A Study to Evaluate the Efficacy and Safety of Genotype-guided Targeted Agents in Combination With POLA-RCHP VERSUS POLA-RCHP in Patients With Previously Untreated Diffuse Large B-cell Lymphoma

The purpose of this study is to compare the efficacy and safety of genotype-guided targeted agents in combination with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola RCHP-X) versus Pola RCHP in Chinese patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

开始日期2024-12-31

申办/合作机构

上海交通大学医学院附属瑞金医院

NCT06520098 / Not yet recruiting临床2期

Benefit of Venetoclax Addition ("Benefit VA") in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

People who have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) are often treated with ibrutinib, acalabrutinib, or zanubrutinib. These are pills that are taken by mouth. This type of pill is called "Bruton Tyrosine Kinase Inhibitor" or BTKi. Another treatment for CLL/SLL is a different pill called venetoclax.
The purpose of this study is to compare continuing the current treatment with BTKi alone, as long as it is working, to another arm of treatment which adds venetoclax to the current treatment (BTKi), for one year. After one year, both pills in this arm of treatment would be stopped and the participants will be closely monitored.

开始日期2024-10-01

申办/合作机构

VA Office of Research and Development

NCT06564038 / Not yet recruiting临床1/2期

A Phase I/II Open-Label Multi-Centre Master Protocol to Evaluate the Safety and Efficacy of AZD0486 Monotherapy or in Combination With Other Anticancer Agents in Participants With Mature B-Cell Malignancies

The purpose of this study is to assess the safety and efficacy of AZD0486 administered as monotherapy or in combination with other anticancer agents in participants with hematological malignancies.

开始日期2024-09-13

申办/合作机构

AstraZeneca PLC

100 项与阿可替尼相关的临床结果

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100 项与阿可替尼相关的转化医学

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100 项与阿可替尼相关的专利（医药）

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402

项与阿可替尼相关的文献（医药）

2024-03-01·Annals of hematology

Small lymphocytic lymphoma infiltrating gastrointestinal tract and mimicking inflammatory bowel disease, successfully treated with acalabrutinib

Letter

作者: Krečak, Ivan ; Smolić, Jelena ; Karaman, Ivana ; Vrbičić, Branka ; Čubrić, Eva ; Skelin, Marko

2024-02-01·Clinical therapeutics

Cardiovascular Adverse Events Associated With Second-generation Bruton Tyrosine Kinase Inhibitor Therapy: A Systematic Review and Meta-analysis

Review

作者: Shtembari, Jurgen ; Proskuriakova, Ekaterina ; Raut, Anuradha ; Khosla, Paramjeet ; Kadariya, Dinesh ; Reddy, Vijay Ketan ; Gaire, Suman ; Jasaraj, Ranjit ; Shrestha, Dhan Bahadur

PURPOSE:

Cardiovascular adverse events (CVAEs) are common adverse effects of first-generation Bruton tyrosine kinase inhibitors (BTKis) and limit their use considerably. This led to the development of second-generation BTKis-acalabrutinib and zanubrutinib-which are more selective, potent, and presumed to have better safety profiles than the previous group of medications. However, there have been sporadic reports of CVAEs associated with second-generation BTKis in clinical practice. To address this issue, a comprehensive meta-analysis to pool the documented CVAEs was performed, including major hemorrhage, any bleeding, atrioventricular block, atrial fibrillation/flutter, pericardial effusion, pericarditis, heart failure, cardiac arrest, myocardial infarction, hypertension, hypotension, and stroke. This meta-analysis incorporated 8 studies. Among these, 6 were Phase III trials and 2 were Phase II trials. These studies collectively enrolled a total of 2938 patients.

METHODS:

Multiple databases, including PubMed, MEDLINE, Cochrane Library, Scopus, and EMBASE, were systematically searched for relevant clinical trials from inception through January 14, 2023. The effect measure used was odds ratio (OR) and 95% CI.

FINDINGS:

Of a total of 1774 studies identified during the initial database search, 8 were included in the meta-analysis. The incidence of overall and cardiovascular mortality was comparable between the 2 groups. There were no significant differences observed for cardiovascular mortality (OR = 0.36; 95% CI, 0.08-1.65; n = 2588; I² = 45%; P = 0.19). Similar results were found for all-cause mortality (OR = 0.85; 95% CI, 0.67-1.07), any bleeding (OR = 1.90; 95% CI, 0.88-4.09), major bleeding (OR = 1.07; 95% CI, 0.65-1.76), atrioventricular block (OR = 0.74; 95% CI, 0.15-3.68), atrial fibrillation/flutter (OR = 0.74; 95% CI, 0.37-1.50), and other CVAEs associated with second-generation BTKis.

IMPLICATIONS:

Based on the available evidence, there is no indication of worse cardiovascular outcomes or superiority of second-generation BTKis compared with standard treatments in terms of safety profile. However, additional large-scale controlled trials are needed to provide robust support for the superior tolerability of new-generation BTKis.

