Abatacept

一种称为免疫检查点抑制剂（immune checkpoint inhibitor, ICI）的癌症免疫疗法在治疗癌症方面引发了治疗变革。然而，一些接受ICI治疗的患者会出现一种危险的心脏炎症，即心肌炎 一种称为免疫检查点抑制剂（immune checkpoint inhibitor, ICI）的癌症免疫疗法在治疗癌症方面引发了治疗变革。然而，一些接受ICI治疗的患者会出现一种危险的心脏炎症，即心肌炎（myocarditis）。 在一项新的研究中，来自布罗德研究所等研究机构的研究人员如今发现了这种心脏炎症的免疫基础。他们确定了心脏中特定类型的免疫细胞和基质细胞的变化是心肌炎产生的基础，并指出了血液中的一些因素可能预示着患者的心肌炎是否会导致死亡。相关研究结果于2024年11月6日在线发表在Nature期刊上，论文标题为“Immune responses in checkpoint myocarditis across heart, blood and tumour”。 该研究项目于2017年启动，是北美首个同类项目，致力于改善对严重免疫疗法并发症的诊断、治疗和了解，这些并发症几乎会影响每个器官系统。作者将心肌炎作为首批研究项目之一，因为尽管心肌炎是ICI治疗较罕见的并发症之一，但却是最致命的并发症。 重要的是，这些发现首次证明了心脏中的免疫反应有别于肿瘤的免疫反应，这表明靶向治疗或许能在解决心肌炎问题的同时，让患者继续接受可能挽救生命的抗肿瘤免疫疗法。 这些研究结果还强调了可能的治疗靶点，这些靶点增强了麻省总医院最近启动的一项临床试验的合理性，该试验正在测试一种治疗这种心脏炎症的药物。 在接受 ICI 治疗的患者中，大约有 1%——美国每年有 2000 多人，会患上心肌炎，而在联合使用某些免疫疗法药物的患者中，这一数字将近 2%。 在 50% 的病例中，心肌炎会导致危险的心脏事件，如心律失常和心力衰竭，尽管目前有治疗方法，但约有三分之一的患者会因此而死亡。此外，用于针对诸如病毒性心肌炎之类的其他形式心肌炎的治疗和支持性护理方法对这种类型的心肌炎不起作用。 论文通讯作者、布罗德研究所的Alexandra-Chloé Villani说，“我们现在没有很好的解决方案来帮助这些患者，所以我们想尽一切办法来关闭免疫系统并逆转心肌炎，但这是一种不精确的方法，本身就存在风险。我们的研究结果为我们提供了一幅更详细的心脏情况图，并为改善患者护理提出了令人感兴趣的新方法。” 论文共同作者、哈佛医学院医学助理教授Kerry Reynolds说，“ICI引起的心肌炎是我们临床上的一大障碍。这项研究改变了游戏规则，为揭示这种并发症的根源铺平了道路。我们非常感谢每一位与我们合作的患者、所有参与他们临床护理的人员，以及我们实验室中使这项研究成为可能的杰出团队。” 论文共同作者、哈佛大学医学院医学副教授Tomas Neilan 说，“这项研究为测试针对ICI导致的心肌炎的更具针对性的疗法提供了生物学基础。这篇论文是向前迈出的重要一步，因为我们需要提高对这种毒性的认识，这将改善治疗效果。” 益处与风险 在美国，约有三分之一的癌症患者有资格接受被称为免疫检查点抑制剂（ICI）的革命性药物治疗，这类药物属于免疫疗法类药物，可解除人体免疫系统的“刹车”，使其能够对抗癌症。 随着每年接受 ICI 治疗的患者越来越多，严重并发症的威胁和如何控制并发症的挑战也越来越大。2020 年，美国有超过 23 万名患者接受了 ICI治疗，随着美国食品药品管理局（FDA）批准了这些药物的 80 多种适应症，这一数字很可能还会继续增长。 大多数服用一种或多种 ICI 药物的患者至少会出现一种毒性，根据所服用药物的不同，10% 到 50%以上的患者会出现严重的并发症。即使停止治疗，并发症也很难停止或逆转，患者可能在服用一次药物后就出现危及生命的器官炎症。 