主要目的是在已完成了2 期 M19-130 研究的SLE受试者中评价Elsubrutinib和Upadacitinib单药治疗或作为 ABBV-599（Elsubrutinib/Upadacitinib ）联合治疗的长期安全性和耐受性。次要目的是获得在RCT 研究（单药治疗和联合治疗）治疗超过48 周后的长期疗效数据，以更充分地评估每种治疗随着时间推移的获益风险。

开始日期2021-08-23

申办/合作机构

AbbVie Deutschland GmbH & Co. KG

[+2]

JPRN-jRCT2031210119

/ Not yet recruiting临床2期IIT

[M20-186] A Phase 2, Long-Term Extension (LTE) Study With Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus Who Have Completed the M19-130 Phase 2 Randomized Controlled Trial (RCT)

开始日期2021-04-27

申办/合作机构-

NCT04451772

/ Completed临床2期

A Phase 2, Long-Term Extension (LTE) Study With Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus Who Have Completed the M19-130 Phase 2 Randomized Controlled Trial (RCT)

Systemic Lupus Erythematosus (SLE) is an immune-mediated disease associated with inflammation of multiple organ systems. This study will evaluate how well elsubrutinib and upadacitinib given alone or as the ABBV-599 combination (elsubrutinib/upadacitinib) works within the body, in participants who completed study M19-130. This study will assess the change in disease symptoms.
ABBV-599 is an investigational drug being developed for the treatment of Systemic Lupus Erythematosus (SLE). This study is "double-blinded", which means that neither the trial participants nor the study doctors will know who will be given which study drug. Study doctors put the participants into 1 of 4 groups called treatment arms. Each group receives a different treatment. Adult participants with a diagnosis of SLE will be enrolled. Around 260 participants will be enrolled in the study in approximately 100 sites worldwide.
Participants will receive the following for up to 56 weeks:
Participants will receive oral elsubrutinib capsules and/or oral upadacitinib tablets once daily for up to 56 weeks. Participants who were receiving elsubrutinib and/or upadacitnib in M19-130 will continue to receive the same treatment in this study. Participants who were receiving placebo in M19-130 will be re-randomized to one of the 2 combination treatment arms in this study.
Arm 1: Elsubrutinib Dose A and Upadacitinib Dose A Arm 2: Elsubrutinib Dose A and Upadacitinib Dose B
There may be higher burden for participants in this trial compared to their standard of care. Participants will attend monthly visits during the course of the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

开始日期2020-07-27

申办/合作机构

AbbVie, Inc.

100 项与 Elsubrutinib 相关的临床结果

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100 项与 Elsubrutinib 相关的转化医学

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100 项与 Elsubrutinib 相关的专利（医药）

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项与 Elsubrutinib 相关的文献（医药）

2024-12-01·International Immunopharmacology

Bruton’s tyrosine kinase: A promising target for treating systemic lupus erythematosus

Review

作者: Feng, Yifan ; Zhang, Tiantai ; Sun, Lan ; Zhou, Yu ; Ding, Qiaoyi

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder involving multiple organs and systems. There is growing evidence that autoreactive B cells occupy a central role in the occurrence and progression of SLE due to their ability to generate pathogenic autoantibodies. Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), a crucial intracellular kinase regulating B cell development and function, emerge as a new strategy to treat SLE in recent years and are superior to biologic agents depleting B cells in many aspects. Supportive data obtained from lupus-prone mice preliminarily demonstrated the promising therapeutic potential of BTK inhibition. However, these BTK inhibitors, including elsubrutinib, evobrutinib, etc., mostly face with unsatisfactory efficacy and certain safety issues during clinical use, driving the quest for new-generation inhibitors with improved potency and higher selectivity. This paper elaborates the importance of BTK involvement in SLE pathogenesis, reviews the clinical research progress of BTK inhibitors for SLE and discusses limitations and challenges the drugs met in development, in order to contribute to a deeper understanding of disease mechanism and provide a reference for new-generation BTK inhibitor research.

