Obinutuzumab

系统性红斑狼疮（SLE）是一种以自身免疫反应为核心机制的系统性炎症性疾病，可累及多器官。由于疾病的复杂性及异质性，其治疗一直面临「疗效有限与毒性累积」的两难困境。长期以来，糖皮质激素（GCs）及广谱免疫抑制剂如环磷酰胺、吗替麦考酚酯（MMF）、硫唑嘌呤（AZA）构成治疗主轴，但感染、骨质疏松及心血管事件等长期副作用成为主要死因之一 [1]。 03 年 EULAR 指南明确提出 []： ● GCs 应仅用于短期诱导或过渡性治疗； ● 尽早联合免疫调节剂（HCQ、MMF、CNI 等）； ● 强调实现低疾病活动状态（LLDAS）或缓解（DORIS）为核心目标。 因此，SLE 治疗正从「免疫抑制」向「免疫精准调控」转变。Tanaka 教授在 05 年综述中指出：未来 SLE 治疗的方向是在最小化激素基础上，通过靶向免疫通路实现免疫重建与无药缓解（drug-free remission）[3]。 发病机制与机制驱动治疗 SLE 是一种由遗传易感性、环境因素、免疫紊乱和表观遗传调控共同驱动的多因素疾病。其核心病理机制是免疫耐受的破坏，导致机体对自身抗原产生持续免疫反应。 01 自身免疫反应的激活：从 T 细胞到 B 细胞 在 SLE 中，自身抗原的持续暴露导致自身反应性 T 细胞的激活及调节性 T 细胞（Treg）功能障碍。滤泡辅助性 T 细胞（Tfh）在生发中心中对 B 细胞进行活化和分化信号传递，促使其在 IL-1 等细胞因子刺激下发生类别转换，最终分化为自身抗体产生的浆细胞。这些自身抗体与自身抗原结合形成免疫复合物，沉积于组织后激活补体系统，引发组织损伤和慢性炎症。 B 细胞除产生抗体外，还分泌 IL-6、TNF 等细胞因子，加剧炎症反应。全基因组关联研究（GWAS）发现，多数 SLE 易感基因在 B 细胞中高表达 [4]，进一步强调了 B 细胞在 SLE 体液免疫与自身免疫中的核心作用。 0 先天免疫激活：树突细胞与 TLR 信号 GWAS 同样发现了多个与先天免疫信号和细胞内通路相关的易感基因，包括 IRF5、IRAK1、TLR7 等，它们在浆细胞样树突细胞（pDC）中高表达。pDC 在 SLE 患者中异常活跃，能识别核酸-抗体复合物并通过 Toll 样受体（TLRs）通路产生大量 I 型干扰素（IFN-I）。 DNA-抗 dsDNA 抗体复合物被树突细胞的 Fc 受体摄取后，通过 TLR7/9-MyD88-IRF7 轴触发 IFN-α 等细胞因子释放。这一过程不仅激活树突细胞自身，还促进 B 细胞、T 细胞的增殖与分化，形成恶性循环。 值得注意的是，TLR7 基因突变（Y64 H）可导致单基因型儿童狼疮。小鼠研究证实该突变导致 TLR7-MyD88 信号过度激活，引起 CD11c⁺ 衰老样 B 细胞积聚与自身抗体持续产生，提示 TLR7 是 SLE 发病的关键分子枢纽 [5]。 03 干扰素信号与 BAFF 通路的「 桥梁作用 」 SLE 患者常存在 I 型干扰素基因特征（IFN signature）过度表达，同时血清中可检测到 IFN-α 和 BAFF（B-cell activating factor）水平升高 [6]。IFN-I 不仅增强抗原呈递能力，还可刺激 BAFF 分泌，促进 B 细胞分化与自身抗体生成。因此，IFN-BAFF 轴成为连接先天与适应性免疫反应的核心通路。 B 细胞靶向治疗的持续进化 B 细胞在 SLE 发病中扮演核心角色，不仅产生自身抗体，还通过抗原呈递和细胞因子分泌维持炎症反应。因此，B 细胞相关靶点（CD0、CD40L、BAFF 等）成为近年来药物研发的重点。 01 抗 CD0 抗体：Obinutuzumab Obinutuzumab 为新一代 II 型抗 CD0 抗体，具有更强的抗体依赖细胞毒活性（ADCC）和吞噬活性，可更彻底清除 B 细胞。在 III 期 REGENCY 研究中，活动性狼疮性肾炎（LN）患者接受 Obinutuzumab 联合标准方案（MMF+GCs）治疗 1 个月后，完全肾缓解率 46.4%，显著高于安慰剂组的 33.1%（P = 0.0）[7]。不良反应以轻中度感染为主，无新的安全信号。该结果证实，强化 B 细胞清除可显著改善肾脏结局。 0 抗 CD40L 抗体：Dapirolizumab pegol CD40-CD40L 通路是 T 细胞与 B 细胞间关键的共刺激信号。早期全 IgG 型抗 CD40L 抗体因血栓风险而终止开发，而 Dapirolizumab pegol 通过去 Fc 结构避免了该风险。 IIb 期研究虽未达主要终点，但在免疫学指标（dsDNA、补体水平）及 SLEDAI 下降方面表现出趋势性改善，安全性良好 [8]。目前 III 期 PHOENYCS 试验正在进行中，预期将进一步验证其在非肾性 SLE 中的疗效。 BAFF/APRIL 通路：B 细胞「生存信号」的双重封锁 BAFF 与 APRIL（A proliferation-inducing ligand）是维持 B 细胞分化、存活及免疫球蛋白产生的核心因子。在 SLE 患者中，两者水平普遍升高，且与疾病活动密切相关。 01 Ianalumab 靶向 BAFF 受体（BAFF-R）的单克隆抗体，既能阻断 BAFF 信号，又可通过 ADCC 机制清除 B 细胞。 在干燥综合征 IIb 期试验中显著改善 ESSDAI 评分，目前 SIRIUS-SLE 及 SIRIUS-LN 两项 III 期研究正在进行 [9]。该药物的独特机制有望在不完全清除 B 细胞的情况下，实现免疫稳态恢复。 0 Telitacicept Telitacicept 是一种重组融合蛋白，与 TACI（BAFF/APRIL 的受体之一）和人 IgG-Fc 结合，从而抑制 BAFF 和 APRIL 信号。在中国开展的随机、对照 IIb 期研究中，49 例中重度活动性 SLE 患者被随机分配至安慰剂或每周一次的 Telitacicept（80/160/40 mg），主要终点为第 48 周 SRI-4。Telitacicept 各剂量组的 SRI-4 应答率（71.0%、68.3%、75.8%）均显著高于安慰剂组（33.9%）；各组不良事件发生率相似 [10]。目前全球 III 期 REMESLE 研究正在进行。 树突细胞与 I 型干扰素通路的新靶点 IFN-I 在 SLE 发病中的中心地位已得到充分证实。Anifrolumab 作为抗 IFNAR1 抗体的成功上市，为后续上游靶点开发奠定了基础。 01 Litifilimab Litifilimab 是一种靶向浆细胞样树突细胞（pDC）特异分子 BDCA 的单克隆抗体，可抑制 IFN-α 的产生，从而降低免疫系统的过度激活。 在一项 IIb 期 LILAC 研究中，Litifilimab 相较安慰剂显著改善关节活动度（总活动关节数下降 15.0 vs 11.6，P = 0.04）及皮肤病变指标，且耐受性良好 [11]。常见不良事件包括带状疱疹及唇疱疹感染。目前 III 期 TOPAZ 研究正在进行，以进一步验证其在 SLE 中的疗效与安全性。 与 Anifrolumab 相比，Litifilimab 作用于更上游的 pDC-IFN 轴，理论上可减少广谱干扰素阻断所致的副作用。 小分子药物 01 Voclosporin 新一代口服钙调神经磷酸酶抑制剂（CNI），为环孢素 A 结构类似物，药代稳定、肾毒性较低。 在 AURORA Ⅲ 期研究 中，Voclosporin + MMF 方案在活动性狼疮性肾炎中显著提高完全肾缓解率（41% vs 3%），并允许显著减量糖皮质激素 1。长期随访（AURORA-）证实疗效持续、安全性良好。适用于活动性 LN，但应避免用于 eGFR＜30 mL/min/1.73 m² 的患者。 Voclosporin 以低激素剂量实现显著肾缓解，是当前狼疮性肾炎治疗的新标准之一。 0 Upadacitinib 选择性 JAK1 抑制剂，已在类风湿关节炎等免疫性疾病中获批。 在一项 II 期 SLE 研究 中，341 例中重度 SLE 患者被随机分配接受 Upadacitinib 单用或与 BTK 抑制剂 Elsubrutinib 联合。在第 4 周，主要终点（SRI-4 应答且泼尼松 ≤ 10 mg/d）达标率为 54.8%（Upa 30 mg + Els 60 mg）vs 37.3%（安慰剂），差异显著。联合组复发更少、首次复发延迟，无新增安全信号 [13]。目前 III 期 SELECT-SLE 研究正在进行。 03 Deucravacitinib（Tyk 抑制剂） 通过抑制 Tyk「假激酶结构域」，实现高选择性，避免传统 JAK 抑制剂的不良反应（如感染风险、血脂异常）。II 期 PAISLEY 研究显示：SRI-4 应答率 58% vs 34%（P < 0.001），且长期耐受良好 [14]。III 期 POETYK SLE 正在开展。 Deucravacitinib 通过精准抑制 Tyk 通路改善多系统 SLE 活动，疗效确切、安全性可控，是 JAK 家族中最具前景的新成员。 04 Cenerimod Cenerimod 是一种选择性口服 S1P1 受体调节剂，可通过阻断 S1P 信号通路抑制淋巴细胞从二级淋巴器官外流，从而减少外周循环中的活化淋巴细胞。 作为与 Fingolimod 类似的新型免疫调控药物，它在系统性红斑狼疮中显示出良好的耐受性和潜在疗效 [15]，目前 Ⅲ 期研究正在进行。