iwCLL 2025 | The emerging promise of targeted protein degraders in CLL and other hematological malignancies

Protein degradation has emerged as a novel approach in oncology. Basically the way these drugs work is part of the molecule will connect with the protein of interest and there could be pretty much theoretically any protein can be degraded. Specifically here I have been focusing on BTK degradation, but also other targets can be employed, including androgen receptors, estrogen receptors, and potentially some hard-to-target proteins such as MYC. And so the other part of the molecule will connect with E3 ligase, and the whole complex will then be shuttled to the proteasome and be degraded. 

So specifically, BTK degraders have been developed to overcome resistance to BTK inhibitors. So mutations in BTK underlie resistance to BTK inhibitors in many cases in CLL and in some cases in mantle cell lymphoma as well. And so by degrading the whole protein, not just blocking the kinase, you’re able to overcome that problem. And the early data with BTK degraders, including the BeOne medicines compounds, the Nurix compounds, are highly promising, with 80% of patients who are refractory to BTK inhibitors and venetoclax actually achieving a response. Of course, it does take a while to achieve complete responses because we are targeting BTK pathway with a single molecule. But nevertheless, responses are durable regardless of the type of the BTK mutation that pre-exists prior to treatment with the degrader and also regardless of other mutations. So patients with deletion 17p still respond. And importantly, the safety profile of these drugs is very, very impressive, with mostly grade 1 to low-grade toxicities. 

So it is a very exciting field. We’re looking forward to combinations as well as moving those drugs into randomized Phase III studies to determine what their space will be in the future.

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