An open label, single arm, extension trial to examine long-term safety of BI 425809 once daily in patients with schizophrenia who have completed previous BI 425809 Phase III trials.(CONNEX-X)

开始日期2024-01-26

申办/合作机构

Boehringer Ingelheim RCV GmbH & Co. KG

NCT06070597 / Recruiting临床1期

Effects of Iclepertin on the QT Interval Following Oral Administration in Healthy Male and Female Subjects (a Double-blind, Randomised, Placebo-controlled, Multiple-dose, Parallel Group With Nested Crossover Design Trial, With Moxifloxacin as Positive Control)

This study aims to evaluate the effects of iclepertin in the range of therapeutic to supra-therapeutic exposures on the (QT/QTc): Electrocardiogram (ECG) time interval from the start of the QRS complex (ECG time interval) to the end of the T wave / QT interval corrected for heart rate, e.g. using the method of Fridericia or Bazett interval and other ECG parameters.

开始日期2024-01-25

申办/合作机构

Boehringer Ingelheim GmbH

EUCTR2020-003726-23-AT / Unknown status临床3期

A phase III randomized, double-blind, placebo-controlled parallel group trial to examine the efficacy and safety of iclepertin once daily over 26 week treatment period in patients with schizophrenia (CONNEX-3)

开始日期2023-07-12

申办/合作机构

Boehringer Ingelheim RCV GmbH & Co. KG

100 项与 Iclepertin 相关的临床结果

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100 项与 Iclepertin 相关的转化医学

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100 项与 Iclepertin 相关的专利（医药）

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项与 Iclepertin 相关的文献（医药）

2023-11-01·Journal of Labelled Compounds and Radiopharmaceuticals

Stable isotope synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites

Article

作者: Latli, Bachir ; Lee, Heewon ; Chevliakov, Maxim ; Hrapchak, Matt J ; Frutos, Rogelio P ; Samankumara, Lalith P

Stable isotope labeled Iclepertin (BI 425809, 1) and its major metabolites are needed as internal standards in bioanalytical studies. BI 425809 consists of two main building blocks, 5‐methylsulfonyl‐2‐[(1R)‐2,2,2‐trifluoro‐1‐methyl‐ethoxy]benzoic acid (2) and 3‐[(1R,5R)‐3‐azabicyclo[3.1.0]hexan‐5‐yl]‐5‐(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. We used fluoro[13C6]benzene as the starting material in the preparation of [13C6]‐2. This intermediate was then employed to access carbon 13 labeled Iclepertin ([13C6]‐1) and other metabolites. The major metabolite BI 761036 (6), which resulted from cytochrome P450 oxidation and amide hydrolysis of BI 425809, was prepared labeled with carbon 13 and nitrogen 15 via two synthetic routes. In the first route, diethyl [13C3]malonate, [13C]methyl iodide, and hydroxyl[15N]amine were used to provide [13C4,15N]‐BI 761036 ([13C4,15N]‐6a) in 13 steps in 6% overall yield, whereas in the second route, [13C3]propargyl alcohol, potassium [13C]cyanide, and [15N]ammonia were used to furnish [13C4,15N]‐BI 761036 ([13C4,15N]‐6b) in 11 steps in 1% overall yield. The detailed stable isotope synthesis of 1 and its major metabolites is described.

2023-10-01·European archives of psychiatry and clinical neuroscience

Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia.

Review

作者: Rosenbrock, Holger ; Desch, Michael ; Wunderlich, Glen

Schizophrenia is a psychiatric disorder characterised by symptoms in three domains: positive (e.g. delusions, hallucinations), negative (e.g. social withdrawal, lack of motivation) and cognitive (e.g. working memory and executive function impairment). Cognitive impairment associated with schizophrenia (CIAS) is a major burden for patients and negatively impacts many aspects of a patient's life. Antipsychotics are the standard-of-care treatment for schizophrenia but only address positive symptoms. So far there are no approved pharmacotherapies for the treatment of CIAS. Iclepertin (BI 425809) is a novel, potent and selective glycine transporter 1 (GlyT1) inhibitor, under development by Boehringer Ingelheim for the treatment of CIAS. Phase I studies have shown it to be safe and well tolerated in healthy volunteers, and central target engagement (inhibition of GlyT1) was achieved in a dose-dependent manner from 5 to 50 mg in healthy volunteers. A Phase II study has demonstrated that iclepertin is safe and well tolerated in patients with schizophrenia and improves cognition at doses of 10 mg and 25 mg. Phase III studies are ongoing to confirm these initial positive safety and efficacy findings with the 10 mg dose, and if successful, iclepertin could become the first approved pharmacotherapy used to treat CIAS.

2023-09-01·Journal of labelled compounds & radiopharmaceuticals

Carbon 14 synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites.

Article

作者: Latli, Bachir ; Frutos, Rogelio P ; Hrapchak, Matt J ; Song, Jinhua J ; Lee, Heewon

Carbon 14 labeled Iclepertin (BI 425809, 1) and its major metabolites were needed for ADME and several other studies necessary for the advancement of this drug candidate in clinical trials. Iclepertin is composed of two main chemical blocks, (R)-5-(methylsulfonyl)-2-([1,1,1-trifluoropropan-2-yl]oxy)benzoic acid (2), and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. In the first synthesis of carbon 14 labeled 1, 2-fluorobenzoic acid, carboxyl-¹⁴ C was converted to [¹⁴ C]-2 in three steps and then coupled to 3 to provide [¹⁴ C]-1a in 45% overall yield. In the second synthesis, [¹⁴ C]-3 was prepared in six radioactive steps and coupled to the acid 2 to furnish [¹⁴ C]-1b in 20% overall yield. Both synthetic routes provided [¹⁴ C]-1a and [¹⁴ C]-1b with specific activities higher than 53 mCi/mmol and radiochemical, chemical, and enantiomeric purities above 98%. Two major metabolites of 1, BI 761036 and BI 758790, were also prepared labeled with carbon 14 using intermediates already available from the synthesis of [¹⁴ C]-1.

