Ibrutinib

Orphan Drug Designation follows positive Phase 1 data presented at the 12th International Workshop on Waldenström Macroglobulinemia First-in-class Bruton’s tyrosine kinase (BTK) degrader NX-5948 assigned nonproprietary name “bexobrutideg” in newly named degrader class of drugs March 17, 2025 -- Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of targeted protein degradation medicines, today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to bexobrutideg (NX-5948) for the treatment of Waldenström macroglobulinemia (WM). Bexobrutideg is an orally bioavailable, brain penetrant degrader of BTK which is being evaluated in an ongoing Phase 1a/b clinical trial in adults with relapsed or refractory B-cell malignancies. The FDA's Orphan Drug Designation program provides orphan status to therapies intended for the treatment, diagnosis, or prevention of rare diseases that affect fewer than 200,000 people in the United States. This designation provides certain benefits, including tax credits for qualified clinical testing, waiver or partial payment of FDA application fees and seven years of market exclusivity, if approved. “The FDA’s Orphan Drug Designation for bexobrutideg, also known as NX-5948, represents an important milestone in our regulatory strategy and underscores the significant unmet medical need for improved treatments for Waldenström macroglobulinemia,” said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Nurix. “Granting of the designation highlights bexobrutideg’s potential to provide patients with WM a promising new therapeutic option. We are also pleased to announce that our investigational therapy bexobrutideg has been assigned a nonproprietary name reflecting its novel mechanism of action, designated with the unique suffix “deg” for degrader.” In collaboration with the national naming authority, United States Adopted Name (USAN) Council, Nurix’s lead BTK degrader, NX-5948, was assigned the nonproprietary name “bexobrutideg.” The U.S. and international drug naming convention is designed to select a single name of worldwide acceptability for each active substance that is intended to be marketed as a pharmaceutical. Most notable with bexobrutideg is the designation of a new suffix, “deg,” which references bexobrutideg’s novel degradation mode of action. Targeted protein degraders are characterized by their bifunctional nature, binding to both a target protein and a ligase to drive ubiquitination and catalytic degradation of the target through the proteasome. The new deg suffix is an important recognition that the mechanism of action, pharmacokinetics and pharmacodynamics of targeted protein degraders are fundamentally different than inhibitors, which all use the “ib” suffix. The central stem of the name, “bruti,” references the target, Bruton’s tyrosine kinase (as used in ibrutinib, zanubrutinib and acalabrutinib). The prefix “bexo” is the unique identifier of a specific agent in the class and is often used for ease of reference to the agent. “We are excited that bexobrutideg has been recognized by the USAN Council as a unique entity and member of a new class of small molecule drugs, targeted protein degraders,” said Gwenn Hansen, Ph.D., chief scientific officer of Nurix. “The catalytic mechanism of action and event driven pharmacology triggering ubiquitination and proteasomal degradation of a target