Abatacept

A key aspect of Parkinson’s disease (PD) pathophysiology is decreased systemic regulatory T cell (Treg) function with associated neuroinflammation in the nigrostriatal pathway of the brain, including the presence of reactive astrocytes and microglia that have an initiating and progressing role in PD; Subcutaneous injection of COYA 302, an anti-inflammatory, Treg-enhancing combination biologic (comprising low dose interleukin-2 and CTLA-4 Ig fusion protein), in an inflammatory mouse model of PD resulted in significant reductions in microglia and astrocyte activation in the nigrostriatal pathway in the brain; Importantly, study illustrates that peripheral administration of COYA 302 is directly immunomodulatory in the brain and associated with significant downregulation of neuroinflammation HOUSTON, TX, USA I September 16, 2024 I Coya Therapeutics, Inc. (NASDAQ: COYA) (“Coya” or the “Company”), a clinical-stage biotechnology company developing biologics intended to enhance regulatory T cell (Treg) function, announces the direct CNS anti-inflammatory effect of subcutaneously administered COYA 302 in a preclinical inflammatory associated mouse model of Parkinson’s Disease (PD). Coya’s Chief Business Officer and incoming Chief Executive Officer Arun Swaminathan, Ph.D. stated: “We believe that the ability of peripherally administered biologics (COYA 302) that potently and directly ameliorate the inflammatory milieu in the brain translates to strategies to suppress CNS neuro-inflammation beyond PD, including other inflammatory mediated neurodegenerative diseases such as Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD).” Parkinson’s disease is characterized by the selective loss of dopaminergic neurons in brain regions responsible for motor control (nigrostriatal pathway), while inflammation and immune dysfunction from the associated loss of systemic Treg function are currently recognized as critical mediators of disease and subsequent progression of PD. Targeting the sustained proinflammatory mechanisms that progress the disease and enhance immunosuppressive cells, such as Tregs, may have the potential to provide disease-modifying benefits in patients with PD. In an inflammatory mouse model of PD, subcutaneous injections of COYA 302 significantly reduced inflammation and microglial activation in nigrostriatal brain regions responsible for motor control (dorsal striatum and substantia nigra). Microglial activation is an important mediator of PD and plays an important role in PD pathology and neurodegeneration. Microglial inhibition may hold promise as a therapeutic strategy to delay the progression of PD.Additionally, subcutaneous injections of COYA 302 resulted in reductions in astrocyte numbers and their activation (astrogliosis) in the nigrostriatal pathway. It is known that pathogenic astrocyte activation leads to neurodegeneration in PD, and mitigating its damage may be another therapeutic target. COYA 302’s direct effect in reducing neuroinflammatory constituents known to drive neurodegeneration is promising and warrants clinical translation into additional preclinical models and, ultimately, into patients. The Company anticipates presenting and/or publishing these data in a peer reviewing