Edralbrutinib

氨基观察-创新药组原创出品 作者 | 蔡九 永远不要低估中国创新药企的“韧性”。 从2022年低谷至今不到3年时间，云顶新耀股价上涨接近7倍，领涨港股市场。随着依嘉、耐赋康进入放量加速期，基本面持续向上，让市场不断重估云顶新耀的价值。 股价上涨的同时，云顶新耀仍在加速创造阿尔法。日前，公司又一座“金矿”浮出水面。 12月4日，云顶新耀公布的数据显示，其BTK抑制剂EVER001胶囊，在治疗原发性膜性肾病的1b/2a期临床试验中显示出积极效果，有潜力成为肾病市场的颠覆者。 这也给云顶新耀埋下了价值、估值共同提升的“戴维斯双击”伏笔。 价值不难理解。云顶新耀拥有EVER001肾病适应症的全球权益，对应出海预期，价值不容小觑。尤其自去年以来，肾病新药受到追捧，诺华35亿美元收购Chinook、Vertex49亿美元收购Alpine、渤健18亿美元收购HI-Bio，为EVER001的BD价值提供了很好的参考。 而估值提升的逻辑，在于云顶新耀战略的推进，从过去的license in到如今的license out，再到接下来的自研管线价值兑现也已经清晰可见。公司不再是市场认为的单纯引进的药企，自然过去的估值逻辑也不再适用。 也正因此，在EVER001数据公布后，云顶新耀受到了更多市场机构的认可。日前，中信证券对云顶新耀进行了首次覆盖，认为云顶新耀引进+自研共筑差异化管线的逻辑越来越清晰，后续进展值得期待，对应“买入”评级，2025年目标价为55港元，合理市值为177.68亿港元。 不过，当前市场对于云顶新耀的上述预期并未一致形成。但这也意味着，其后续获得更大价值弹性空间的概率，随之放大。 / 01 / 蓝海硬逻辑 EVER001的高价值，与其所处的市场有关。 潜在治疗群体规模庞大、临床负担重、有效疗效稀缺，决定了肾病领域是一个超级蓝海市场。 以原发性膜性肾病市场为例。作为成人肾病最常见的病理类型，中国原发性膜性肾病患者数近200万例，美国、欧洲、日本等国家总患者病例超20万。 原发性膜性肾病会引发肾衰竭。2023年8月份在临床肾病杂志上发表的《Future landscape for the management of membranous nephropathy》显示，如果不治疗，14%的持续性肾病综合征患者在5年时可能发生肾衰竭，35%在10年时发生，41%在15年时发生肾衰竭。 遗憾的是，全球没有特效药物获批，临床上主要是以利妥昔超适应症使用为主的治疗手段，局限性明显： 大约30%患者没有效果，而有效果的群体中，一半的病人仍患有肾病综合征，1/3的患者仍会进展为终末期肾病。 也正因此，目前原发性膜性肾病已是导致透析的第一大原因，占比高达37%，甚至超过糖尿病肾病和高血压肾病透析的总和（约30%）。 所以，一款得到临床验证的原发性膜性肾病治疗药物，销售额预期不会太低。而EVER001，不仅能治疗原发性膜性肾病，总共可以治疗4种原发性肾小球肾病，以及继发性狼疮性肾炎。 上述适应症潜在群体规模约1000万人，且除了IgA肾病有云顶新耀的耐赋康上市，其他适应症均未有治疗手段获批。 因此，EVER001备受市场瞩目。而机制、分子的多重优势，更是赋予其更高的价值期待。 作为BTK抑制剂，EVER001作用于疾病发病机制的上游，减少B细胞的活化、增殖和分化，从而减少B细胞产生的自身抗体。除了B细胞，BTK抑制剂还能对多种细胞类型产生免疫调节作用。 而目前在肾病领域探索较多的B细胞靶向抗体，包括利妥昔单抗、CD38抗体或BAFF/APRIL抗体等，均只能影响B细胞的特定亚群。 同时，EVER001是为数不多的口服小分子药物，进一步提高了“上限”。 一方面，为其提供了额外安全性优势，允许在必要时停止治疗，并能使B细胞功能在停药后快速恢复； 另一方面，为联合疗法探索提供更多可能。肾病在研疗法较多，不同机制药物或能互补，EVER001安全性良好，且口服带来依从性优势明显，因此未来联用潜力不小。 而相比于同类BTK抑制剂，EVER001在分子设计方面具有独特优势。 BTK抑制剂分为三类：共价不可逆、非共价可逆、共价可逆。目前，全球原发性膜性肾病进展较快的BTK抑制剂中，只有EVER001属于共价可逆的设计思路，具备更出色的选择性、更强效靶点结合能力、更少的多脱靶毒性等综合优势。 也正因此，EVER001或能带来更大的临床价值，最终体现更高的商业价值。 / 02 / BD预期升温 在1b/2a期临床研究中，EVER001秀出了肌肉。 根据剂量不同，该研究分为队列1（100mg QD、100mg BID）、队列2（200mg BID）。 结果显示，在队列1中，抗-PLA2R抗体水平在第24周时已观察到超过90%的下降；在队列2中，第12周时已观察到90%的下降。 抗PLA2R抗体水平和临床疗效紧密相关，其降低预示临床缓解，尤其是免疫学完全缓解。这在患者蛋白尿的下降层面得到了体现。第12周时，两组的蛋白尿基本都下降了30%左右。 在快速起效的同时，EVER001展现了极佳的效果。 队列2在第24周时，免疫学完全缓解率达到100%，队列1在第36周也达到90%。 蛋白尿下降方面，队列1在第36周时下降78.3%，队列2在第24周时下降73.8%。