ASH 2024 | Evaluating two novel BTK degraders, NX-2127 and NX-5948, in CLL

Patients who progress on BTK inhibitors have limited options. At this ASH annual meeting we presented data on two clinical-stage degraders, NX-2127 and NX-5948, which are both currently in clinical trials in CLL and lymphoid malignancies. So what we have shown is that those BTK degraders both effectively degrade BTK. However, they have also been designed differently where NX-2127 has immunomodulatory activity and which will be lenalidomide-like. So it actually modulates cereblon activity and assigns some neosubstrate for that ligase. So what basically happens, both degraders are able to very effectively degrade BTK in malignant B-cells, but NX-2127 also modulates T-cell function resulting in reprogramming and repolarization of T-cells towards more cytotoxic phenotype. So we see increased T-cell mediated cytotoxicity. We see T-cell repolarization towards Th1 subset, which has higher potency, anti-tumor effects. We see increased immunologic synapse formation. And also by analyzing patient samples from clinical trial, we are able to see that this immunomodulatory effect does seem to contribute to efficacy of NX-2127. So both degraders are currently in clinical trials. Updated data on NX-5948 actually we are presenting at this ASH as well; overall response rate in that group among patients with CLL is 70% and responses are ongoing and this agent is very well tolerated so stay tuned for more data on both the degraders.

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