2022-06-01·The Lancet Rheumatology

Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial

Article

作者: Blanco, Ricardo ; Housley, William ; Drescher, Edit ; Singhal, Atul ; Cortes-Maisonet, Gregorio ; Wang, Zailong ; Taylor, Peter C. ; Fleischmann, Roy ; Cohen, Stanley ; Lu, Wenjing ; Doan, Thao ; Friedman, Alan ; Nader, Ahmed

BACKGROUNDABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile.METHODSWe conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America. We enrolled patients who were 18 years or older with rheumatoid arthritis and inadequate response or intolerance to biological disease-modifying antirheumatic drugs. Eligible patients were randomly assigned (3:2:2:2:2:1) via interactive response technology to receive daily, orally administered ABBV-599 (ie, upadacitinib 15 mg plus elsubrutinib 60 mg), elsubrutinib 60 mg, elsubrutinib 20 mg, elsubrutinib 5 mg, upadacitinib 15 mg, or placebo. Randomisation was stratified by the number of previous biological disease-modifying antirheumatic drugs. The investigator, study site personnel, and patients were masked throughout the study. The primary endpoint was change from baseline in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 for all patients who received a study drug. Pharmacokinetics and safety were also assessed. This study is registered with ClinicalTrials.gov, number NCT03682705.FINDINGSBetween Oct 8, 2018, and March 26, 2020, 242 patients were randomly assigned to receive ABBV-599 (n=62), elsubrutinib 60 mg (n=41), elsubrutinib 20 mg (n=39), elsubrutinib 5 mg (n=41), upadacitinib 15 mg (n=40), or placebo (n=19). Of the 242 patients, 204 (84%) were female, 38 (16%) were male, and 220 (91%) were White; the mean age at baseline was 58·0 years (SD 11·3). Compared with placebo, the least squares mean changes from baseline in DAS28-CRP were -1·44 (90% CI -2·03 to -0·85; p<0·0001) for ABBV-599, -0·40 (-1·03 to 0·23; p=0·29) for elsubrutinib 60 mg, -0·20 (-0·85 to 0·44; p=0·61) for elsubrutinib 20 mg, -0·21 (-0·84 to 0·41; p=0·57) for elsubrutinib 5 mg, and -1·75 (-2·38 to -1·13; p<0·0001) for upadacitinib. No significant improvements in efficacy measures for elsubrutinib alone (any dose) versus placebo were detected, despite adequate plasma exposure and target engagement. Treatment-emergent adverse events were observed in 113 (47%) of 242 patients, with similar proportions for all groups.INTERPRETATIONSignificant improvements in disease activity metrics of rheumatoid arthritis with ABBV-599 were driven by the JAK inhibitor upadacitinib with no discernible effect by the BTK inhibitor elsubrutinib.FUNDINGAbbVie.

2019-05-04·Modern Rheumatology4区 · 医学

ABBV-105, a selective and irreversible inhibitor of Bruton’s tyrosine kinase, is efficacious in multiple preclinical models of inflammation

4区 · 医学

Article

作者: Mathieu, Suzanne ; Sampson, Erik ; Harris, Christopher M. ; Murdock, Sara ; Twomey, Rachel ; Perham, Matthew ; Goess, Christian ; McCarthy, Richard W. ; Long, Andrew J. ; Mario, Regina ; Goedken, Eric R.

OBJECTIVESBruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease.METHODSABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production. Efficacy of ABBV-105 in chronic inflammatory disease was evaluated in animal models of arthritis and lupus. Measurement of BTK occupancy was employed as a target engagement biomarker.RESULTSABBV-105 irreversibly inhibits BTK, demonstrating superior kinome selectivity and is potent in B cell receptor, Fc receptor, and TLR-9-dependent cellular assays. Oral administration resulted in rapid clearance in plasma, but maintenance of BTK splenic occupancy. ABBV-105 inhibited antibody responses to thymus-independent and thymus-dependent antigens, paw swelling and bone destruction in rat collagen induced arthritis, and reduced disease in an IFNα-accelerated lupus nephritis model. BTK occupancy in disease models correlated with in vivo efficacy.CONCLUSIONABBV-105, a selective BTK inhibitor, demonstrates compelling efficacy in pre-clinical mechanistic models of antibody production and in models of rheumatoid arthritis and lupus.

项与 Elsubrutinib 相关的新闻（医药）

2024-11-04

·PRNewswire

Lupus Research Alliance Announces Lupus Research Highlights at ACR Convergence 2024

