Trospium Chloride/Xanomeline

First in Class类新药开发绝非易事，内外部的经验皆可借鉴。【First in Class类新药开发系列】将通过一些案例的介绍，希望能够给国内生物医药公司First in Class类新药开发提供经验和思考。 70年来精神分裂症First in Class新药KarXT即将于今年9月底获得FDA批准！ KarXT是由xanomeline（一种新型毒蕈碱乙酰胆碱受体激动剂）和曲司氯铵（一种FDA批准上市的毒蕈碱受体拮抗剂）组成，已证明不会进入中枢神经系统。 百时美施贵宝于2023年12月收购Karuna Therapeutics获得的用于治疗成人精神分裂症新药KarXT有望于2024年9月26日之前获得FDA批准。值得一提的是，再鼎医药在2021年11月与Karuna Therapeutics达成独家许可协议，获得了KarXT在大中华区的权益。 20世纪50年代初，氯丙嗪被意外发现可以用于治疗精神分裂症。在接下来的20年里，研究人员发现，该药物治疗精神分裂症主要通过作用于多巴胺2(D2)受体来减少大脑中的多巴胺，精神分裂症的多巴胺假说于1966年流行起来。 70多年过去了，目前所有获批的抗精神病药物仍然以D2受体为靶点。不幸的是，这些药物会引起各种不良反应，并且不能治疗所有精神分裂症症状。研究表明，会有多达70%的患者停止服用抗精神病药物。尽管新型抗精神病药物非常急需，但患者没有其他更好的选择。 KarXT并非通过阻断D2受体来降低大脑中的多巴胺水平，而是针对与乙酰胆碱结合的毒蕈碱受体。在五种毒蕈碱乙酰胆碱受体中，KarXT针对M1和M4。根据迄今为止的研究，KarXT对M1受体的调节（可增强乙酰胆碱信号传导）似乎可以带来认知益处，因为M1受体在大脑中对学习和记忆很重要的区域（如海马体）和前额叶皮质中的执行功能有表达。另一方面，对M4受体的调节会产生抗精神病作用，因为它们在与感知相关的大脑区域中有表达。 尽管KarXT等毒蕈碱受体激动剂不会直接阻断多巴胺受体，但研究人员认为，其有益作用源于其调节多巴胺水平的能力。毒蕈碱乙酰胆碱受体不仅通过乙酰胆碱调节多巴胺水平，还通过乙酰胆碱与神经递质γ-氨基丁酸(GABA)和谷氨酸的相互作用调节多巴胺水平。 不同的机制可能意味着患者有更多选择。 如果FDA今年批准百时美施贵宝的抗精神病药物KarXT，这种局面最终可能会改变，该药物模仿神经递质乙酰胆碱并与毒蕈碱乙酰胆碱受体1（M1）和4（M4）结合。 KarXT在3项关键的Ⅲ期临床试验中（EMERGENT-1、2、3）优异的结果也让业界对其顺利获得批准坚信不疑。 在主要终点方面，EMERGENT-3在第五周使KarXT的阳性和阴性症状量表(PANSS)总分降低了8.4分，略低于EMERGENT-2中的9.6分和EMERGENT-1的11.6分。 在次要终点方面，与安慰剂相比，EMERGENT-3研究中KarXT治疗在第五周使PANSS阳性分量表评分降低了3.5分，高于EMERGENT-2中降低的2.9分和EMERGENT-1中降低的3.2分。 尽管EMERGENT-3研究中KarXT未达到阴性症状终点（在第四周时，显示出PANSS阴性分量表分数的统计学显著性减少，第五周时终点未达标似乎是由于安慰剂组的差异造成的），而之前的研究EMERGENT-1和EMERGENT-2达到了该终点；然而，这不会影响其在更广泛的精神分裂症适应症中获批的可能性。 值得注意的是，KarXT显示出快速起效，早在第二周就观察到了统计学上显着的效果，并且在第一周有分离趋势。 在安全性方面，EMERGENT-3研究中治疗组的停药率高于EMERGENT-2（37%比25%）；然而，安慰剂组的停药率也更高（29%比21%）。EMERGENT-3研究中因治疗出现的不良事件而停药的人数（KarXT为6%，安慰剂为5%）与EMERGENT-2相当（KarXT为7%，安慰剂为6%）。这些比率与其他非典型抗精神病药物的试验一致，不会对药物的潜力产生负面影响。 而且在长期开放标签试验的中期汇总分析表明，在52周的试验中，门诊精神分裂症患者对KarXT的耐受性普遍良好。 由于缺乏头对头试验，有研究进行了网络荟萃分析（Doi：10.18553/jmcp.2024.30.6.624），以间接比较KarXT与3种第二代抗精神病药物（阿立哌唑、利培酮和奥氮平）。 与安慰剂相比，所有干预措施均显示PANSS总分和PANSS反应显著改善。然而，KarXT和3种抗精神病药物在任一结果上均无显著差异。与奥氮平和利培酮相比，KarXT导致的体重增加显著减少，但与阿立哌唑相比差异不大。相比之下，KarXT的全因停药率显著高于奥氮平和利培酮。 继KarXT之后，其他针对毒蕈碱乙酰胆碱受体治疗精神分裂症的药物也正在开发中。Cerevel、Neumora和Neurocrine Biosciences等公司都在进行临床试验靶向M4受体的药物。虽然所有这些药物都作用于M4，但它们的作用机制不同；KarXT和Neurocrine Biosciences的药物是激动剂，而Cerevel和Neumora的药物是正向变构调节剂。 然而，精神分裂症需要更多具有新颖和不同作用机制的新药物。其中默沙东正在开发进入Ⅱb期临床试验的磷酸二酯酶10A (PDE10A) 抑制剂就是典型例子。 备注：本文已刊载《医药经济报》有删改。 敬请期待下一期【First in Class类新药开发系列】：First in Class精神分裂靶点PDE10A“三连败”后：默沙东MK-8189初步看到更广泛潜力。 “新药前沿”格言 要从挫折中吸取教训克服困难继续向前迈进，而不是害怕失败。 本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。 免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。 限于作者水平和专业知识所限，如有谬误，欢迎指正！

BOSTON--( BUSINESS WIRE )-- PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to changing the lives of patients with devastating diseases, noted that its Founded Entity, Vor Bio (Nasdaq: VOR), a clinical-stage cell and genome engineering company, announced new clinical data from its ongoing Phase 1/2 VBP101 study of patients with relapsed/refractory AML receiving trem-cel followed by Mylotarg™. The data demonstrated reliable engraftment, shielding from Mylotarg on-target toxicity, a broadened Mylotarg therapeutic window, and early evidence of patient benefit. The full text of the announcement from Vor is as follows: New Clinical Data Validates Vor Bio’s Approach of Using Shielded Transplants to Deliver Targeted Therapies Trem-cel + Mylotarg demonstrated engraftment, shielding, broadened therapeutic window, and patient benefit VCAR33 ALLO demonstrates encouraging biomarker data at lowest dose New asset VADC45 with significant potential opportunities across oncology, gene therapy, and autoimmune disorders CAMBRIDGE, Mass., Sept. 05, 2024 -- Vor Bio (Nasdaq: VOR), a clinical-stage cell and genome engineering company, today announced new clinical data from its ongoing Phase 1/2 VBP101 study of patients with relapsed/refractory AML receiving trem-cel followed by Mylotarg™. The data demonstrated reliable engraftment, shielding from Mylotarg on-target toxicity, a broadened Mylotarg therapeutic window, and early evidence of patient benefit. “ We are encouraged by this data and the potential benefit that trem-cel in combination with Mylotarg may offer to patients in a disease that has extremely poor outcomes even after transplant,” said Dr. Eyal Attar, Vor Bio’s Chief Medical Officer. “ With this data, we plan to explore a registrational trial