项与 Iclepertin 相关的新闻（医药）

2024-03-25

·药渡Daily

MNC巨头为何押注同一个方向？

3月13日，勃林格殷格翰与“中国血王”上海莱士达成合作，为后者的血友病创新药物SR604注射液提供工艺转移及临床生产制造服务。3月14日，阿斯利康以10.5亿美元收购罕见病疗法公司Amolyt，将治疗甲状旁腺功能减退症的Eneboparatide（AZP-3601）收入囊中。更早前的2月27日，诺和诺德以总价14.6亿美元与Neomorph达成合作，共同开发和商业化治疗心血管疾病和罕见病的分子胶降解剂。这三项交易看似没有任何关系，但定睛一看就会发现，巨头们都押注了同一个方向——罕见病领域。01MNC巨头为何联手“中国血王”？去年10月，勃林格殷格翰（BI）在“中国研发日”上宣布，未来五年计划在华人药业务研发投入超35亿人民币。如今，BI开始用实际行动兑现承诺。但BI作为一家拥有近140年历史的MNC巨头，为何会与从事血液制品业务的“中国血王”达成合作？实际上，勃林格殷格翰在中国市场的投入早已开始。追溯到2018年，当许多MNC巨头都趋向欧美市场时，BI选择打破常规，启动了“中国纳入”（China IN）项目，率先将中国全面纳入全球早期临床开发研究。如今，BI已在中国落地多个管线，包括新型PDE4B抑制剂BI1015550、高效口服小分子MDM2-p53拮抗剂Brigimadlin（BI907828）、DLL3/CD3双抗BI764532、Iclepertin（GlyT1i）和新型抗肥胖药物Survodutide（GCGR/GLP-1R双重激动剂），涉及肿瘤、自免、精神分裂症和肥胖等多个疾病领域。此次BI与上海莱士达成的重磅合作，是针对血友病创新药物SR604注射液。SR604是一种人源化高亲和力结合人活化蛋白C，特异性抑制人活化蛋白C抗凝血功能的单克隆抗体制剂，其优势在于每4周一次的皮下注射预防治疗，相比目前国内外血友病的常规预防治疗（每周2-3次静脉注射血源或重组凝血因子），更具依从性优势。就在本月初，SR604获国家药监局批准开展临床试验，用于血友病及先天性凝血因子Ⅶ缺乏症患者出血发作的预防治疗。目前全球尚无与该药物同靶点的产品上市，市场先发优势显著。除药物自身优势显著外，上海莱士在血液制品领域的实力，也是促成此次交易的关键。作为“中国血王”，上海莱士一直专注于血液制品业务，产品覆盖了白蛋白类、免疫球蛋白类及凝血因子类三大类，是国内同行业中凝血因子类产品种类最为齐全的生产企业之一，早已在凝血领域打造了强劲优势。如今切入血友病创新药物的研发，也是水到渠成的事情。更何况，血友病药物本就有着可观的销售表现。02罗氏摘得血友病“药王”，基因疗法登上历史舞台血友病是一种罕见的遗传性疾病，分为血友病A（甲型血友病）和血友病B（乙型血友病），其中前者占比高达80%-85%。血友病的患者人数不在少数。根据弗若斯特沙利文数据，全球血友病患病人数复合增长率为1.3%，从2015年的74.2万上升到2019年的78.3万，预计到2030年患者人数将增长到89万人。在已获批的药物中，除罗氏9/10因子双抗Hemlibra（艾美赛珠单抗）外，大多数药物类型主要为重组凝血八因子，如今全球已获批20款左右，竞争相当激烈。罗氏开发的艾美赛珠单抗，是近20年来FDA批准的首个用于治疗A型血友病的新药，2023年实现销售额达41.47亿瑞士法郎，同比增长16%，在罗氏畅销产品榜单中排名第二，并摘得血友病“药王”宝座。除上述两种药物外，在罕见病领域具有功能性治愈潜力的基因疗法，也登上历史舞台。2022年8月，BioMarin研发的Roctavian（Valoctocogene roxaparvovec）获批上市，用于治疗无FVIII因子抑制剂史且AAV5抗体阴性的严重血友病A成人患者；11月，美国FDA批准UniQure开发的Hemgenix（Etranacogene dezaparvovec），用于治疗18岁及以上血友病B患者。这意味着，针对血友病A和血友病B的基因疗法均已面世。辉瑞相当看好基因疗法，一口气布局了3条管线，其中从Spark Therapeutics引进的Beqvez（Fidanacogene elaparvovec，SPK-9001），已于今年1月在加拿大获批上市，用于治疗18岁或以上中重度至重度乙型血友病成人患者。此次批准是基于一项积极的III期研究：接受Beqvez治疗三个月，出血率可减少71%。目前，Beqvez已在美国、欧洲处于上市审评阶段，预计今年二季度揭晓结果。