CM-383

▎药明康德内容团队报道 随着全球人口老龄化的加速，阿尔茨海默病（Alzheimer's Disease, AD）这一神经退行性疾病正以前所未有的速度成为全球公共卫生领域的重大挑战。根据《柳叶刀》最新报告[1]，预计到2050年，全球痴呆症人数将翻2倍，相比于2019年的5700万痴呆症患者，这一数字将增加到1.53亿。而阿尔茨海默病正是痴呆症的主要类型。面对如此庞大的患者群体和日益沉重的疾病负担，研发出有效治疗AD的药物成为全球生物医药界的重要目标。 好消息是，近年来针对AD的新药研发取得重要进展，例如靶向Aβ的单抗疗法、乙酰胆碱酯酶抑制剂口服疗法等陆续获批上市。国际权威期刊《自然》2023年发表的一篇特稿指出，近年来AD领域创新治疗方式不断涌现，且一些在研疗法展现出未来前景，包括针对Tau的疗法与抗淀粉样蛋白疗法联合使用；通过抗体、小分子药物或基因疗法来阻止致病性Tau蛋白的产生，或者降低淀粉样蛋白；以及抗Tau和抗淀粉样蛋白的疫苗等。此外，随着对疾病发病机理更深入的理解，更多新机制新靶点的研发管线持续涌现并迈入临床。 在中国，除了已获批的药物，更多针对AD的在研新药管线的研发也在持续向前推进。本文根据公开资料盘点12款正在中国开展临床研究的阿尔茨海默病在研新药。（注：本文为不完全统计，仅盘点在中国开展AD临床研究的部分在研新药。） 图片来源：123RF 礼来：donanemab注射液 作用机制：β淀粉样蛋白（Aβ）抗体 中国研发阶段：申请上市 Donanemab注射液是礼来公司（Eli Lilly and Company）开发的一款与β淀粉样蛋白亚型N3pG结合的单克隆抗体， 已经于今年7月获美国FDA批准治疗出现早期症状的阿尔茨海默病成年人。在中国，donanemab曾于2023年被CDE公示纳入突破性治疗品种，用于治疗早期症状性阿尔茨海默病，包括阿尔茨海默病所致的轻度认知障碍以及轻度阿尔茨海默病。 2023年11月，donanemab的新药上市申请被CDE纳入优先审评，拟用于治疗早期阿尔茨海默病。根据礼来披露的临床数据，关键性3期研究显示，donanemab与安慰剂相比减缓了最高达35%认知和功能衰退，在18个月内降低了最高达39%的疾病进展风险；与研究开始时相比，每月一次30分钟的输液平均使淀粉样蛋白斑块减少了84%。此外，有证据表明donanemab在淀粉样斑块清除后可停止治疗，因此预计该疗法可以降低治疗成本并减少输液次数。 通化金马：琥珀八氢氨吖啶片 作用机制：乙酰胆碱酯酶抑制剂 中国研发阶段：申请上市 琥珀八氢氨吖啶片是通化金马开发的一款小分子乙酰胆碱酯酶抑制剂，可以同时抑制乙酰胆碱酯酶和丁酰胆碱酯酶，主要开发用于治疗轻中度阿尔茨海默病。今年8月29日，通化金马申报的琥珀八氢氨吖啶片1类新药上市申请获得受理。2023年9月，通化金马宣布琥珀八氢氨吖啶片治疗轻中度阿尔茨海默病的3期研究完成。结果显示，该产品对阿尔茨海默病评定量表认知部分（ADAS-cog）的改善效果具有显著的临床意义。安全性方面的不良事件的发生率低于对照组，其结果具有统计学意义。 再鼎医药/百时美施贵宝：KarXT 作用机制：M1/M4毒蕈碱乙酰胆碱受体激动剂 中国研发阶段：3期临床 KarXT（xanomeline trospium）是由Karuna公司所开发的一款口服M1/M4型毒蕈碱乙酰胆碱受体激动剂，代表了一种创新的抗精神/神经类疾病作用机制。再鼎医药拥有KarXT在大中华区的开发、生产和商业化权益。目前，KarXT治疗成人精神分裂症的新药上市申请已被美国FDA受理，PDUFA日期为2024年9月26日。 2024年5月，中国药物临床试验登记与信息公示平台显示，Karuna公司等在中国启动了一项评价KarXT治疗阿尔茨海默病相关的精神行为症状的国际多中心（含中国）3期临床研究。该研究拟在中国招募80名受试者，在国际范围内纳入360名受试者。该3期临床针对阿尔茨海默病相关的精神行为症状。其主要目的是根据神经精神问卷-临床医生等级评定量表（NPI-C）中的幻觉和妄想评分，评价KarXT相较于安慰剂治疗阿尔茨海默病相关的精神行为症状受试者的有效性。 恒瑞医药：SHR-1707 作用机制：抗β淀粉样蛋白（Aβ）抗体 中国研发阶段：2期临床 SHR-1707是由恒瑞医药自主研发的人源化抗Aβ的单克隆抗体（IgG1亚型）。中国药物临床试验登记与信息公示平台公示显示，恒瑞医药目前已经启动了该产品针对早期阿尔茨海默病的2期临床研究。2023年7月，恒瑞医药在2023年阿尔茨海默病协会国际会议（AAIC）上公布了SHR-1707在中国与澳大利亚健康受试者中完成的单次剂量递增的1期研究结果，以及目前正在中国阿尔茨海默病患者中进行的多次剂量递增1b期研究设计。单次剂量递增的1期研究结果显示，在年轻健康和老年受试者中，2~60mg/kg单次静脉给予SHR-1707的安全性和耐受性良好，PK、PD数据支持进一步临床研发。 润佳医药：RP902片 作用机制：靶向Aβ的小分子新药 中国研发阶段：2期临床 RP902片是润佳医药自主研发的稳定同位素取代小分子1类创新药，以β淀粉样蛋白（Aβ）为主要靶点，拟用于治疗阿尔茨海默病。根据润佳医药公开资料介绍，该产品可显著抑制大脑中与AD患者认知功能下降直接相关的可溶性淀粉样蛋白寡聚体的形成，消除或降低淀粉样蛋白对神经细胞的毒性，对血脑屏障损伤亦存在一定的缓解和保护作用。临床前多项药效学研究表明，RP902能够显著改善AD模型小鼠的形象识别记忆、空间记忆和长期记忆障碍；显著改善模型小鼠海马及大脑皮层神经细胞及树突损伤、提高突触可塑性；降低模型小鼠脑内Aβ沉积以及脑内（不）可溶性Aβ1-40和Aβ1-42含量，且安全性良好。根据润佳医药官网信息，该产品目前处于2期临床阶段。 卓凯生物：50561片 作用机制：针对主动遗忘生物机制 中国研发阶段：2a期临床 根据卓凯生物此前新闻稿，50561片是其正在研发的一款通过抑制主动遗忘、挽救阿尔茨海默病认知缺陷的药物。此前，为了解决AD疾病机制复杂，传统靶点和疾病症状距离较远、药效较差等问题，清华大学生命科学学院钟毅教授课题组建立了果蝇表型筛选平台，以表型筛选的方式探索AD疾病的治疗范式。基于该平台，钟毅教授于2010年发现了影响记忆的“主动遗忘生物机制”，并将其研究成果发表在了知名学术期刊Cell上，成为了治疗阿尔茨海默病的潜在新路径。根据中国药物临床试验登记与信息公示官网，卓凯生物目前正在开展50561片治疗轻中度阿尔茨海默病的两项2a期临床研究。 强生（Johnson & Johnson）：posdinemab 作用机制：抗tau蛋白单抗 中国研发阶段：1期临床 Posdinemab（JNJ-63733657注射液）是强生研发管线中的一款阿尔茨海默病在研新药，在全球范围内处于2期临床阶段。