protein is highly differentiated from inhibitors and allows degraders to eliminate the totality of a protein’s function. In our BTK degrader clinical program, we have also established that degraders can eliminate mutant oncoproteins that have proven to be resistant to inhibitor therapy.” Bexobrutideg is an investigational, orally bioavailable, brain penetrant, small molecule degrader of BTK that is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Nurix has previously reported encouraging safety and efficacy data in patients with WM treated in the ongoing Phase 1a/b clinical trial of bexobrutideg demonstrating early promise of clinical benefit with potential for durable outcomes. Nurix continues to enroll patients with WM in an ongoing Phase 1b expansion cohort and anticipates sharing additional clinical data in 2025. Additional information on the ongoing clinical trial can be accessed at clinicaltrials.gov (NCT05131022). Nurix is also developing bexobrutideg for the potential treatment of inflammatory diseases. WM is a rare, slow growing type of non-Hodgkin’s lymphoma that is characterized by the replacement of normal bone marrow cells by malignant lymphocytic cells that produce monoclonal IgM. This replacement leads to anemia, bleeding, and impaired immune function, while the elevated IgM levels may cause neurologic symptoms. The incidence of Waldenström macroglobulinemia ranges from 0.361,2 to 0.573 per 100,000 people in the United States or approximately 1,200 to 1,900 annually. With a median disease duration approaching 10 years, 4 approximately 12,000 to 19,000 patients are living with Waldenstrom’s macroglobulinemia in the United States. Recommended first-line treatments including chemoimmunotherapy and BTK inhibitor (BTKi) therapy. There are no therapies approved to treat WM patients after a BTKi. Nurix Therapeutics is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of targeted protein degradation medicines, the next frontier in innovative drug design aimed at improving treatment options for patients with cancer and inflammatory diseases. Nurix’s wholly owned, clinical stage pipeline includes degraders of Bruton’s tyrosine kinase (BTK), a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B (CBL-B), an E3 ligase that regulates activation of multiple immune cell types including T cells and NK cells. Nurix also is advancing multiple potentially first-in-class or best-in-class degraders and degrader antibody conjugates (DACs) in its preclinical pipeline. Nurix’s partnered drug discovery pipeline consists of preclinical stage degraders of IRAK4 and STAT6, as well as multiple additional programs under collaboration agreements with Gilead Sciences, Inc., Sanofi S.A. and Pfizer Inc., within which Nurix retains certain options for co-development, co-commercialization and profit sharing in the United States for multiple drug candidates. Powered by a fully AI-integrated discovery engine capable of tackling any protein class, and coupled with unparalleled ligase expertise, Nurix’s dedicated team has built a formidable advantage in translating the science of targeted protein degradation into clinical advancements. Nurix aims to establish degrader-based treatments at the forefront of patient care, writing medicine’s next chapter with a new script to outmatch disease. Nurix is headquartered in San Francisco, California. For additional information visit http://www.nurixtx.com. 