COYA-301

iStock, Nuthawut Somsuk Despite the definitive failure of Novo Nordisk’s semaglutide in Alzheimer’s, biotech executives, analysts and other industry experts see potential in more testing of GLP-1s for the neurodegenerative disease, particularly in a combination approach. The failure of Novo Nordisk’s GLP-1 semaglutide in treating Alzheimer’s disease was pretty definitive. But the blockbuster obesity drug did affect the biomarkers underlying the devastating neurodegenerative disease and experts say it’s just a matter of finding the right combination of therapies to push that into a clinically effective regimen. Coya Therapeutics CEO Arun Swaminathan, for one, did not see a complete failure in the Phase III results from the EVOKE program. The executive was heartened by the 10% improvement on key markers of Alzheimer’s and thinks that result could easily be boosted into the therapeutic range with a drug like COYA-301. “Coya has always predicted that alone, [GLP-1s] won’t work,” Swaminathan told BioSpace . “That’s been our whole hypothesis, is that you got to combine it with something else.” Swaminathan is not alone in that view. BMO Capital Markets analysts, who dubbed the semaglutide trial “clearly disappointing,” were open to the possibility of more testing. “GLP-1 treatment for Alzheimer’s remains an interesting pursuit with positive biomarkers from EVOKE/EVOKE+ potentially providing more potential for clinical benefit in the long term,” BMO wrote in reaction to the November readout . “Results clearly represent a step back in what could have been a breakthrough for the field, but future study may still be necessary to further understand how results may differ with presymptomatic treatment over a longer time horizon.” Alzheimer’s disease Biogen’s Leqembi Rises After Novo GLP-1 Fails in Alzheimer’s Analysts agree that the failure of Novo Nordisk’s semaglutide to reduce Alzheimer’s disease progression removes a “modest” or “perceived” overhang on Biogen and the anti-amyloid antibody class in general, clearing the way for increased uptake of Leqembi and Eli Lilly’s Kisunla. November 24, 2025 · 3 min read · Heather McKenzie It’s unclear if Novo will be the one to do that work. The company discontinued an extension of the Phase III EVOKE program. After antibodies like Leqembi and Kisunla finally broke through in Alzheimer’s, gaining approval as disease-modifying options, experts like Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, began to turn to the idea of combination approaches, much like in cancer care. These agents “are only about 30%, 35% at most [effective] at slowing the course of the disease,” Fillit told BioSpace in December. “It’s clear we need other pathways and other drugs to get to a much higher rate of efficacy with the equivalent or better safety pro a setting of precision medicine with the right biomarkers and combination therapy.” Could GLP-1s do the trick? Swaminathan would be happy to offer Coya’s services for testing a combination approach. COYA-301 is a low-dose IL-2 agent that promotes the survival of Tregs to