2024-01-01·Future oncology (London, England)

Time to Next Treatment in Patients with Chronic Lymphocytic Leukemia Initiating First-Line Ibrutinib or Acalabrutinib

Article

作者: Lefebvre, Patrick ; Lu, Xiaoxiao ; Emond, Bruno ; Qureshi, Zaina P ; Khan, Wasiulla ; Morrison, Laura ; Lafeuille, Marie-Hélène ; Wu, Linda H ; Kinkead, Frederic ; Jacobs, Ryan ; Levy, Moshe Yair

Aim: To investigate real-world time to next treatment in patients with chronic lymphocytic leukemia initiating first-line (1L) ibrutinib or acalabrutinib. Materials & methods: US specialty pharmacy electronic medical records (21/11/2018–30/4/2022) were used; patients initiated 1L on/after 21/11/2019 (acalabrutinib approval). Results: Among 710 patients receiving ibrutinib, 5.9% initiated next treatment (mean time to initiation = 9.2 months); among 373 patients receiving acalabrutinib, 7.5% initiated next treatment (mean time to initiation = 5.9 months). Adjusting for baseline characteristics, acalabrutinib-treated patients were 89% more likely to initiate next treatment (hazard ratio = 1.89; p = 0.016). Conclusion: This study addresses a need for real-world comparative effectiveness between 1L ibrutinib and acalabrutinib and shows that next treatment (a clinically meaningful measure for real-world progression) occurred less frequently with 1L ibrutinib.

465

项与阿可替尼相关的新闻（医药）

5 小时之前

·PRNewswire

Mantle Cell Lymphoma Clinical Trial Pipeline Insights Featuring 20+ Companies | DelveInsight

