英矽智能完成新型泛TEAD抑制剂ISM6331的首次患者给药

⦿ ISM6331的全球多中心I期临床试验在中国和美国同步进行，已于近期在中国完成了首次患者给药；

⦿作为一种具有新颖结构的强效泛TEAD抑制剂，ISM6331在临床前研究中表现出卓越的疗效和安全性；

⦿ISM6331不仅能有效靶向hippo通路异常的肿瘤，有望与靶向疗法、化疗和免疫疗法联合用药，发挥协同抗肿瘤作用并克服耐药性。

1月23日--由生成人工智能（AI）驱动的临床阶段生物医药科技公司英矽智能今天宣布，公司自主研发的新型泛TEAD抑制剂ISM6331，已在全球多中心I期临床试验中完成首次患者给药，用于治疗间皮瘤和其他实体瘤。ISM6331是由英矽智能的生成化学引擎Chemistry42辅助开发的，是目前公司全资拥有的人工智能驱动发现的药物资产中进展最为领先的肿瘤管线，2024年6月，这款候选药物已被美国FDA授予孤儿药资格认定，用于治疗间皮瘤。

这项全球多中心I期临床试验在中国和美国同时进行，旨在评估ISM6331单药治疗晚期或转移性恶性间皮瘤或其他实体瘤患者的安全性、耐受性、药代动力学、药效学和初步抗肿瘤活性。该研究由两部分组成，一部分是剂量递增研究，第一例患者已于近期在中国入组；另一部分是剂量选择优化研究，将在第一部分完成后启动。关于ISM6331这项临床试验的更多信息，可以访问ClinicalTrials.gov（NCT06566079）了解。

英矽智能首席医学官 Sujata Rao博士表示， "我们很高兴地宣布，作为全球临床开发计划的一部分，ISM6331的首例患者给药于近期在中国完成。我们也将继续推进美国的患者招募工作，加快项目的临床转化，致力于为尚为满足的医疗需求提供创新疗法。”

作为一种强效的泛TEAD 抑制剂，ISM6331旨在通过阻断促进癌症进展的多个基因的转录，从而有效恢复 Hippo 通路的平衡，防止肿瘤细胞的增殖和存活。它还有望与靶向疗法、化疗和免疫疗法联合用药，发挥协同抗肿瘤作用并克服耐药性。

在早期药物发现过程，ISM6331 新型非共价结构的设计在Chemistry42 基于结构的药物设计策略的指导下大大加快。临床前研究显示，ISM6331 在多个细胞系中表现出广泛的抗肿瘤疗效，在动物模型中表现出低剂量下的强效活性，同时它具有良好的 ADMET 特性和理想的安全性。凭借卓越的疗效和安全性数据，ISM6331显示出了同类最佳的潜力，进一步驱动了英矽智能将该管线推向临床验证阶段。

英矽智能联合首席执行官兼首席科学官任峰博士表示，"通过靶向TEAD家族，ISM6331 有望抑制肿瘤的生长和恶化，为由hippo通路异常导致的恶性肿瘤提供针对性的治疗策略。我们期待着进一步对ISM6331开展临床验证，并将这些具有前景的临床前研究结果转化对患者切实的临床获益。”

2016年，英矽智能全球首次在同行评审期刊上阐述了使用生成式人工智能设计新型分子的概念，为涵盖生成生物学、化学和医学等领域的商业化Pharma.AI 平台奠定了基础。自2021年以来，英矽智能在自有人工智能平台Pharma.AI的支持下，建立了超过30条丰富的自研管线组合，并从中提名了22款临床前候选项目，其中10款化合物获得临床试验许可。

2024年初，英矽智能在Nature Biotechnology发布论文，介绍了领先自研AI药物ISM001-055从人工智能算法到II期临床试验的整个研发历程。该候选药物具有人工智能发现的靶点和人工智能设计的结构，针对其进行评估的一项IIa期临床试验（NCT05938920）于近期发布积极初步结果。数据表明，ISM001-055在用药12周后显示出全剂量组中的良好安全性和用力肺活量（FVC）的剂量依赖性药效趋势。

⦿ The global multicenter Phase I trial of ISM6331 that is enrolling patients in China and the United States has advanced with the dosing of the first patient in this study for the treatment of mesothelioma and other solid tumors.