Cenerimod 代表了 S1P 通路调控在 SLE 中的新方向，为小分子免疫调节药物的重要成员。 免疫重建疗法：从药物控制到「 治愈 」探索 01 CAR-T 疗法 CAR-T（嵌合抗原受体 T 细胞）疗法是一种创新性细胞免疫治疗，通过改造患者自身 T 细胞，使其识别并清除 B 细胞。常见靶点为 CD19 或 BCMA。其在血液肿瘤中的成功经验被延伸至自身免疫病，包括 SLE。 01 年，Schett 等首次报道难治性 SLE 患者接受 CD19-CAR-T 治疗后实现快速、持久的缓解，B 细胞暂时清除、尿蛋白消失、血清学指标恢复正常，且副作用轻微 [16]。随后多例研究显示，患者均在 3 个月内达到 DORIS 缓解，B 细胞约在 3~4 个月后重新出现，提示该疗法可重建免疫稳态。 在 I/II 期 CASTLE 研究中，4 例患者（其中 SLE 10 例、IIM 5 例、SSc 9 例）接受自体 CD19-CAR-T 治疗后均取得临床改善，并能停用免疫抑制剂。主要不良反应为轻中度细胞因子释放综合征（CRS），未见严重神经毒性或局部免疫反应。 CAR-T 疗法为难治性 SLE 提供了「免疫系统重启」的新思路，虽仍面临安全性与成本挑战，但其治愈潜力备受关注。 0 T 细胞双特异抗体（TCE） TCE 是一种能同时结合 T 细胞与 B 细胞靶点的双特异抗体，通过桥接 T 细胞与靶 B 细胞，诱导 T 细胞介导的 B 细胞裂解 [17]。该机制已在难治性 B 细胞淋巴瘤中验证有效，代表药物包括： ● CD19-TCE：blinatumomab ● CD0-TCE：mosunetuzumab、epcoritamab、glofitamab 这类药物通过同时结合 B 细胞表面抗原（CD19/CD0）与 T 细胞上的 CD3，绕过传统 MHC 限制，直接形成免疫突触，从而激活 T 细胞杀伤 B 细胞。 目前已观察到 CD8⁺T 细胞介导的靶细胞裂解效应，相关 SLE 临床试验正在规划中。 表 1. SLE 新药与疗法进展 迈向低激素、精准与免疫重建的新时代 03 年 EULAR 指南标志着 SLE 治疗理念的重大转变 —— 从依赖激素控制向「免疫精准调控与缓解维持」过渡。 目前，多种新型生物制剂与小分子药物正重塑 SLE 治疗格局： 1 B 细胞通路靶向药物如 Belimumab、Ianalumab、Obinutuzumab、Dapirolizumab pegol； I 型干扰素及树突细胞靶向药物如 Anifrolumab、Litifilimab； 3 信号通路抑制剂如 Upadacitinib（JAK）、Deucravacitinib（Tyk）； 4 以及细胞重建疗法如 CAR-T 和 TCE。 这些新策略共同推动 SLE 从传统免疫抑制走向低激素甚至免疫重塑的「药物性缓解」阶段。 随着病理机制的深入理解和多靶点药物的出现，SLE 治疗正处于从「广谱免疫抑制」到「免疫平衡重建」的转型阶段：靶点更加多样（如 BAFF、IFN-I、Tyk、S1P 等通路），安全性不断优化（如 Fc 修饰、选择性免疫抑制），免疫重建理念逐渐成型（CAR-T/TCE 探索长期缓解）。未来研究将聚焦于不同亚型的精准用药、长期安全性与可及性评估。总体来看，SLE 治疗正迈向「低激素化、个体化与免疫重建」的新时代。 ✩ 本文仅供医疗卫生等专业人士参考 投稿邮箱：huanghaihua@dxy.cn 策划：黄海花 参考资料： [1] . Ugarte-Gil MF, Mak A, Leong J, et al. Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies. Lupus Sci Med 01; 8(1). [] . Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 03 update. Ann Rheum Dis 04; 83(1): 15-9. [3] . Tanaka Y. Novel therapies in treatments of SLE. Best Pract Res Clin Rheumatol 05: 10101. [4] . Liu Z, Davidson A. Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med 01; 18(6): 871-8. [5] . Brown GJ, Cañete PF, Wang H, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 0; 605(7909): 349-56. [6] . Tanaka Y. State-of-the-art treatment of systemic lupus erythematosus. Int J Rheum Dis 00; 3(4): 465-71. [7] . Furie RA, Rovin BH, Garg JP, et al. Efficacy and Safety of Obinutuzumab in Active Lupus Nephritis. N Engl J Med 05; 39(15): 1471-83. [8] .  Furie RA, Bruce IN, Dörner T, et al. Phase , randomized, placebo-controlled trial of dapirolizumab pegol in patients with moderate-to-severe active systemic lupus erythematosus. Rheumatology (Oxford) 01; 60(11): 5397-407. [9] . Dörner T, Bowman SJ, Fox R, et al. Safety and Efficacy of Ianalumab in Patients With Sjögren's Disease: 5-Week Results From a Randomized, Placebo-Controlled, Phase b Dose-Ranging Study. Arthritis Rheumatol 05; 77(5): 560-70. [10] . Wu D, Li J, Xu D, et al. Telitacicept in patients with active systemic lupus erythematosus: results of a phase b, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 04; 83(4): 475-87. [11] . Furie RA, van Vollenhoven RF, Kalunian K, et al. Trial of Anti-BDCA Antibody Litifilimab for Systemic Lupus Erythematosus. N Engl J Med 0; 387(10): 894-904. [1] . Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 01; 397(1089): 070-80. [13] . Merrill JT, Tanaka Y, D'Cruz D, et al. Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Patients With Systemic Lupus Erythematosus: A Phase Randomized Controlled Trial. Arthritis Rheumatol 04; 76(10): 1518-9. [14] . Morand E, Pike M, Merrill JT, et al. Deucravacitinib, a Tyrosine Kinase Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 03; 75(): 4-5. [15] . Askanase AD, D'Cruz D, Kalunian K, et al. Cenerimod, a sphingosine-1-phosphate receptor modulator, versus placebo in patients with moderate-to-severe systemic lupus erythematosus (CARE): an international, double-blind, randomised, placebo-controlled, phase trial. Lancet Rheumatol 05; 7(1): e1-e3. [16] . Mougiakakos D, Krönke G, Völkl S, et al. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med 01; 385(6): 567-9. [17] . Reed DR, Lum LG. Looking ahead to CD3, T-cell engager bispecific antibodies for hematological malignancies. Expert Opin Biol Ther 04; 4(8): 761-7.