Mantle cell lymphoma is a rare and aggressive type of non-Hodgkin lymphoma originating from B-cells in the "mantle zone" of the lymph nodes. The development of novel targeted therapies and immunotherapies, such as Bruton's tyrosine kinase (BTK) inhibitors, is improving treatment outcomes and driving market growth for Mantle cell lymphoma. LAS VEGAS, Sept. 19, 2024 /PRNewswire/ -- DelveInsight's ' Mantle Cell Lymphoma Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline mantle cell lymphoma therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the mantle cell lymphoma pipeline domain. Key Takeaways from the Mantle Cell Lymphoma Pipeline Report DelveInsight's mantle cell lymphoma pipeline report depicts a robust space with 20+ active players working to develop 22+ pipeline therapies for mantle cell lymphoma treatment. Key mantle cell lymphoma companies such as AbbVie, Adicet Bio, InnoCare Pharma Inc., Guangzhou Lupeng Pharmaceutical Company LTD., BeiGene, Nurix, LegoChem Biosciences, Xynomic Pharmaceuticals, Merck & Co, Incyte Corporation, TG Therapeutics, Janssen/Pharmacyclics, Eternity Bioscience, Traws Pharm, Advenchen Laboratories, and others are evaluating new mantle cell lymphoma drugs to improve the treatment landscape. Promising mantle cell lymphoma pipeline therapies such as Venetoclax, ADI-001, Orelabrutinib, LP-168, BGB-11417, NX 2127, LCB 71, NX 5948, Abexinostat, Pembrolizumab, Parsaclisib, Umbralisib, Ibrutinib, Edralbrutinib, Narazaciclib, Lucitanib, and others are under different phases of mantle cell lymphoma clinical trials. In May 2024, AstraZeneca had announced positive interim results from the Phase III ECHO clinical trial, which evaluated Bruton's tyrosine kinase (BTK) inhibitor Calquence (acalabrutinib) in combination with standard chemoimmunotherapy for treating mantle cell lymphoma (MCL). In March 2024, BeiGene, Ltd. announced the presentation of emerging oncology pipeline data at the American Association for Cancer Research (AACR) Annual Meeting. Additional highlights include preclinical characterization data for an investigational BTK degrader, BGB-16673, currently in clinical development for B-cell malignancies, including mantle cell lymphoma In October 2023, Ascentage Pharma announced that it has entered into a clinical collaboration with AstraZeneca Investment. The two companies will jointly conduct a registrational Phase III study of the Bcl-2 inhibitor, APG-2575 (lisaftoclax), in combination with AstraZeneca's Bruton's tyrosine kinase (BTK) inhibitor, CALQUENCE® (acalabrutinib), in treatment-naive patients with first-line chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In January 2023, the FDA granted an orphan drug designation to LP-284, a novel small-molecule, next-generation acylfulvene, for the treatment of mantle cell lymphoma (MCL), a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL), according to an announcement from Lantern Pharma. Request a sample and discover the recent advances in mantle cell lymphoma treatment drugs @ Mantle Cell Lymphoma Pipeline Report The mantle cell lymphoma pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage mantle cell lymphoma drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the mantle cell lymphoma clinical trial landscape. Mantle Cell Lymphoma Overview Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphomas (NHLs) characterized by the (11,14) translocation, leading to overexpression of the cyclin D1 (CCND1) gene. Its various morphological variants can make diagnosis challenging, though some cases are straightforward. Many individuals with MCL are asymptomatic in the early stages, but may later seek medical attention due to persistent, typically painless swelling of lymph nodes, especially in the neck and throat region (e.g., Waldeyer's ring). MCL is marked by a reciprocal chromosomal translocation t(11;14)(q13;q32), which places the cyclin D1 gene next to the immunoglobulin heavy chain gene, causing continuous cyclin D1 expression. This overexpression contributes to tumor cell proliferation through cell cycle dysregulation, chromosomal instability, and epigenetic changes. Rarely, MCL cases without this translocation may involve CCND2 or CCND3 translocations. Hypothetical molecular subtypes, based on the cell of origin, correlate with clinical phenotypes: classical or aggressive MCL arises from naive B cells lacking or having limited iGVH mutations and expressing SOX11, a neural transcription factor inhibiting terminal B cell differentiation. The indolent variant originates from antigen-experienced B cells with IGVH somatic hypermutations, typically SOX11-negative and genetically stable. Diagnosis of MCL involves detailed patient history, thorough clinical evaluation, and specialized tests, including biopsy of an affected lymph node or bone marrow. These tests confirm the NHL type and subtype, assess disease extent, and determine appropriate treatments. Treatment for MCL is multifaceted and tailored to each patient, often including chemotherapy, immunotherapy drugs like rituximab, targeted therapies such as ibrutinib, and stem cell transplants, particularly for aggressive disease or younger patients. Radiation therapy may target specific lymphoma areas. Participation in clinical trials can offer new treatment options. Treatment plans are developed collaboratively by healthcare professionals and patients, considering disease stage, overall health, and personal preferences. Regular monitoring and follow-up care are essential to track treatment response and manage side effects effectively. Find out more about mantle cell lymphoma treatment drugs @ Drugs for Mantle Cell Lymphoma Treatment A snapshot of the Mantle Cell Lymphoma Pipeline Drugs mentioned in the report: Learn more about the emerging mantle cell lymphoma pipeline therapies @ Mantle Cell Lymphoma Clinical Trials Mantle Cell Lymphoma Therapeutics Assessment The mantle cell lymphoma pipeline report proffers an integral view of the mantle cell lymphoma emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Mantle Cell Lymphoma Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Parenteral, Intravenous, Subcutaneous, Topical Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Therapeutics Assessment By Mechanism of Action: Apoptosis stimulants, Proto-oncogene protein c-bcl-2 inhibitors, Proteasome inhibitors, Immunologic cytotoxicity, T lymphocyte replacements, Agammaglobulinemia tyrosine kinase inhibitors Key Mantle Cell Lymphoma Companies: AbbVie, Adicet Bio, InnoCare Pharma Inc., Guangzhou Lupeng Pharmaceutical Company LTD., BeiGene, Nurix, LegoChem Biosciences, Xynomic Pharmaceuticals, Merck & Co, Incyte Corporation, TG Therapeutics, Janssen/Pharmacyclics, Eternity Bioscience, Traws Pharm, Advenchen Laboratories, and others Key Mantle Cell Lymphoma Pipeline Therapies: Venetoclax, ADI-001, Orelabrutinib, LP-168, BGB-11417, NX 2127, LCB 71, NX 5948, Abexinostat, Pembrolizumab, Parsaclisib, Umbralisib, Ibrutinib, Edralbrutinib, Narazaciclib, Lucitanib, and others Dive deep into rich insights for new drugs for mantle cell lymphoma treatment, visit @ Mantle Cell Lymphoma Drugs Table of Contents For further information on the mantle cell lymphoma pipeline therapeutics, reach out @ Mantle Cell Lymphoma Treatment Drugs Related Reports B-Cell Lymphoma Epidemiology B-Cell Lymphoma Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology as well as the B-cell lymphoma epidemiology trends. B-Cell Lymphoma Market B-Cell Lymphoma Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key B-cell lymphoma companies, including Vincerx Pharma, Ubix Therapeutics, Biomea Fusion Inc, Shanghai Hengrui Pharmaceutical, BeiGene, Hanmi Pharmaceutical, among others. Diffuse Large B-Cell Lymphoma Pipeline Diffuse Large B-Cell Lymphoma Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key DLBCL companies, including Genmab, Roche, Acerta Pharma, Autolus, Xynomic Pharmaceuticals, Genentech, Celgene, AbbVie, Mabion, among others. Diffuse Large B-Cell Lymphoma Market Diffuse Large B-Cell Lymphoma Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key B-cell lymphoma companies, including AbbVie, Genmab, Merck, Roche, Xencor and Janssen, Denovo Biopharma, Calithera Biosciences, IMV, Biogen, Autolus Therapeutics, Allogene Therapeutics, Novartis, Miltenyi Biomedicine, Regeneron Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期免疫疗法孤儿药

