VG-3927

▎药明康德内容团队编辑 本期看点 1. 治疗天使综合征（Angelman syndrome，AS）的在研反义寡核苷酸（ASO）疗法ION582在一项早期临床试验中使高达97%接受中、高剂量患者的整体AS症状获得缓解。 2. 希望之城（City of Hope）开发的用于治疗转移性去势抵抗性前列腺癌（mCRPC）的嵌合抗原受体（CAR）T细胞疗法在1期临床试验中使1例患者的前列腺特异性抗原（PSA）水平下降＞90%。 3. 多款治疗阿尔茨海默病的创新疗法获积极早期结果。 药明康德内容团队整理 ION582：布1/2a期临床试验数据 Ionis Pharmaceuticals公司宣布，其在研ASO疗法ION582治疗天使综合征的1/2a期研究HALOS已完成多次剂量递增（MAD）部分，并取得积极成果。ION582是一款通过脊椎穿刺鞘内给药的在研ASO疗法，旨在抑制UBE3A反义转录本（UBE3A-ATS）的表达，并激活来自父体的UBE3A等位基因以增加患者大脑中UBE3A蛋白的产生，为天使综合征的潜在疗法。临床前研究显示，ION582能够显著增加动物的学习和记忆功能，以及其大脑中UBE3A蛋白的表达。美国FDA在2022年授予ION582孤儿药资格和罕见儿科疾病资格。 ▲在HALOS试验中，绝大部分患者在各个临床指标中皆获得改善（图片来源：参考资料[2]） 此次公布的结果显示，ION582持续改善了患者的沟通、认知和运动功能，高达97%接受中、高剂量患者的整体AS症状获得缓解。根据此积极结果，Ionis计划与监管单位进行讨论，并于2025年上半年启动关键3期研究。 PSCA-CAR-T Cells：公布1期临床试验数据 《自然-医学》（Nature Medicine）杂志发表了一项由希望之城开展的单中心1期临床试验的积极结果。该研究旨在评估前列腺干细胞抗原（PSCA）靶向CAR-T细胞疗法治疗转移性去势抵抗性前列腺癌的效果。该细胞疗法是在希望之城的GMP工厂制造的，只提供给参加试验的患者。 此次公布的结果显示，该CAR-T细胞扩增和持续至输注后28天，3个剂量队列分别有1例、3例和3例患者的PSA水平下降，14例患者中有4例患者的PSA降幅＞30%。其中，队列2中有1例患者在输注CAR-T细胞后的首个28天内，PSA降幅＞90%。三个队列的疾病控制率分别为0%、67%和60%，6个月生存率分别为33%、67%和40%。该临床研究结果表明PSCA-CAR-T细胞疗法治疗mCRPC是安全的，有望成为mCRPC患者治疗新选择。 PMN310：公布1a期临床试验数据 ProMIS Neurosciences公司宣布，其用于治疗阿尔茨海默病的新型单克隆抗体PMN310在健康受试者中进行的1a期临床试验的前四个队列均获得了积极结果。PMN310能够高选择性地靶向被认为是阿尔茨海默病主要驱动因素的β淀粉样蛋白（Aβ）寡聚体。在临床前研究中，PMN310与其他靶向Aβ的抗体相比，对Aβ寡聚体表现出更强大的体外靶向作用。此外，PMN310未观察到与斑块的结合，可能会降低使用斑块结合抗体引起的淀粉样蛋白相关成像异常（ARIA）的风险。这些数据支持该疗法具有潜在的差异化临床特征。 该初步研究的结果表明，在健康受试者中，四种递增剂量水平的PMN310的安全性和耐受性良好，患者脑脊液中的PMN310抗体水平与剂量有关，这表明该抗体有可能成为阿尔茨海默病患者的靶向药物。 VG-3927：公布1期临床试验的中期数据 Vigil Neuroscience公司公布了其阿尔茨海默病疗法VG-3927在健康受试者中进行的1期临床试验的中期数据。VG-3927是一种新型小分子TREM2激动剂，用于治疗与小胶质细胞功能障碍相关的常见神经退行性疾病，最初主要针对阿尔茨海默病患者，包括一些携带TREM2和其他疾病相关突变体的患者。 此次公布的结果显示，VG-3927的安全性、耐受性、药代动力学和药效学特征支持将其作为治疗阿尔茨海默病的潜在每日一次口服疗法继续进行开发。此外，VG-3927能显著降低患者脑脊液中的可溶性TREM2，证明其具有临床靶向性。VG-3927重复给药后，骨桥蛋白/分泌磷蛋白1（SPP1）增加，这是一种与神经保护性小胶质细胞相关的生物标志物。该公司计划在2025年第一季度报告完整的1期临床数据。 NEO212：1期临床试验开始招募第三个队列的患者 NeOnc Technologies公司宣布，其用于治疗原发性和继发性恶性脑肿瘤的新型混合药物NEO212的1期临床试验已开始招募第三个队列的患者。NEO212是该公司的主要候选药物NEO100和替莫唑胺（TMZ）的生物偶联物。相比于将NEO100和TMZ简单混合，共价键合的NEO212有望提供更有效的脑癌治疗。临床前动物研究表明，与TMZ相比，NEO212的毒性可能较小，有望以三倍的效率穿透血脑屏障，并发挥十倍的效力。  ▲NEO212的分子式（图片来源：参考资料[9]） OST-HER2：公布1期临床试验数据 OS Therapies公司宣布，其生物治疗候选药物OST-HER2在HER2表达实体瘤（乳腺癌和其他癌症）患者中的1期临床试验数据良好。OST-HER2是一种以单核细胞增生李斯特氏菌（Listeria monocytogenes，Lm）为载体的现货型免疫治疗疫苗，旨在预防骨肉瘤和其他实体瘤患者的转移、延缓复发并提高总生存率。 OST-HER2的作用机制是通过激活抗原呈递细胞生成靶向HER2的特异性T细胞，这些T细胞增殖后定位、渗透并直接攻击肿瘤病灶，杀死肿瘤细胞并暴露出更多抗原。随后，免疫系统会根据新抗原生成更多的T细胞。该机制通过循环产生和激活T细胞，以持续延长抗肿瘤效果。此次公布的数据显示，OST-HER2在表达HER2的实体瘤患者中是安全的，并且耐受性良好。 Lomab-ACT：IND申请获得FDA许可 Actinium Pharmaceuticals公司宣布，FDA批准了其用于镰状细胞病患者在骨髓移植（BMT）前进行靶向调理的候选疗法Iomab-ACT的IND申请。这项试验旨在评估Iomab-ACT在接受同种异体BMT的镰状细胞病患者中的安全性。