NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton's Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies
Abstract
Introduction: Bruton's tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR) signaling pathway. Targeting this pathway has proven highly effective in patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies. However, mutations in BTK develop with both covalent (cBTKi) and non-covalent inhibitors (ncBTKi) resulting in treatment resistance and disease progression. In addition, increased expression of the transcription factor IKZF3 may contribute to resistance to cBTKi/ncBTKi. Thus, novel therapeutic mechanisms are needed that target BCR signaling, particularly in patients whose disease has relapsed or is refractory (R/R) to existing BTK targeting therapies. NX-2127 is a novel small molecule that drives targeted BTK and IKZF3 degradation through ubiquitination and proteasomal degradation. This BTK degradation and immunomodulatory activity represents a novel mechanism of action and may overcome resistance to currently available novel agents including cBTKi and ncBTKi, addressing the unmet medical needs of patients whose disease is R/R to any BTKi (including ncBTKi) and a BCL2 inhibitor. Methods: NX-2127-001 is a first-in-human, multicenter, US-based, open-label, Phase 1 dose-escalation (Phase 1a) and cohort-expansion (Phase 1b) trial, evaluating the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with R/R CLL and B-cell malignancies. Patients receive NX-2127 orally once daily in 28-day cycles starting at 100 mg. We…
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In a phase 1 first-in-human trial of NX-2127 in patients with CLL, more than 80% BTK degradation was achieved and clinical responses occurred in 79% of evaluable patients.
“Preliminary results of a phase 1, first-in-human clinical trial of NX-2127 in patients with CLL have demonstrated that >80% BTK degradation was achieved, and clinical responses were seen in 79% of evaluable patients (41, 90).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [90]
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Protein degraders enter the clinic — a new approach to cancer therapy
Chirnomas, D., Hornberger, K. R., & Crews, C. M. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00736-3 · Cited by 658 · see citing works
Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy
Gruessner, C., Wiestner, A., & Sun, C. (2025) · Leukemia & Lymphoma · doi:10.1080/10428194.2025.2466101 · Cited by 6 · see citing works
“Preliminary results of a phase 1, first-in-hu-man clinical trial of NX-2127 in patients with cll have demonstrated that >80% BtK degradation was achieved, and clinical responses were seen in 79% of evaluable patients [40,89].”
Self-citation
- Authors
- Mato, A. R., Wierda, W. G., Ai, W. Z., Flinn, I. W., Tees, M., Patel, M. R., Patel, K., O'Brien, S., Bond, D. A., Roeker, L. E., Siddiqi, T., Wang, M. L., Sun, C., Abdel-Wahab, O., Schwab, A., Tan, M., Meredith, E., Gessner, M. A., Kim, S. Y., Wiestner, A., & Danilov, A. V.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California San Francisco Medical Center (US)
- Tennessee Oncology (US)
- Colorado Blood Cancer Institute (US)
- 6Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL
- 7Swedish Cancer Institute, Center for Blood Disorders and Cellular Therapy, Seattle,
- University of California, Irvine (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- City Of Hope National Medical Center (US)
- National Institutes of Health (US)
- Nurix (United States) (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2022-11-15
- Volume
- 140
- Issue
- Supplement 1
- Pages
- 2329-2332
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W4310107959
- Cited by
- 74
- References
- 0
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 26 · 2023: 20
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- Bruton's tyrosine kinase, chronic lymphocytic leukemia, relapsed/refractory disease, B-cell malignancies, B cell receptor signaling, BTK inhibitor resistance, proteasomal degradation, dose escalation, safety and tolerability, oral small molecule
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