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2025年3月19日，上海交通大学医学院附属瑞金医院/美国杜克大学的研究团队在期刊《Cell Reports Medicine》上发表了题为“Practical microenvironment classification in diffuse large B cell lymphoma using digital pathology”的研究论文。 2025年3月19日，上海交通大学医学院附属瑞金医院/美国杜克大学的研究团队在期刊《Cell Reports Medicine》上发表了题为“Practical microenvironment classification in diffuse large B cell lymphoma using digital pathology”的研究论文。 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00103-X https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00103-X 这项研究建立了实用的基于染色的DLBCL LME分类工具，为未来DLBCL精准治疗中实施以LME分类为指导的定制免疫疗法提供了理论基础和实践方向。 这项研究建立了实用的基于染色的DLBCL LME分类工具，为未来DLBCL精准治疗中实施以LME分类为指导的定制免疫疗法提供了理论基础和实践方向。 01 01 研究背景 研究背景 根据基因表达谱，DLBCL最早被按照起源细胞 (COO) 分成B细胞发育的3个阶段，即生殖中心B细胞 (GCB)、活化B细胞 (ABC) 和未分类B细胞。最近，科学界利用大规模转录组数据确定了DLBCL中4种不同的LME亚型，包括生殖中心样（GC-like）亚型，其特征是大量存在生殖中心（GC）相关细胞，尤其是T细胞；间质（MS）亚型，其特点是富含间质细胞和细胞外基质成分；炎症（IN）亚型，其特点是富含炎症免疫细胞；以及贫化（DP）亚型，其明显缺乏其他3种亚型中的重要非肿瘤成分。LME分类与COO或遗传亚型并不重叠，但在治疗反应和预后方面却有很大差异，这说明它是导致DLBCL异质性的一个重要因素。 根据基因表达谱，DLBCL最早被按照起源细胞 (COO) 分成B细胞发育的3个阶段，即生殖中心B细胞 (GCB)、活化B细胞 (ABC) 和未分类B细胞。最近，科学界利用大规模转录组数据确定了DLBCL中4种不同的LME亚型，包括生殖中心样（GC-like）亚型，其特征是大量存在生殖中心（GC）相关细胞，尤其是T细胞；间质（MS）亚型，其特点是富含间质细胞和细胞外基质成分；炎症（IN）亚型，其特点是富含炎症免疫细胞；以及贫化（DP）亚型，其明显缺乏其他3种亚型中的重要非肿瘤成分。LME分类与COO或遗传亚型并不重叠，但在治疗反应和预后方面却有很大差异，这说明它是导致DLBCL异质性的一个重要因素。 图形摘要 图形摘要 02 02 基于染色的LME亚型的肿瘤微环境特征 基于染色的LME亚型的肿瘤微环境特征 NK亚簇表达高水平的GNLY和KLRB1，而CD8+效应T细胞（CD8 Teff）亚簇表达颗粒酶K（GZMK）、颗粒酶A（GZMA）和IFNG。CD8+衰竭T细胞（CD8 Tex）和CD8+增殖T细胞（CD8 Prolif细胞）表达检查点基因（LAG3、HAVCR2、TIGIT和CTLA4），CD8 Prolif还表达细胞周期相关基因，如MKI67和TOP2A。幼稚T亚群表达SELL、TCF7和IL7R，而CD4-Treg则表达FOXP3。此外，CD4-Tfh细胞表达TIGIT、CTLA4、PDCD1、CXCR5和ICOS。除了亚簇1，所有亚簇中都观察到了染色体扩增和缺失。因此，亚簇1可能由非恶性B细胞组成，而其余亚簇则被认为代表恶性B细胞。 NK亚簇表达高水平的GNLY和KLRB1，而CD8+效应T细胞（CD8 Teff）亚簇表达颗粒酶K（GZMK）、颗粒酶A（GZMA）和IFNG。CD8+衰竭T细胞（CD8 Tex）和CD8+增殖T细胞（CD8 Prolif细胞）表达检查点基因（LAG3、HAVCR2、TIGIT和CTLA4），CD8 Prolif还表达细胞周期相关基因，如MKI67和TOP2A。幼稚T亚群表达SELL、TCF7和IL7R，而CD4-Treg则表达FOXP3。此外，CD4-Tfh细胞表达TIGIT、CTLA4、PDCD1、CXCR5和ICOS。除了亚簇1，所有亚簇中都观察到了染色体扩增和缺失。因此， 亚簇1可能由非恶性B细胞组成，而其余亚簇则被认为代表恶性B细胞。 通过单细胞RNA测序分析基于染色的LME亚型的肿瘤微环境特征。 通过单细胞RNA测序分析基于染色的LME亚型的肿瘤微环境特征。 03 03 总结 总结 1. 基于染色的LME分类构建及验证 ：基于选定的染色标志物构建基于染色的LME分类，其微环境成分、病理和分子特征，以及治疗反应和预后意义与基于转录组的LME分类发现一致，证实了其可靠性。LME分析显示不同亚型预后存在显著差异，GC和MS亚型在R-CHOP治疗后PFS（无进展生存期）和OS（总生存期）显著有利；IN和DP亚型患者从R-CHOP-X方案（来那度胺和依鲁替尼）中受益。 1. 基于染色的LME分类构建及验证 ： 基于选定的染色标志物构建基于染色的LME分类，其微环境成分、病理和分子特征，以及治疗反应和预后意义与基于转录组的LME分类发现一致，证实了其可靠性。LME分析显示不同亚型预后存在显著差异，GC和MS亚型在R-CHOP治疗后PFS（无进展生存期）和OS（总生存期）显著有利；IN和DP亚型患者从R-CHOP-X方案（来那度胺和依鲁替尼）中受益。 2. 各亚型免疫逃逸机制及治疗靶点探索：深入分析转录组数据，揭示各亚型免疫逃逸机制，为免疫治疗提供见解。如GC亚型过表达Treg衍生的CTLA4和TIGIT，提示其为潜在治疗靶点；MS亚型以CAF（癌相关成纤维细胞）为特征，CD70是其潜在靶点；IN亚型PD-L1和IDO1升高，可能适用PD1/PD-L1和IDO1抑制剂，CD47作为其标志物和巨噬细胞介导吞噬作用调节因子也显示出治疗潜力。 2. 各亚型免疫逃逸机制及治疗靶点探索： 深入分析转录组数据，揭示各亚型免疫逃逸机制，为免疫治疗提供见解。如GC亚型过表达Treg衍生的CTLA4和TIGIT，提示其为潜在治疗靶点；MS亚型以CAF（癌相关成纤维细胞）为特征，CD70是其潜在靶点；IN亚型PD-L1和IDO1升高，可能适用PD1/PD-L1和IDO1抑制剂，CD47作为其标志物和巨噬细胞介导吞噬作用调节因子也显示出治疗潜力。 参考资料： 参考资料： 1.Siegel, R.L. ∙ Miller, K.D. ∙ Jemal, A. 1.Siegel, R.L. ∙ Miller, K.D. ∙ Jemal, A. Cancer statistics, 2019 Cancer statistics, 2019 CA Cancer J. Clin. 2019; 69:7-34 CA Cancer J. Clin. 2019; 69:7-34 2.Wang, L. ∙ Qin, W. ∙ Huo, Y.J. ... 2.Wang, L. ∙ Qin, W. ∙ Huo, Y.J. ... Advances in targeted therapy for malignant lymphoma Advances in targeted therapy for malignant lymphoma Signal Transduct. Target. Ther. 2020; 5:15 Signal Transduct. Target. Ther. 2020; 5:15