Sixteen presentations of preclinical studies funded by the Lupus Research Alliance (LRA) to advance understanding of lupus and potential treatment pathways, including four oral presentations Two reports by Lupus Therapeutics, the clinical affiliate of the LRA, and the Lupus Clinical Investigators Network (LuCIN) on promoting equity in lupus clinical trials, and identifying trial barriers and solutions Fifteen industry-sponsored clinical research studies supported by Lupus Therapeutics and LuCIN, including positive results from the late-breaking Phase 3 dapirolizumab pegol trial NEW YORK, Nov. 4, 2024 /PRNewswire/ -- The Lupus Research Alliance (LRA), the largest private funder of lupus research worldwide, today announced that a total of 33 studies, funded by the organization or supported by its clinical research affiliate Lupus Therapeutics, will be presented at ACR Convergence 2024. The annual meeting of the American College of Rheumatology takes place November 14-19, at the Walter E. Washington Convention Center in Washington, D.C. The LRA, which seeks to accelerate the discovery and development of patient-centered treatments and diagnostics, pursues strategies to spur advancements from "bench to bedside." LRA-supported studies presented at ACR Convergence 2024 represent the full continuum of lupus research, from foundational research exploring new avenues of knowledge, to clinical trials evaluating potential new treatments. "ACR Convergence 2024 is met with pride and excitement by the Lupus Research Alliance and Lupus Therapeutics – pride in seeing the fruits of our funding and other initiatives to accelerate drug discovery and development, and excitement as we stand on the precipice of some important advancements," said LRA President and CEO Albert T. Roy. "There are more trials in mid-to-late-stage development than ever before, including dapirolizumab pegol in Phase 3 from UCB/Biogen, a Lupus Therapeutics partner. And we are gratified to witness the volume of CAR T cell therapy approaches in clinical development, having invested in 2014 in early research suggesting this approach as a promising intervention to explore for treating lupus," Roy added. Foundational Research Funded by the LRA Sixteen studies of LRA-funded research (four oral presentations and 12 posters) will be presented. Several focus on Childhood-Onset Systemic Lupus Erythematosus (cSLE), including: a detailed characterization of the disease; the effects of fatigue on pediatric patients' mental and physical health; and the discovery of Anti-Mitochondrial Antibodies (AMA), which are linked to higher disease activity. Other studies include: the development of a precision immunotherapy to target harmful B cells in Antiphospholipid Syndrome (APS) patients; the discovery of innate signaling pathways crucial in causing inflammation in lupus patients; and the epidemiology of strokes in children and adults with lupus. ORAL PRESENTATIONS Saturday, Nov. 16 Abstract #0837: Bispecific Autoantigen-T Cell Engagers (BaiTE) to Selectively Target Autoreactive B Cells in Antiphospholipid Syndrome 3:00-3:15 PM, Room 103AB Sunday, Nov. 17 Abstract #1702: Placental Developmental Defects in a Humanized-TLR8 Mouse Model of Spontaneous Anti-Phospholipid Antibody Induced Pregnancy Loss 3:15-3:30 PM , Room 103AB Monday, Nov. 18 Xist and XChromosome Inactivation in Female Biased Autoimmunity 9:00-9:30 AM, Room 145AB Abstract #2625: Brain Injury Markers Correlate with Impaired Executive Function and Disease Activity in Children with Systemic Lupus Erythematosus 3:30-3:45 PM, Room 202AB POSTERS Saturday, Nov. 16 Poster Session A, 10:30 AM-12:30 PM, Poster Hall: Abstract #0091: Targeting Endothelial Dysfunction in Lupus Nephritis: Effect of Sepiapterin, a Drug That Restores Endothelial Nitric Oxide Synthase Function, in a Murine Model of Lupus Nephritis Abstract #0098: Anti-HSP90α as a Protective Natural Antibody Against Secondary Antiphospholipid Syndrome in Systemic Lupus Erythematosus Sunday, Nov. 17 Poster Session B, 10:30 AM-12:30 PM , Poster Hall: Abstract #1266: Anti-Mitochondrial Antibodies Associate with Disease Activity and IFNα Expression in Childhood-onset Systemic Lupus Erythematosus Abstract #1273: An Investigation of Traumatic