另一条管线Marstacimab（PF-06741086），通过靶向组织因子途径抑制剂（TFPI），可用于治疗血友病A和血友病B患者，而且无需考虑患者体内是否存在对外来凝血因子产生的中和抗体。目前，Marstacimab的关键临床III期试验已达到主要终点：与在导入期内接受按需治疗因子替代静脉治疗的患者队列相比，出血率降低92%，与接受预防性治疗队列相比，年化出血率降低了35%，均显示出优越性。此前，Marstacimab已获得FDA授予快速通道资格，若顺利获批，将可能成为首款只需每周一次皮下注射的血友病B疗法，同时也是首款按固定剂量给药的血友病A或B药物。辉瑞和Sangamo共同研发的Giroctocogene fitelparvovec（SB-525），是一款肝靶向AAV（腺病毒相关载体）的基因疗法，目前正在开展针对中度或重度A型血友病成年男性的III期研究，预计今年上半年获得顶线数据，下半年向FDA提交BLA。03国内药企征战血友病赛道面对如此巨大的市场蛋糕，国产药企必然不会错过。我国血友病患者众多且呈现持续增加的趋势。根据《血友病A诊疗指南（2022年版）》，2022年国内血友病患病人数为14.6万人，其中80-85%属于甲型血友病。另外，根据弗若斯特沙利文预测，中国血友病用药市场将于2026年达到115亿元，成为百亿赛道。目前，国内获批的血友病药物主要为重组凝血八因子，且以进口产品为主，其中神州细胞凭借国产首个重组八因子安佳因（重组人凝血因子VIII）抢得了一席之地，并且在首个完整销售年度即成为销售额10亿量级的市场重磅产品。得益于安佳因销售收入的持续增长，神州细胞预计2023年交出亮眼的成绩单：实现总营收18.5亿元至19.1亿元，同比增长81.12%到86.98%，同比减少净亏损21.19%到26.98%。如今，也有一些国产药企想进场“分蛋糕”，从FVIII/vWF-XTEN融合蛋白、TFPI单抗、Ffactor X激活剂等方向研发血友病新药，进度领先的有晟斯生物、康宁杰瑞、舒泰神。其中，晟斯生物自主研发的注射用重组人凝血因子VIII-Fc融合蛋白（FRSW107），能有效延长半衰期，实现3天一次给药或一周两次给药，是首款国产长效重组凝血因子VIII产品1类新药。2023年6月，晟斯生物向国家药监局提交了FRSW107的上市申请，用于12岁以上青少年与成年人先天性八因子缺乏的血友病A患者的出血控制，有望在今年上半年获批上市。康宁杰瑞布局的KN057，是一种靶向组织因子途径抑制物（TFPI）的单克隆抗体，可维持凝血酶水平，达到预防出血的作用，具有半衰期长、皮下注射等特点，目前已启动预防治疗血友病的III期临床研究。2023年9月，康宁杰瑞将KN057在大中华区的权益授予远大生命科学全资子公司远大蜀阳，将获得最高人民币5亿元的权益付款（包括首付款和里程碑款）及分级销售提成。需要注意的是，外资巨头已在抗TFPI药物赛道领先一步。其中，诺和诺德的Concizumab（康赛珠单抗）已于2023年9月在日本获批上市，用于有凝血因子VIII或IX抑制剂的先天性血友病患者出血倾向的抑制。III期试验数据显示：康赛珠单抗可使血友病A患者的自发性和创伤性出血减少86%，使血友病B患者的出血减少79%。另外，辉瑞的Marstacimab（马塔西单抗），针对血友病A和血友病B的III期临床试验已达到主要终点，与按需静脉注射凝血因子相比，能使患者年出血率（ABR）降低92%。舒泰神研发的凝血因子X激活剂STSP-0601，已于2023年11月取得Ib/II期临床研究总结报告，治疗伴抑制物血友病A或B患者出血事件的疗效显著，有效止血率＞94%，而且安全性良好，试验过程中未发生与药物相关的SAE，无血栓栓塞事件发生，未发现与试验药物相关的抗药抗体产生。可见，国产药企的血友病新药已处于临床后期阶段，未来几年将迎来收获期。04结语总体来看，MNC巨头们之所以争相押注罕见病领域，特别是血友病这一细分赛道，既源于罕见病药物市场巨大的潜力，也因为这些疾病领域仍存在大量未被满足的临床需求。而在这股全球的热潮中，国产药企也嗅到了这一领域的机会。尽管外资巨头在某些方面已领先一步，但国产药企也在不断努力追赶，有望在未来几年取得突破性进展。参考资料1.各家公司的财报、公告、官网2.《有望成为首款！只需一周接受一次治疗，辉瑞长效血友病疗法达3期关键试验主要终点》，药明康德，2023-05-313.《跨国药企争夺血友病赛道，诺和诺德3期临床数据不敌辉瑞》，中为股权投资，2023-06-30