医生目前还没有有效的靶向治疗方法，因此往往不得不停止抗肿瘤治疗或给予大量类固醇，而类固醇本身也有不良副作用，如降低 ICI 抗肿瘤治疗的疗效。 免疫疗法最令人担忧的并发症之一是检查点心肌炎（checkpoint myocarditis），即由ICI治疗引起的心肌炎，它对患者的危害明显高于其他原因引起的心肌炎，目前尚不清楚原因何在。 论文共同第一作者、Villani 实验室博士后研究员Daniel Zlotoff说，“自从不到十年前我们首次发现检查点心肌炎以来，它在很大程度上一直是个黑箱。直到现在，我们才开始回答基本的生物学问题，我们希望这将阐明最佳治疗方法，使其更容易忍受，并改善患者的预后。” 在这项新研究中，Villani团队收集了在接受 ICI 治疗期间患上心肌炎并同意参与研究的患者的血液，以及来自一些患者的配对心脏和肿瘤组织。他们在实验室进行了单细胞RNA测序分析、显微镜检查、蛋白质组分析和T细胞受体测序，以确定参与驱动和维持心肌炎相关炎症过程的细胞。 在患者的心脏组织中，他们观察到有助于招募和保持参与炎症的免疫细胞的分子通路上调。他们还发现，一些免疫细胞亚群的数量有所增加，由特定细胞毒性T细胞、经典树突细胞（cDC）和炎性成纤维细胞组成的某些细胞群体的数量也有所增加。在血液中，他们发现浆细胞样树突细胞（pDC）、cDC 和 B谱系细胞减少，其他单核吞噬细胞数量增加。 Villani团队还分析了T细胞受体，这是一种独特的蛋白复合物，能与称为抗原的外来颗粒结合并做出反应。受影响心脏组织中丰富的T细胞受体与肿瘤中的T细胞受体不同，这一结果与其他研究人员的发现——患者心脏和肿瘤中的免疫反应是相同的，是不同的。 PBMC细胞亚群和转录变化与心肌炎发病相关 Villani团队还没有发现T细胞受体识别α-肌球蛋白的证据，其中α-肌球蛋白曾被报道为驱动检查点心肌炎的关键抗原。这些结果表明受影响心脏组织中最丰富的T细胞受体能识别未确定的抗原。 在未来的研究工作中，Villani团队希望确定在心脏和肿瘤中起作用的特定抗原，并辨别它们是正常蛋白、变异的肿瘤蛋白、外来颗粒（如病毒）还是新的抗原。 论文共同第一作者、Villani 实验室博士后研究员 Steven Blum 说，“由于肿瘤和心脏的免疫反应不同，这让我们对有朝一日能将两者分开并分别治疗充满希望。” 血液中T细胞亚型的模式还显示了哪些人更有可能患心肌炎，这表明有朝一日可以利用基于血液的测量来标记风险增加的患者，并对其进行密切监测或完全避免使用免疫疗法。他们还在外周血中发现了源自心脏的T细胞，它们与疾病的严重程度相关。这些发现为开发一种诊断性血液测试打开了大门，这种测试可能取代对疑似心肌炎患者进行的侵入性心脏活检。 这项研究还为正在进行的一项临床试验（ATRIUM，NCT05335928）提供了支持，该试验是在麻省总医院进行的，旨在探索使用一种关节炎药物阿巴西普（abatacept）来控制这些患者的心肌炎。 Reynolds说，“我们一直希望患者能获得更好的治疗效果，但我们需要临床试验的确凿证据来证明如何在保持抗肿瘤反应的同时解决心脏炎症问题。这些细胞图谱有助于指导我们应该研究什么。” 通过治疗和研究不同器官系统的并发症，Villani团队希望找到既有区别又有共通之处的机制，从而揭示影响这些患者身体不同部位（往往同时发生）的不良事件。 Villani说，“重要的是要记住，免疫疗法药物是拯救生命的神奇药物，患者不应该害怕它们。我们只需要让它们更好地发挥作用，从而最大限度地提高它们的抗肿瘤治疗效果，同时最大限度地降低不良反应的风险。”（生物谷Bioon.com） 参考资料： Daniel Zlotoff et al. Immune responses in checkpoint myocarditis across heart, blood and tumour. Nature, 2024, doi:10.1038/s41586-024-08105-5.