reduce inflammation. Coya is developing the agent alone for Alzheimer’s and in combination as COYA-302, which adds a CTLA-4 immunoglobulin to boost the function of regulatory T cells. COYA-302 is currently being tested in a Phase II trial for amyotrophic lateral sclerosis, but Coya is aiming to expand clinical testing into Alzheimer’s, frontotemporal dementia and Parkinson’s disease. ALS Coya Exec Daniel Barvin Is on a Mission To End Genetic ALS and FTD The BioSpace 40 Under 40 winner opens up about his very personal career transformation from wealth management to biotech—and what it’s like to develop a drug for amyotrophic lateral sclerosis and frontotemporal dementia as a potential patient himself. October 27, 2025 · 5 min read · Heather McKenzie If a GLP-1 can spur a 10% improvement in Alzheimer’s biomarkers, such as indicators of inflammation in the brain, Swaminathan reasons that adding another drug on top of that could move the needle into a therapeutic and clinically beneficial range. “That magical number that people have in their head is 20% to 25% movement in these markers can translate to a clinical outcome,” he said. Coya will need a partner to test the theory, preferably one with a GLP-1 in its portfolio. This could be done in smaller clinical trials. “I would not write off GLP-1,” Swaminathan concluded. From Theory to Fact The Alzheimer’s space has seen a lot of failures. The Coya CEO pointed to recent hits to the tau theory in Alzheimer’s, such as Johnson & Johnson’s posdinemab not slowing the decline of the disease in a Phase II study. This kind of activity is simply a reminder of how tough developing drugs for the disease is, BMO said in a Nov. 24 note. And for Swaminathan, every step—positive or negative—adds to a greater understanding of the disease. “They’re all actually, in a way, advancing science in a fantastic way that I think we’re going to start seeing breakthroughs come,” he said. In particular, neuroscience in general is beginning to zero in on inflammation as a driver of these difficult degenerative diseases. Patients in the EVOKE trials experienced improvements in plasma high sensitivity C-reactive protein (hs-CRP), a key marker of inflammation, according to a detailed presentation by Novo at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in November. “My personal view is that inflammation is a very important target in this illness, both systemic and neuroinflammation,” Fillit said. Swaminathan noted that while Fillit and others have been saying this for decades, now the biopharma world—and the clinical data—is catching on in a meaningful way. “You’re seeing a consistent pattern that addressing inflammation is the way to maybe address neurodegenerative diseases,” he said. “I think more and more companies are going to start pivoting towards that and away from just focusing on plaque removal.” Indeed, according to Fillit, there are over 30 other active clinical trials in Alzheimer’s with anti-inflammatory targets—including those being run by Coya and Therini Bio, both of which ADDF has invested in. The pivot to inflammation