并购申请上市临床研究

2024-03-14

·Insight数据库

再落一子，MNC 巨头「豪赌」CNS 领域

又一巨头出手中枢神经系统（CNS）新药领域。3 月 11 日，勃林格殷格翰与 Sosei Heptares 宣布达成合作，双方将共同开发和商业化治疗精神分裂症的潜在 FIC 药物 GPR52 激动剂疗法，交易总金额超 7 亿欧元。就在几个月前，艾伯维和 BMS 两大跨国制药巨头接连加码，一个月内达成了两项高额收购项目。其中，艾伯维以 87 亿美元收购神经科学公司 Cerevel，将治疗精神分裂症、帕金森病以及情绪障碍等多种疾病的潜力候选药物收入囊中；BMS 更是斥资 140 亿美元收购 Karuna，后者的核心产品 KarXT 已于 2023 年 9 月在美申报上市，PDUFA 目标日期为今年 9 月 26 日，有望成为 50 年来用于治疗精神分裂症的首个新机制药物。MNC 巨头频频出手，CNS 领域为何有如此大的吸引力？国产药企又在这一领域中扮演着怎样的角色？MNC 巨头的算盘精神分裂症，只是中枢神经系统疾病的其中一个分支，其他还有阿尔茨海默症、帕金森病、抑郁症、偏头痛等诸多适应症。以精神分裂症为例，据世界卫生组织统计，全球约 2400 万人患精神分裂症。2022 年，中国精神分裂症患病人数达到约 824.9 万例，预计 2030 年将达到 918.2 万例。庞大的患者人数，带来了较为可观的市场前景。根据 expertmarketresearch 测算，全球精神分裂症药物的市场规模有望于 2023 年的 81.8 亿美金增长至 2032 年的 129.7 亿美金，年复合增长率为 5.4%。市场增速受限制，在于当前极度缺乏疗效和安全性俱佳的抗精神病新式药物，与巨大未被满足的临床需求相矛盾。未来随着更多新式药物获批上市，市场空间必将更大。中国抗精神分裂药物市场有望逐步扩容数据来源：Frost&Sullivan，国泰君安证券研究除市场潜力大外，企业的战略规划和显著的药物优势，也是吸引 MNC 巨头频频落子的重要原因。就艾伯维而言，除了贡献收入「大头」的免疫学、肿瘤业务，神经科学也是其主要聚焦的疾病领域之一，尤其 2023 年以 18.2% 的同比增速贡献了 77.17 亿美元收入，是众多业务中唯一实现正增长的。这得益于多款重磅药物的正向增长，其中精神分裂症药物 Vraylar（卡利拉嗪）销售额达 27.59 亿美元，同比增长 35.4%，是艾伯维神经科学业务收入排行前列的「重磅炸弹」；3 款偏头痛药物 Botox、Ubrelvy、Qulipta 分别实现收入 29.91 亿美元、8.15 亿美元、4.08 亿美元，帕金森病药物 Duodopa 销售额为 4.68 亿美元。精神科学业务表现亮眼，再加上其他业务板块的下滑，尤其 Humira（修美乐）面临专利悬崖危机、「药王」神话不再，此时选择加码 CNS 领域自然是水到渠成的事情。无独有偶，BMS 也有它的「苦恼」，虽然 2023 年核心产品 O 药销售额达到 100 亿美元，却要面临专利到期问题。为了延长其生命周期，除拓展更多适应症外，还把中国 10 个省份的销售权交给再鼎医药。此外，BMS 还选择「买买买」、持续发力 BD 业务，其中最负盛名的便是以总价 140 亿美元现金收购 Karuna，拿下精神分裂症新式药物 KarXT，以及以最高可达 84 亿美元引进百利天恒潜在 FIC 的 HER3/EGFR 双抗 ADC 产品 BL-B01D1。对于勃林格殷格翰而言，这已经不是第一次布局 CNS 领域。现有管线中，就有一款新型 Gly-T1 抑制剂 Iclepertin（BI-425809），正在开展 Ⅲ 期临床试验，预计 2025 年 1 月读出数据。此前，FDA 基于良好的 Ⅱ 期试验结果（登记号：NCT02832037），授予 Iclepertin 治疗精神分裂症的突破性疗法认定。在 CNS 领域尝到了「甜头」，自然更有信心加码这一赛道。更何况，此时再大动干戈的挤进众多 MNC 巨头争抢的肿瘤、自免领域，必然要仔细权衡利弊。选择 CNS 领域、实现差异化突破，或许是个明智的选择。下一代抗精神病药集体亮相实际上，在此之前，CNS 领域并非没有 MNC 巨头入局，只是由于发病机制复杂、研发失败率高等原因，过去数十年来折戟的管线高达上百款。目前市场上销售的抗精神病药主要为非典型抗精神病药，即 20 世纪 60 年代-21 世纪初上市的第二代抗精神病药，比如氯氮平、利培酮、布南色林，以及 2002 年至今上市的第三代抗精神病药，例如阿立哌唑、布瑞哌唑、卡利拉嗪。