Researchers have identified a next-generation Bruton’s tyrosine kinase (BTK) degrader that could help patients with chronic lymphocytic leukemia (CLL) and related hematologic malignancies overcome treatment resistance, according to a recent study published by Montoya et al in Science. The findings could lead to the development of a novel therapeutic option for patients whose tumors become resistant or unresponsive to frontline therapy.
Background
CLL—an incurable malignancy of the blood and bone marrow diagnosed mainly among older adults—affects about 20,000 U.S. patients per year and accounts for roughly 25% of new leukemia cases, according to the American Cancer Society.
Patients diagnosed with CLL are often prescribed BTK inhibitors that are capable of shrinking tumors, minimizing symptoms, and improving survival. However, some patients develop resistance to the BTK inhibitors, thereby limiting their therapeutic options.
Currently approved drugs such as ibrutinib work by inactivating the cellular molecule BTK without destroying their targets. Instead, the agents bind to them and modulate their activity.
For instance, ibrutinib and other inhibitors bind to the BTK enzyme that acts to keep B cells alive in leukemia. By repressing BTK activity, the inhibitors can cause B-cell death in CLL and other hematologic malignancies.
“This new compound not only inhibits the cellular molecule BTK, but goes further by taking aim at the target and destroying it,” explained co–senior study author Justin Taylor, MD, a hematologist-researcher at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “It’s a new and exciting drug class called BTK degraders,” he added.
Study Methods and Results
In the recent study—involving laboratory analyses and a phase I clinical trial—the researchers examined the efficacy of the novel BTK degrader NX-2127 in patients with treatment-resistant or unresponsive CLL. They noted that NX-2127 was constructed with two modules: one binding to the BTK molecule and a second degrading and eliminating the molecule.
The researchers found that the novel BTK degrader was effective at destroying the cellular targets in both petri dishes and patients’ cells.
“More specifically, this compound destroyed BTK cells in tumors resistant to currently used BTK inhibitors, while shrinking tumors in 11 of 14 patients [with CLL] participating in our study,” detailed co–senior study author Omar Abdel-Wahab, MD, of Memorial Sloan Kettering Cancer Center.
Further, one of the patients who had developed treatment resistance to pirtobrutinib after 2 years of treatment as well as other therapies experienced symptom and quality-of-life improvements after receiving NX-2127. The researchers reported that the patient no longer needed transfusions for anemia.
Although this study had a September 2022 data cutoff for publication, the researchers provided an update in December 2023. Overall, 41% of the patients with CLL involved in the trial responded to treatment with NX-2127 and the patient with treatment resistance was still responding favorably to the agent.
Additionally, the researchers showed that treatment resistance occurred when BTK acquired mutations that gave the molecule an entirely new function. These mutations caused BTK to operate as a scaffold by recruiting other cellular molecules to keep B cells alive.
Notably, NX-2127 appeared to overcome resistance caused by virtually all of the BTK mutations identified.
Conclusions
The recent findings suggested that BTK degraders may have the potential to treat other B-cell malignancies or autoimmune conditions such as multiple sclerosis. The researchers are currently enrolling patients in another study evaluating a more potent and selective BTK degrader, NX-5948.
“CLL is an incurable disease, but with treatments like BTK inhibitors and these promising new BTK degraders, we have more ways to alleviate symptoms and get patients back to their normal everyday routines,” underscored lead study author, Skye Montoya, BS, a graduate student in the Taylor Lab at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “The future looks brighter for them,” she concluded.
Disclosure: For full disclosures of the study authors, visit science.org.