2024-09-16

·药智网

当沪指失守2800点，这家Biotech已经涨超60%

在全球市场环境的影响下，沪指再次失守2800点。依旧处在“寒冬”中的A股医药股更是惨不忍睹。6月以来，截至9月12日，A股495只医药股中，只有50只实现股价正增长，占比仅10.1%，其中涨幅超过20%的医药股，仅有11家。然而，在不经意间，低调的诺诚健华从6月份起，股价开启单边上涨模式，从6月份低点7.28元/股，涨至最高12元/股，上涨幅度超过60%。诺诚健华何以成为2024年下半年的黑马，与其他在“寒风”中瑟瑟发抖的Biotech又有何不同？超额完成业绩目标一款超级单品对一家Biotech有多重要，诺诚健华给出了很好的答案。 2024年上半年，诺诚健华实现营业收入4.2亿元，同比增长11.17%；归母净利润-2.62亿元，亏损大幅收窄37.6%。其联合创始人、董事长兼首席执行官崔霁松博士将增长的原因归功于“商业化业绩超额完成既定目标，收入大幅增加。” 诺诚健华的商业化产品有两款，分别是奥布替尼和Tafasitamab。作为绝对主力，奥布替尼上半年销售收入4.18亿元，同比增加29.97%，其中二季度销售收入2.53亿元，同比增长49%，增长势头明显。由于核心产品商业化进展顺利，诺诚健华自信地将2024年全年奥布替尼销售收入从至少同比增长30%调高至35%。 2020年12月获批上市的奥布替尼是国内第三款，国产第二款BTK抑制剂，获批的适应症包括慢性淋巴细胞白血病（CLL）/小淋巴细胞淋巴瘤（SLL）、套细胞淋巴瘤（MCL）以及边缘区淋巴瘤（MZL），并全部进入国家医保。其中，MZL是中国第二常见的非霍奇金淋巴瘤（NHL），奥布替尼是国内首个且唯一获批针对复发或难治性MZL适应症的BTK抑制剂，市场需求广阔。 2021年-2023年，奥布替尼销售额逐年增长，分别为2.56亿元、5.66亿元、6.72亿元，其实2023年增速已大幅放缓，但随着新适应商业化进展顺利，2024年又重回高速发展轨道。当然，奥布替尼面对的竞争也十分激烈。2023年，阿斯利康的阿卡替尼获NMPA批准，国内获批的BTK抑制剂增加到4款。其中，百济神州的泽布替尼在与曾经的药王，伊布替尼对比的大规模头对头研究中完胜，令其有望快速取代伊布替尼的市场地位。诺诚健华虽然未就奥布替尼进行“头对头”试验以证明其拥有更好的药效，但其采用单环母核设计，这种设计可以提升药物的选择性，降低脱靶副作用。公开数据显示，奥布替尼不良事件发生率低于伊布替尼、阿卡替尼和泽布替尼。正因为其独特的安全性优势，奥布替尼在自身免疫性疾病的治疗领域相比其他BTK抑制剂更有优势。目前，治疗ITP的中国注册性III期临床试验正在进行；其他自免疾病包括SLE、MS、NMOSD的II期临床试验也取得了积极进展。更多适应症的获批，尤其是自免治疗领域适应症取得突破，能够让奥布替尼不断获得增长动力，甚至有望实现弯道超车。诺诚健华在自免领域的开发策略图片来源：诺诚健华半年报此外，得益于奥布替尼销售额的增长以及营业收入结构的改变，2022年-2024年上半年，诺诚健华毛利率分别为77.07%、82.61%、85.67%，连续增长。 5-6款创新药即将上市毫无疑问，奥布替尼是一款具有“Pipeline in a drug”潜力的产品，仅一款奥布替尼就为诺诚健华带来了一整个研发管线。同时，与仅靠一款产品“单腿走路”的创新药企不同，诺诚健华早早地就布局了一系列差异化的研发管线，并持续稳步推进，多款产品蓄势待发，预计将在未来3-5年推动5-6款创新药上市。在研发管线布局上，诺诚健华有着相当清晰的规划，即聚焦具有广阔市场空间的肿瘤与自身免疫性疾病领域，坚持源头创新与差异化竞争。在血液瘤领域，诺诚健华以奥布替尼为核心，加上其他在研药物（如Tafasitamab、ICP-248、ICP-B02、ICP-490、ICP-B05等），目标是通过单药或联合疗法覆盖NHL、MM及白血病全领域，成为血液瘤领域的领导者。其中，Tafasitamab是诺诚健华于2021年8月从Incyte公司引进，其用于复发或难治性DLBCL（弥漫性大B细胞淋巴瘤）已在美国和欧洲获批上市，并于2022年底在香港、海南获批使用。2024年6月，Tafasitamab联合疗法的BLA获得CDE受理并纳入优先审评，预计将于2025年上半年获得批准。