相比第一代抗精神病药，非典型抗精神病药在疗效上有显著的改善，但仍存在一定的副作用，针对阴性症状的治疗也有待提升，而且作用机制主要为多巴胺受体和 5-HT 受体，亟需新机制、新式药物获批上市。抗精神病药分类数据来源：中国新药与临床杂志，药学学报，国泰君安证券研究由于精神分裂症发病机制复杂未明，药企们选择从各个可能的方向进行探索研发。这也让下一代抗精神病药集中亮相，登上了历史舞台。例如，勃林格殷格翰引进 Sosei Heptares 的潜在 FIC 药物 GPR52 激动剂疗法、艾伯维拿下的 Emraclidine、BMS 拿下的 KarXT，均为治疗精神分裂症的新式药物。其中，GPR52 是一种 G 蛋白偶联受体（GPCR），在中枢神经系统和周围组织中都有表达，而 GPR52 激动剂是能够与 GPR52 结合并激活其信号转导通路的小分子化合物，可通过同时解决精神分裂症的全部三组症状（阳性、阴性和认知症状）来改善患者预后。Emraclidine 是一款高度选择性靶向毒蕈碱 M4 的正向变构调节剂（PAM），具有治疗精神分裂症的 BIC 潜力，目前正在开展两项 II 期注册性临床试验。有意思的是，KarXT 也属于毒蕈碱类抗精神病药物，是一种口服 M1/M4 毒蕈碱激动剂，可以改善精神分裂症的三组症状，意味着未来或将与 Emraclidine 展开同类竞技。进度上，KarXT 已率先向美国 FDA 申报上市，如无意外今年将获批，成为 50 年来首个精神分裂症新式药物。有机构预测，2028 年 KarXT 的销售额将达到 28 亿美元。除上述新式药物外，目前也有一些新机制药物备受关注，包括 TAAR1 激动剂、γ-氨基丁酸（GABA）受体激动剂、5-羟色胺（5-HT）受体拮抗剂，以及勃林格殷格翰在研的甘氨酸转运蛋白 1（Gly-T1）抑制剂 Iclepertin 等。例如，住友制药/大冢制药共同研发的 Ulotaront（SEP-363856）就属于 TAAR1 和 5-HT1A 受体双重激动剂，但很遗憾，治疗急性精神分裂症的两项 III 期研究均未达到主要研究终点，目前正在开发用于精神分裂症、广泛性焦虑症和重度抑郁障碍的辅助治疗。从仿到创，步步为营抗精神病药研发之路，道阻且长。基于此，国内药企选择了较为稳妥的布局方式，先在仿制药和改良型新药/创新剂型上「小试牛刀」，这样既不用担忧投入的高额研发费用可能会「石沉大海」，又不会错过百亿赛道，先拿到「入场券」再说。例如，丽珠集团、海正药业、豪森制药等布局了盐酸鲁拉西酮片仿制药；华海药业、恩华药业、康弘药业等布局了阿立哌唑仿制药；豪森药业、齐鲁制药等布局了奥氮平药物。也有一些国产药企选择布局抗精神病新药/创新剂型，比如绿叶制药、京新药业、再鼎医药等。绿叶制药自研的 Rykindo（利培酮缓释微球注射制剂，LY03004）于 2023 年 1 月获 FDA 批准上市，用于治疗精神分裂症成人患者、以及作为单药或作为锂盐或丙戊酸盐的辅助疗法用于双相障碍 I 型成人患者的维持治疗，成为首个在美获批的国产抗精神病药长效针剂。另一款管线即将迎来商业化上市，棕榈酸帕利哌酮缓释混悬注射液（LY03010）为棕榈酸帕利哌酮长效注射剂，每月给药一次，目前在中美两国均已处于上市审评阶段，用于治疗精神分裂症和分裂情感性障碍。绿叶制药中枢神经药物管线资料来源：绿叶制药官网京新药业研发的 1 类新药 JX11502MA 胶囊，是艾伯维 Vraylar（卡利拉嗪）的类似物，二者作用机制相似但结构不同，主要靶点是多巴胺受体及 5-HT 受体，适应症均为精神分裂阴性症状，目前已处于临床Ⅱ期阶段。在 BD 交易盛行的当下，国产药企向海外企业引进突破性的新机制药物，已是司空见惯之事。例如，再鼎医药于 2021 年与 Karuna 签订合作，拿下了 KarXT 在大中华区开发、生产及商业化的权益，目前正在中国开展用于精神分裂症的 III 期桥接注册研究。在帕金森症领域，京新药业与以色列公司 P2B 达成合作，引进了多巴胺受体激动剂药物 P2B001 复方制剂（普拉克索+雷沙吉兰）在中国的独家开发和商业化权益，目前该药正在海外开展Ⅲ期临床试验，国内已进入临床研究阶段。结语：期待在不久的将来，CNS 新药领域能涌现出更多国产药企的身影。参考文献：1. 各家公司的财报、公告、官网；2. 《20230618-京新药业-002020-首次覆盖报告：精神神经领域龙头，创新转型曙光初现》，国泰君安研报；免责声明：本文为外部作者投稿，仅作消息分享，并不构成投资建议，也不代表 Insight 数据库的立场，文章观点仅供分享行业见解，请广大投资者谨慎。封面来源：站酷海洛 Plus编辑：HebePR 稿对接：微信 insightxb投稿：微信 insightxb；邮箱 insight@dxy.cn

