acalabrutinib, and zanubrutinib, have revolutionized the management of CLL and other B cell malignancies. BGB-16673 is a potent inhibitor against tumors expressing wildtype and clinical-relevant BTK mutations. In addition, it is superior to ibrutinib and LOXO-305 equivalent for more durable anti-tumor activities and less metastasis. Absolute lymphocyte count, Tumor model, Lymphoma, Mouse model

P1, N=116, Recruiting, BeiGene | N=76 --> 116

Results This is a trial in progress; safety and tolerability results of BGB-16673 are expected. Conclusion BGB-16673-101 is the first in-human study of the BTK degrader BGB-16673.