SAN CARLOS, Calif.--(BUSINESS WIRE)--BeOne Medicines Ltd. (Nasdaq: ONC; HKEX: 06160; SSE: 688235), a global oncology company, advances its vision to become the world’s leading oncology company with extensive new data from its differentiated hematology portfolio at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, December 6-9. Nearly 50 abstracts have been accepted, including six oral presentations, featuring the company’s three transformative approved and investigational hematology assets – BTK inhibitor BRUKINSA® (zanubrutinib), BCL2 inhibitor sonrotoclax, and BTK degrader BGB-16673. Key presentations include: SEQUOIA: BRUKINSA demonstrated sustained overall survival (84%; 88% after COVID adjustment) and landmark progression-free survival (PFS) superiority vs bendamustine + rituximab with an estimated 74% PFS at 6 years in treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (Poster Presentation: 2129) ALPINE: Post-hoc analysis from Phase 3 study of BRUKINSA versus ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL, using longitudinal patient-reported outcomes (PRO) (Oral Presentation: 711) BGB-11417-201: Phase 1/2 study of sonrotoclax in patients with R/R mantle cell lymphoma (MCL) previously treated with a BTK inhibitor (Oral Presentation: 663) BGB-11417-101: Updated safety and efficacy results, including undetectable minimal residual disease (uMRD) data, from ongoing Phase 1/1b study of sonrotoclax plus BRUKINSA in treatment-naïve CLL/SLL (Poster Presentation: 3891) CaDAnCe-101: Updated efficacy and safety results of BGB-16673 in patients with R/R CLL/SLL and R/R Waldenström macroglobulinemia (WM) (Oral Presentation: 85; Poster Presentation: 3583) “Our data at ASH 2025 raises the bar for patient and physician expectations of what’s possible. Our long-term data drives confidence in duration of response in CLL treatment decisions,” said Lai Wang, Ph.D., Global Head of R&D at BeOne. “Six-year SEQUOIA and long-term extension data from patients originally enrolled in ALPINE cement BRUKINSA’s role as the backbone of CLL therapy, and our three innovative B-cell treatment modalities of BTK inhibition, BCL2 inhibition, and BTK degradation have the potential to advance options that evolve with patient needs across all stages of disease.” Additional highlights include: Never-before-presented clinical data from BeOne’s emerging pipeline will also be shared at the meeting, including in new combinations and disease areas. BGB-11417-101: Results from Phase 1/1b study: MRD-guided therapy of sonrotoclax plus obinutuzumab in patients with treatment-naïve CLL/SLL (Oral Presentation: 793) Initial results of treatment with sonrotoclax plus BRUKINSA plus obinutuzumab in patients with treatment-naïve CLL/SLL (Poster Presentation: 3890) MRD-guided therapy of sonrotoclax plus obinutuzumab in patients with treatment-naïve CLL/SLL (Oral Presentation: 793) Initial results of treatment with sonrotoclax plus BRUKINSA plus obinutuzumab in patients with treatment-naïve CLL/SLL (Poster Presentation: 3890) BGB-11417-202: Phase 2 study of sonrotoclax monotherapy in patients with R/R CLL/SLL (Poster Presentation: 5666) BGB-11417-105: Initial results from Phase 1b/2 study of sonrotoclax plus carfilzomib and dexamethasone in patients with t(11;14)-positive R/R multiple myeloma (Oral Presentation: 102) CaDAnCe-101 Preliminary results from the ongoing Phase 1 study of BGB-16673 in patients with R/R Richter’s transformation (Poster Presentation: 3895) Ongoing clinical data from BRUKINSA continue to demonstrate clinically meaningful benefit for patients with CLL/SLL. SEQUOIA Arm D: Single-arm study of BRUKINSA plus venetoclax in patients with first-line CLL/SLL, with del(17p) and/or TP53 mutation or without both (Poster Presentation: 5669) ALPINE thru LTE1: Up to 6 years of follow-up of patients with R/R CLL/SLL who were originally