Lomab-ACT是一种靶向CD45的抗体偶联放射物（ARC），旨在取代目前在细胞和基因疗法之前用于调理患者的非靶向化疗和全身放射治疗，从而使镰状细胞病患者能够更广泛地获得有望治愈疾病的同种异体BMT或基因治疗。 NKX019：启动1期临床试验 Nkarta公司宣布，哥伦比亚大学Irving医学中心（CUIMC）的研究人员已经启动了一项由研究者发起的试验，旨在评估Nkarta的同种异体CD19靶向CAR自然杀伤（NK）细胞疗法NKX019在系统性红斑狼疮患者中的应用。NKX019是一种异体、低温保存、现货型候选免疫疗法，它使用从健康成人供体外周血中提取的NK细胞。NKX019采用人源化的CD19靶向CAR进行设计，增强了细胞的靶向性，并采用专有的膜结合型白细胞介素-15（IL-15），在没有外源细胞因子支持的情况下提高了持久性和活性。 Allocetra：启动1期临床试验 Enlivex Therapeutics公司宣布，以色列卫生部已批准启动一项1期临床试验，旨在评估Allocetra治疗银屑病关节炎患者的安全性和耐受性。败血症、骨关节炎、银屑病关节炎等疾病会使巨噬细胞失去平衡状态。这些非稳态巨噬细胞在很大程度上导致了相应疾病的严重性。Allocetra是一种通用、现货型细胞疗法，通过对巨噬细胞进行重编程，旨在恢复其稳态（homeostasis），进而治疗疾病。Allocetra提供创新的免疫调节机制，具潜力作为单药或组合疗法治疗这些具未竟医疗需求的疾病。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料（可上下滑动查看） [1] Ionis announces positive detailed results from the HALOS Study of ION582 in people with Angelman syndrome. Retrieved July 22, 2024 from https://ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-detailed-results-halos-study-ion582 [2] Angelman Syndrome Webcast. Retrieved July 22, 2024 from https://ir.ionis.com/static-files/3be48746-13cb-473c-8c43-18fa0717c2c0 [3] NKARTA ANNOUNCES INITIATION OF INVESTIGATOR-SPONSORED CLINICAL TRIAL EVALUATING NKX019 FOR SYSTEMIC LUPUS ERYTHEMATOSUS. Retrieved July 24, 2024 from https://ir.nkartatx.com/news-releases/news-release-details/nkarta-announces-initiation-investigator-sponsored-clinical [4] Dorff TB, Blanchard MS, Adkins LN, Luebbert L, Leggett N, Shishido SN, Macias A, Del Real MM, Dhapola G, Egelston C, Murad JP, Rosa R, Paul J, Chaudhry A, Martirosyan H, Gerdts E, Wagner JR, Stiller T, Tilakawardane D, Pal S, Martinez C, Reiter RE, Budde LE, D'Apuzzo M, Kuhn P, Pachter L, Forman SJ, Priceman SJ. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2024 Jun;30(6):1636-1644. doi: 10.1038/s41591-024-02979-8. Epub 2024 Jun 12. PMID: 38867077; PMCID: PMC11186768. [5] Enlivex Receives Regulatory Authorization For The Initiation Of A Phase I Clinical Trial To Evaluate Allocetra In Patients With Psoriatic Arthritis. Retrieved July 24, 2024 from https://www.globenewswire.com/news-release/2024/07/23/2917164/0/en/Enlivex-Receives-Regulatory-Authorization-For-The-Initiation-Of-A-Phase-I-Clinical-Trial-To-Evaluate-Allocetra-In-Patients-With-Psoriatic-Arthritis.html [6] OS Therapies Announces Positive Safety Data from Phase 1 Clinical Trial of OST-HER2 in HER2-Expressing Breast Cancer and in Preclinical Efficacy in Models of Breast Cancer. Retrieved July 24, 2024 from https://www.businesswire.com/news/home/20240724194701/en [7] Vigil Neuroscience Announces Interim Data from its Ongoing Phase 1 Clinical Trial Evaluating VG-3927 in Healthy Volunteers Supporting Continued