并购抗体药物偶联物上市批准

2024-03-11

·BioSpace

Boehringer Ingelheim and Sosei Heptares join forces to develop first-in-class treatments targeting all symptoms of schizophrenia

Single-target agreement focused on development of novel, small molecule agonists of GPR52 discovered by Sosei Heptares with the potential to simultaneously address positive, negative and cognitive symptoms of schizophrenia Sosei Heptares will receive EUR 25 million upfront from Boehringer Ingelheim and is eligible for an option exercise payment of EUR 60 million and further milestone payments totaling up to EUR 670 million plus tiered royalties Ingelheim, Germany, Tokyo, Japan and Cambridge, UK, 11 March 2024 – Today, Boehringer Ingelheim and Sosei Group Corporation (“Sosei Heptares”; TSE: 4565) announced they have entered a global collaboration and exclusive option-to-license agreement. At the center is a joint mission to develop and commercialize Sosei Heptares’ portfolio of first-in-class GPR52 agonists, a novel G protein-coupled receptor (GPCR) target, with the intent to improve patient outcomes by simultaneously addressing positive, negative, and cognitive symptoms of schizophrenia1,2,3. Schizophrenia is a serious condition that affects about 1 in 100 people worldwide4. It is characterized by three clusters of symptoms5,6: ‘Positive’ symptoms – such as psychosis, delusions and hallucinations ‘Negative’ symptoms – such as social withdrawal and apathy Cognitive symptoms – such as attention, planning and memory deficits The impact of these symptoms on people’s ability to cope with normal day-to-day life is significant and the related burden on carers and society at large is substantial, especially since the age of onset of the disease is typically in the 20s7. While ‘positive’ symptoms can be stabilized with antipsychotics, some of which can have side effects, there are currently no approved medicines for ‘negative’ or cognitive symptoms. The development of a new schizophrenia treatment targeting GPR52 has the potential to address all three aspects of schizophrenia1,2 providing a novel precision treatment. This is based on the location of the receptor in the two areas of the brain that drive the positive (the striatum) and the negative and cognitive symptoms (the prefrontal cortex). The GPR52 agonism calms the striatum while boosting frontal cortical function, which achieves further precision in treatment8. “We’re very excited to enter this partnership with Sosei Heptares with this novel approach, which aims to address a huge unmet need of those living with schizophrenia. This partnership is highly complementary to our other development programs aiming to bring a new precision medicine approach to the treatment of mental health disorders with therapies, which we hope will transform the lives of those living with schizophrenia,” states Hugh Marston, Global Head CNS Discovery Research at Boehringer Ingelheim. Matt Barnes, President of Heptares Therapeutics and Head of UK R&D at Sosei Heptares, commented: “This collaboration highlights the significant potential GPR52 has shown in preclinical research as a novel, first in class target for the treatment of schizophrenia and related neurological disorders. We’re delighted to partner with Boehringer Ingelheim and leverage its leading expertise in neurological disease research and innovation. Together, we will focus on accelerating the development of this highly innovative program, which is currently in a Phase 1 clinical study, towards patients in need.” About the Agreement Sosei Heptares will receive an upfront payment of EUR 25 million from Boehringer Ingelheim upon signing and is eligible for an option exercise payment of EUR 60 million and further development, regulatory and commercialization milestone payments totaling up to EUR 670 million plus customary tiered royalties for a clinical-stage asset on future Boehringer Ingelheim product sales. Under the terms of the agreement, Boehringer Ingelheim has the exclusive option to license Sosei Heptares’ portfolio of GPR52 agonists following the completion of Sosei Heptares’ ongoing Phase 1 and subsequent Phase 1b trial and further Phase 2 enabling activities with HTL0048149, a first-in-class GPR52 agonist. Sosei Heptares will retain control and act as sponsor of these trials until option exercise, estimated in 2025. The licensed portfolio will include HTL0048149 as well as multiple differentiated back-up compounds designed by Sosei Heptares using its StaR® technology and structure-based drug design (SBDD) platform. ### About GPR52 and HTL0048149 GPR52 is an orphan G protein-coupled receptor (GPCR) highly expressed in the brain, especially in the striatum and the prefrontal cortex, and represents a potential emerging therapeutic target for a range of neurological and neuropsychiatric disorders9. Sosei Heptares has developed a portfolio of selective GPR52 agonists and modulators leveraging proprietary insights from its StaR® technology SBDD platform, the most advanced of which (HTL0048149) entered a first-in-human clinical trial in 202310. HTL’149 has been designed to selectively target GPR52 as a once-daily, oral drug with an antipsychotic and pro-cognitive profile. Uniquely, HTL‘149 aims to treat positive symptoms (e.g. psychosis, delusions, hallucinations), negative symptoms (e.g. social withdrawal and apathy) and cognitive impairment (e.g. attention, planning and memory deficits) associated with schizophrenia and to minimize adverse effects associated with some of the available antipsychotic drugs9,11,12,13. Through this novel mechanism of action, HTL’149 aims to address the significant proportion of schizophrenia patients who do not respond to existing treatments or are unable to tolerate some of the side effects of antipsychotics, which potentially results in a lack of compliance to antipsychotic treatments. Furthermore, current antipsychotic drugs do not effectively treat the negative or cognitive symptoms of disease. HTL‘149 is under investigation in a Phase 1a/b randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study to assess its safety, pharmacokinetics, and pharmacodynamics in healthy volunteers aged 18-55 years. The trial is being conducted in the UK and initial data are expected in 20259,14. About Boehringer Ingelheim Boehringer Ingelheim is working on breakthrough therapies that transform lives, today and for generations to come. