EHA 2025 | BTK degraders in CLL: mechanism of action, patient responses, and a look to the future

PROTACs are, so called, proteolysis targeting chimeras. Another word for it is protein degraders. So, degraders is a new class of drugs which are distinct from small molecule therapeutics such as kinase inhibitors, where they don’t simply inhibit the function of the protein, they actually shuttle it to the proteasome resulting in complete elimination of the target protein. So the structure of the degrader is such that it can actually process several molecules of target protein over its life. So you may need fairly low concentrations of the protein degrader. Specifically, Bruton’s kinase degraders have been designed to overcome the resistance mutation which we see emerging with both covalent BTK inhibitors, such as ibrutinib, acalabrutinib, sanubrutinib, and non-covalent BTK inhibitors, such as pirtobrutinib. So what BTK degraders do is, regardless of these mutations, they are actually able to completely eliminate Bruton’s tyrosine kinase from the CLL cell. And there are several agents currently being investigated, such as NX2127, which is a degrader which also has immunomodulatory function, and NX5948 or bexubrutideg, which is a degrader without an immunomodulatory function. And also there is a compound from Biogen and AbbVie, ABBV-011. So they’re in different stages of clinical development. But the data with these drugs is very impressive. In heavily pretreated patients who progressed on both BTK inhibitors and venetoclax patients with CLL, response rate is 80 to 90 percent. And the safety of these drugs is very impressive, where most side effects are essentially limited to those which we see with BTK inhibitors in these patients. And there are very few grade 3 adverse events. So most adverse events are very mild and are limited to mild bruising, neutropenia. And the responses to these drugs are also durable. So progression-free survival with degrader molecules is certainly over a year in these heavily pretreated patients. I personally have patients who have been treated, patients with multiple refractory CLL who have been treated with degraders for over three years now. So it is a very exciting new class of drugs, which I believe will once again revolutionize how we approach so-called double refractory patients with CLL. And these drugs also potentially in the future will make it to earlier lines of CLL therapy.

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