在自免领域，针对B细胞信号通路异常及T细胞通路异常的自身免疫性疾病，诺诚健华布局了多个全球前沿靶点，包括奥布替尼、ICP-332、ICP-488、ICP-B02等。其中，ICP-332是一款新型TYK2抑制剂，在治疗中重度特应性皮炎（AD）的II期临床中展现了极佳的临床数据，在疗效优于多款已获批药物的同时，具有优异的安全性，是诺诚健华在自免领域潜在的王牌产品。其AD的III期临床试验预计将于2024年第四季度启动，并启动白癜风的临床试验。在实体瘤领域，诺诚健华通过靶向治疗和肿瘤免疫方法的结合，不断扩充实体瘤疾病在研管线，包括潜在同类最佳药物ICP-723，以及早期管线，潜在的基石疗法ICP-189、ICP-B05等。其中，ICP-723(Zurletrectinib)是第二代TRK抑制剂，不仅能够有效抑制TRK家族中的TRKA、TRKB、TRKC，而且可以克服第一代TRK抑制剂的耐药性，为接受第一代TRK抑制剂后耐药的患者带来希望。目前该药已进入新药上市申请准备阶段（pre-NDA），预计在2025年初递交NDA。自免及实体瘤领域产品管线图片来源：诺诚健华半年报随着越来越多的研发管线进入临床后期，诺诚健华的研发投入也逐年增加，2024年上半年，研发费用4.21亿元，同比增长16.67%。虽然研发费用不菲，但诺诚健华的现金储备在创新药资本“寒冬”中显得十分亮眼。截至2024年上半年，诺诚健华剩余现金和其他金融资产80亿元，强劲的现金流有助于其加速全球临床试验开发，并投资有竞争力的产品管线。这些现金储备也将支持在研产品商业化，随着未来5-6款创新药商业化的成功推进，带来新的业绩增长点，企业经营也将步入正向循环。出海，Biotech的必答题从Biotech迈向Biopharma的过程中，创新是基础，国际化则是加速剂。百济神州公布的半年报显示，2024年上半年，同为BTK抑制剂的百悦泽（泽布替尼）全球销售额超过11亿美元，同比增长122%，是奥布替尼的19倍，其中美国贡献了59.03亿元，占比73.8%。一款国产创新药的成功出海，意味着身价的暴涨。在国内，泽布替尼的医保价为5440元（80毫克，64粒）。相比之下，其在美国的价格为15264美元（80毫克，120粒），折算成人民币大概是国内售价的10倍。不仅是泽布替尼，君实生物的特瑞普利单抗在国内PD-1内卷下售价为1912.96元/瓶，但相同规格产品在美国上市后售价高达8892.03美元/瓶，是国内售价的33倍。国内创新药“出海”后身价暴增，主要是因为海外市场，尤其是美国市场拥有更强的支付能力。据西南证券数据，2018年，美国总医疗费用支出是中国的16倍，人均医疗费用支出是中国的44倍。2022年，中美医疗费用支出仍存在14倍的差距，人均医疗费用仍有42倍的差距。因此，对于中国创新药企尤其是Biotech而言，“出海”已经不是一个选择题，而是一个必答题。与百济神州类似，诺诚健华同样具备国际化基因，主要管理团队成员拥有美国默克、辉瑞、葛兰素史克、百时美施贵宝、强生公司等大型跨国药企的资深工作经验，兼具国际创新视野与深刻的行业洞察。虽然与Biogen的合作遭遇挫折，但诺诚健华全球化的步伐并未停止。核心产品奥布替尼已在新加坡获批用于治疗MCL，同时FDA已授予该药品适用于R/R MCL的突破性疗法认定，预计2024年向美国FDA递交NDA上市申请；潜力产品ICP-248已于2024年1月在美国获批IND，并已启动临床试验；王牌管线ICP-332的IND也于2024年6月获FDA批准。国际化是诺诚健华战略目标，也是其发展的必经之路，通过创新药“出海”，不仅可以提升该产品在全球市场的表现，还能反哺其国内持续创新的能力。虽然“出海”之路依然面临诸多困难和挑战，但手握巨额现金的诺诚健华拥有更多的试错成本和时间。结语诺诚健华清晰的发展蓝图让未来充满了确定性，也正因此，获得了资本更多的青睐。参考资料： 1.诺诚健华、百济神州年报、季报，官网 2.《BD越玩越花，出海的泡沫能维持多久》，新浪医药，2024年08月06日 3.《5款中国创新药在美定价高于国内30倍，为何国产药出海后更贵了？》，凤凰新闻，2024年01月03日声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 史密斯转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

