ICML 2025 | Findings from a Phase I study of bexobrutideg in patients with R/R CLL

Bexobrutideg belongs to a new class of drugs called proteolysis-targeting chimeras. So it is a degrader, a Bruton’s tyrosine kinase degrader, which essentially eliminates Bruton’s tyrosine kinase from the malignant cell. As you know, bruton’s tyrosine kinase is involved in B-cell receptor signaling and is pathogenic in lymphoid malignancies. However, resistance to inhibitors of Bruton’s tyrosine kinase eventually emerges. And this resistance is dependent on mutations which emerge in Bruton’s tyrosine kinase, such as C481S is one of the most common mutations that we observe in patients with chronic lymphocytic leukemia who progress on the ibrutinib, acalabrutinib, and zanubrutinib, the BTK inhibitors that we currently have in clinical practice. So the BTK degraders, they have been designed to essentially overcome this problem where they actually target the whole BTK for degradation through the proteasome. In essence, it not only overcomes the BTK function, but also it overcomes the BTK scaffolding effect. So BTK actually can partner with different other molecules in the B-cell receptor signaling pathway to propagate the oncogenic signal. So that’s what degraders do. So they impair the BTK function twofold. They disrupt the kinase activity and they also disrupt the scaffolding function. So bexobrutideg is a PROTAC, BTK degrader which is investigated in a Phase I study which now completed enrollment. There were several dose levels and two dose levels were selected for further study as part of Project Optimus, bexobrutideg 200 milligram by mouth daily and 600 milligram by mouth daily. And so we have close to 50 patients on that study. And these patients actually were heavily treated, median four prior lines of therapy. The majority of these patients received chemoimmunotherapy at some point. All but one patient received prior BTK inhibitor, such as ibrutinib, acalabrutinib. About a third also were treated with pirtobrutinib, a non-covalent BTK inhibitor. And the majority of patients were also double refractory, meaning they were refractory to both BTK inhibitor and venetoclax. So these patients also, about a third of them had P53 mutations. So very difficult to treat patient population. So they received bexobrutideg daily by mouth and were followed for response and responses emerged very rapidly. So by eight weeks, majority of patients were in response, and overall response rate was in excess of 80% in this study. Complete responses were still rare, but still we continue to follow these patients as responses are durable. And we already saw one case of complete response, which was achieved after two years on therapy. So this is this is fairly typical with BTK targeting agents where achievement of complete responses does take some time. The drug also was very well tolerated where essentially all toxicities were low grade, grade 1, 2. Most toxicities were those which we typically see with BTK inhibitors such as light bruising, mild neutropenia. There were no excess infectious complications. There was one case of atrial fibrillation in a patient who had pre-existing atrial fibrillation. And there were no drug-related deaths on the study. So responses continue to be durable. There are quite a few patients who have been treated with this drug for over a year now. So overall, very good results with this study, very well-tolerated agent, which also shows high efficacy in BTK inhibitor resistant patients.

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