setting. About Parkinson’s Disease Parkinson’s disease (PD) is the most common movement disorder and the second most common neurodegenerative disease, affecting approximately 1% of individuals over the age of 60. Its prevalence increases significantly with age, and as the global population continues to age, the incidence of PD is expected to rise further. The hallmark of PD is the progressive degeneration of dopaminergic neurons, particularly in the substantia nigra, a region of the brain integral to the nigrostriatal pathway, which plays a crucial role in coordinating motor control. This neuronal loss leads to the characteristic motor symptoms of PD, such as bradykinesia, rigidity, and tremors, while patients also exhibit non-motor manifestations, such as cognitive decline, mood disturbances, and sleep disorders. While the exact cause of the dopaminergic neuron loss is not fully understood, growing evidence highlights chronic neuroinflammation and immune dysfunction as central drivers of PD pathogenesis and progression. A key aspect of PD pathophysiology is neuroinflammation in the nigrostriatal pathway, including the presence of reactive astrocytes. This neuroinflammation has long been considered a downstream response to the death of dopaminergic neurons. However, increased evidence suggests that astrocytes have an initiating role in PD pathophysiology. Regulatory T cells (Tregs), a subset of T cells responsible for maintaining immune homeostasis and preventing excessive immune responses, are decreased and impaired in PD patients and preclinical models. Subsequently, chronic pro-inflammatory immune cell activation, oxidative stress, and mitochondrial dysfunction all contribute to neuronal damage. The combination of targeting the chronic, proinflammatory activation and enhancing the Treg immunosuppressive function offers promising therapeutic potential for a disease-modifying therapy that could effectively alter the course of the disease, reduce neuronal loss, and improve patient outcomes. References 1. Kouli, Torsney, and Kuanl. Chapter 1 – Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis; Parkinson’s Disease: Pathogenesis and Clinical Aspects, Codon Publications, 2018 2. Booth, Hirst, and Wade-Martins. The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis; Trends in Neuroscience , 2017 June, 40(6): 358-370 About COYA 302 COYA 302 is an investigational and proprietary biologic combination therapy with a dual immunomodulatory mechanism of action intended to enhance the anti-inflammatory function of regulatory T cells (Tregs) and suppress the inflammation produced by activated monocytes and macrophages. COYA 302 is comprised of proprietary low dose interleukin-2 (LD IL-2) and CTLA4-Ig fusion protein and is being developed for subcutaneous administration for the treatment of patients with ALS, AD, FTD, and PD. These mechanisms may have additive or synergistic effects. In February of 2023, Coya announced results from a proof-of-concept, open-label clinical study evaluating commercially available LD IL-2 and CTLA4-Ig fusion protein in a small cohort of patients with ALS conducted at the Houston Methodist Research Institute (Houston, Texas) by Stanley Appel, M.D., Jason Thonhoff, M.D., Ph.D., and David