randomized to receive BRUKINSA as part of the ALPINE study and continued BRUKINSA treatment in a long-term extension study (LTE-1) (Poster Presentation: 2123) Presentations also include data leveraging real-world evidence and validated modeling approaches to refine understanding of real-world experience and outcomes achieved with covalent BTK inhibitors. A model analysis of number needed to treat (NNT) estimates that treating patients with BRUKINSA instead of ibrutinib for CLL could potentially prevent approximately 255 cardiac deaths in the second-line or later (2L+) setting and 266 in the first-line (1L) setting over a 10-year period. (Abstract Number: 13636) Model evaluating BRUKINSA vs other covalent BTK inhibitors in R/R CLL and the number of patients needed to treat to avoid progression or death (Poster Presentation: 4553) Observational study examining patient-reported outcomes in U.S. patients with CLL/SLL and treated with BRUKINSA or acalabrutinib in the community oncology setting (Poster Presentation: 2768) “In CLL, selecting the right therapy for the right patient at the right time is essential, and continuous treatment with BTK inhibitors like BRUKINSA has become central to achieving enduring disease control,” said Dany Habr, M.D., Senior Vice President and Head of Medical Affairs, North America & International Markets at BeOne. “Emerging data from real-world settings suggest that BRUKINSA may offer a more manageable side effect profile, including for symptoms such as fatigue, pain, headache – further supporting its role as the BTKi of choice.” BeOne Presentations at ASH 2025 (organized chronologically by asset) BRUKINSA: The backbone of the hematology franchise Abstract Title Presentation Details Final analysis of the randomized Phase 2 ROSEWOOD study of zanubrutinib + obinutuzumab vs obinutuzumab monotherapy in patients with R/R follicular lymphoma Oral Presentation: 227 Session Title: Mantle Cell, Follicular, Waldenstrom's, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: FL and WM Session Date/Time: December 6, 2025, 2:00-3:30 PM EST Pier Luigi Zinzani Sustained efficacy of zanubrutinib vs bendamustine + rituximab in treatment- naïve CLL/SLL with continued favorable survival in non-randomized patients with del(17p): 6-year follow-up in the Phase 3 SEQUOIA study Poster Presentation: 2129 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Constantine S. Tam Long-term results of patients receiving zanubrutinib in the Phase 3 ALPINE study confirm sustained benefit of zanubrutinib in patients with R/R CLL/SLL: Up to 6 years of follow-up with the long-term extension Poster Presentation: 2123 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Constantine S. Tam Symptom-based progression-free survival as a clinically relevant and patient-centric endpoint in CLL/SLL: Results from the ALPINE trial Oral Presentation: 711 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Quality of Life and Supportive Care in Lymphoid Malignancies Session Date/Time: December 7, 2025, 4:30-6:00 PM EST Jennifer R. Brown Progression-free survival in patients with low health-related quality of life treated with zanubrutinib versus ibrutinib monotherapy: Post-hoc analysis of the ALPINE trial Poster Presentation: 6275 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Quality of Life and Supportive Care in Lymphoid Malignancies Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Loic Ysebaert Zanubrutinib + venetoclax for treatment-naïve CLL/SLL, including patients with del(17p) and/or TP53 mutation and unmutated immunoglobulin heavy-chain variable status: 3-year results from SEQUOIA arm D Poster Presentation: 5669 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Mazyar Shadman Evaluation of factors from established prognostic models in patients with CLL treated with zanubrutinib: A post-hoc analysis of two Phase 3 studies (SEQUOIA and ALPINE) Poster Presentation: 5681 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Inhye