zelebrudomide (NX-2127)

P1, N=248, Recruiting, Nurix Therapeutics, Inc. | Trial completion date: Dec 2026 --> May 2027 | Trial primary completion date: Dec 2025 --> May 2026

While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance-both intrinsic and acquired-poses a significant challenge, often associated with BTK mutations like C481S...Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials...These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy.

We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL.

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

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=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.

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).