上市批准医药出海财报

2024-09-12

·CPHI制药在线

百济神州BTK降解剂获FDA快速通道资格，还有哪些玩家在布局？

关注并星标CPHI制药在线近日，美国FDA授予百济神州BGB-16673快速通道资格，用于治疗既往接受过至少两线治疗（包括BTK抑制剂和BCL2抑制剂）的复发/难治性（R/R）慢性淋巴细胞白血病或小淋巴细胞淋巴瘤（CLL/SLL）成年患者。 BGB-16673是一种BTK降解剂，同时也是一种异双功能小分子，通过泛素化诱导BTK降解。在临床前模型中，BGB-16673可降解野生型BTK以及已知的共价和非共价BTKi抗性突变蛋白，导致肿瘤消退。早在2021年，泽布替尼还未曾大显神威的时候，百济神州就开始将PROTAC技术应用到BTK的药物开发上。资料显示，百济神州启动的首个临床PROTAC项目便是BGB-16673，于2021年8月百济神州在ClinicalTrials.gov进行了临床试验登记，2022年3月又在国内启动临床。 BGB-16673通过泛素化诱导BTK降解，展现出在解决BTK抑制剂耐药性问题上的巨大潜力。本次快速通道认定的申请主要基于BGB-16673用于解决发生疾病进展的CLL/SLL患者尚未满足的医疗需求的潜力。在今年6月举行的2024年欧洲血液学协会年会上，百济神州公布了该项正在进行的1/2期首次人体试验数据，研究突显出该药物用于治疗既往接受过多线治疗的R/R CLL/SLL患者具有可耐受的安全性和良好的有效性。 BTK抑制剂耐药难题日益凸显 BTK抑制剂是2013年首次在美国上市，它的出现延展了B细胞淋巴瘤患者的生存期，使部分患者向慢性病方向发展，带病生存成为了常态。攻下血液肿瘤之后，多数的已上市BTK药物拓展适应症势在必行，自免领域的相关适应症成了BTK的下一个用武之地。据华创证券统计，当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。然而，随之而来亟待解决的就是BTK耐药后的痛点。第一代BTK抑制剂-伊布替尼，和第二代抑制剂-阿可替尼、泽布替尼、奥布替尼、太拉布替尼，它们通过共价结合BTK蛋白第481半胱氨酸，封闭了ATP结合口袋，从而阻断BTK自磷酸化和下游事件。BTK共价抑制剂治疗后，BTK激酶获得C481到S的耐药突变。第三代BTK抑制剂为非共价抑制剂，目前有吡妥布鲁替尼获准上市。非共价抑制剂同样阻断了ATP结合，并且不依赖于C481，因此可用于既往BTK抑制剂治疗并产生耐药的患者。在接受吡妥布鲁替尼临床实验的病人中，出现了新的耐药突变。意想不到的是，虽然新的耐药突变同样位于激酶功能域，突变造成了BTK自磷酸化水平降低。但检查BCR下游事件发现，AKT，ERK没有受到影响，甚至B细胞BCR活性相关的钙离子流出现了异常增高。这一研究提示了第三代BTK抑制剂的耐药突变造成了BCR通路的持续激活。临床治疗需要新的分子克服新的耐药突变。获批上市的6款BTK抑制剂图片来源：医药经济报 5款BTK降解剂已进入临床阶段共价BTK抑制剂长期使用存在BTK C481突变耐药的问题，Pirtobrutinib是唯一一款已上市的非共价结合型BTK抑制剂，不需要通过C481与BTK结合，可以解决BTK C481突变耐药的问题。但除C481外，BTK尚存在多种其他获得性突变，这些突变可能会导致ncBTKi出现耐药，甚至出现交叉耐药。此外，BTK除激酶活性外，还存在"支架功能"，即使激酶活性受损，仍能维持BCR信号通路的激活。 BTK降解剂可以解决"获得性耐药"和"BTK的支架功能"两大问题，相比BTK抑制剂，理论上可以使患者得到更大的获益。目前尚无BTK降解剂上市，很多药企在开发BTK的蛋白质降解靶向嵌合体（PROTACs），如百济神州的BGB-16673、海思科的HSK29116、Nurix的NX2127和NX-5948等。均处于早期临床阶段。部分临床在研的BTK的PROTACs 图片来源：药渡 NX-2127 NX-2127是Nurix Therapeutics开发的一种将BTK降解与Aiolos (IKZF3)和Ikaros (IKZF1)降解的免疫调节活性相结合的新型异双功能口服给药的PROTACs药物。 Nurix Therapeutics在2023年12月的美国血液学会年会上披露了NX-2127临床数据，数据表示NX-2127具有剂量依赖性的药代动力学，平均半衰期为2-4天。此外，无论患者的绝对BTK起始水平、肿瘤类型或剂量如何，NX-2127都会快速、强大和持续降解BTK 今年3月Nurix Therapeutics宣布随着生产工艺的改进，NX-2127在B细胞恶性肿瘤中的1期研究已被FDA批准继续进行，之前Nurix Therapeutics主动向FDA提出为改进生产工艺，试验暂时搁置。