Atacicept

风湿免疫病是一类慢性系统性自身免疫性疾病，治疗难度大且易复发。传统治疗多依赖糖皮质激素联合传统改善病情药物，但长期使用带来的并发症和副作用严重影响了患者的生活质量。近年来，以B细胞为靶向的药物已逐渐应用于治疗多种自身免疫性疾病，但是如何合理选择和应用B细胞靶向药物是一个亟待解决的临床问题。 近日，由国家皮肤与免疫疾病临床医学研究中心发起，中国医师协会风湿免疫专科医师分会、中国康复医学会风湿免疫病康复专业委员会、中国研究型医院学会风湿免疫专业委员会、北京整合医学学会风湿免疫分会、兰州大学健康数据科学研究院以及中国医学科学院循证评价与指南研究创新单元协助共同撰写的《B细胞靶向药物治疗风湿免疫病中国专家共识（2024版）》（以下简称为“共识”）权威发布[1]。基于此，医学界特邀请到北京协和医院曾小峰教授，就B细胞靶向药物治疗在风湿免疫病中的应用进行分享，以期为风湿免疫病的诊疗带来新的思考。 01  B细胞靶向药物的临床应用将更加规范化、合理化、安全化 风湿免疫病的发病机制复杂，具有治疗困难、复发率高的特点，可导致重要脏器损伤，危及生命。传统治疗手段虽有一定疗效，但其显著的副作用限制了长期使用的可能性。研究显示，B细胞靶向药物已在多种风湿免疫病的治疗中展现出巨大潜力，不仅有效降低了糖皮质激素的用量，还显著改善了患者的预后[2]。 然而，曾小峰教授也指出了当前临床实践中普遍存在的超适应证使用现象，“目前，我国B细胞靶向治疗药物的适应证还不够广泛，临床上经常采用‘off-label’（超适应证）应用。国家皮肤与免疫疾病临床医学研究中心希望通过制订这部共识，规范临床应用，为患者提供更安全有效的治疗。” 谈及共识的亮点时，曾小峰教授强调了其循证医学的严谨性和创新性。共识严格遵循循证医学原则，全面评估了B细胞靶向药物的疗效、安全性及适用疾病谱，并深入探讨了超适应证使用，为临床医生提供了科学依据。此外，共识充分考虑了患者的偏好和价值观，以患者为中心，旨在提升患者的生活质量和治疗满意度。 曾小峰教授进一步表示：“这部共识不仅有助于规范B细胞靶向药物的临床应用，还能在一定程度上缓解当前紧张的医患关系。患者将获得更坚实的安全保障，医生在用药时也有更科学的循证支持。这将促进风湿免疫病的治疗更加规范化、合理化与安全化。” 02  同时阻断BLyS和APRIL，泰它西普成为SLE治疗新选择 系统性红斑狼疮（SLE）是一种常见的风湿免疫病，其临床表现多样、病程不可预测、治疗反应高度异质[3]，增加了疾病长期管理的复杂性，因此其治疗一直是医学界关注的重点。 B细胞作为适应性免疫应答的主要组成部分，被认为是SLE发病机制的核心之一。过度激活的B细胞分化为浆细胞，分泌自身反应性抗体，这些抗体与自身抗原结合形成的免疫复合物沉积于全身各组织和器官，引起多器官、多系统的病变[4]。 基于对这一机制的深刻认识，科学家们创新性地研发了B细胞靶向药物。曾小峰教授对此类药物的作用机制做出了深入浅出的解释：“B细胞靶向药物通过抑制B细胞的分化增殖，抑制异常的免疫应答，从而控制SLE的炎症反应和疾病进展，改善患者预后。B淋巴细胞刺激因子（BLyS）和增殖诱导配体（APRIL）作为B细胞通路中的关键因子，在SLE等多种风湿免疫病中水平升高（图1）[5,6]。” 图1：BLyS和APRIL共同参与SLE等多种风湿免疫病的发生发展 泰它西普是我国自主研发的一种融合蛋白类生物制剂，能够同时阻断BLyS和APRIL的作用，抑制B细胞活化和抗体分泌[7,8]。国内Ⅲ期研究数据显示，泰它西普治疗SLE，4周快速起效，52周SRI4应答率达82.6%，显著改善了皮肤黏膜、肌肉骨骼、免疫系统和血液系统的受累情况，并表现出良好的安全性和耐受性[9]。 对于泰它西普在未来SLE治疗中的应用前景，曾小峰教授持乐观态度：“泰它西普已在国内获批用于治疗SLE，是否能成为一线治疗，还需要更多的临床研究证据。” 03  从SLE到多种疾病的探索，泰它西普开启风湿免疫治疗新时代 SS：泰它西普可有效降低疾病活动度，改善疲劳症状与免疫球蛋白水平 干燥综合征（SS）是常见的风湿免疫病之一，其临床表现错综复杂，长久以来缺乏经过严格循证医学验证的有效治疗手段，多依赖于经验性疗法或借鉴他病策略。在这部共识中，泰它西普首次被推荐用于SS（共识表2），标志着该病的治疗模式有了重要转变。 曾小峰教授指出，泰它西普凭借其独特的双靶点作用机制，在SS的治疗中也展现出了良好的有效性和安全性。国内Ⅱ期研究数据表明，在使用泰它西普治疗24周后，患者的疾病活动指数（ESSDAI）及多维疲劳量表（MFI-20）评分均显著降低，免疫球蛋白（IgG、IgA、IgM）及CD19+B细胞水平也呈现持续下降趋势（图2、图3）[10]，适用于系统受累和出现高球蛋白血症的SS患者。其良好的安全性也为患者提供了安心的治疗选择。 图2：泰它西普组的ESSDAI得分和MFI-20评分 图3：IgG、IgA、IgM和CD19+B细胞迅速而持续地减少 值得注意的是，泰它西普治疗原发性SS的国内Ⅲ期临床试验已完成全部患者入组。目前全球并无用于治疗SS的生物药物获批，泰它西普有望填补这一领域的空白，为患者带来新的治疗希望。 RA：泰它西普4周快速起效，有效缓解关节损伤，提高达标率 当谈论到类风湿性关节炎（RA）时，曾小峰教授认为，RA和SLE、SS是类似的，B细胞靶向药物能有效抑制B细胞活性和抗体产生，对RA也同样可以达到治疗的效果。 机制研究揭示了BLyS与APRIL在RA进程中的关键作用。BLyS通过NF-κB通路激活B细胞，与RA的疾病活动度和骨质破坏相关[11]；APRIL则在血清阳性RA患者中高表达，可能参与其发病过程[12]。 曾小峰教授介绍了泰它西普在RA治疗中的显著疗效：“在Ⅲ期临床研究中，泰它西普4周快速起效，48周时，ACR20应答率达到72.2%（图4），将近90%的患者无影像学进展，显著缓解了关节结构的损伤进展，达标患者的比例也显著增加，安全性也是很好的[13]。” 图4：使用泰它西普48周时，ACR20应答率达72.2% 此外，在中国，高达20%的RA患者合并了SLE、SS、自身免疫性肝炎等其他自身免疫性疾病[14]。针对这一现象，曾小峰教授指出：“对于这些合并其他自身免疫性疾病的RA患者，泰它西普的双靶点作用机制可通过抑制共同的免疫病理途径，对多种疾病产生协同治疗效果，为他们提供了更多治疗选择，期待未来也能带来更多临床获益。” 结 语 随着《B细胞靶向药物治疗风湿免疫病中国专家共识（2024版）》的权威发布，风湿免疫病的治疗领域迎来了新的突破。该共识为临床医生提供了严谨、科学的用药指导，推动了B细胞靶向药物在临床应用中的规范化、合理化和安全化进程。曾小峰教授的深入解读，揭示了B细胞靶向药物在风湿免疫病治疗中的巨大潜力和广阔前景。 未来，随着临床数据的不断积累和研究的深入，泰它西普有望在风湿免疫病的治疗领域发挥更多作用。科学的诊疗共识和创新的药物治疗，将为风湿免疫病患者带来更高的生活质量，同时也为医患关系的和谐发展贡献力量。 专家简介 曾小峰 教授 国家皮肤与免疫疾病临床医学研究中心主任 中国医学科学院北京协和医学院长聘教授（Tenured Professor） 中国医师协会常务理事兼风湿免疫科医师分会会长 中华医学会风湿病学分会前任主任委员（第九、十届） 中国康复医学会常务理事及风湿免疫康复专业委员会主任委员 中国研究型医院学会理事及风湿免疫专业委员会主任委员 海峡两岸医药交流协会常务理事及风湿免疫专委会名誉主任委员 首都中西医结合风湿免疫病研究所所长（西医部） 北京整合医学会副会长兼风湿免疫专业委员会主任委员 中国系统性红斑狼疮研究协组织（CSTAR）& 国家风湿病数据中心（CRDC）创始人和负责人 英文《Rheumatology and Immunology Research》杂志主编 《中华风湿病学杂志》主编 国家重点研发项目首席科学家 北京协和医院风湿免疫科教授、主任医师、前任科主任 亚太风湿病学会联盟（APLAR）前副主席 参考文献： [1]国家皮肤与免疫疾病临床医学研究中心, 等. B细胞靶向药物治疗风湿免疫病中国专家共识（2024版）[J]. 