HOUSTON--( BUSINESS WIRE )-- Coya Therapeutics, Inc. (NASDAQ: COYA) (“Coya” or the “Company”), a clinical-stage biotechnology company developing biologics intended to enhance Treg function, releases the following letter to stockholders from Chief Executive Officer Dr. Arun Swaminathan. Dear Fellow Stockholder, Given my recent transition to the role of CEO, I wanted to share my thoughts on Coya and our future and to express my gratitude to our founder and Executive Chair, Dr. Howard Berman, whose bold vision has instilled the “innovation and get-it-done” culture in Coya’s DNA. We have made tremendous strides in 2024, repeatedly executing on our promises. As I look to 2025, I am confident that our nimble and highly experienced team will continue to exceed expectations. I have spent my entire 25-year career in the biotech space, and I believe that Coya has the most promise of any company that I have represented. I truly believe our novel science, strong clinical proof of concept data, pharmaceutical partnership validation, cash runway, and clear path to a commercial drug differentiates us. Prior to serving at Coya, I helped spearhead and lead pharmaceutical transactions worth billions of dollars that led to significant value creation. I believe the opportunities ahead of us in 2025 and beyond are what investors, stockholders, and patients should be most excited about. Our science and approach of regulating Tregs is now validated in multiple trials across multiple neurodegenerative diseases, we have a track record of executing value-creating non-dilutive deals, and our strong cash position allows us to be prudent in our decisions. Year Ahead We expect our activities in 2025 to be focused on the following indications: ALS (Amyotrophic Lateral Sclerosis) Program: We have alignment with the FDA on the data required to initiate our potentially pivotal COYA 302 Phase 2 double-blind randomized study in patients with ALS. We are targeting the submission of the requested data package by 2Q 2025 and initiation of the clinical trial upon FDA clearance. The roadmap to topline results is now clear with reduced uncertainty. In late 2023, we partnered with Dr. Reddy’s Laboratories, a multi-billion-dollar drug developer, to license COYA 302 in ALS in a deal that is worth up to $700 million. We still retain the rights to COYA 302 in ALS in Japan and South/Central America and Mexico, thus providing us direct upside and optionality in this indication alone. FTD (Frontotemporal Dementia) Program: We expect to see topline results in 2H 2025 from the investigator-initiated, open-label study of Low Dose IL-2 (LD IL-2) + CTLA4-Ig in FTD. Study endpoints will measure safety, peripheral and central inflammation, FTD progression, and pharmacodynamic effects on Treg cell populations. The data are expected to guide our planned COYA 302 Phase 2 double-blind randomized study (which will be funded by the Alzheimer’s Drug Discovery Foundation) and further optimize the design for success. The guidance from the FDA on the ALS IND reduces uncertainty on the planned IND filing for FTD in 2H of 2025. We have retained full commercial rights on this program thus far, providing us optionality to develop the program to BLA approval ourselves and capture the full potential upside or partner at a later stage once we obtain additional clinical data. AD (Alzheimer’s disease) Program: Complementing the promising data that was presented at CTAD in Madrid for LD IL-2 in mild to moderate AD, the investigators will disclose additional data in 1H 2025 that summarizes the changes in inflammation in the peripheral system (blood) and central nervous system (CSF and brain) and other molecular measurements for the two IL-2 dosing arms vs. placebo. These important data will help to further address the basic science associated with the promising clinical response observed in the lower dose IL-2 arm and its association with better Treg enhancement. We retain full rights to the AD indication for COYA 302 and are already in the process of exploring non-dilutive and strategic partnering opportunities. While the CTAD data was based on LD IL-2 alone and proved highly promising in and of itself, COYA 302, which is a proprietary combination of LD IL-2 and CTLA4-Ig, targets multiple pathways and is developed to more significantly and durably enhance Treg function, which we believe will be highly attractive to potential partners. Strategic Partnerships Dr. Reddy’s Partnership: Our partnership with Dr. Reddy’s Laboratories is approaching its one-year anniversary, and our collaboration could not be stronger. We have a reliable partner for ALS, and leveraging its resources and expertise has created value beyond the milestone payments. In 2025, we anticipate receiving $8.4 million upon initiation of the Phase 2 ALS clinical trial and will continue to evaluate opportunities to further deepen the relationship. Other Strategic Possibilities: As I have described, my background is one of deal-making, and I intend to leverage my network and capabilities to maximize opportunities for Coya in 2025. We have only partnered COYA 302 in ALS, and the optionality to partner, co-develop, or license the asset in other indications exists. Any potential transaction will be evaluated based on maximizing stockholder value. The positive data from the investigator-initiated trial of LD IL-2 in patients with Alzheimer’s disease increases our confidence in obtaining value-creating pharma partnerships that combine our proprietary LD IL-2, COYA 301, with other modalities. I can envision multiple opportunities with LD IL-2 serving as a backbone adjuvant with standard of care agents and other novel pathways. Moreover, the opportunity for grant funding and financial support from foundations exists and will be vigorously pursued. We believe the data emerging on Tregs in autoimmune disease (such as lupus, rheumatoid arthritis, and scleroderma) and, in particular, treatment with LD IL-2 is compelling and may strengthen the role of COYA 302 and LD IL-2 combinations in this space. I intend to actively pursue partnerships in this arena that would further place us in a strong position to pursue value-creating deals. Value-Creating Pipeline Like many experts in the scientific community, we believe combination strategies are the future to address devastating neurodegenerative diseases. We believe targeting one mechanism or pathway is likely insufficient to achieve maximal effect - hence our approach with COYA 