Nirav N. Shah, MD, highlights the potential of NX-5948, a novel BTK degrader, in treating patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). This oral drug induces specific protein degradation of both wild-type and mutant forms of BTK, offering a new mechanism of action compared to existing BTK inhibitors.
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Efficacy Data: In the phase 1a/b NX-5948-301 trial, NX-5948 showed an objective response rate (ORR) of 75.5% at 8 weeks and 84.2% at 16 weeks among patients with CLL/SLL. This indicates a significant response even in patients who have previously been treated with BTK inhibitors.
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Mechanism of Action: Unlike traditional BTK inhibitors that bind to specific sites, NX-5948 recruits E3 ligase to ubiquitinate and degrade the entire BTK enzyme. This mechanism may allow it to overcome resistance mutations seen in patients who have progressed on other BTK drugs.
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Safety Profile: NX-5948 has demonstrated a favorable safety profile, with low rates of grade 3 or higher toxicities. The most common adverse effect was neutropenia, but the drug was well-tolerated, with only one patient discontinuing due to a treatment-emergent adverse effect.
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Future Directions: The ongoing phase 1b trial in CLL and development in other B-cell malignancies are paving the way for pivotal trials. NX-5948 could fill an unmet need for patients with relapsed or refractory CLL, offering a new treatment modality that could potentially be used earlier in the treatment sequence.
This advancement represents a significant step forward in the treatment of B-cell malignancies, with the potential to improve outcomes for patients who have limited options after progressing on current therapies.