Ahn Zanubrutinib is well tolerated and effective in acalabrutinib-intolerant patients with B-cell malignancies: A long-term follow-up Poster Presentation: 5663 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Mazyar Shadman Single-arm, open-label, multicenter study of the BTKi zanubrutinib in patients with CD79B-mutated R/R diffuse large B-cell lymphoma Poster Presentation: 3684 Session Title: Aggressive Lymphomas: Targeted and Pharmacologic Therapies: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Li Wang Sonrotoclax: Potential best-in-class next-generation BCL2 inhibitor Abstract Title Presentation Details Lead Author Initial Phase 1b/2 study results with sonrotoclax in combination with carfilzomib and dexamethasone in patients with t(11;14)-positive R/R multiple myeloma Oral Presentation: 102 Session Title: Multiple Myeloma: Pharmacologic Therapies: Advancing the Standard: Improving Myeloma Treatment through Diagnosis, Maintenance and Relapse Session Date/Time: December 6, 2025, 10:45-11:00 AM EST Hang Quach A Phase 3, randomized, open-label, multicenter study of sonrotoclax plus anti-CD20 antibody therapies vs venetoclax plus rituximab in patients with R/R CLL/SLL (CLL-RR1/CELESTIAL-RRCLL) Trial-in-progress Poster Presentation: 2137 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Othman Al-Sawaf Sonrotoclax monotherapy in patients with relapsed/refractory mantle cell lymphoma previously treated with BTKi: Early results from a Phase 1/2 study Oral Presentation: 663 Session Title: Mantle Cell, Follicular, Waldenstrom's, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological - Novel Treatments for and Insights into Mantle Cell Lymphoma Session Date/Time: December 7, 2025, 4:30-6:00 PM EST Michael Wang Frontline treatment of sonrotoclax and zanubrutinib for CLL/SLL demonstrates high undetectable minimal residual disease rates with favorable tolerability: Updated data from BGB-11417-101, an ongoing Phase 1/1b study Poster Presentation: 3891 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Constantine S. Tam Zanubrutinib + obinutuzumab + sonrotoclax in patients with treatment-naïve CLL/SLL: Initial results from an ongoing Phase 1/1b study, BGB-11417-101 Poster Presentation: 3890 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Jacob D. Soumerai MRD-guided therapy of sonrotoclax + obinutuzumab in patients with treatment-naive CLL: Initial results from an ongoing Phase 1/1b study, BGB-11417-101 Oral Presentation: 793 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: MRD Guided Therapy and Emergence of Resistance Session Date/Time: December 8, 2025, 10:30 AM-12:00 PM EST Marc S. Hoffmann Primary analysis of a multicenter, open-label, Phase 2 study of sonrotoclax monotherapy in patients with R/R CLL/SLL Poster Presentation: 5666 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Shuhua Yi BGB-16673: Potential first-in-class BTK protein degrader Abstract Title Presentation Details Lead Author Updated efficacy and safety results of the BTK degrader BGB-16673 in patients with R/R CLL/SLL from the ongoing Phase 1 CaDAnCe-101 study Oral Presentation: 85 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Treatment of CLL in Relapse and in Richter Transformation Session Date/Time: December 6, 2025, 9:30-11:00 AM EST Inhye E. Ahn CaDAnCe-104, an ongoing, open-label, Phase 1b/2 master protocol study of BTK degrader BGB-16673 in combination with other agents in patients with R/R B-cell malignancies Trial-in-Progress Poster Presentation: 1839 Session Title: Mantle Cell, Follicular, Waldenstrom's, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Chan Y. Cheah Updated efficacy and safety results of the BTK degrader BGB-16673 in patients with R/R indolent non-Hodgkin lymphoma from the ongoing Phase 1 CaDAnCe-101 study Poster Presentation: 3584 Session Title: Mantle Cell, Follicular, Waldenstrom's, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Romain Guièze Preliminary efficacy and safety of the