它靶向tau蛋白中间区域的一个超磷酸化表位，研究人员希望这一设计能够让抗体只与致病的tau蛋白结合，而非与所有的tau蛋白亚型结合。Tau蛋白是神经细胞中和微管结合的可溶性蛋白，病理性tau蛋白的沉积和在大脑的扩散，与AD患者的认知能力下降有紧密的相关性。 2021年11月，posdinemab在中国获批临床，适用于延缓被确诊为前驱期AD和轻度AD痴呆阶段患者的认知下降。根据中国药物临床试验登记与信息公示平台官网，强生已经在中国完成该产品针对中国健康受试者的1期临床研究。 康诺亚：CM383注射液 作用机制：靶向Aβ原纤维的单抗 中国研发阶段：1期临床 CM383注射液是康诺亚研发的一款靶向Aβ原纤维的单抗，已经于今年5月在中国启动针对阿尔茨海默病的1期临床研究。目前，靶向Aβ的单抗疗法被称为“疾病修饰治疗”方法，其核心在于其对阿尔茨海默病的疾病发病机制进行干预，靶向清除患者大脑中过多的Aβ原纤维，从“源头”解决问题，而不仅仅是缓解症状或对症状进行管理。 绿叶制药：LY03020马来酸盐缓释片 作用机制：TAAR1/5-HT2CR双靶点激动剂 中国研发阶段：1期临床 LPM787000048马来酸盐缓释片（LY03020）为绿叶制药基于新分子实体/新治疗实体技术平台开发，为一款痕量胺相关受体1（TAAR1）和5-羟色胺2C受体（5-HT2CR）双靶点激动剂，为新一代抗精神病药物。该产品针对阿尔茨海默病精神病性障碍（ADP）适应症已经在中国获批临床。今年8月，该产品单次剂量递增1期临床研究已经登记启动。 据绿叶制药此前新闻稿介绍，与现有抗精神病药物相比，TAAR1和5-HT2CR双靶点作用机制可起到提高疗效，减少不良反应的作用，有望减少锥体外系反应（EPS）和代谢综合征等不良反应。临床前研究表明该产品可显著改善ADP阳性症状和阴性症状。 魁特迪生物：QD202 作用机制：突触功能调节 中国研发阶段：1期临床 QD202是魁特迪生物在研的一款化药1类新药，拟用于治疗轻度、中度阿尔茨海默病，目前已经在中国启动1期临床研究。魁特迪生物致力于神经退行性疾病诊断与创新药研发。该公司创始团队在神经退行性疾病研究深耕20余载，尤其在神经突触传递对感认知功能研究方面具有深厚经验。QD202即是具有突触功能调节作用的一款产品，它通过增加神经递质的释放、增强溶酶体功能，进而达到治疗AD的效果。同时，相关机制也具有开发脑卒中后认知功能障碍适应症药物的潜力。 博芮健制药：BrAD-R13 作用机制：小分子TrkB受体激动剂 中国研发阶段：1期临床 根据博芮健制药新闻稿，BrAD-R13是该公司在研的一款1类创新药，其靶点机制为对脑源性神经营养因子BDNF-TrkB信号通路的神经保护和调节，并抑制天冬酰胺内肽酶AEP参与的多种中枢神经系统（CNS）疾病的致病蛋白剪切作用。该产品已在多种动物模型上验证了靶点机制，相关文献发表在Nature、Cell系列刊物上，且临床前研究表明，BrAD-R13具有良好的安全性，后续可逐步开展针对阿尔茨海默病、帕金森病等多个CNS适应症的开发。该产品已经先后在美国和中国获批临床，拟开发治疗轻、中度阿尔茨海默病。目前该产品1期临床研究已经登记启动。 新华制药：OAB-14干混悬剂 作用机制：清除脑内Aβ等多靶点机制 中国研发阶段：1期临床 OAB-14干混悬剂由新华制药和沈阳药科大学联合研发，拟用于治疗轻至中度阿尔茨海默病（AD）。根据新华制药今年8月发布的公告介绍，OAB-14目前已经完成1期临床试验研究，达到预期目标，拟进入2期药物临床研究阶段。OAB-14是一类全新作用机制的抗AD候选药物，其作用主要与清除脑内Aβ有关，也与中枢抗炎、抗氧化、抑制神经元凋亡等多靶点的机制有关。研究表明OAB-14能显著减少脑内β淀粉样蛋白沉积，降低Tau蛋白过度磷酸化，同时保护大脑皮层及海马神经细胞及突触结构与功能。 此外，值得一提的是，在全球范围内，基于对衰老和阿尔茨海默病发病机理更深入的理解，现有研发管线已不仅仅关注Aβ和tau蛋白，而是呈现出多样化的创新靶点或作用机制，比如提高神经突触中镁离子水平、5-HT6受体拮抗剂、神经毒性聚集蛋白转移抑制剂、回复FLNA蛋白构象和功能、诱导慢性轻度酮症等等。 尽管如此，阿尔茨海默病仍然是一种复杂且具有挑战性的疾病，寻找更加安全有效的治疗方法仍然是一个漫长而艰巨的过程。期待业界持续的科研投入与创新，能够为患者带来更好的选择，改变他们的生活。 参考资料： [1] Gill Livingston, Jonathan Huntley, Kathy Y Liu, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The Lancet. Published:July 31, 2024DOI:https://doi.org/10.1016/S0140-6736(24)01296-0 [2]各公司官网及官方新闻稿. [3] 中国药物临床试验登记与信息公示平台官网. 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。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。 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。

CHENGDU, China , Aug. 27, 2024 /PRNewswire/ -- Keymed Biosciences Inc. (HKEX: 02162) today announced its interim results for the first half of 2024, along with a corporate update. Rapid development of our pipeline products Stapokibart (CM310) (IL-4Rα antibody) In June 2024, the long-term efficacy and safety data from the Phase III clinical trial of Stapokibart injection for the treatment of moderate-to-severe AD were presented by way of oral presentation at the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2024. The study showed that at week 52, the rates of achieving EASI-75 and EASI-90 