was also backed up by the 2025 Nobel Prize award in physiology or medicine for Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi, who discovered peripheral immune tolerance and its role in preventing the immune system from harming the body. The October award helped turn 2025 into “a spotlight year for the inflammation hypothesis around neurodegeneration,” Swaminathan said. “I really don’t think it’s even a hypothesis anymore,” he continued. “It has been proven that that is the trigger.” For now, Coya is moving ahead with its programs and searching for partners. Swaminathan will be keeping an eye out for the release of full data from the EVOKE trials to glean more learnings into GLP-1’s potential role in Alzheimer’s. “That,” he said, “will give us a lot of insights on how potentially we could move forward with this combination.” Editor’s note: Heather McKenzie contributed reporting to this story.

编者按 近日， 北京大学人民医院风湿免疫科张霞、何菁、栗占国教授团队 在期刊 《Annals of the Rheumatic Diseases》 （影响因子20.6）发表重要研究成果。作为首个Ld-IL2治疗难治性复发性多软骨炎（RP）患者的临床研究，在纳入10例难治性RP患者的临床试验中， 经12周Ld-IL2治疗后，66.7%的患者实现完全缓解，75%的患者成功减量激素。免疫学反应结果显示，治疗期间调节性T细胞（Treg）及Treg/Tcon比值显著升高。 同时，在治疗过程中，未见感染事件发生。 研究背景 复发性多软骨炎（RP）以软骨反复炎症和破坏为特征，作为一种罕见的、可导致软骨破坏和变形的全身性疾病，其治疗方案有限且充满挑战 [1,2] 。调节性T细胞（Treg）稳态紊乱被认为在RP的发病机制中起关键作用 [3] 。低剂量白细胞介素-2（IL-2）可选择性恢复Treg失衡，选择性修复调节性T细胞（Treg）与常规T细胞的功能紊乱，在多种自身免疫性疾病中显示出治疗潜力 [4] 。 在这一背景下， 北京大学人民医院风湿免疫科张霞、何菁、栗占国教授团队 开展了首个探讨Ld-IL2治疗RP患者疗效与安全性的临床研究，取得了令人鼓舞的证据。研究证明，Ld-IL2在治疗RP方面具有显著疗效，本文对研究要点内容进行整理，以飨读者。 研究设计与方法 研究共纳入10例复发性多软骨炎（RP）患者，所有患者均接受为期12周的低剂量白细胞介素-2（Ld-IL2）治疗，最初4周予以持续的皮下注射Ld-IL2治疗（100万IU/d，每周连续给药5天），随后间隔1周注射，直至第12周研究结束。同期治疗包括至少4周稳定的糖皮质激素（剂量。 患者招募标准为符合Michet诊断标准且对常规糖皮质激素、免疫抑制剂或生物制剂治疗反应不佳的RP患者。其中难治性RP定义为既往治疗12周后疾病控制不佳或因任何原因无法耐受治疗。 疗效采用复发性多软骨炎疾病活动指数（RPDAI）进行评估。每4周评估临床及实验室数据，采用SPSS 22.0版进行数据分析，P值通过Wilcoxon符号秩检验计算，双侧P 主要研究结果 10例难治性RP患者共9例患者完成12周Ld-IL2治疗周期，均为女性患者，中位年龄39岁（范围：30-62岁）中位病程2年（范围：0.5-4年）。 基线特征 10例难治性RP患者均为女性，年龄30至62岁、病程0.5至4年；其中7例存在耳/鼻软骨炎受累，2例伴有关节炎受累，1例合并右侧病毒性视网膜炎，3例有肺部病变（含1例喉狭窄、声嘶）。既往治疗多涉及糖皮质激素、甲氨蝶呤等传统免疫抑制剂，部分患者用过生物制剂；当前多合并使用免疫抑制剂，泼尼松日剂量0至25mg不等，复发性多软骨炎疾病活动指数（RPDAI）中位数9分（范围1-23），呈现出个体病情与治疗方案的差异性。患者基线时纳入研究的临床特征见表1。 表1 基线时纳入研究的RP患者的临床特征 注：CsA,环孢素A;CYC,环磷酰胺；FK506，他克莫司（tacrolimus） ；GC,糖皮质激素；IS,免疫抑制剂；JAKi,Janus激酶抑制剂；LEF,来氟米特；MMF,麦考酚酯；MTX, 甲氨喋呤； pred, 泼尼松； RP, 复发性多软骨炎； RPDAl, 复发性多软骨炎疾病活动指数； TNFi, 肿瘤坏死因子抑制剂。如果先前进行的治疗在12周内未能有效控制疾病发展，或者由于任何原因患者无法耐受，则这些治疗将被视为失败。 a.若既往治疗持续 12 周仍未实现充分的疾病控制，或患者因任何原因无法耐受，则视为治疗失败。 b.伴喉狭窄及声音嘶哑。 c.伴右眼病毒性视网膜炎。 疗效 经12周治疗后， RPDAI评分显著降低，尤其在耳鼻软骨炎改善及糖皮质激素减量方面表现突出 ，表明Ld-IL2在治疗RP方面具有显著疗效。 至第12周，9名患者 RPDAI从基线中位数9分（范围：9-23分）显著降至第12周0分（范围：0-14分）（P=0.011）（图1） ，其中6名患者（66.7%）在第12周达到完全RPDAI反应（RPDAI=0）。8例接受泼尼松治疗的患者中，有6例（75%）在基线剂量15mg（范围10-22.5mg）基础上实现≥25%的剂量减量。 图1 患者复发性多软骨炎疾病活动指数(RPDAI)评分。从基线至第12周显著下降。红色圆圈标记仅患耳部或鼻部软骨炎的患者，蓝色圆圈标记存在其他表现的患者 至于患者器官受累情况，7例患者耳软骨炎在Ld-IL2治疗4周后改善，最终实现完全缓解（图2）。此外，4例气管支气管受累患者亦有不同程度的症状缓解与改善（图3）。 图2 患者10号经Ld-IL2治疗4周后耳软骨炎改善的代表性照片 图3 患者4号经Ld-IL2治疗12周后气管壁环状增厚改善的代表性照片 免疫学机制探索 治疗期间 调节性T细胞（Treg）及Treg/Tcon（常规T细胞，定义为CD4 + CD25 lo CD127 + 细胞）比值显著升高 。免疫学反应结果显示，CD4+T细胞中CD4 + CD25 hi CD127 lo Foxp3 + 调节性T细胞的绝对计数和比例显著增加（P3 + Treg/Tcon比例上升（图4 A-C）。 