队列1在36周时蛋白尿缓解率达81.8%；队列2在24周时蛋白尿缓解率则达85.7%。 作为对比，现在指南推荐的利妥昔单抗联合疗法，在国内开展的一些研究显示，12个月的缓解率在60%左右，部分甚至低至40%。 同时，EVER001的疗效还能维持较长的时间。数据显示，不管是队列1和队列2在停药随访期（最长至52周）内，免疫效应均保持稳定。在数据截止日期，两组抗-PLA2R抗体水平下降比例都在100%。 效果突出，EVER001的安全性也非常良好。其大多数不良反应为1级或2级，且未观察到传统BTK抑制剂典型的不良反应，也没有严重的肝毒性。 不同于肿瘤药物，肾病作为一种需要长期用药的疾病，对安全性的要求更严苛。很显然，良好的安全性，是EVER001的一个加分项。 从最新临床数据看，EVER001不仅能显著优于利妥昔等现有药物，还优于潜在的BTK抑制剂竞对，有望更大程度满足原发性膜性肾病市场的临床需求，从而获得巨大的成功。 这也预示，EVER001的BD预期要开始升温了。 在肾病市场探索的前沿疗法并不少，上文提及的HI-Bio、Chinook、Alpine更是凭借核心管线，收获大药企青睐，创造了多个巨额收购案。 这不仅体现了市场对肾病创新疗法价值的高度认可，也将成为EVER001估值的一个重要参考。 / 03 / 估值逻辑重塑 EVER001更是让市场看到，云顶新耀估值重塑的可能。 基于稳扎稳打的思路，云顶新耀定下了license in、license out再到自主研发走向全球的循序渐进的战略目标。但license in模式的过于成功，让市场认为云顶新耀只有“引进”逻辑，而忽视了其他的价值。 EVER001最新数据的公布，则展示出公司正加速走向战略的第三阶段，并且有能力兑现所有预期。 不只是引进，云顶新耀拥有EVER001在全球范围内开发用于治疗肾病领域的权益。潜台词是，其做到了EVER001在原发性膜性肾病领域从0到1的开发。 这并不容易。因为该病患者对治疗的反应存在很大的异质性，加上长期管理和预后难度较大，研发难度极高。 也正因此，肾病是BTK抑制剂较少涉足的领域。Insight数据库显示，2021年9月份云顶新耀踏入该领域之时，国内22款BTK抑制剂中仅恒瑞医药的SHR-1459申报了膜性肾病。 可以说，EVER001在原发性膜性肾病领域的研发，是云顶新耀完全基于自己的理解和探索、实践，最终实现“破冰”，这验证了其全面的R&D能力，不存在研发短板。 因此，云顶新耀有能力继续拓展新分子和开发新适应症，保证其在肾病，以及更多领域的布局持续深入，带来更多高价值的“全球权益”产品。 而公司过往突出的前瞻布局能力，更是保证了这一点。 过去很长一段时间，由于机制复杂、临床周期较长，肾病一直都是冷门领域。传统的肾脏病临床研究将死亡、终末期肾病等“硬”终点作为主要评估指标，面临长时间随访等综合痛点，一定程度上造成了肾病高质量的临床试验相对较少。 但2021年以来，先是KDIGO指南建议将蛋白尿下降指标作为药物缓解IgA肾病进展的合理替代终点，又是耐赋康成为FDA首个基于蛋白尿下降的替代临床终点批准首款IgA肾病药物，预示了肾病的研发门槛大幅降低。 也正因此，近年来肾病市场才会呈现火热的趋势。而云顶新耀则做到了提早布局、完成卡位，证明了管理层的过人之处。 这背后，得益于公司打造了成功的作战体系。 在特定疾病领域，云顶新耀通常会通过自有的顶尖科研团队组合全球资源，构筑从研发、临床甚至后续全球商业化运作的能力。 正因此，在肾病领域，云顶新耀的理解绝对是行业领先的，这保证了公司能够不断挖掘肾病领域的潜力分子，并制定合适的临床策略，确保研发成果的转化，实现全球价值最大化。在电话会议上，公司表示，未来将会基于获益维度考虑，推进EVER001相应的国际化工作。 可以说，EVER001的突围，看似偶然，实则必然。未来，云顶新耀在研发、出海层面会给市场带来更多惊喜。这个过程，也将伴随着公司估值逻辑的切换。 / 04 / 总结 春天的希望总是在寒冬中埋下，伟大的变革通常源于至暗时刻。 过去几年，中国创新药行业的发展超出所有人预料。环境的突然变化，打了很多药企一个措手不及，云顶新耀也一度未达市场预期，股价跌至冰点。 但也恰恰是在过去几年应对极端挑战时的思考和播种，推动了公司的脱胎换骨。 2022年9月，随着罗永庆加入，云顶新耀开启一系列战略改革。一方面，捋顺了“聚焦蓝海+双轮驱动”的高效战略打法，完成肾病、抗感染和自免等领域的布局，同时强化自研和mRNA技术平台布局。 另一方面，推动公司文化重塑，凝聚人心、提升战斗力。得益于此，云顶新耀快速迎来了新生，2023年至今3款商业化产品上市，如今“双轮驱动”的模式也即将进入收获期。 可以说，虽然在2022年之前交了一笔学费，但公司却获得了穿越周期的能力，也成功重新赢回了市场的认可。今年以来，其股价涨幅超120% 能够在动荡中不断重塑自我，预示着云顶新耀未来的路会越走越宽。这不仅是云顶新耀的故事，也是中国创新药产业的根本逻辑。 PS：欢迎扫描下方二维码，添加氨基君微信号交流。

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 . 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