BTK BGB-16673 in patients with R/R Richter transformation: Results from the ongoing Phase 1 CaDAnCe-101 study Poster Presentation: 3895 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Meghan C. Thompson Updated efficacy and safety results of the BTK BGB-16673 in patients with R/R Waldenström macroglobulinemia from the ongoing Phase 1 CaDAnCe-101 study Poster Presentation: 3583 Session Title: Mantle Cell, Follicular, Waldenstrom's, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Constantine S. Tam CaDAnCe-304, a Phase 3, open-label, randomized study to evaluate the safety and efficacy of BTK degrader BGB-16673 compared with pirtobrutinib in patients with R/R CLL/SLL Trial-in-progress Poster Presentation: 5691 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Meghan C. Thompson Other hematology assets: BGB-21447, next-generation BCL2 inhibitor Abstract Title Presentation Details Lead Author Preliminary results from a Phase 1/1b first-in-human study of BGB-21447, a next-generation BCL2 inhibitor, in patients with B-cell non-Hodgkin lymphoma Poster Presentation: 1910 Session Title: Aggressive Lymphomas: Targeted and Pharmacologic Therapies: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Fei Li Integrative evidence generation and health economics related to BRUKINSA Abstract Title Presentation Details Lead Author Matching-Adjusted Indirect Comparison Indirect comparison of efficacy of zanubrutinib vs ibrutinib for the treatment of R/R MCL Poster Presentation: 5365 Session Title: Mantle Cell, Follicular, Waldenstrom's, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Toby A. Eyre A matching-adjusted indirect comparison of zanubrutinib vs venetoclax + ibrutinib in treatment-naive CLL Abstract Number: 7756 Talha Munir Health Economic and Outcomes Research Outcomes during BTKi treatment for CLL: Insights from remote therapeutic monitoring Poster Presentation: 2768 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Gurjyot Doshi Number needed to treat to avoid progression or death: Zanubrutinib vs other covalent BTKis in R/R CLL Poster Presentation: 4553 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Mazyar Shadman Estimated cardiac deaths associated with treating CLL with ibrutinib versus zanubrutinib in the United States Abstract Number: 13636 Jennifer R. Brown Number of patients needed to treat to prevent one atrial fibrillation event with zanubrutinib versus ibrutinib and acalabrutinib in B-cell malignancies Abstract Number: 14445 Talha Munir Number of cardiac deaths associated with ibrutinib versus zanubrutinib for the treatment of CLL: A European risk-based estimation Abstract Number: 14028 Talha Munir Real-World Evidence Mediators of racial and ethnic inequities in access to front-line therapies for CLL in the United States: A real-world evidence study Poster Presentation: 2720 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Jacqueline C. Barrientos Real-world treatment patterns and biomarker utilization among patients aged ≥65 years with CLL/SLL from 2020 to 2024 Poster Presentation: 2723 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Paul Hampel Chemo ± immunotherapy remains utilized for CLL in the real-world practice: Unmet needs, treatment patterns, and age disparities in the United States Poster Presentation: 2762 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster I Session Date/Time: December 6, 2025, 5:30-7:30 PM EST Javier Pinilla-Ibarz Impact of testing for genetic markers on treatment selection and clinical outcomes among patients with CLL Poster Presentation: 3894 Session Title: Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Brian Koffman Treatment patterns and outcomes among patients treated with second-generation BTK inhibitors in CLL Poster Presentation: 4528 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Aryan Ayat Changes in real-world treatment patterns over time by patient characteristics and time burden of treatment in CLL/SLL Poster Presentation: 6283 