Beers, Ph.D. This study was the first-of-its-kind evaluating this dual-mechanism immunotherapy for the treatment of ALS. Patients in the study received investigational treatment for 48 consecutive weeks and were evaluated for safety and tolerability, Treg function, serum biomarkers of oxidative stress and inflammation, and clinical functioning as measured by the ALSFRS-R scale. During the 48-week treatment period, the therapy was well tolerated. The most common adverse event was mild injection-site reactions. No patient discontinued the study, and no deaths or other serious adverse events were reported. Patients’ disease progression was measured using the ALSFRS-R scale, a validated rating tool for monitoring the progression of disability in patients with ALS. The mean (±SD) ALSFRS-R scores at week 24 (33.75 ±3.3) and week 48 (32 ±7.8) after initiation of treatment were not statistically different compared to the ALSFRS-R score at baseline (33.5 ±5.9), suggesting significant amelioration in the progression of the disease over the 48-week treatment period. Treg suppressive function, expressed as percentage of inhibition of proinflammatory T cell proliferation, showed a statistically significant increase over the course of the treatment period and was significantly reduced at the end of the 8-week washout post-treatment period. Treg suppressive function at 24 weeks (79.9 ±9.6) and 48 weeks (89.5 ±4.1) were significantly higher compared to baseline (62.1 ±8.1) (p<0.01), suggesting enhanced and durable Treg suppressive function over the course of treatment. In contrast, Treg suppressive function (mean ±SD) was significantly decreased at the end of the 8-week washout period compared to end-of-treatment at week 48 (70.3 ±8.1 vs. 89.5 ±4.1, p <0.05). The study also evaluated serum biomarkers of inflammation, oxidative stress, and lipid peroxides. The available data up to 16 weeks after initiation of treatment suggest a decrease in these biomarker levels, which is consistent with the observed enhancement of Treg function. The evaluation of the full biomarker data is ongoing. COYA 302 is an investigational product not yet approved by the FDA or any other regulatory agency. 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 SOURCE: Coya Therapeutics

近期，国产自免药物正上演着一场精彩的「速度与激情」。 先是恒瑞医药、智翔金泰两款国产 IL-17A 单抗率先冲线、获得上市批准，接着恒瑞的 JAK1 抑制剂艾玛昔替尼在国内提交新适应症（用于治疗斑秃）的上市申请，康诺亚的司普奇拜单抗也在昨日获批上市，成为首个国产 IL-4Rα 靶向药物，可见国产自免药物迎来了密集收获期。 更引人注目的是，还有不少国内药企在积极布局自免领域潜力新靶点。这让人不禁遐想，国产自免药物的未来究竟还有多少令人期待的惊喜？ 迎密集收获期 国产自免药物新纪元 此前，自免领域的主流药物是以艾伯维的阿达木单抗等为代表的 TNF-α抑制剂。而今，白介素（IL）和 JAK 靶向药物成为了新一代的自免药物。 以白介素抑制剂为例，目前全球已获批上市的靶点类型，包括 IL-4R、IL-17A、IL-12/IL-23 等，而且各个细分赛道都诞生了年销售额超 10 亿美元的「重磅炸弹药物」，甚至是年销售额超百亿美元的「超级重磅炸弹」。 2023 年自免领域销售额头部产品图片来源：Insight 数据库整理 现如今，国内药企也在这一领域迎来了密集收获期。 IL-4R 药物领域的头部产品是赛诺菲/再生元的度普利尤单抗，2023 年销售额高达 115.89 亿美元，尤其 2024 年上半年销售额约 66.6 亿美元，超越阿达木单抗、强生的乌司奴单抗，成为新一代自免「药王」。 值得一提的是，国产首款 IL-4R 单抗已经诞生：康诺亚/石药集团的司普奇拜单抗（CM310）昨日获批上市，成为国产首款 IL-4R 单抗。根据非头对头研究数据显示，司普奇拜单抗治疗特应性皮炎的疗效优于度普利尤单抗。 巨大的市场蛋糕，注定了这一领域竞争激烈。根据 Insight 数据库，目前还有 8 款国产 IL-4R 单抗处于Ⅲ期临床，包括康方生物的曼多奇单抗、智翔金泰 GR1802、恒瑞医药 SHR-1819、三生国健 SSGJ-611、康乃德生物 CBP-201 等。 IL-4R 单抗国内研发进度 图片来源：Insight 数据库，统计截止 20240912 IL-17 单抗领域的头部产品是诺华的司库奇尤单抗，2023 年销售额达 49.8 亿美元。 不久前，两款国产 IL-17A 单抗相继获批上市，打破了既往外资药企垄断的局面，分别是恒瑞医药的夫那奇珠单抗、智翔金泰的赛力奇单抗，均用于治疗中重度斑块状银屑病。 