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, N=32, Recruiting, Nurix Therapeutics, Inc.

P1, N=266, Recruiting, Nurix Therapeutics, Inc. | Active, not recruiting --> Recruiting | N=160 --> 266 | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=128, Recruiting, AbbVie | Trial completion date: Jun 2027 --> Apr 2029

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

Consequently, it is not difficult to understand that BP001 effectively inhibits inflammation. In conclusion, the present study provides evidence that BP001, a BTK degrader, can serve as a novel immunomodulator of inflammation induced by high glucose, making it an attractive candidate for further investigation.

No abstract available

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

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

Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

P1, N=128, Recruiting, AbbVie | N=188 --> 128

P1, N=226, Recruiting, Nurix Therapeutics, Inc. | N=130 --> 226

P1, N=160, Active, not recruiting, Nurix Therapeutics, Inc. | Recruiting --> Active, not recruiting

This first-in-human study of NX-2127 is actively enrolling and dose-expansion cohorts in DLBCL and MCL have been initiated at the 300 mg daily dose. Findings include dose-dependent PK accompanied by degradation of BTK and Ikaros. Encouraging and persistent responses were observed in heavily pretreated patients with relapsed/refractory CLL and NHL with a manageable safety profile.

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.

Current findings in this heavily pre-treated population of patients with CLL and NHL are encouraging and indicate that NX-5948 is safe and well tolerated and has clinical activity, supporting continuation of its development in CLL and NHL. NX-5948 also exhibits dose-proportional PK, resulting in rapid, robust and sustained BTK degradation. Additional data with higher dose levels and longer treatment duration will be presented at the meeting.

ABBV-101 is currently in phase 1 clinical trial for a variety of B-cell malignancies. ClinicalTrials.gov identifier: NCT05753501

P1, N=130, Recruiting, Nurix Therapeutics, Inc. | Trial completion date: May 2024 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Dec 2025

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

P1, N=160, Recruiting, Nurix Therapeutics, Inc. | Trial completion date: Nov 2023 --> Dec 2025 | Trial primary completion date: Oct 2023 --> Dec 2024

In addition to direct anti-neoplastic effects, BTK inhibitors ibrutinib and acalabrutinib were found to favorably modulate T-cell function in pre-clinical and clinical studies of CLL...In vitro polarization assays indicated that treatment with 1 μM NX-2127, but not NX-5948, resulted in a dramatic and significant upregulation of both IFN-γ and IL-2 under TH1-polarizing conditions, to a degree which significantly exceeded the effect of either ibrutinib or lenalidomide... CRBN-recruiting BTK degraders NX-2127 andNX-5948 induce degradation of BTK in primary CLL cells and do not interfere with T-cell activation and survival in vitro. More importantly, CRBN-immunomodulatory activity was required to upregulate CD38 (an IFN response gene), promote T-cell differentiation towards a TH1 phenotype, downregulate Treg differentiation, and facilitate immunological synapse formation, suggesting NX-2127 has the potential to reverse the immunosuppressive environment of CLL. Overall, our findings provide a strong rationale for continued investigation of these BTK degraders in CLL and lymphoid malignancies.

The C481S and C481R mutations eliminated the anti-proliferative effects of covalent inhibitors ibrutinib, acalabrutinib, and zanubrutinib, whereas the V416L, T474I, and L528W mutations had variable effects on the covalent inhibitors. By contrast, the non-covalent inhibitors pirtobrutinib, vecabrutinib, and fenebruitnib maintained activity against C481S but displayed partially reduced potency against the C481R mutation and dramatically reduced potency against the V416L, T474I, and L528W mutations...These degrader molecules may also have utility in earlier lines of therapy due to their ability to suppress scaffold-mediated BTK signaling. Phase 1a/b trials of NX-5948 and NX-2127 in patients with relapsed or refractory B-cell malignancies are ongoing (NX-5948: NCT05131022; NX-2127: NCT04830137).

Approximately 110 patients (30 in phase 1a, 80 in phase 1b) may be enrolled and treated until confirmed progression or unacceptable toxicity. Enrollment in the phase 1a portion of this study is underway in the UK and the US, and is anticipated to begin in the Netherlands in 2023.

P1, N=188, Recruiting, AbbVie | N=128 --> 188

P1, N=128, Recruiting, AbbVie | Not yet recruiting --> Recruiting

Enrollment in the phase 1a portion of this study is underway in the U.K. and is anticipated to begin in the United States and the Netherlands in 2023.

Preliminary findings suggest that NX-5948 exhibits dose-proportional PK and supports daily dosing, resulting in rapid, robust and sustained BTK degradation. Additional indications, including CLL, and additional dosing levels are currently being explored.

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

Combination therapy with ibrutinib, lenalidomide and rituximab demonstrated clinical activity in recurrent DLBCL [Goy et al. In this first-in-human, first-in-class study of a BTK degrader, NX-2127 was well tolerated and showed promising activity in a patient with non-GCB DLBCL. These data support further clinical development of NX-2127 in B cell lymphoid malignancies including DLBCL.

In pre-clinical safety studies, NX-2127 demonstrates an acceptable safety profile. NX-2127 is currently in phase 1 clinical trials (NCT04830137) for hematological malignancies.

In summary, HZ-Q1070 is a potent and highly selective BTK degrader against both BTK-WT and multiple BTK inhibitors-resistant mutations. In vivo, HZ-Q1070 exhibits excellent pharmacokinetic properties, BTK degradation activity and robust tumor growth inhibition in TMD8 and Mino mouse xenograft tumor model. These findings support further clinical development of HZ-Q1070 for the treatment of B cell malignancies.

Exploratory analyses will evaluate the relationship between HSK29116 anti-tumor activity and BTK gene mutations, as well as BTK protein degradation effects of HSK29116 . Descriptive statistics will be used to summarize all data.

P1, N=128, Not yet recruiting, AbbVie

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

Preclinical data support the activity of NX-2127 in tumor models harboring either wild-type BTK or BTK-mutants conferring clinical resistance to approved and investigational inhibitors. NX-2127 is currently being evaluated in an ongoing Phase 1 trial for patients with relapsed or refractory B-cell malignancies (ClinicalTrials.gov NCT04830137).

In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR mediated signaling, transcriptional programs, and chemokine secretion. Oral bioavailability, >90% degradation of BTK at sub-nanomolar concentrations and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).

All have previously received a BTKi and 76.5% had also received venetoclax. Double- and emerging triple-refractory CLL (patients who progressed on cBTKi, ncBTKi, and a BCL2 inhibitor) represents a major unmet medical need with no approved therapeutic options and poor survival. These patients may thus benefit from the interruption of BTK kinase-independent scaffolding signaling. In this first-in-human, first-in-class study of a BTK degrader, clinical responses and benefit were observed in heavily pretreated (median 6 prior therapies) patients with CLL who have poor prognostic factors, including those with BTK mutations resistant to cBTKi and ncBTKi, BCL2 mutations and those who were previously treated with both BTKi and BCL2 inhibitors.