中华风湿病学杂志, 2024;28(10):706-722. [2]Sun F, Wu H, Wang Z, et al. Effectiveness and Safety of Belimumab in Chinese Lupus Patients: A Multicenter, Real-World Observational Study[J]. Biomedicines, 2023, 11(3): 962. [3]沈南, 赵毅, 段利华, 等. 系统性红斑狼疮诊疗规范[J]. 中华内科杂志, 2023, 62(7): 775-784. [4]崔峥, 李鸿斌. 靶向B细胞治疗系统性红斑狼疮研究进展[J]. 内蒙古医科大学学报, 2023, 45(3): 324-328, 333. [5]Cheema GS, Roschke V, Hilbert DM, et al. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases[J]. Arthritis Rheum, 2001, 44(6): 1313-1319. [6]Dillon SR, Harder B, Lewis KB, et al. B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin[J]. Arthritis Res Ther, 2010, 12(2): R48. [7]Salzer U, Grimbacher B. TACI deficiency - a complex system out of balance[J]. Curr Opin Immunol, 2021, 71: 81-88. [8]Chen X, Hou Y, Jiang J, et al. Pharmacokinetics, pharmacodynamics, and tolerability of single ascending doses of RCT-18 in Chinese patients with rheumatoid arthritis[J]. Clin Pharmacokinet, 2014, 53(11): 1033-1044. [9]Wu D, et al. 2023 EULAR. OP037. [10]Xu D, Fang J, Zhang S, et al. Efficacy and safety of telitacicept in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled, phase 2 trial[J]. Rheumatology (Oxford), 2024, 63(3): 698-705. [11]Zhang LL, Xiao H, Zhang F, et al. BAFF, involved in B cell activation through the NF-κB pathway, is related to disease activity and bone destruction in rheumatoid arthritis[J]. Acta Pharmacol Sin, 2021, 42(10): 1665-1675. [12]Zhao J, Guo J, Wang L, Zhou W, Zhang Z. The role of a proliferation-inducing ligand (APRIL) in the pathogenesis of rheumatoid arthritis[J]. Scand J Rheumatol, 2014, 43(6): 462-469. [13]Wang L, Xu D, Fang J, et al. Telitacicept, a Human Recombinant Fusion Protein Targeting and Neutralizing B Lymphocyte Stimulator (BlyS)and a Proliferation-Inducing Ligand (APRIL), in Rheumatoid Arthritis (RA) Patients with an Inadequate Response to Methotrexate (MTX): A Randomized, Double-Blind, Phase 3 Study, 2023 ACR. Abstract number: L20. [14]蔡文心, 李仕成, 刘一鸣, 等. 类风湿关节炎临床分层及其特征的横断面研究[J]. 北京大学学报（医学版）, 2022, 54(6): 1068-1073. 来源 | 医学界风湿免疫频道 荣昌生物 科创板上市  |  港交所上市 挺进医保  |  License out 维迪西妥单抗  |  泰它西普 RC28  |  RC108  |  RC118

Participants with nephrotic syndrome in NEPTUNE Match will receive information about the PIONEER study and other clinical trials based on their individual disease characteristics;PIONEER study expands the investigation of atacicept into multiple autoimmune glomerular diseases, supported by the disease-modifying potential of BAFF/APRIL dual inhibition; BRISBANE, Calif., Nov. 11, 2024 (GLOBE NEWSWIRE) -- Vera Therapeutics, Inc. (Nasdaq: VERA), a late clinical-stage biotechnology company focused on developing and commercializing transformative treatments for patients with serious immunological diseases, is partnering with the University of Michigan on the Nephrotic Syndrome Study Network (NEPTUNE) Match project. NEPTUNE is a multicenter consortium of more than 30 North American academic centers that conducts clinical and translational research on kidney diseases that present as nephrotic syndrome (NS), including primary membranous nephropathy (pMN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). Through NEPTUNE Match, participants and their nephrologists receive information about clinical trials targeting mechanisms that match the participant’s molecular disease