Events and Mental Health in cSLE Abstract #1274: Comparing Performance-Based Measures and Self-Reported Questionnaires for Assessment of Executive Function for Youth with Childhood-Onset Systemic Lupus Erythematosus Abstract #1278: The Effects of Fatigue on Self-Reported Mental and Physical Health in Childhood-Onset Systemic Lupus Erythematosus: A Cross-Sectional Study Abstract #1279: Cerebrovascular Accidents in Pediatric and Adult Systemic Lupus Erythematosus: A Comparison of Epidemiology and Outcomes Abstract #1280: Abnormal Cortical Gyrification Patterns in Adolescents with Childhood-onset SLE: Early Associations with Perceived Fatigue Abstract #1504: Novel Analytes Associated with Cognitive Impairment in Patients with Systemic Lupus Erythematosus: Serum S100A8/A9, MMP-9 and IL-6 Abstract #1506: Cognitive Impairment Prevalence and Most Affected Domains in Patients with SLE by the ACR Comprehensive Neuropsychological Battery Monday, Nov. 18 Poster Session C, 10:30 AM-12:30 PM, Poster Hall: Abstract #1788: Memory B Cell Activation and Dysregulation in Systemic Lupus Erythematosus Abstract #2380: Characterizing SLE Patients into Type 1 and Type 2 Disease States: Insights from a Single Lupus Cohort Research Conducted by Lupus Therapeutics and the Lupus Clinical Investigators Network (LuCIN) Lupus Therapeutics, the clinical affiliate of the Lupus Research Alliance, oversees the Lupus Clinical Investigators Network (LuCIN), consisting of 50+ premier, leading medical research institutions in North America, comprised of 200+ providers with expertise in lupus care and clinical trials. The following studies are based on annual surveys of LuCIN investigators and research teams on promoting equity in lupus clinical trials and identifying trial barriers and solutions. POSTERS Saturday, Nov. 16 Abstract 0180: Collaborative Solutions to Lupus Trial Challenges for Underrepresented Participant Recruitment & Engagement: Perspectives from the Lupus Clinical Investigators Network (LuCIN) Poster Session A, 10:30 AM-12:30 PM, Poster Hall Sunday, Nov. 17 Abstract #1039: Through the LuCIN Lens: Defining Barriers and Forging Solutions for Lupus Clinical Trials in North America Poster Session B, 10:30 AM-12:30 PM, Poster Hall Clinical Research Supported by Lupus Therapeutics and LuCIN The primary goal of Lupus Therapeutics and LuCIN is to accelerate and enhance the quality of lupus clinical trials through clinical expertise, advisory services, patient engagement and partnership/collaboration with biopharmaceutical companies and research partners. Lupus Therapeutics and LuCIN are involved in nearly 25% of active lupus clinical trials. Fifteen Lupus Therapeutics/LuCIN-supported programs and collaborations are being presented at ACR Convergence 2024: ORAL PRESENTATIONS Sunday, Nov. 17 Abstract #1773: Safety and Efficacy of CABA-201, a Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Patients with Immune-Mediated Necrotizing Myopathy and Systemic Lupus Erythematosus from the RESET-MyositisTM and RESET-SLETM Clinical Trials 3:30-3:45 PM, Room 145AB Monday, Nov. 18 Abstract #2577: Efficacy and Safety of ABBV-599 (Elsubrutinib and Upadacitinib Combination) and Upadacitinib Monotherapy for the Treatment of Systemic Lupus Erythematosus: Results Through 104 Weeks in a Long-Term Extension Study 1:30-1:45 PM, Room 146AB Abstract #2580: Safety and Efficacy of Subcutaneous Ianalumab (VAY736) for up to 68 Weeks in Patients with Systemic Lupus Erythematosus: Results from Phase 2 Study 2:15-2:30 PM Room 146AB Tuesday, Nov. 19 ***LATE-BREAKING ABSTRACT*** Abstract #L16: Dapirolizumab Pegol Demonstrated Significant Improvement in Systemic Lupus Erythematosus Disease Activity: Efficacy and Safety Results of a Phase 3 Trial 8:00-9:30 AM, 146AB POSTERS Saturday, Nov. 16 Poster Session A, 10:30 AM-12:30 PM, Poster Hall: Abstract #0087: SYNCAR: An Engineered IL-2/IL-2R-system That Selectively Enhances CD19 CAR T Cells to Deplete B Cells and Provide Therapeutic Benefit in SLE and RA Mouse Models Without Lymphodepletion Abstract #0324: Correlative Studies of CABA-201, a Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Patients with Immune-Mediated Necrotizing Myopathy and Systemic Lupus Erythematosus from the RESET-MyositisTM