NX-5948, a novel oral Bruton's tyrosine kinase (BTK) degrader, is showing promise in treating patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). According to Nirav N. Shah, MD, MSHP, early efficacy data from a phase 1a/b trial suggests the agent is nearing examination in a pivotal clinical trial. The drug has demonstrated high response rates, even in patients previously treated with a BTK inhibitor, marking a potential advancement in targeting BTK.
Mechanism of Action
NX-5948 induces specific protein degradation of both wild-type and mutant forms of BTK by recruiting the cereblon E3 ligase. Unlike traditional BTK inhibitors that bind to C481 or noncovalent inhibitors, NX-5948 leads to ubiquitination and degradation of the entire BTK enzyme. This mechanism may overcome resistance mutations to covalent or noncovalent inhibitors, potentially making it an effective targeted agent.
Efficacy Data from Phase 1 Trial
Data from the phase 1a/b NX-5948-301 trial (NCT05131022), presented at the 2024 ASH Annual Meeting and Exposition, showed an objective response rate (ORR) of 75.5% (95% CI, 61.1%-86.7%) at 8 weeks in patients with CLL/SLL (n = 49). Furthermore, at 16 weeks, patients (n = 38) experienced an ORR of 84.2% (95% CI, 68.7%-94.0%). Responses were observed across the board, independent of mutational profiles, including in patients with BTK, TP53, and PLCG2 mutations. Blood samples from treated patients showed BTK degradation occurred in almost all patients, regardless of mutations present at enrollment.
Safety Profile
NX-5948 has demonstrated a favorable safety profile. The most common grade 3 or higher toxicity was neutropenia, which was anticipated due to the trial allowing enrollment of neutropenic patients. Only one patient in the CLL cohort discontinued the drug due to a treatment-emergent adverse effect. Traditional BTK inhibitor-related toxicities were generally low, with low rates of hypertension, no new cases of atrial fibrillation, and no significant high-grade bleeding complications other than low-grade petechiae.
Unmet Need and Future Directions
As more patients receive BTK and BCL2 inhibitors upfront, a growing population will progress on these drugs, creating a need for new treatments like BTK degraders. NX-5948 is currently in phase 1b development for CLL and other B-cell malignancies. The hope is that these data will lead to pivotal trials and make the drug available to patients, initially in those with relapsed/refractory CLL who have progressed on other medications, and potentially as an earlier line of treatment.