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term, sustainable perspective. More than 53,000 employees serve over 130 markets in the two business units Human Pharma and Animal Health. Learn more at (global) or (for UK) Boehringer Ingelheim has an innovative mental health pipeline focused on precision psychiatry approaches in indications of high unmet patient need. In pivotal trials, it includes a glycine transporter type-1 (GlyT1) inhibitor with iclepertin, addressing cognitive impairment associated with schizophrenia (CIAS) (NCT04846868, NCT04846881)15,16 and a prescription digital therapeutic (PDT), CT-155, for people experiencing negative symptoms of schizophrenia (NCT05838625 )17. About Sosei Heptares Sosei Heptares is a fully integrated biopharmaceutical company focused on bringing life-changing medicines based on world-class science to patients globally. Our vision is to become one of Japan’s global biopharmaceutical champions. Our global business combines our world-leading GPCR-targeted StaR® technology, structure-based drug design and early development capabilities in the UK with a highly experienced clinical development capability and a commercial operation in Japan. We are leveraging these capabilities to generate and advance a broad and deep pipeline of novel medicines across multiple therapeutic areas, including neurology, immunology, gastroenterology and inflammatory diseases. We intend to develop these opportunities for patients in Japan and globally both internally and through our partnerships with global biopharmaceutical companies and emerging technology companies. Sosei Heptares operates from key locations in Tokyo and Osaka (Japan), London and Cambridge (UK), Basel (Switzerland) and Seoul (South Korea). “Sosei Heptares” is the corporate brand and trademark of Sosei Group Corporation, which is listed on the Tokyo Stock Exchange (ticker: 4565). Sosei, Heptares, the logo and StaR® are trademarks of Sosei Group companies. For more information, please visit LinkedIn: @soseiheptaresco | X: @soseiheptaresco | YouTube: @soseiheptaresco Enquiries: For Boehringer Ingelheim Reinhard Malin, Innovation Unit Comms, Corp. Affairs +49 6132 77 90815 | reinhard.malin@boehringer-ingelheim.com, Linda Ruckel, Innovation Unit Comms, Corp. Affairs +1 (203) 791-6672 | linda.ruckel@boehringer.ingelheim.com, For Sosei Heptares Kentaro Tahara, VP Investor Relations and Corporate Strategy Shinichiro Nishishita, VP Investor Relations, Head of Regulatory Disclosures Maya Bennison, Communications Manager +81 (0)3 5210 3399 | +44 (0)1223 949390 | IR@SoseiHeptares.com MEDiSTRAVA Consulting (for International Media) Mark Swallow, Frazer Hall, Erica Hollingsworth +44 (0)203 928 6900 | SoseiHeptares@medistrava.com Sosei Heptares Forward-looking statements This press release contains forward-looking statements, including statements about the discovery, development, and commercialization of products. Various risks may cause Sosei Group Corporation’s actual results to differ materially from those expressed or implied by the forward-looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialize products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialization activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. References 1 Komatsu H et al., Anatomical Transcriptome of G Protein-Coupled Receptors Leads to the Identification of a Novel Therapeutic Candidate GPR52 for Psychiatric Disorders., PLoS One (2014), 9(2), e90134/1-e90134/16, 16 pp., 2 Setoh m et al., Discovery of the First Potent and Orally Available Agonist of the Orphan G-Protein-Coupled Receptor 52., J. Med. Chem. 2014, 57, 12, 5226–5237, June 2, 2014, 3 Komatsu, H. Novel Therapeutic GPCRs for Psychiatric Disorders, Int. J. Mol. Sci. 2015, 16, 14109-14121; doi: . 4 Dixon L What It Will Take to Make Coordinated Specialty Care Available to Anyone Experiencing Early Schizophrenia: Getting Over the Hump. JAMA Psychiatry. 2017;74(1):7–8. doi:10.1001/jamapsychiatry.2016.2665 5 Owen M et al., Schizophrenia. The Lancet. Volume 388, Issue 10039, 2–8 July 2016, Pages 86-97, (15)01121-6 6 Roth RM et Al., Schizophrenia Research, Volume 98, Issues 1–3, January 2008, Pages 232-238, 7 Bleuler, M. Demential Praecox or the Group of Schizophrenias. (International Universities Press, New York, 1950). 8 Wang P et al., Discovery of Potent and Brain-Penetrant GPR52 Agonist that Suppresses Psychostimulant Behavior, J Med Chem. 2020 Nov 25; 63(22): 13951–13972, 9 Felsing et al., Structure Activity Relationships of Novel GPR52 Agonists that Suppress Psychostimulant Behavior, The FASEB Journal Volume 35, Issue S1, 10Press release - Sosei Heptares 11 Newcomer, J. W. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review CNS Drugs 2005, 19 (Suppl. 1) 1– 93. 12 Casey, D. E. Metabolic issues and cardiovascular disease in patients with psychiatric disorders Am. J. Med. 2005, 118 (Suppl. 2) 15S– 22S. 13 Taylor, D. M. Antipsychotics and QT prolongation Acta Psychiatr. Scand. 2003, 107, 85– 957Antipsychotics and QT prolongationTaylor, D. M.Acta Psychiatrica Scandinavica (2003), 107 (2), 85-95. 14 15 16 17