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Mengyang Di Real-world treatment patterns and patient characteristics of venetoclax combination time-limited therapy for CLL Poster Presentation: 6317 Session Title: Outcomes Research: Lymphoid Malignancies Excluding Plasma Cell Disorders: Poster III Session Date/Time: December 8, 2025, 6:00-8:00 PM EST Jing-Zhou Hou Real-world treatment utilization, sequencing, and outcomes in mantle cell lymphoma: Emerging treatment patterns in the United States Abstract Number: 13378 Alvaro Alencar Real-world zanubrutinib treatment patterns in CLL/SLL among a curated sample of US community oncology patients with prior acalabrutinib therapy Abstract Number: 8798 Jing-Zhou Hou Incidence of cardiac-related deaths among patients aged ≥65 years with B-cell malignancies treated with ibrutinib Abstract Number: 7341 Ryan Jacobs Real-world CLL-specific biomarker testing patterns and frontline treatment patterns in patients with CLL/small lymphocytic lymphoma Abstract Number: 7773 Timothy Reynolds Real-world CLL/SLL treatment patterns at Florida Cancer Specialists & Research Institute among patients receiving zanubrutinib immediately following prior BTKi therapy Abstract Number: 13894 Amanda Warner Patient Preference Patient preferences and factors affecting patient treatment decisions for CLL in Japan Poster Presentation: 4406 Session Title: Health Services and Quality Improvement: Lymphoid Malignancies: Poster II Session Date/Time: December 7, 2025, 6:00-8:00 PM EST Sikander Ailawadhi Evaluating patient preferences for CLL in Korea: A discrete choice experiment Abstract Number: 4019 Byung Woo Yoon Systemic Literature Review Patients with high-risk features in mantle cell lymphoma: A systematic literature review of clinical trials and real-world studies Abstract Number: 14130 Christine E. Ryan For additional information about our presence at the 2025 ASH Annual Meeting and Exposition, please visit our meeting hub: congress.beonemedicines.com. About Sonrotoclax (BGB-11417) Sonrotoclax is a next-generation and potentially best-in-class investigational B-cell lymphoma 2 (BCL2) inhibitor with a unique pharmacokinetic and pharmacodynamic profile. Studies in the lab and during early drug development have shown that sonrotoclax is a highly potent and specific BCL2 inhibitor with a short half-life and no drug accumulation. Sonrotoclax has shown promising clinical activity across a range of B-cell malignancies and is in development as a monotherapy and in combination with other therapeutics, including BRUKINSA. Notably, in early clinical trials, sonrotoclax plus BRUKINSA has demonstrated rapid and unprecedented undetectable minimal residual disease (uMRD) rates in treatment-naïve patients with CLL. To date, more than 2,200 patients have been enrolled across the broad global development program. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) for sonrotoclax for the treatment of adult patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL). In addition, the FDA has granted sonrotoclax Fast Track Designation for MCL and Waldenström macroglobulinemia, as well as Orphan Drug Designation for the treatment of adult patients with MCL, WM, multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome. About BGB-16673 BGB-16673 is a potential first-in-class Bruton’s tyrosine kinase (BTK) protein degrader and is the most advanced protein degrader in the clinic, with nearly 800 patients dosed to date in an extensive global clinical development program. This program includes three randomized Phase 3 trials in R/R CLL, including the head-to-head Phase 3 trial versus pirtobrutinib which began enrolling in Q4 2025. Originating from BeOne’s chimeric degradation activation compound (CDAC) platform, BGB-16673 is designed to promote the degradation, or breakdown, of both wildtype and mutant forms of BTK, including those that commonly result in resistance to BTK inhibitors in patients who experience progressive