and RESET-SLETM Clinical Trials Abstract #0620: Clinical Efficacy and Patient-Reported Outcomes in Anti-Ro/Sjögren's Syndrome–Related Antigen a Antibody–Positive Patients with Active SLE Treated With Deucravacitinib in the Phase 2 PAISLEY Trial Abstract #0659: Obinutuzumab Benefits Patients with Active Lupus Nephritis Irrespective of Baseline Proteinuria Severity: A Post Hoc Analysis of a Phase II Trial Abstract #0662: Deucravacitinib, a First-in-Class, Oral, Selective, Allosteric Tyrosine Kinase 2 Inhibitor, in SLE: Efficacy by Baseline Demographics and Disease Characteristics in the Phase 2 PAISLEY Trial Abstract #0671: Effect of Litifilimab on Cutaneous Lupus Disease Area and Severity Index–Activity (CLASI-A) Subcomponents and Physician Global Assessment–Skin (PGA–Skin) in Patients with Cutaneous Lupus Erythematosus (CLE) in a Phase 2 Study Sunday, Nov. 17 Poster Session B, 10:30 AM-12:30 PM, Poster Hall: Abstract #1496: Dysregulated Serum Cytokines in Association with Clinical Manifestations in Patients with Systemic Lupus Erythematosus Abstract #1552: Kinetics of Mucocutaneous and Musculoskeletal Responses to Deucravacitinib in Patients with Active SLE in the Phase 2 PAISLEY Trial Abstract #1553: Safety, Pharmacokinetics, Clinical Efficacy and Exploratory Biomarker Results from a Randomized, Double-Blind, Placebo-Controlled Phase 1b Study of Enpatoran in Active Systemic and Cutaneous Lupus Erythematosus (SLE/CLE) Monday, Nov. 18 Poster Session C, 10:30 AM-12:30 PM, Poster Hall: Abstract #2425: Ianalumab Induced Durable Depletion of Circulating B Cell Subsets and Associated Changes in B Cell and Neutrophil Transcriptomic and Proteomic Profiles in Patients with Systemic Lupus Erythematosus: 52-Week Treatment Results from a Phase 2 Trial Abstract #2430: Dapirolizumab Pegol Impacts Important Immunologic Pathways in Systemic Lupus Erythematosus: Pharmacodynamic Analysis of T Cell and Antigen Presenting Cell Pathways from a Phase 2b Trial About Lupus Lupus is a chronic, complex autoimmune disease that affects millions of people worldwide. In lupus, the immune system, meant to defend against infections, produces autoantibodies that mistake the body's own cells as foreign, causing other immune cells to attack organs such as the kidneys, brain, heart, lungs and skin, as well as blood and joints. Ninety percent of people with lupus are women, most often diagnosed between the ages of 15-45. Black, Latinx, Indigenous, Asian and Pacific Islander people are disproportionately affected by lupus and more likely to experience severe lupus symptoms. About the Lupus Research Alliance The Lupus Research Alliance is the largest non-governmental, non-profit funder of lupus research worldwide. The organization aims to transform treatment by funding the most innovative lupus research, fostering diverse scientific talent, and driving discovery toward better diagnostics, improved treatments and ultimately a cure for lupus. Because the Lupus Research Alliance's Board of Directors funds all administrative and fundraising costs, 100% of all donations goes to support lupus research programs. For more information, please visit the LRA at LupusResearch.org and on social media at: X, Facebook, LinkedIn, and Instagram. About Lupus Therapeutics Lupus Therapeutics, the clinical research affiliate of the Lupus Research Alliance, aims to accelerate the development of curative treatments for all patients living with lupus. Lupus Therapeutics collaborates with premier research institutions, biopharmaceutical partners, and those living with lupus through the unprecedented Lupus Clinical Investigators Network (LuCIN) to drive rapid and meaningful progress in treatment development. The organization elevates the patient voice, engages community stakeholders, and strives for representation of the diverse lupus community in the clinical research process with the most innovative and renowned experts throughout North America. Visit LupusTherapeutics.org for more information. This information is brought to you by the Lupus Research Alliance and is not sponsored by, nor a part of, the American College of Rheumatology. SOURCE Lupus Research Alliance WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床2期临床结果临床3期免疫疗法