for the Stapokibart group was 92.5% and 77.1%, respectively. The rates of achieving an IGA score of 0 or 1 point with a reduction of ≥ 2 points from baseline was 67.3%. Long-term treatment with Stapokibart can consistently improve dermatitis symptoms and quality of life in subjects with moderate-to-severe AD. In terms of safety, Stapokibart was safe and well-tolerated after 52 weeks of administration, with safety profiles consistent with those observed at week 16 and no new safety signals identified. Advanced and completed the 52-week treatment and safety follow-up of the Phase III clinical study of Stapokibart injection for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in the first half of 2024. In June 2024, the new drug application of Stapokibart injection for the treatment of CRSwNP was accepted by the NMPA and granted priority review. Advanced and completed the unblinding of data and the statistical analysis of the Phase III clinical study of Stapokibart injection for the treatment of seasonal allergic rhinitis (SAR) in the first half of 2024, with the clinical data meeting the primary endpoints. In April 2024, the new drug application of Stapokibart injection for the treatment of SAR was accepted by the NMPA. Launched a randomized, double-blinded, placebo-controlled Phase III clinical study to evaluate the efficacy and safety of Stapokibart injection in adolescent subjects with moderate-to-severe AD in February 2024. Launched a randomized, double-blinded, placebo-controlled Phase III clinical study to evaluate the efficacy and safety of Stapokibart injection in prurigo nodularis subjects in May 2024. Our partner CSPC initiated the critical Phase II/III clinical study for the treatment of moderate-to-severe asthma and moderate-to-severe COPD. CMG901/AZD0901 (Claudin 18.2 ADC) As of the date of this announcement, AstraZeneca has conducted multiple clinical studies regarding CMG901 (AZD0901) for the treatment of advanced solid tumors. Among these, an international multi-center Phase III study comparing CMG901 (AZD0901) monotherapy versus investigator's choice as second-line or later-line treatment in patients with advanced or metastatic gastric and gastroesophageal junction (G/GEJ) cancer expressing Claudin 18.2 was publicly announced on the drug clinical trial registration and information publicity platform in March 2024. The first patient has received the initial dose in April 2024. In June 2024, the latest data from a Phase I clinical study of CMG901 (AZD0901) in the treatment of advanced G/GEJ cancer were presented by way of oral presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting 2024. The study results indicated that as of February 2024, among 89 evaluable patients with Claudin 18.2-high expressing (defined as Claudin 18.2 membrane intensity ≥2+ in ≥20% of tumor cells) G/GEJ cancer in three cohorts, confirmed