bexobrutideg (NX-5948)

Phase 1 studies of docirbrutinib and rocbrutinib demonstrated target engagement across wild-type and resistance-associated BTK mutations with encouraging safety profiles and preliminary efficacy signals in heavily pretreated populations...BTK degraders, including bexobrutideg and BGB-16673, demonstrated rapid and deep responses, activity in high-risk molecular subgroups, and manageable toxicity profiles, with recommended phase 2 doses established. Collectively, these latest updates support continued clinical development of novel agents to address resistance and disease progression in R/R CLL/SLL.

P1/2, N=150, Not yet recruiting, Nurix Therapeutics, Inc.

P3, N=620, Not yet recruiting, Nurix Therapeutics, Inc.

P1/2, N=41, Recruiting, Nurix Therapeutics Inc.

P1/2, N=40, Recruiting, Nurix Therapeutics Inc.

P1, N=18, Recruiting, Nurix Therapeutics, Inc. | Trial completion date: Dec 2025 --> Aug 2026 | Trial primary completion date: Nov 2025 --> Apr 2026

P1, N=18, Recruiting, Nurix Therapeutics, Inc. | Trial completion date: Mar 2025 --> Dec 2025 | Trial primary completion date: Feb 2025 --> Nov 2025

P2, N=100, Recruiting, Nurix Therapeutics, Inc.

P1, N=32, Completed, Nurix Therapeutics, Inc. | Active, not recruiting --> Completed

P1, N=8, Completed, Nurix Therapeutics, Inc. | Recruiting --> Completed

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.