SOHO 2025 | Safety & efficacy of the BTK degrader bexobrutideg in R/R CLL: results from an ongoing Phase I study

We were excited to be part of the Nurix trial with bexobrutideg, this is a first-in-class BTK degrader, and so this is a different mechanism of action than the BTK inhibitors that are available to date. As part of this Phase Ia updated result clinical trial that we presented, we looked at sort of longer-term follow-up on patients treated at multiple dose levels with this BTK degrader. A BTK degrader works differently than inhibitors in that it uses sort of the ubiquitin system and proteasome system to bind to BTK and degrade the entire enzyme, and therefore helping it overcome potential resistance mutations that may occur to other BTK-targeting drugs. As far as this clinical trial, we took patients with relapsed/refractory CLL, patients that had a median of four prior lines of treatment. Almost every single patient had prior exposure to a BTK inhibitor, and about 80% were exposed to both BCL2 inhibitors and BTK. Demonstrating that this is a tough-to-treat population is that it’s an area where we really need additional therapeutics. In this clinical trial, the safety of the drug was really favorable. There were low rates of grade 3 to 4 toxicities, and the traditional BTK inhibitor toxicities were not present. There was no new atrial fibrillation. There were low rates, generally grade 1 to 2, of bruising, and neutropenia was sort of the most common complication, which is not surprising given the nature of CLL, especially in someone who has seen multiple lines of treatment. In terms of response, the overall response rate was about 81%, which is really encouraging, thinking about how refractory this population is. That was largely dominated by partial responses, but I will note the trial did have about five patients who actually had CNS involvement of CLL, which is a late complication, really showing this drug’s ability to overcome a lot of different sort of difficult to treat situations. One of the most interesting things about this drug was when they looked at sort of the dynamics of it, they found that this degrader could degrade BTK really regardless of the baseline mutations present. So some patients had kinase dead mutations, kinase proficient mutations, BTK mutations, and really we saw degradation in all of these different patient populations, really showing the ability of a degrader to overcome traditional mutations that may make other BTK inhibitors ineffective. And so we hope to share future results at ASH as part of the Ib arm of this clinical trial. But, you know, to put it simply, I think degraders are going to be a very important and exciting class of drugs. We need more treatments for the dual-exposed, dual-refractory CLL. And this degrader has shown high efficacy, favorable tolerability, and maybe a new oral agent for patients. And potentially, you know, it could replace an inhibitor and actually help prevent some of these mutations from occurring. So that’s many years out, but I think we’re really excited by the data we have so far.

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