while we continue to pursue other synergistic opportunities for Vor Bio’s platform such as VCAR33 ALLO and VADC45.” The data released today included 18 patients treated with trem-cel of which ten had received Mylotarg as of the data cut-off date of July 19, 2024. The data demonstrated: Reliable engraftment, with 100% of patients achieving primary neutrophil engraftment​ (median 9 days) and robust platelet recovery (median 16.5 days)​. High CD33 editing efficiency (median 89%, range 71-94%)​ and full myeloid chimerism ​at Day 28. Shielding of the blood system, with maintained neutrophil and platelet counts across multiple Mylotarg doses of 0.5, 1, and 2 mg/m 2 . Broadened therapeutic index for Mylotarg with drug exposure represented by AUC which is related to efficacy, consistent with labeled Mylotarg doses, and with maximal concentrations, measured by C max and related to veno-occlusive disease, well below known toxic range. Early evidence suggesting patient benefit as measured by relapse-free survival when compared to published high-risk AML comparators 1 . “ All the hope I had in the safety of this approach has been supported by the data from this trial thus far,” said Guenther Koehne, MD, PhD, an investigator on the VBP101 study and Deputy Director and Chief of Blood & Marrow Transplant and Hematologic Oncology at Miami Cancer Institute of Baptist Health South Florida. “ I look forward to treating my next patients at high risk of relapse on this trial as their outcomes are otherwise limited with standard transplants.” Vor Bio plans to approach the U.S. Food & Drug Administration to discuss a pivotal trial design for trem-cel + Mylotarg by around year end. Continued progress with VCAR33 ALLO VCAR33 ALLO represents another potentially significant synergistic treatment option after trem-cel. The VBP301 study continues enrolling patients with initial focus on relapsed/refractory AML post-transplant. Vor Bio is encouraged by in vivo CAR-T expansion data from three patients treated to date, all at the lowest dose of 1 x 10 6 CAR+ cells/kg. Vor Bio announced today, a new preclinical asset, VADC45, which has a number of potential opportunities in oncology, gene therapy, and autoimmune disorders. VADC45 is an ADC that targets the CD45 protein. CD45 is a well-validated target for a wide variety of blood cancers with clinical proof of concept. The linker-payload used in VADC45 is also clinically validated. VADC45 has the potential to treat a number of diseases, including treatment of hematologic malignancies, as a targeted conditioning agent for gene therapies such as for sickle cell disease, holistic immune reset for autoimmune disorders, and for Vor Bio’s approach of combining this asset with epitope modification of CD45 to shield healthy stem cells. Vor Bio already has robust preclinical data for VADC45 and is progressing IND-enabling studies to enable future Phase 1 studies. About Vor Bio Vor Bio is a clinical-stage cell and genome engineering company that aims to change the standard of care for patients with blood cancers by engineering hematopoietic stem cells to enable targeted therapies post-transplant. For more information, visit: www.vorbio.com . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The words “aim,” “anticipate,” “can,” “continue,” “could,” “design,” “enable,” “expect,” “initiate,” “intend,” “may,” “on-track,” “ongoing,” “plan,” “potential,” “should,” “target,” “update,” “will,” “would,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements in this press release include Vor Bio’s statements regarding the potential of its product candidates to positively impact quality of life and alter the course of disease in the patients it seeks to treat, the timing of regulatory filings and initiation of clinical trials, the timing and pace of patient enrollment and dosing in clinical trials and the availability of data therefrom, the expected safety profile of its product candidates, its intentions to use VCAR33 ALLO in combination with trem-cel as a Treatment System, the potential of trem-cel to enable targeted therapies in the post-transplant setting including Mylotarg and CD33-targeted CAR-Ts, and the ability of VADC45 to treat hematologic malignancies and to be used as a targeted conditioning agent for gene therapies, as