302. COYA 302 is a “Pipeline within a Product” and has strong potential in ALS, FTD, AD, Parkinson’s disease, and other indications. We are continuously building our intellectual property to further enhance the value of Coya. One recent development is the combination of COYA 301 and GLP-1 agonists. Data suggests that the mechanism of action appears additive and/or synergistic in ameliorating inflammation. This is yet another opportunity for value-creating strategic partnerships. We intend to publish more detailed data in 1Q 2025. Conclusion As you can see from our past performance, our entire management team is committed to the success of Coya. We expect to recognize a number of clinical, regulatory, and/or commercial milestones in 2025 that will help us advance the treatment of neurodegenerative diseases. On behalf of the entire Coya team, please accept our sincere gratitude for both your support and belief in our science, our story, and our team. We look forward to presenting additional clinical data and updating you on our additional corporate developments as they unfold. Onwards and upwards! About Coya Therapeutics, Inc. Headquartered in Houston, TX, Coya Therapeutics, Inc. (Nasdaq: COYA) is a clinical-stage biotechnology company developing proprietary treatments focused on the biology and potential therapeutic advantages of regulatory T cells (“Tregs”) to target systemic inflammation and neuroinflammation. Dysfunctional Tregs underlie numerous conditions, including neurodegenerative, metabolic, and autoimmune diseases, and this cellular dysfunction may lead to sustained inflammation and oxidative stress resulting in lack of homeostasis of the immune system. Coya’s investigational product candidate pipeline leverages multiple therapeutic modalities aimed at restoring the anti-inflammatory and immunomodulatory functions of Tregs. Coya’s therapeutic platforms include Treg-enhancing biologics, Treg-derived exosomes, and autologous Treg cell therapy. COYA 302 – the Company’s lead biologic investigational product or "Pipeline in a Product" – is a proprietary combination of COYA 301 (Coya’s proprietary LD IL-2) and CTLA4-Ig for subcutaneous administration with a unique dual mechanism of action that is now being developed for the treatment of Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, and Alzheimer’s Disease. Its multi-targeted approach enhances the number and anti-inflammatory function of Tregs and simultaneously lowers the expression of activated microglia and the secretion of pro-inflammatory mediators. This synergistic mechanism may lead to the re-establishment of immune balance and amelioration of inflammation in a sustained and durable manner that may not be achieved by either low-dose IL-2 or CTLA4-Ig alone. For more information about Coya, please visit www.coyatherapeutics.com . Forward-Looking Statements This press release contains “forward-looking” statements that are based on our management’s beliefs and assumptions and on information currently available to management. Forward-looking statements include all statements other than statements of historical fact contained in this presentation, including information concerning our current and future financial performance, business plans and objectives, current and future clinical and preclinical development activities, timing and success of our ongoing and planned clinical trials and related data, the timing of announcements, updates and results of our clinical trials and related data, our ability to obtain and maintain regulatory approval, the potential therapeutic benefits and economic value of our product candidates, competitive position, industry environment and potential market opportunities. The words “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “expect,” and similar expressions are intended to identify forward-looking statements. Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors including, but not limited to, those related to risks associated with the impact of COVID-19; the success, cost and timing of our product candidate development activities and ongoing and planned clinical trials; our plans to develop and commercialize targeted therapeutics; the progress of patient enrollment and dosing in our preclinical or clinical trials; the ability of our product candidates to achieve applicable endpoints in the clinical trials; the safety profile of our product candidates; the potential for data from our clinical trials to support a marketing application, as well as the timing of these events; our ability to obtain funding for our operations; development and commercialization of our product candidates; the timing of and our ability to obtain and maintain regulatory approvals; the rate and degree of market acceptance and clinical utility of our product candidates; the size and growth potential of the markets for our product candidates, and our ability to serve those markets; our commercialization, marketing and manufacturing capabilities and strategy; future agreements with third parties in connection with the commercialization of our product candidates; our expectations regarding our ability to obtain and maintain intellectual property protection; our dependence on third party manufacturers; the success of competing therapies or products that are or may become available; our ability to attract and retain key scientific or management personnel; our ability to identify additional product candidates with significant commercial potential consistent with our commercial objectives; and our estimates regarding expenses, future revenue, capital requirements and needs for additional financing. We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy, short-term and long-term business operations and objectives, and financial needs. Moreover, we operate in a very competitive and rapidly changing environment, and new risks may emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed herein may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Although our management believes that the expectations reflected in our forward-looking statements are reasonable, we cannot guarantee that the future results, levels of activity, performance or events and circumstances described in the forward-looking statements will be achieved or will occur. We undertake no obligation to publicly update any forward-looking statements, whether written or oral, that may be made from time to time, whether because of new information, future developments or otherwise.