characteristics. This evidence-based approach to selecting clinical trials is aimed at improving treatment response and more successful outcomes across trials. In partnership with Vera Therapeutics, NEPTUNE Match will inform potential participants about the PIONEER study. PIONEER represents the expansion of the atacicept development program into multiple autoimmune kidney indications based on the presence of antibodies to glomerular antigens. In addition to a broader population of IgAN, the PIONEER study will evaluate the efficacy and safety of atacicept in anti-PLA2R podocytopathies (pMN) and anti-nephrin podocytopathies (FSGS and MCD). NEPTUNE Match will help participants with anti-PLA2R and anti-nephrin antibodies learn about the PIONEER study and support an informed decision about clinical trial participation. “Based on the positive long-term data from the ORIGIN Phase 2b study presented at ASN Kidney Week, we’re excited to offer a clinical trial with atacicept to patients with nephrotic syndrome who have biomarkers that may predict a positive response to B cell modulation,” said Marshall Fordyce, M.D., Founder and CEO of Vera Therapeutics. “In addition to providing patients with crucial resources and education about their individual disease biology, NEPTUNE Match will support the enrollment of eligible participants for the PIONEER study. We look forward to announcing initial data from PIONEER in 2025.” “We are thrilled to partner with Vera Therapeutics in NEPTUNE Match. With the new, disruptive insights into pathobiology of NS gleaned in NEPTUNE, we can now target specific antibody-mediated glomerular damage. Testing the efficacy of atacicept among patients identified with active, antibody-mediated disease will truly bring the latest science meaningfully back to our study participants and patients who are in urgent need of new therapies,” stated Matthias Kretzler, M.D., Warner Lambert-Parke Davis Professor of Medicine, University of Michigan and principal investigator of NEPTUNE. About NEPTUNEThe Nephrotic Syndrome Study Network (NEPTUNE) is a multi-site collaborative study that conducts clinical and translational research on FSGS, MCD, and MN that present as NS, pediatric incident NS without a diagnostic kidney biopsy and Alport syndrome. With the NEPTUNE Match precision medicine research platform, NEPTUNE connects patients’ individual disease mechanisms to ongoing drug trials to ensure the right patients participate in the right trial at the right time. For more information, visit NEPTUNE-STUDY.org. About VeraVera Therapeutics is a late clinical-stage biotechnology company focused on developing treatments for serious immunological diseases. Vera’s mission is to advance treatments that target the source of immunological diseases in order to change the standard of care for patients. Vera’s lead product candidate is atacicept, a fusion protein self-administered as a subcutaneous injection once weekly that blocks both B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL), which stimulate B cells to produce autoantibodies contributing to certain autoimmune diseases, including IgAN, also known as Berger’s disease, and lupus nephritis. In addition, Vera is evaluating additional diseases where the reduction of autoantibodies by atacicept may prove medically useful. Vera is also developing MAU868, a monoclonal antibody designed to