a holistic immune reset for autoimmune disorders, and in combination with opitope modification of CD45 to shield healthy stem cells. Vor Bio may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of Vor Bio’s product candidates; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; uncertainties regarding regulatory approvals to conduct trials or to market products; the success of Vor Bio’s in-house manufacturing capabilities and efforts; and availability of funding sufficient for its foreseeable and unforeseeable operating expenses and capital expenditure requirements and Vor Bio’s ability to continue as a going concern. These and other risks are described in greater detail under the caption “Risk Factors” included in Vor Bio’s most recent annual or quarterly report and in other reports it has filed or may file with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Vor Bio expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise, except as may be required by law. About PureTech Health PureTech is a clinical-stage biotherapeutics company dedicated to giving life to new classes of medicine to change the lives of patients with devastating diseases. The Company has created a broad and deep pipeline through its experienced research and development team and its extensive network of scientists, clinicians and industry leaders that is being advanced both internally and through its Founded Entities. PureTech's R&D engine has resulted in the development of 29 therapeutics and therapeutic candidates, including two that have received both U.S. FDA clearance and European marketing authorization and a third (KarXT) that has been filed for FDA approval. A number of these programs are being advanced by PureTech or its Founded Entities in various indications and stages of clinical development, including registration enabling studies. All of the underlying programs and platforms that resulted in this pipeline of therapeutic candidates were initially identified or discovered and then advanced by the PureTech team through key validation points. For more information, visit www.puretechhealth.com or connect with us on X (formerly Twitter) @puretechh. Cautionary Note Regarding Forward-Looking Statements This press release contains statements that are or may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation those related to Vor’s Bio’s statements regarding the potential of its product candidates to positively impact quality of life and alter the course of disease in the patients it seeks to treat, the timing of regulatory filings and initiation of clinical trials, the timing and pace of patient enrollment and dosing in clinical trials and the availability of data therefrom, the expected safety profile of its product candidates, its intentions to use VCAR33 ALLO in combination with trem-cel as a Treatment System, the potential of trem-cel to enable targeted therapies in the post-transplant setting including Mylotarg and CD33-targeted CAR-Ts, and the ability of VADC45 to treat hematologic malignancies and to be used as a targeted conditioning agent for gene therapies, as a holistic immune reset for autoimmune disorders, and in combination with opitope modification of CD45 to shield healthy stem cells. The forward-looking statements are based on current expectations and are subject to known and unknown risks, uncertainties and other important factors that could cause actual results, performance and achievements to differ materially from current expectations, including, but not limited to, those risks, uncertainties and other important factors described under the caption "Risk Factors" in our Annual Report on Form 20-F for the year ended December 31, 2023, filed with the SEC and in our other regulatory filings. These forward-looking statements are based on assumptions regarding the present and future business strategies of the Company and the environment in which it will operate in the future. Each forward-looking statement speaks only as at the date of this press release. Except as required by law and regulatory requirements, we disclaim any obligation to update or revise these forward-looking statements, whether as a result of new information, future events or otherwise. 1 Araki et al. JCO 2016; Jentzsch et al. Blood Cancer Journal 2022.