Development in Alzheimer’s Disease. Retrieved July 24, 2024 from https://www.globenewswire.com/news-release/2024/07/24/2917876/0/en/Vigil-Neuroscience-Announces-Interim-Data-from-its-Ongoing-Phase-1-Clinical-Trial-Evaluating-VG-3927-in-Healthy-Volunteers-Supporting-Continued-Development-in-Alzheimer-s-Disease.html [8] Actinium Announces FDA Clearance of Iomab-ACT Targeted Conditioning IND Application for Sickle Cell Disease Patients Undergoing Bone Marrow Transplant in Collaboration with Columbia University. Retrieved July 25, 2024 from https://www.prnewswire.com/news-releases/actinium-announces-fda-clearance-of-iomab-act-targeted-conditioning-ind-application-for-sickle-cell-disease-patients-undergoing-bone-marrow-transplant-in-collaboration-with-columbia-university-302206540.html [9] NeOnc Initiates Cohort 3 in Phase 1 Clinical Trial of NEO212™, a Patented Novel Hybrid Drug Designed to Deliver ‘Double Punch’ Against Malignant Brain Tumors. Retrieved July 25, 2024 from https://www.globenewswire.com/news-release/2024/07/24/2918220/0/en/NeOnc-Initiates-Cohort-3-in-Phase-1-Clinical-Trial-of-NEO212-a-Patented-Novel-Hybrid-Drug-Designed-to-Deliver-Double-Punch-Against-Malignant-Brain-Tumors.html [10] ProMIS Neurosciences Reports Positive Top-Line Data from its Phase 1a Alzheimer's Trial. Retrieved July 25, 2024 from https://www.globenewswire.com/news-release/2024/07/26/2919566/0/en/ProMIS-Neurosciences-Reports-Positive-Top-Line-Data-from-its-Phase-1a-Alzheimer-s-Trial.html [11] OCUGEN, INC. ANNOUNCES COMPLETION OF DOSING IN SUBJECTS WITH GEOGRAPHIC ATROPHY SECONDARY TO DAMD IN HIGH-DOSE COHORT OF PHASE 1/2 ARMADA CLINICAL TRIAL OF OCU410—A NOVEL MODIFIER GENE THERAPY. Retrieved July 25, 2024 from https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-completion-dosing-subjects-geographic [12] Zymeworks Announces FDA Clearance of Investigational New Drug Application for ZW191, a Novel Folate Receptor-⍺ Targeted Topoisomerase I Inhibitor Antibody-Drug Conjugate. Retrieved July 25, 2024 from https://www.globenewswire.com/news-release/2024/07/22/2916373/0/en/Zymeworks-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-ZW191-a-Novel-Folate-Receptor-Targeted-Topoisomerase-I-Inhibitor-Antibody-Drug-Conjugate.html [13] INIMMUNE ANNOUNCES FIRST CANCER PATIENT DOSED IN PHASE 1 CLINICAL STUDY USING THE IMMUNOTHERAPEUTIC INI-4001, A NOVEL TLR7/8 AGONIST. Retrieved July 25, 2024 from https://www.prnewswire.com/news-releases/inimmune-announces-first-cancer-patient-dosed-in-phase-1-clinical-study-using-the-immunotherapeutic-ini-4001-a-novel-tlr78-agonist-302204890.html [14] Cytoki Pharma