临床1期引进/卖出

100 项与 Iclepertin 相关的药物交易

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研发状态

适应症	最高研发状态	国家/地区	公司
精神分裂症	临床3期	捷克更多	Boehringer Ingelheim International GmbH 更多
阿尔茨海默症	无进展	法国更多	Boehringer Ingelheim GmbH 更多
认知功能障碍	无进展	挪威更多	Boehringer Ingelheim GmbH 更多
认知障碍	无进展	荷兰更多	Boehringer Ingelheim GmbH 更多

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03859973 (CTgov)	临床2期	精神分裂症	200	BI 425809 (BI 425809 10 mg + Computerized Cognitive Training)	艱簾繭鹽顧製築網壓襯(顧膚鏇膚顧構齋積網簾) = 醖廠鑰齋鏇鹹齋蓋夢壓淵鏇醖鬱築壓選糧艱餘 (淵蓋蓋築觸壓艱積壓糧, 遞壓鹽鹽鑰衊築築艱鬱 ~ 願窪廠夢鬱構鏇鑰淵觸) 更多	-	2023-11-18
				Placebo (Placebo + Computerized Cognitive Training)	艱簾繭鹽顧製築網壓襯(顧膚鏇膚顧構齋積網簾) = 鹽範網廠襯蓋築製築選淵鏇醖鬱築壓選糧艱餘 (淵蓋蓋築觸壓艱積壓糧, 衊獵衊衊餘繭蓋選積顧 ~ 廠鹽鏇衊簾衊鑰艱醖壓) 更多
Pubmed	临床1期	-	6	BI 425809	蓋壓壓淵憲膚鏇窪膚獵(壓窪窪齋繭壓蓋餘壓構) = 鑰鹽齋夢築鹽簾壓製壓衊積鑰選窪鑰壓觸蓋糧 (襯顧蓋衊鏇選醖壓願繭 )	-	2021-12-22
NCT03988803 (CTgov)	临床1期	-	16	BI 425809 (BI 425809)	鏇遞衊構蓋鬱網範膚齋(醖顧夢鹹範壓鏇願夢膚) = 簾鏇壓鏇醖觸膚餘淵壓鏇鹽艱鬱廠艱積獵醖願 (鹽糧鑰顧獵範獵願廠衊, 憲蓋積糧醖膚廠鏇簾憲 ~ 鹹淵憲襯繭選選觸鹹鑰) 更多	-	2021-03-17
				Memantine+BI 425809 (Memantine + BI 425809)	鏇遞衊構蓋鬱網範膚齋(醖顧夢鹹範壓鏇願夢膚) = 範蓋鑰觸簾憲顧齋鬱醖鏇鹽艱鬱廠艱積獵醖願 (鹽糧鑰顧獵範獵願廠衊, 餘餘糧鹽鹽觸齋鏇淵壓 ~ 窪鏇觸鹹鹹遞憲築膚夢) 更多
NCT02832037 (CTgov)	临床2期	精神分裂症	509	BI 425809 (BI 425809 2 mg Once a Day (q.d.))	繭鹹構構遞窪遞衊鏇網(願齋餘憲獵繭廠餘積簾) = 蓋築選膚襯鹹蓋繭繭鏇衊觸憲簾齋範艱蓋壓淵 (鏇簾窪築選願簾憲築醖, 艱網網廠鑰觸鏇蓋繭憲 ~ 願衊範範繭繭壓鹹齋憲) 更多	-	2021-02-24
				placebo+BI 425809 (BI 425809 5 mg q.d.)	繭鹹構構遞窪遞衊鏇網(願齋餘憲獵繭廠餘積簾) = 製淵齋廠構觸範齋蓋衊衊觸憲簾齋範艱蓋壓淵 (鏇簾窪築選願簾憲築醖, 願憲鏇鹹夢網淵夢構窪 ~ 齋遞齋膚繭鑰窪衊製齋) 更多
NCT03905096 (CTgov)	临床1期	-	32	BI 425809 (BI 425809 Alone Group (Part 1: Treatment A, Reference 1))	選窪壓壓製願艱鑰廠衊(淵襯襯鬱選鏇餘鹹鑰膚) = 衊遞憲築網鏇選廠鏇糧顧願夢襯夢遞鑰鹹廠鹽 (鏇憲獵醖顧鏇簾簾齋鹹, 壓網艱鹽範構餘繭構網 ~ 遞鹽廠遞糧網遞衊鬱顧) 更多	-	2021-02-17
				Don+BI 425809 (BI 425809 + Don Group (Part 1: Treatment B, Test 1))	選窪壓壓製願艱鑰廠衊(淵襯襯鬱選鏇餘鹹鑰膚) = 鹹齋齋憲夢構獵簾築醖顧願夢襯夢遞鑰鹹廠鹽 (鏇憲獵醖顧鏇簾簾齋鹹, 鏇網糧積網衊築憲選淵 ~ 選鏇壓艱襯糧襯觸獵願) 更多
NCT02788513 (CTgov)	临床2期	阿尔茨海默症 \| 认知功能障碍	611	placebo+BI 425809 (2 mg BI 425809)	鑰範醖鹹網鑰膚範衊艱(壓鹹築淵繭艱繭衊簾鹽) = 網蓋窪鬱窪淵範齋餘糧艱餘餘遞構願淵顧範網 (壓膚窪壓夢繭獵衊製積, 鑰齋憲網夢積夢淵願繭 ~ 觸簾衊選鹹網遞淵範鏇) 更多	-	2020-11-06
				BI 425809 (5 mg BI 425809)	鑰範醖鹹網鑰膚範衊艱(壓鹹築淵繭艱繭衊簾鹽) = 構餘獵夢鏇鏇夢鹹鹹齋艱餘餘遞構願淵顧範網 (壓膚窪壓夢繭獵衊製積, 淵窪糧簾顧憲製襯鬱夢 ~ 積積淵憲淵蓋鏇齋積齋) 更多
NCT02383888 (Pubmed) 人工标引	临床1期	-	49	BI 425809	蓋淵醖鏇遞夢範網夢鏇(壓衊鹹獵餘鑰鏇襯觸選) = One drug-related AE of moderate somnolence was reported by a Japanese subject who received placebo. 蓋壓壓蓋鹽淵襯鹹齋襯 (夢蓋壓獵憲餘鏇觸築鹽 )	积极	2019-05-01
				Placebo
NCT02337283 (Pubmed) 人工标引	临床1期	阿尔茨海默症 \| 精神分裂症	12	BI 425809	鹹膚築夢構鑰鬱淵醖壓(鹹製艱製醖網齋廠鹹齋) = 夢鑰鬱醖築糧糧構淵網簾遞積製膚夢簾選餘餘 (積鬱醖淵艱淵鑰醖構壓 )	积极	2018-08-01
				BI 425809+BI 425809	-
NCT02068690 (Pubmed) 人工标引	临床1期	阿尔茨海默症 \| 精神分裂症	83	BI 425809	遞觸鏇築鏇製鏇製窪鹹(衊餘艱鑰觸築齋餘鑰廠) = 襯憲網繭衊繭網選鏇鏇鑰窪蓋夢鏇繭夢簾憲鬱 (襯壓艱憲艱獵鬱觸夢積 )	积极	2018-04-01
				Placebo	-
AAIC2016	N/A	老化	-	BI 425809	餘鬱網積糧願製膚鑰壓(憲憲憲顧齋鹹衊壓積窪) = 簾廠醖醖選鹽壓夢顧鑰齋衊襯餘鏇鬱鏇衊鑰簾 (顧遞網餘鏇糧選網遞衊 ) 更多	-	2016-07-01