2024-10-31

·凯莱英Asymchem

【行研】全球市场超百亿美元的热门靶点——BTK

BTK是BCR(B-Cell Receptor，B细胞表面抗原受体)通路的关键激酶，在B细胞抗原受体受体（BCR）的信号传导中起关键作用，而BCR信号通路对于淋巴瘤中恶性B细胞的增殖和存活至关重要。目前已发现BTK 在各种B细胞恶性肿瘤中调节着细胞增殖、存活和迁移等生命活动，BTK靶点已成为最具潜力的涉及B细胞和巨噬细胞活化的靶点之一。自从第一个BTK抑制剂伊布替尼于2013年上市以来，BTK抑制剂在血液瘤中得到了广泛应用，在该领域取得了较大成功，其疗效和安全性都得到了充分的论证，总体销售额已经达到上百亿美元。据公开资料显示，2022年全球BTK抑制剂市场规模为115亿美元，并以接近30%的增速逐年增长；据弗若斯特沙利文数据，全球BTK抑制剂市场规模预计2025年达219亿美元，2030年达251亿美元，中国BTK抑制剂的市场规模将从2022年的43亿元人民币增长至2030年的225亿元，年复合增长率达到33%。明朗和广阔的市场吸引了不少药企入局。图.全球及中国BTK抑制剂市场规模来源：Frost & Sullivan，交银国际业界习惯将BTK划分为3代产品： 1）一代BTKi为共价抑制剂：伊布替尼2013年被FDA批准上市，目前已获批MCL、CLL、WM、MZL、cGVHD共5项适应症； 2）二代BTKi同样为共价抑制剂，相较于一代产品提升了BTK的选择性因此有更好的疗效和安全性，如阿卡替尼、泽布替尼、奥布替尼； 3）三代BTKi为非共价抑制剂，可治疗对前2代BTKi耐药的C481突变。2023年礼来的吡托布替尼（Loxo-305）的3L MCL和3L CLL适应症获FDA加速批准。表1.已上市BTK抑制剂药物情况来源：根据公开资料整理全球市场来看，伊布替尼凭借先发优势和获批适应症最多，2021年达到销售峰值97.8亿美元，2022年源于竞争加剧销售额开始下滑至83.5亿美元（-14.6%）。而阿卡替尼，泽布替尼销售额高速增长，2022年阿卡替尼全球销售额达20.6亿美元（+66.2%），泽布替尼实现全球销售5.7亿美元（+159%），2023年1月泽布海外获批2L CLL/SLL适应症，带动2023前三季度全球销售额达8.7亿美元。国内市场来看，国产药品泽布替尼、奥布替尼二代BTK抑制剂凭借疗效、安全性、价格优势，公立医院市占率不断提升，且纳入医保巨额提升销售放量。以奥布替尼为例，2022年奥布替尼进入医保后，国内城市公立医院市占率从2021年2.8%提升至6.5%，截至2023上半年，市占率达12.1%。图左. 全球BTK靶点研发阶段概况图右. 中国BTK靶点研发阶段概况来源：医药魔方 2024年4月23日，赛诺菲宣布BTK 抑制剂Rilzabrutinib（SAR444671/PRN-1008）治疗持续性或慢性免疫性血小板减少症（ITP）成年患者的III期LUNA 3研究达到主要终点，并计划于今年年底前向FDA递 Rilzabrutinib的上市申请。如若Rilzabrutinib顺利获批，将成为全球第7款上市的BTK抑制剂，与已获批的BTK抑制剂的适应症不同，赛诺菲的Rilzabrutinib以ITP作为首发适应症，将是全球首款获批ITP适应症的BTK抑制剂。目前BTK抑制剂的研发方向主要为非共价BTK抑制剂，适应症也从血液瘤拓展到自免领域拓展，药物类型从小分子延伸到PROTACs类。在非共价BTK抑制剂研究领域，基于非共价的优势，目前全球的非共价（可逆）BTK抑制剂赛道也聚集了诸多企业，已有多款药物进入临床试验阶段，如LOXO-305、MK-1026、BN102（AS-1763）、HMPL-760。在适应症方面，BTK抑制剂已被证明治疗自身免疫疾病和炎症临床有效，包括原发免疫性血小板减少症（ITP）、系统性红斑狼疮（SLE）、多发性硬化症（MS）、类风湿性关节炎（Rheumatoid arthritis,RA）等，当前BTK抑制剂在自免领域的研发正如火如荼地进行。据华创证券统计，目前在自身免疫性疾病领域探索的BTK抑制剂超过20款，适应症聚焦在多发性硬化症（MS）、自发性荨麻疹、系统性红斑狼疮、类风湿性关节炎等疾病。除诺华的Remibrutinib，赛诺菲的另一款BTK抑制剂Tolebrutinib瞄准了MS，目前也在临床Ⅲ期；渤健针对MS的BIB091，艾伯维针对系统性红斑狼疮、类风湿关节炎的Elsubrutinib都已进入临床Ⅱ期。在药物类型方面，目前国内外已有多家企业开发的BTK-PROTAC进入临床阶段。NX-2127由Nurix Therapeutic开发，是first-in-class的口服BTK降解剂，目前在开展针对B细胞恶性肿瘤临床试验Ⅰ期。此外，国外还有Baylor College of Medicine开发的RC-1；Yale University的MT-802也是BTK-PROTAC产品；国内有海思科自主开发的HSK29116、百济神州开发的BGB-16673等产品。整体来说，全球针对BTK-PROTACs的临床实验尚在早期阶段，但若能成功上市，有效解决BTK患者的耐药难题， PROTACs或将成为BTK抑制剂的焦点。 References 参考资料 1.https://baijiahao.baidu.com/s?id=1774822688581233271&wfr=spider&for=pc 2.https://baijiahao.baidu.com/s?id=1798716367638420557&wfr=spider&for=pc 3.平安证券 -始于创新、强于执行力，血液瘤及自免领域管线双开花20240321 4.https://news.yaozh.com/archive/42009 5.https://xueqiu.com/6410972106/288071404?_ugc_source=ugcbaiducard