图4 (A-C) 接受Ld-IL2治疗后，RP患者外周血中CD4+T细胞内Foxp3 ⁺ 调节性T细胞比例变化。 （A）Foxp3⁺调节性T细胞绝对计数（B）及基于绝对计数的Foxp3 ⁺ 调节性T细胞/常规T细胞比值（C）常规T细胞（Tcon）定义为CD4 + CD25 lo CD127 + 细胞。流式细胞术数据以中位数（四分位间距）表示。*P ；**P ；与第0周相比 治疗安全性分析 研究结果表明Ld-IL2对RP具有疗效且安全可靠。其中最常见的不良事件是注射部位反应，无需干预。在Ld-IL2治疗期间，并 未看到因IL-2而额外增加感染负担 。并且在合并气管支气管软骨炎或狭窄的高风险RP患者中亦未出现感染。 研究总结与展望 作为针对Ld-IL2治疗RP患者的首次探索性研究，研究为RP患者呈现了靶向性免疫治疗新方法。虽然研究仍需更大规模的研究来进一步验证，但是研究阐明了Ld-IL2在RP中发挥作用的精确免疫调节机制，有望揭示新的治疗靶点和策略，对于目前可选疗法有限的RP患者具有重要的临床意义。 大咖点评 低剂量IL-2治疗难治性RP的这项初步研究，为这一临床处理棘手的疾病提供了新的免疫调节思路与有希望的治疗选择。 Ld-IL-2是一种通过精准调节免疫平衡（重塑Treg细胞）来治疗RP的有效且安全的策略 ，并有望成为一类“Treg缺陷型”自身免疫病的通用疗法。 研究不仅证实了 Ld-IL-2可快速、显著降低RPDAI评分，使多数患者实现完全缓解 ，更关键的是，它在有效控制耳鼻软骨炎等典型症状的同时，成功助力大部分合并器官受累患者实现糖皮质激素减量，直击临床治疗痛点。此外， 免疫学上观察到的Treg细胞数量与功能同步恢复 ，为临床疗效提供了坚实的机制佐证。 在合并气管支气管受累、本易发生呼吸道感染的患者群体中， 治疗期间未报告任何感染事件 ，这一发现至关重要。它初步提示Ld-IL-2在精准调节免疫平衡、恢复Treg功能的同时，可能不会损害甚至有利于维持机体的抗感染防御，为将其用于高风险RP患者提供了重要的安全性依据。 研究强化了“Treg稳态失衡”是RP关键发病机制的观点。那些炎症活跃但结构性损伤尚轻、且存在Treg功能潜在恢复可能的患者，最有可能从Ld-IL-2治疗中获益。这为未来精准筛选治疗优势人群提供了重要的临床与免疫学线索。 本研究作为该领域的开创性探索，有力地证明了Ld-IL-2在难治性RP治疗中的有效性与安全性，结果令人鼓舞，为RP的治疗开启了靶向性免疫精准调节的新篇章。在以往的研究中，低剂量IL-2疗法亦能够增强CD8+T细胞的病毒控制能力，选择性恢复Treg失衡,选择性恢复调节性T细胞（Treg）和常规T细胞的紊乱，导致诱导系统性红斑狼疮患者（SLE）缓解 [5,6] 。这可能表明了Ld-IL-2疗法在这一类自身免疫性疾病的治疗潜力。期待未来通过更广泛的研究、更深刻的探索来验证这些发现，从而推动该治疗策略早日惠及更多患者。 作者简介 - 张霞 副教授 - 北京大学人民医院 北京大学人民医院风湿免疫科 副主任医师、副教授、硕士生导师 中国老年医学会风湿免疫学分会委员 获中国免疫学会青年学者奖、北京大学优秀青年医师奖、北京大学人民医院学术新星奖 主持国家自然科学基金2项 成果在《NATURE MEDICINE》、《ARD》等杂志上发表 作者简介 - 何菁 教授 - 北京大学人民医院 北京大学人民医院风湿免疫科 主任，教授，主任医师，博士生导师 国家中青年科技创新领军人才、国家万人 获茅以升青年科技奖 北京免疫学会副理事长 中华医学会风湿病学分会青年委员 《Immunology》副主编，《Clinical Rheumatology》副主编 长期致力于系统性红斑狼疮、干燥综合征等自身免疫病研究。以第一/通讯作者在Nature Medicine、Immunity、Lancet Rheum，JAMA Netw open和Ann Rheum Dis发表SCI论文80余篇 作者简介 - 栗占国 教授 - 北京大学人民医院 教授，主任医师，博士生导师 北京大学人民医院临床免疫中心主任 风湿免疫研究所所长 北京大学首钢医院专家院长 中国免疫学会自身免疫分会主任委员·中国医促会风湿免疫分会主任委员 973首席科学家 国家杰出青年基金获得者亚太风湿病联盟(APLAR)前主席《中华风湿病学杂志》名誉总编《RHEUMATOLOGY&AUTOIMMUNITY》主编 审核专家：张霞副教授,栗占国教授 参考文献： [1]Zhang, Xia et al.Low-dose interleukin-2 in the treatment of refractory relapsing polychondritis. Annals of the Rheumatic Diseases, Received May 9, 2025; Accepted October 5, 2025; Published online October 30, 2025. [2] De Montmollin N, Dusser D, Lorut C, Dion J, Costedoat-Chalumeau N, Mouthon L, et al Tracheobronchial involvement of relapsing polychondritis. Autoimmun Rev 2019;18(9):102353. doi: 10.1016/j.autrev.2019.102353. [3] Hu FY, Wang J, Zhang SX, Su R, Yan N, Gao C, et al. Absolute reduction of peripheral regulatory T cell in patients with relapsing polychondritis. Clin Exp Rheumatol 2021;39(3):487–93. doi: 10.55563/clinexprheumatol/qndtvt. [4] Kolios AGA, Tsokos GC, Klatzmann D. Interleukin-2 and regulatory T cells in rheumatic diseases. Nat Rev Rheumatol. 2021;17(12):749-66. [5] Zhou P, Chen J, He J, et al. Low-dose IL-2 therapy invigorates CD8+ T cells for viral control in systemic lupus erythematosus. PLOSPathog.2021;17(10):e1009858. [6]Zhang, X., Feng, R., Shao, M. et al. Low-Dose Interleukin-2 as an Alternative Therapy for Refractory Lupus Nephritis. Rheumatol Ther 8, 1905–1914 (2021). 医脉通是专业的在线医生平台，“感知世界医学脉搏，助力中国临床决策”是平台的使命。医脉通旗下拥有「临床指南」「用药参考」「医学文献王」「医知源」「e研通」「e脉播」等系列产品，全面满足医学工作者临床决策、获取新知及提升科研效率等方面的需求。