再次归来，1期试验的入组将重新启动，将优先考虑先前已出现耐药反应的侵袭性非霍奇金淋巴瘤患者，包括弥漫性大B细胞淋巴瘤（DLBCL）和套细胞淋巴瘤（MCL）。该研究的主要终点是剂量限制性毒性、最大耐受剂量、总体缓解率以及不良事件和实验室异常的发生率。次要终点包括药代动力学、缓解持续时间、无进展生存期、总生存期和完全缓解率，该研究预计将于2025年12月完成。 NX-5948 NX-5948是Nurix的第二代BTK降解剂，区别在于NX-5948可以通过血脑屏障，在颅内发挥BTK降解作用。在临床前研究中，NX-5948能够显著降低动物大脑中的肿瘤负担，并且延长动物的生命。目前NX-5948在1a/b期临床试验的积极数据。分析显示，NX-594在复发难治性慢性淋巴细胞白血病（CLL）患者身上引起快速、深度的缓解，客观缓解率（ORR）达近70%，这些患者之前曾接受大量治疗并带有BTK抑制剂耐药突变。Nurix预计在2025年启动NX-5948的关键临床试验。 NX-5948 作用机制图片来源：参考来源6 HSK29116 HSK29116是海思科自主研发的一种口服BTK-PROTAC小分子抗肿瘤药物，是由靶向BTK蛋白的配体、E3泛素连接酶的招募配体和连接两个配体的linker组成的三联体。HSK29116能够直接诱导BTK和BTK C481S的降解，抑制B细胞淋巴瘤细胞的生长与增殖。且在不同的小鼠移植瘤模型中，有效抑制荷瘤小鼠皮下移植瘤的生长。目前，HSK29116针对复发/难治性B细胞恶性肿瘤患者的国际多中心1期临床试验正在推进中。参考来源： 1. E. Wang et al., Mechanisms of resistance to noncovalent Bruton's tyrosine kinase inhibitors. N. Engl. J. Med. 386,735-743 (2022). 2. Seymour et al. First Results from a Phase 1, First-in-Human Study of the Bruton's Tyrosine Kinase (BTK) Degrader BGB-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies. ASH 2023 3. Montoya S, Bourcier J, Noviski M, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127[J]. Science, 2024, 383(6682): eadi5798. 4. Woyach J A, Flinn I W, Awan F T, et al. Efficacy and safety of nemtabrutinib, a wild-type and C481S-mutated Bruton tyrosine kinase inhibitor for B-Cell malignancies: Updated analysis of the open-label phase 1/2 dose-expansion bellwave-001 study[J]. Blood, 2022, 140(Supplement 1): 7004-7006. 5. Danilov A, Tees M T, Patel K, et al. A First-in-Human Phase 1 Trial of NX-2127, a First-in-Class Bruton's Tyrosine Kinase (BTK) Dual-Targeted Protein Degrader with Immunomodulatory Activity, in Patients with Relapsed/Refractory B Cell Malignancies[J]. Blood, 2023, 142: 4463. 6. Searle E, Forconi F, Linton K, et al. Initial Findings from a First-in-Human Phase 1a/b Trial of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed/Refractory B Cell Malignancies[J]. Blood, 2023, 142: 4473. END 【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床1期蛋白降解靶向嵌合体临床2期临床结果