此外，还有不少国产 IL-17A 单抗进入Ⅲ期临床，包括康方生物 AK111（古莫奇单抗）、君实生物 JS005、三生国健 SSGJ-608、荃信生物 QX002N、丽珠医药/鑫康合 XKH004。而且，百奥泰、石药集团和甘李药业还布局了司库奇尤单抗生物类似药，市场竞争激烈。 IL-12/IL-23 靶点的竞争同样激烈，这一领域的头部产品是强生 IL-12/23 抑制剂乌司奴单抗，2023 年销售额达 108.58 亿美元，以及艾伯维 IL-23 抑制剂瑞莎珠单抗，2023 年销售额同比增长 50.3% 至 77.63 亿美元。 不过，由于专利到期的影响，2024 年上半年乌司奴单抗的销售额仅同比微增 1.8% 至 53.36 亿美元。反过来，瑞莎珠单抗今年上半年销售额继续同比大增 46% 至 47.35 亿美元。 国内方面，也有不少药物临近商业化，其中康方生物 IL-12/23 单抗 AK101（依若奇单抗）、艾伯维 IL-23 抑制剂利生奇珠单抗均已申报上市，信达生物 IL-23p19 抗体匹康奇拜单抗（IBI112）正在递交上市申请，礼来 IL-23p19 抑制剂 mirikizumab 正在开展Ⅲ期临床。 今年 4 月，翰森制药斥资超 11 亿元引进荃信生物 IL-23p19 抑制剂 QX004N 在大中华区的权益，目前该药正在开展针对银屑病的Ⅱ期临床和针对克罗恩病的Ⅰa 期临床试验。 另外，乌司奴单抗生物类似药方面，百奥泰、华东医药/荃信生物均已申报上市，石药集团 SYSA-1902 也已处于Ⅲ期临床。 国产 JAK 抑制剂： 迪哲领跑，泽璟、恒瑞接力 除白介素抑制剂外，JAK 抑制剂也是新一代的热门自免药物。 目前，全球已有近 20 款 JAK 抑制剂获批上市，其中头部产品包括诺华/Incyte 的芦可替尼、艾伯维的乌帕替尼，2023 年销售额分别达 43 亿美元、39.7 亿美元。 2024 年上半年，乌帕替尼销售额继续同比增长 57.3% 至 25.23 亿美元，仅次于诺华的 IL-17 单抗司库奇尤单抗（28.52 亿美元），同期芦可替尼的销售额也达到 24.34 亿美元。 国内方面，JAK 抑制剂市场竞争相当激烈。据 Insight 数据库显示，截止 2024 年 9 月 12 日，已有 10 款 JAK 抑制剂在中国获批上市，4 款 JAK 抑制剂处于 NDA 阶段，另外还有 53 款 JAK 靶点的临床阶段药品，主要适应症集中于类风湿关节炎、特异性皮炎等自免疾病。 JAK 抑制剂国内研发进度 图片来源：Insight 数据库 国产 JAK 抑制剂方面，迪哲医药的戈利昔替尼进度处于第一梯队（已获批上市），已于今年 6 月获批上市，单药适用于既往至少接受过一线系统性治疗的复发或难治的外周 T 细胞淋巴瘤（r/r PTCL）成人患者。但是其适应症布局主要集中在肿瘤领域，自免相关领域适应症尚未进入临床阶段。 PTCL 在所有非霍奇金淋巴瘤中生存率最低，r/r PTCL 患者的生存预后极差，针对这一群体的既往单药治疗效果极为有限，3 年生存率仅为 23%， 中位总生存期（OS）仅 5.8 个月，并且该领域近十年没有创新药上市。 由此，戈利昔替尼成为了全球首个且唯一作用于 JAK/STAT 通路的治疗 r/r PTCL 的新药物，突破了这一领域的临床治疗瓶颈。 进度处于第二梯队（已申报上市）的国产 JAK 抑制剂，包括恒瑞医药的艾玛昔替尼（SHR0302）、泽璟制药的吉卡昔替尼（曾用名：杰克替尼）。 艾玛昔替尼是恒瑞自研的新一代高选择性 JAK1 抑制剂，对 JAK1 的选择性是对 JAK2 的 16 倍，目前已在国内递交了 4 项适应症的上市申请，包括用于强直性脊柱炎、特应性皮炎、类风湿关节炎和斑秃，其中前 3 项适应症有望于 2025 年上半年获批上市，目前在自免领域是国产 JAK 抑制剂中进展最快的。 吉卡昔替尼是一种新型 JAK 和 ACVR1 双抑制剂类药物，对 Janus 激酶包括 JAK1、JAK2、JAK3 和 TYK2 具有显著的抑制作用，目前除已提交治疗中、高危骨髓纤维化的上市申请外，针对斑秃、特应性皮炎、强直性脊柱炎、特发性肺纤维化、斑块状银屑病等适应症均已处于 II 期临床及以上阶段。 此外，国内其他在研的 JAK 抑制剂，还包括信达生物的伊他替尼（Itacitinib）、先声药业/凌科药业的 LNK01001、科伦药业 KL130008 等。 潜力新靶点层出不穷 自免药物研发的故事还未结束。 从 TNF-α逐渐被白介素、JAK 替代，自免药物靶点呈现出明显的代际更迭。如今，自免领域还在不断冒出潜力新靶点，吸引了跨国制药巨头和国内药企的目光。 这几年，MNC 巨头频繁布局炎症性肠病（IBD）等存在巨大未满足需求的自免疾病。 IBD 终生可复发，被称为「不死的癌症」，主要包括溃疡性结肠炎（UC）和克罗恩病（CD）两种类型，目前尚无根治 IBD 的方法，且患者人数庞大。据流行病学数据显示，目前全球约有 600-800 万 IBD 患者，主要集中在欧美地区。 目前，MNC 巨头在 IBD 领域的布局方向主要集中在 TL1A 和整合素 α4β7。 例如，默沙东豪掷 108 亿美元收购 Prometheus Biosciences，拿下了治疗 UC 的 TL1A 单抗 PRA023；罗氏斥资 72.5 亿美元收购 Telavant，获得了治疗 IBD 的潜在首创新型 TL1A 抗体 RVT-3101。 尤其是 α4β7 靶点已诞生了大药，武田制药的 α4β7 整合素抑制剂 Entyvio（维得利珠单抗）2023 年销售额超过 50 亿美元，而且在针对 UC 的头对头试验中击败了阿达木单抗。 基于此，礼来进行了频繁布局，先是以 24 亿美元收购 Dice Therapeutics，获得口服α4β7 项目和 IL-17 小分子抑制剂，后又斥资 32 亿美元收购 Morphic Therapeutics，拿下口服α4β7 整合素小分子抑制剂 MORF-057。 尽管当前国内药企鲜有布局 IBD 领域，但管线也深受 MNC 巨头青睐。今年 6 月，「自免一哥」艾伯维斥资超 17 亿美元引进了明济生物的临床前 TL1A 单抗 FG-M701，其中首付款达 1.5 亿美元，足见这类药物的市场潜力。 全球 IBD 领域在研的热门靶点 图片来源：Insight 数据库 除 TL1A、α4β7 外，其他自免类药物靶点也层出不穷，并已验证了成药性，包括靶向 CD80/CD86 的阿巴西普，靶向 PDE-4 的阿普米司特、罗氟司特、克立硼罗，靶向 BAFF 的贝利尤单抗、泰它西普（BAFF/APRIL）等。 目前，也有一些国内药企布局这类管线，其中济川药业引进恒翼生物的 PDE-4 抑制剂 HPP737。以及海南海灵的 PDE-4 抑制剂 Hemay005，均已处于 III 期临床。 另外，荣昌生物的泰它西普是全球首款、同类首创 BLyS/APRIL 双靶点新型重组 TACI-Fc 融合蛋白新药，可「双管齐下」阻止 B 细胞的异常分化和成熟，从而治疗自免疾病，目前已获批治疗系统性红斑狼疮、类风湿关节炎，针对重症肌无力、原发性干燥综合症、免疫球蛋白 A 肾病（IgAN）和视神经脊髓炎频谱系疾病均已处于 III 期临床。 结语 国产自免药物的密集收获仅是序幕，商业化大战才是检验成果的试金石。在各个细分赛道上，国内药企需面对外资巨头的强劲挑战，以及国内同行的激烈竞争。 与此同时，潜力新靶点的不断涌现，也为国产自免药物的崛起提供了无限可能，未来或许还有更多惊喜等待揭晓。 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！