neutralize infection with BK virus (BKV), a polyomavirus that can have devastating consequences in certain settings such as kidney transplant. Vera retains all global developmental and commercial rights to atacicept and MAU868. For more information, please visit www.veratx.com. About AtaciceptAtacicept is an investigational recombinant fusion protein that contains the soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) receptor that binds to the cytokines B-cell activating factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL). These cytokines are members of the tumor necrosis factor family that promote B-cell survival and autoantibody production associated with certain autoimmune diseases, including IgAN and lupus nephritis. The Phase 2b ORIGIN clinical trial of atacicept in IgAN met its primary and key secondary endpoints, with statistically significant and clinically meaningful proteinuria reductions and stabilization of eGFR versus placebo through 36 weeks. The safety profile during the randomized period was comparable between atacicept and placebo. Through 96 weeks, atacicept demonstrated further reductions in Gd-IgA1, hematuria, and proteinuria, as well as stabilization of eGFR reflecting a profile consistent with that of the general population without IgAN. Atacicept has received FDA Breakthrough Therapy Designation for the treatment of IgAN, which reflects the FDA’s determination that, based on an assessment of data from the Phase 2b ORIGIN clinical trial, atacicept may demonstrate substantial improvement on a clinically significant endpoint over available therapies for patients with IgAN. Vera believes atacicept is positioned for best-in-class potential, targeting B cells to reduce autoantibodies and having been administered to more than 1,500 patients in clinical studies across different indications. Forward-looking StatementsStatements contained in this press release regarding matters, events or results that may occur in the future are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, Vera’s expectations regarding the expansion of its development pipeline for atacicept, atacicept’s potential to be a best-in-class treatment, Vera’s expectations regarding the potential for B cell modulation through BAFF/APRIL dual inhibition to transform the treatment landscape for certain autoimmune diseases, Vera’s plans to initiate the PIONEER study in 2025, Vera’s anticipated presentations of clinical trial data, and Vera’s product candidates, strategy, and regulatory matters. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “substantial,” “will,” “may,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Vera’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks related to the regulatory approval process, results of earlier clinical trials may not be obtained in later clinical trials, preliminary results may not be predictive of topline results, risks and uncertainties associated with Vera’s business in general, the impact of macroeconomic and geopolitical events, and the other risks described in Vera’s filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Vera undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. For more information, please contact: Investor Contact:Joyce AllaireLifeSci Advisors212-915-2569jallaire@lifesciadvisors.com Media Contact:Madelin HawtinLifeSci CommunicationsMHawtin@lifescicomms.com