Announces Positive Phase 1 Data Showing Potential of CK-0045 to Improve Cardiometabolic Risk Factors. Retrieved July 25, 2024 from https://www.prnewswire.com/news-releases/cytoki-pharma-announces-positive-phase-1-data-showing-potential-of-ck-0045-to-improve-cardiometabolic-risk-factors-302201481.html [15] Sonnet BioTherapeutics Reports Encouraging Data from Phase 1b/2a Clinical Trial of SON-080 in Chemotherapy-Induced Peripheral Neuropathy (CIPN) That Support Advancement into Phase 2 Study. Retrieved July 25, 2024 from https://www.globenewswire.com/news-release/2024/07/24/2917996/0/en/Sonnet-BioTherapeutics-Reports-Encouraging-Data-from-Phase-1b-2a-Clinical-Trial-of-SON-080-in-Chemotherapy-Induced-Peripheral-Neuropathy-CIPN-That-Support-Advancement-into-Phase-2-.html [16] Kaerus Bioscience Announces Initiation of Phase 1 Clinical Trial for its Novel BK Channel Modulator KER-0193 being developed for Fragile X Syndrome. Retrieved July 25, 2024 from https://www.globenewswire.com/news-release/2024/07/25/2918613/0/en/Kaerus-Bioscience-Announces-Initiation-of-Phase-1-Clinical-Trial-for-its-Novel-BK-Channel-Modulator-KER-0193-being-developed-for-Fragile-X-Syndrome.html 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Sanofi gained an exclusive option on Vigil Neuroscience’s small-molecule TREM2 agonist programme for Alzheimer’s disease after making a $40-million investment in the biotech firm. “We view Sanofi’s investment in Vigil as a validation of our promising precision medicine approach,” remarked Vigil CEO Ivana Magovčević-Liebisch.Vigil’s lead TREM2 agonist, dubbed VG-3927, is currently being evaluated in a Phase I study, with interim data expected in mid-2024. “Recent discoveries have highlighted the role of microglial signalling and neuroinflammation in neurodegenerative diseases. TREM2 is a well credentialed microglia target in this context,” noted Erik Wallstroem, Sanofi's global head of neurology development.In connection with the equity investment – priced at $7.44 per share – Sanofi gained the exclusive right of first negotiation for a licence, grant or transfer of rights to research, develop, manufacture and commercialise Vigil’s small-molecule TREM2 agonist program, including VG-3927. Vigil indicated on Thursday that the proceeds will be used to fund its R&D activities, extending its cash runway into 2026. The biotech’s lead programme is luzanebart, a fully-human monoclonal antibody agonist targeting TREM2, which is currently in Phase II development for people with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.Vigil’s shares jumped more than 30% on the news.