objective response rate (ORR) and confirmed disease control rate (DCR) were 35% and 70%, respectively. In the 2.2 mg/kg dose group, the confirmed ORR was 48%. The median progression free survival (mPFS) for all 93 patients with Claudin 18.2-high expressing G/GEJ cancer was 4.8 months, and the median overall survival (mOS) was 11.8 months. CM313 (CD38 antibody) Continued to advance a multi-center, open-label, dose-escalation and dose-expansion Phase I clinical study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CM313 injection in patients with RRMM, lymphoma, and other hematological malignancies. Continuously proceeded with a randomized, double-blinded, placebo-controlled, dose-escalation, multiple-dose Phase Ib/IIa clinical study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of CM313 injection in subjects with SLE. In June 2024, a research paper titled "A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia" was published in The New England Journal of Medicine. This is an investigator-initiated, single-arm, open-label, exploratory clinical study to evaluate the safety and preliminary efficacy of CM313 in adult patients with primary immune thrombocytopenia. The results showed that 95.5% of patients (21/22) achieved a platelet count of ≥50 × 109/L within 8 weeks upon the first acceptance of CM313 infusion, with a median cumulative duration for a platelet count of ≥50 × 109/L of 23 weeks (interquartile range: 17-24). Additionally, the durable platelet count response rate (defined as a platelet count of ≥50 × 109/L observed six or more times among the final eight platelet counts) was 63.6% (14/22). In June 2024, we have submitted an IND application to further assess the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of CM313 in patients with primary immune thrombocytopenia. CM326 (TSLP antibody) In May 2024, we initiated a randomized, double-blinded, placebo-parallel Phase II clinical study to evaluate the efficacy and safety of CM326 in patients with CRSwNP, further exploring the optimal dosage. Our partner CSPC initiated the Phase II clinical study for the treatment of moderate-to-severe asthma. CM355/ICP-B02 (CD20xCD3 bispecific antibody) Continuously proceeded with a Phase I/II clinical trial in the first half of 2024 to assess the safety, tolerability, pharmacokinetics, and the preliminary anti-tumor activity of CM355 in relapsed or refractory non-Hodgkin's lymphoma (NHL). As of the date of this announcement, dose escalation of the intravenous infusion formulation (IV) was completed and the subcutaneous formulation (SC) is in the process of patient evaluation. CM336 (BCMAxCD3 bispecific antibody) Continuously proceeded with a Phase I/II clinical study to assess the safety, tolerability, pharmacokinetics, and the anti-tumor activity of CM336 in RRMM. CM350 (GPC3xCD3 bispecific antibody) Continuously