disease. The U.S. Food and Drug Administration (FDA) granted Fast Track Designation to BGB-16673 for the treatment of adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), and adult patients with R/R mantle cell lymphoma (MCL). Additionally, the European Medicines Agency (EMA) granted BGB-16673 PRIority MEdicines (PRIME) designation for the treatment of patients with Waldenstrom’s macroglobulinemia (WM) previously treated with a BTK inhibitor. About BRUKINSA® (zanubrutinib) BRUKINSA is an orally available, small molecule inhibitor of Bruton’s tyrosine kinase (BTK) designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared with other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues. BRUKINSA has the broadest label globally of any BTK inhibitor and is the only BTK inhibitor to provide the flexibility of once or twice daily dosing. BRUKINSA is also the only BTK inhibitor to demonstrate superiority to another BTK inhibitor in a Phase 3 study. The global BRUKINSA clinical development program includes about 7,100 patients enrolled in 30 countries and regions across more than 35 trials. BRUKINSA is approved in more than 75 markets, and more than 247,000 patients have been treated globally. Select Important Safety Information Serious adverse reactions, including fatal events, have occurred with BRUKINSA, including hemorrhage, infections, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity (including drug-induced liver injury). In the pooled safety population (N=1729), the most common adverse reactions (≥30%), including laboratory abnormalities, in patients who received BRUKINSA were neutrophil count decreased (51%), platelet count decreased (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%). Please see full U.S. Prescribing Information including U.S. Patient Information. The information provided in this press release is intended for a global audience. Product indications vary by region. About BeOne BeOne Medicines is a global oncology company domiciled in Switzerland that is discovering and developing innovative treatments that are more accessible to cancer patients worldwide. With a portfolio spanning hematology and solid tumors, BeOne is expediting development of its diverse pipeline of novel therapeutics through its internal capabilities and collaborations. With a growing global team of nearly 12,000 colleagues spanning six continents, the Company is committed to radically improving access to medicines for far more patients who need them. To learn more about BeOne, please visit www.beonemedicines.com and follow us on LinkedIn, X, Facebook and Instagram. Forward-Looking Statement This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding the potential benefits of BeOne’s product and product candidates; bringing innovative and transformative medicines to patients; and BeOne’s plans, commitments, aspirations and goals under the caption “About BeOne.” Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeOne’s ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; BeOne’s ability to achieve commercial success for its marketed medicines and drug candidates, if approved; BeOne's ability to obtain and maintain protection of intellectual property for its medicines and technology; BeOne’s reliance on third parties to conduct drug development, manufacturing, commercialization, and other services; BeOne’s limited experience in obtaining regulatory approvals and commercializing pharmaceutical products; BeOne’s ability to obtain additional funding for operations and to complete the development of its drug candidates and achieve and maintain profitability; and those risks more fully discussed in the section entitled “Risk Factors” in BeOne’s most recent quarterly report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in BeOne’s subsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeOne undertakes no duty to update such information unless required by law. To access BeOne media resources, please visit our Newsroom.