上市批准加速审批医药出海细胞疗法

2024-10-29

·Insight数据库

刚刚！礼来重磅 BTK 抑制剂在国内获批上市

10 月 29 日，NMPA 官网显示，礼来的匹妥布替尼片（Pirtobrutinib）获批上市，用于治疗既往接受过布鲁顿氏酪氨酸激酶（BTK）抑制剂的复发或难治性套细胞淋巴瘤（MCL）成人患者（JXHS2300110/111)。截图来源：NMPA 官网匹妥布替尼一款口服、高选择性、可逆 BTK 抑制剂，它通过广泛的氢键与ATP 结合位点附近的水分子和 BTK 残基相互作用，而不是与 C481 位点结合发，显示出克服对共价 BTKI 耐药性的潜力，对野生型和 C481 获得性耐药突变型 BTK 均有抑制效果。匹妥布替尼最初 Redx Pharma 研发，2017 年 7 月被 Loxo Oncology 买入。2019 年 1 月，礼来斥资 80 亿美元收购 Loxo Oncology，将其收入囊中。2022 年 3 月，信达生物以 4500 万美元的首付款获得匹妥布替尼在中国的商业化权益的优先谈判权。目前，匹妥布替尼已在美国获批两项适应症：既往曾接受过包含 BTK 抑制剂在内的至少两线系统性疗法的复发/难治性套细胞淋巴瘤（MCL）（2023.01）；既往接受过至少两线包括 BTK 抑制剂和 BCL-2 抑制剂在内治疗的成人慢性淋巴细胞白血病或小淋巴细胞淋巴瘤（CLL/SLL）（2023.12）。值得一提的是，匹妥布替尼是 FDA 批准的首个可逆 BTK 抑制剂，也是首个获批用于治疗已对 BTK 共价抑制剂产生抗性的 MCL 患者的 BTK 抑制剂。匹妥布替尼 MCL 适应症在 FDA 的获批是基于 I/II 期临床研究 BRUIN 的积极结果。该研究是一项开放标签、多中心、单臂试验，在 120 名曾接受过至少 1 线以上包含 BTK 共价抑制剂的 MCL 患者中，匹妥布替尼治疗患者的总缓解率为 50%，其中 13% 与 38% 的患者达到了完全缓解和部分缓解，中位缓解持续时间为 8.3 个月。 2023 年 ASH 年会上，礼来公布了匹妥布替尼治疗接受过共价 BTK 抑制剂治疗的中国 MCL 患者的 Ⅱ 期研究结果。研究的主要分析组 (PAS，N=28)中包括了经中心确认的非母细胞样 MCL 患者，这些患者接受过先前的共价 BTK 抑制剂治疗，数据显示： IRC 评估的 ORR 为 71.4%，其中 4 名患者获得完全缓解 (CR)，16 名患者获得部分缓解 (PR)。截至数据截止日期，IRC 评估的中位 DOR 尚未达到，6 个月 DOR 率为 66.02%。IRC 评估的 mPFS 为 9.43 个月，mOS 为 15.47 个月。疗分析组(EAS,N=35）也显示出了相似的疗效结果，IRC 评估的 ORR 为 62.9%，6 个月 DOR 率为 64.45%。在国内，匹妥布替尼于 2023 年 12 月被 CDE 纳入优先审评，单药用于治疗既往接受过 BTK 抑制剂治疗的复发或难治性 MCL 成人患者。此次其获批，将为复发或难治性 MCL 治疗提供新选择，同时进一步加剧国内 BTK 抑制剂之间的竞争。 BTK 被认为是自身免疫性疾病和 B 细胞恶性肿瘤治疗的潜力靶点。Insight 数据库显示，此前国内已批准 4 款 BTK 抑制剂（包括 2 款进口和 2 款国产）。截图来源：Insight 数据库上述四款均以不可逆共价方式与 BTK 的 ATP 结合口袋的半胱氨酸 481 位结合，长期使用共价 BTK 抑制剂可通过 BTK 结合位点（C481）的突变或 BTK 下游底物 PLCγ2 的激活突变导致耐药的产生，匹妥布替尼正好可以克服 C481 结合位点突变耐药的问题。市场表现上：伊布替尼凭借先发优势，2021 年销售额达到峰值，约 97.77 亿美元，但在二代 BTK 抑制剂获批上市后，其 2022 年销售额开始下滑。而且随着专利到期，伊布替尼仿制药也已出现，国内先声药业已于 2022 年取得其首仿生产批件。泽布替尼上市后销售额逐年攀升，2023 年全球销售额达 91.38 亿元（约为 12.97 亿美元），成为国内首个年销售额超过十亿美元的创新药。奥布替尼是国内上市的第三款 BTK 抑制剂，2022 年、2023 年销售额分别为 5.7 亿元和 6.7 亿元。阿可替尼是阿斯利康 BTK 抑制剂领域的王牌产品，近年销售额增势迅猛，2023 年达到 25.14 亿美元。此外，据 Insight 数据库，国内还有多款在研 BTK 抑制剂，Tolebrutinib、Rilzabrutinib 等几款处于临床 III 期，Elsubrutinib、CT-1530 等处于临床 II 期。与已上市 BTK 抑制剂不同，在研 BTK 抑制剂还被开发用于治疗多发性硬化、等自身免疫性疾病，而且在研 BTK 抑制剂除了化药，还包括 PROTAC。封面来源：企业 logo 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。编辑：vvy PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验点击阅读原文，立刻解锁！