⦿ ISM6331, a potent pan-TEAD inhibitor with novel scaffold, demonstrates superior efficacy and safety in preclinical studies.

⦿ ISM6331 not only effectively targets tumors with abnormalities in the hippo pathway but also shows synergistic anti-tumor effects and overcomes drug resistance in combination therapy.

CAMBRIDGE, Mass., January 23 --- Insilico Medcine( “Insilico”) , a clinical stage generative artificial intelligence (AI)-driven biotechnology company today announced the first patient has been dosed in the global multicenter Phase I Trial of ISM6331, a novel pan-TEAD inhibitor developed from Insilico's generative chemistry engine Chemistry42, for the treatment of mesothelioma and other solid tumors. Currently, ISM6331 is the leading oncology program among Insilico's wholly owned AI-driven drug discovery pipelines, which was granted orphan drug designation (ODD) by the FDA for the treatment of mesothelioma.

The Phase I trial conducted concurrently in China and the United States, was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ISM6331 as a single agent in patients with advanced or metastatic malignant mesothelioma or other solid tumors. The study consists of two parts, a dose escalation part, with the first patient enrolled in China recently, and a dose selection optimization part which will be initiated after part 1 is completed. For more information about Insilico's clinical trials please visit ClinicalTrials.gov (NCT06566079).

“We are pleased to announce the dosing of the first patient in our Phase I ISM6331 clinical trial in mesothelioma and other solid tumors.” says Sujata Rao, MD, Chief Medical Officer of Insilico Medicine. “We will also move forward to advance patient enrollment in the United States and accelerate the clinical translation to deliver innovative therapies that address unmet medical needs.”

As a potent pan-TEAD inhibitor, ISM6331 was developed to effectively restore the balance of the Hippo pathway and prevent the proliferation and survival of tumor cells through blocking the transcription of multiple genes that promote cancer progression. It is also expected to be used in combination with targeted therapies, chemotherapies and immunotherapies for the treatment of solid tumors, showing potential synergistic anti-tumor effects and overcoming drug resistance.

The design of ISM6331's novel non-covalent structure was greatly accelerated during early drug discovery, guided by Chemistry42's structure-based drug design strategy. In preclinical studies, ISM6331 demonstrated broad anti-tumor efficacy in multiple cell lines, potent activity at low doses in animal models, and a favorable safety profile with favorable ADMET characteristics. With superior efficacy and safety data, ISM6331 showed Best-in-class potential and further encouraged Insilico to advance the asset into clinical validation. 

“By inhibiting TEAD, ISM6331 has the potential to suppress tumor growth and progression, providing a targeted therapeutic strategy for malignancies driven by alterations in the Hippo pathway. ” says Feng Ren, Ph.D., Co-CEO and Chief Scientific Officer of Insilico Medicine. “We look forward to further clinical validation of ISM6331 and to translating these promising preclinical findings into tangible clinical benefits for patients.”

In 2016, Insilico first described the concept of using generative AI for the design of novel molecules in a peer-reviewed journal, which laid the foundation for the commercially available Pharma.AI platform. Since then, Insilico keeps integrating technical breakthroughs into Pharma.AI platform, which is currently a generative AI-powered solution spanning across biology, chemistry, medicine development and science research. Powered by Pharma.AI, Insilico has nominated 22 preclinical candidates in its comprehensive portfolio of over 30 assets since 2021 and has received IND clearance for 10 molecules. 

In early 2024, Insilico published a Nature Biotechnology paper presenting the entire R&D journey from AI algorithms to Phase II clinical trials of ISM001-055, the company's lead drug pipeline with AI-discovered target and AI-designed structure. Following that, Insilico has recently announced positive preliminary results from a Phase IIa trial (NCT05938920), where ISM001-055 showed favorable safety and tolerability across all dose levels, as well as dose-dependent response in forced vital capacity (FVC), after only 12 weeks of dosage.