proceeded with a Phase I/II clinical study to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of CM350 in patients with advanced solid tumors. CM369/ICP-B05 (CCR8 antibody) Continuously proceeded with a Phase I clinical study in the first half of 2024 to evaluate the safety, tolerability, pharmacokinetic characteristics, and efficacy of CM369 in subjects with advanced solid tumors and relapsed or refractory NHL. CM383 (Aβ protofibrils antibody) Initiated a Phase I clinical study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of single dose-escalation administration of CM383 in healthy subjects. The enrollment of the first subject was completed in June 2024. CM380 (GPRC5DxCD3 bispecific antibody) Submitted IND application, and planned to conduct a multi-center, open-label Phase I/II clinical study for evaluation of CM380 in treatment of patients with relapsed or refractory multiple myeloma. Financial and Business Highlights Actively carry out the out-licensing collaboration In July 2024, Chengdu Keymed and Belenos entered into an out-license agreement, which grants Belenos an exclusive right to develop, manufacture and commercialize the Group's drug candidates, CM512 and CM536, globally excluding the Greater China region. In return, Chengdu Keymed shall receive an upfront and nearterm payment of US$15 million, and iBridge HK Holdings Limited, a wholly-owned subsidiary of the Group, shall receive approximately 30.01% of the equity interest in Belenos as consideration. Subject to achievement of certain development, regulatory and commercial milestones, Chengdu Keymed may also receive additional payments of up to US$170 million. Chengdu Keymed is also entitled to receive tiered royalties from Belenos on net sales for a specified period of time commencing after the first commercial sale of CM512 and CM536. Expand manufacturing capacity and efficiently prepare for commercialization We continue to recruit talents to meet the growing needs of commercialization, research and development, clinical, production and operation of the Company. We further expanded our cGMP-compliant manufacturing capacity, efficiently prepared for the company to become a commercial organization. As of the date of this announcement, the production capacity of our production base has reached 18,600 litres in total, and all the designs thereof are in compliance with the requirements of cGMP of the NMPA and FDA. Financial highlights As of June 30, 2024, the Company held cash (including bank wealth management products) of RMB 2.58 billion. R&D expenses of the Group increased by RMB 81 million to RMB 331 million, from RMB 250 million for the six months ended June 30, 2023. During the Reporting Period, the Group's revenue amounted to RMB 54.6 million, mainly consisted of the 1st milestone revenue from AZ on the CMG901 license transaction. SOURCE Keymed