100 项与阿可替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10893	阿可替尼	L01XE51	DB11703

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
小淋巴细胞淋巴瘤	美国	AstraZeneca UK Ltd.	2019-11-21
慢性淋巴细胞白血病	加拿大	AstraZeneca Canada, Inc.	2019-10-02
套细胞淋巴瘤	美国	AstraZeneca UK Ltd.	2017-10-31

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
大B细胞淋巴瘤	临床3期	德国	AstraZeneca PLC	2023-06-07
弥漫性大B细胞淋巴瘤	临床3期	美国	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	中国	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	日本	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	澳大利亚	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	奥地利	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	比利时	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	巴西	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	加拿大	AstraZeneca PLC	2020-10-08
弥漫性大B细胞淋巴瘤	临床3期	捷克	AstraZeneca PLC	2020-10-08

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临床结果

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


NCT02717624 (phase 1b, Pubmed \| Blood Adv)	临床1期	套细胞淋巴瘤 minimal residual disease (MRD)	-	Acalabrutinib	衊鏇廠鬱襯廠膚簾製鹽(顧製遞觸鏇淵積膚齋襯) = 襯簾窪鹽齋顧淵遞憲窪壓鬱壓遞襯艱蓋願齋築 (衊觸襯顧積觸膚願鹽選 ) 更多	积极	2024-09-10
NCT02477696 (ELEVATE-RR, Pubmed \| Blood)	临床3期	慢性淋巴细胞白血病 BTK mutations \| TP53 mutations \| PLCG2 mutations	-	Acalabrutinib-treated patients	繭顧願艱襯製餘顧壓繭(製繭鏇衊鏇願構願構顧) = 觸繭鬱鹹積構構觸襯窪繭鑰願構蓋築鏇夢鏇鑰 (獵壓繭鑰構襯鑰築鏇鹹 ) 更多	-	2024-09-05
				Ibrutinib-treated patients	繭顧願艱襯製餘顧壓繭(製繭鏇衊鏇願構願構顧) = 壓構夢襯蓋醖壓製窪窪繭鑰願構蓋築鏇夢鏇鑰 (獵壓繭鑰構襯鑰築鏇鹹 ) 更多
NCT02475681 \| NCT03336333 (Pubmed \| Blood Adv) 人工标引	临床3期	慢性淋巴细胞白血病一线 del(17p)	-	Acalabrutinib plus obinutuzumab	-	积极	2024-06-11
				Acalabrutinib monotherapy
NCT02972840 (ECHO, EHA2024) 人工标引	临床3期	套细胞淋巴瘤一线	598	Acalabrutinib + Bendamustine + Rituximab	鑰鹽蓋衊積衊餘憲範醖(範選襯範範醖願餘艱遞) = 構鏇襯襯鑰積願構觸鏇觸膚憲鏇膚願窪簾廠積 (網鹽衊壓積齋襯衊廠鬱 ) 更多	积极	2024-06-03
				Placebo + Bendamustine + Rituximab	鑰鹽蓋衊積衊餘憲範醖(範選襯範範醖願餘艱遞) = 鹹選製餘壓願淵鏇鹹繭觸膚憲鏇膚願窪簾廠積 (網鹽衊壓積齋襯衊廠鬱 ) 更多
NCT04657094 (CTgov)	临床2期	慢性淋巴细胞白血病 \| 自身免疫性溶血性贫血	4	Acalabrutinib	鹽製構憲遞鑰範觸網觸(淵艱製廠構鹹網網窪顧) = 廠願鬱範鑰鏇衊壓窪鏇遞觸艱遞鹽憲獵選鏇衊 (淵獵簾網齋願構簾憲鹽, 製網艱襯積觸選醖襯醖 ~ 齋構鑰夢網範衊構築蓋) 更多	-	2024-05-29
ASCEND (ASCO2024) 人工标引	N/A	慢性淋巴细胞白血病	-	Zanubrutinib (High-Risk With COVID-19 Adjustment)	願淵鏇積憲鬱廠願憲繭(遞積鏇糧範蓋淵膚選廠): 0.54 (95% CI, 0.32 ~ 0.92) 更多	积极	2024-05-24
				Acalabrutinib (High-Risk With COVID-19 Adjustment)
NCT05557695 (EPIC, EHA2024) 人工标引	N/A	慢性淋巴细胞白血病一线 ATM Mutation \| Gene \| del(17p13.1) \| ... 更多	170	Acalabrutinib	襯廠艱觸齋觸選壓壓鑰(積積艱廠淵淵築窪壓鑰) = most common adverse events leading to discontinuations (≥1 AE could be reported per discontinuation) included cardiovascular, haematoma, and Richter transformation (n=2 each) 鹽齋範選憲觸夢鬱獵醖 (鹹鑰獵顧鑰窪鹽積繭獵 )	积极	2024-05-14
NCT04008706 (ASSURE, EHA2024) 人工标引	临床3期	慢性淋巴细胞白血病 del(17p)/TP53m \| uIGHV	552	Acalabrutinib 100 mg	範艱膚獵夢觸簾鹽繭膚(齋襯願糧窪選衊鹹築壓) = 築鹽艱廠糧廠鏇淵壓鹹鑰鑰範憲鏇襯夢觸願遞 (餘觸夢鬱憲廠鹽選憲襯 ) 更多	积极	2024-05-14
NCT02213926 \| NCT02343120 \| NCT03206970 (BGB-3111-206, EHA2024) 人工标引	临床1/2期	套细胞淋巴瘤	247	Zanubrutinib	鹹築網遞積積製鬱簾網(鬱製構簾鏇願衊鹹餘夢): OR = 2.05 (95% CI, 0.72 ~ 5.84), P-Value = 0.1798 更多	积极	2024-05-14
				Acalabrutinib
NCT04722172 (EHA2024) 人工标引	临床2期	慢性淋巴细胞白血病一线 TP53 deletion \| del13q \| tri12 ... 更多	55	Acalabrutinib + obinutuzumab	範製鏇遞鹽蓋蓋糧獵願(積鑰衊鹽鹽選醖鑰窪繭) = 糧觸繭廠蓋鏇積鬱壓顧簾淵獵鬱窪願鑰艱範蓋 (繭獵鑰蓋顧壓襯窪繭鹽 ) 更多	积极	2024-05-14
				Acalabrutinib + obinutuzumab (del11q)	範製鏇遞鹽蓋蓋糧獵願(積鑰衊鹽鹽選醖鑰窪繭) = 襯築衊憲壓齋艱願構壓簾淵獵鬱窪願鑰艱範蓋 (繭獵鑰蓋顧壓襯窪繭鹽 )