上市批准优先审批并购临床结果临床2期

100 项与 Elsubrutinib 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
类风湿关节炎	临床1期	捷克	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床1期	波兰	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	西班牙	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	西班牙	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	匈牙利	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	波兰	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	捷克	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	匈牙利	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	加拿大	AbbVie, Inc.	2018-10-08
类风湿关节炎	临床前	加拿大	AbbVie, Inc.	2018-10-08

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适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03978520 (SLEek, CTgov)	临床2期	系统性红斑狼疮	341	Placebo for upadacitinib (Elsubrutinib Placebo/Upadacitinib Placebo)	積餘築襯衊遞構築窪製(淵壓餘顧製蓋鹹醖夢廠) = 鏇壓艱艱鹽構觸齋鑰遞網鹽積壓築醖窪範廠夢 (觸選蓋網簾糧製衊淵鹽, 醖簾窪範鬱製顧窪簾憲 ~ 選繭鬱餘壓蓋鹽製選選) 更多	-	2023-07-21
				Elsubrutinib+Upadacitinib (ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg))	積餘築襯衊遞構築窪製(淵壓餘顧製蓋鹹醖夢廠) = 膚鹹範範獵獵選鹹網觸網鹽積壓築醖窪範廠夢 (觸選蓋網簾糧製衊淵鹽, 簾簾簾遞構糧鏇築艱艱 ~ 鹽遞鹹窪醖齋獵餘齋簾) 更多
NCT03823378 (CTgov)	临床2期	类风湿关节炎	97	Elsubrutinib+Upadacitinib (ABBV-599 in M16-063/ABBV-599 in M16-763)	觸網範鬱憲齋鹹憲壓糧(製壓鏇網淵壓鹽醖鏇築) = 憲鹹網構獵鑰製鏇繭築顧繭築獵鏇願艱鑰製築 (築壓觸廠鹽選壓製夢淵, 憲簾夢積齋淵衊積衊築 ~ 窪獵襯窪築衊艱衊製鏇) 更多	-	2021-09-16
				Placebo for upadacitinib+Elsubrutinib (ABBV-105 60 mg/UPA Placebo)	觸網範鬱憲齋鹹憲壓糧(製壓鏇網淵壓鹽醖鏇築) = 製襯齋遞壓淵築襯餘網顧繭築獵鏇願艱鑰製築 (築壓觸廠鹽選壓製夢淵, 衊觸夢壓範餘艱簾構淵 ~ 鬱遞顧獵膚衊鬱蓋艱鹽) 更多
NCT03682705 (CTgov)	临床2期	类风湿关节炎	242	Placebo for upadacitinib (ELS Placebo/UPA Placebo)	鹹構糧觸範鬱艱鏇襯顧(糧餘選遞觸餘製顧淵襯) = 壓獵製製繭範壓遞壓襯蓋遞網鏇築蓋範淵鹽鏇 (觸顧鏇廠窪積膚構蓋鏇, 醖顧積網壓醖觸艱範網 ~ 廠壓鹹願鹽蓋窪遞齋壓) 更多	-	2021-05-03
				Elsubrutinib+Upadacitinib (UPA 15 mg/ELS 60 mg)	鹹構糧觸範鬱艱鏇襯顧(糧餘選遞觸餘製顧淵襯) = 壓壓憲憲獵艱願網簾蓋蓋遞網鏇築蓋範淵鹽鏇 (觸顧鏇廠窪積膚構蓋鏇, 憲齋築憲餘顧選鏇憲鬱 ~ 繭憲顧鹹艱選願憲構網) 更多