英矽智能宣布提名口服NLRP3小分子抑制剂为临床前候选化合物

作为人体内抵抗微生物感染或内源性细胞损伤的第一道防线，先天免疫系统利用NLRs（NOD样受体）探测引发微生物感染和机体损伤的分子，进而确保正常的免疫应答功能。在NLRs家族中，NLRP3是科学界研究最为深入的成员，其过度激活会导致促炎细胞因子和趋化因子的过度产生，从而驱动多种炎症性疾病的病理过程。

马萨诸塞州剑桥市，2024年12月10日 --- 由生成式AI驱动的临床阶段生物科技公司英矽智能宣布提名ISM8969，一款口服给药的NLRP3抑制剂作为临床前候选化合物（PCC）。该候选化合物由英矽智能自有Pharma.AI平台辅助开发，具有可穿透血脑屏障（blood-brain barrier, BBB）性质，潜在用于痛风、哮喘、克罗恩病、阿尔茨海默病、癫痫等多种炎症相关疾病治疗。

NLRP3（NOD样受体热蛋白结构域相关蛋白3）可以形成称为“炎症小体”的多分子复合物，经激活后会触发先天性免疫级联反应。因此，NLRP3在微生物感染和机体损伤识别过程中发挥关键作用。研究显示，抑制NLRP3可以调节炎症反应，进而防止组织损伤、抑制IL-1β和IL-18的释放、减低细胞炎性坏死（细胞焦亡）。然而，目前仍未有特异性靶向NLRP3的药物获批上市，该领域仍需深入探索研究。

英矽智能联合首席执行官兼首席科学官任峰博士表示，“患者需求一直是驱动英矽智能管线开发决策的重要因素。考虑到全球范围内庞大的患者群体规模，研发团队已经关注到了包括炎症相关疾病在内的慢性病。此次临床前候选化合物提名意味着英矽智能在炎症疾病干预领域又迈出了一步，我们期待在AI驱动平台现有成就的基础上，进一步发挥人工智能优势，为患者获益持续努力。”

在临床前评估研究中，ISM8969表现出整体均衡的成药性特征，具有令人鼓舞的体外活性和安全性、良好的体内药代动力学和药效动力学特征，并在包括急性炎症疾病和慢性疾病模型的多个小鼠疾病模型中展现出针对炎症的药效。

与某些进入临床阶段的外周限制性NLRP3抑制剂不同，ISM8969具有理想的血脑屏障穿透性，能够穿过中枢神经系统和人体血液循环之间的天然屏障，提供了对抗神经炎症相关疾病的可能性。目前，英矽智能研发团队正在多种神经系统疾病模型中针对ISM8969应用进行评估。

英矽智能创始人兼首席执行官Alex Zhavoronkov博士表示，“慢性炎症与衰老和许多其他严重健康问题密切相关，针对性的干预因此变得格外关键。令人兴奋的是，AI正在加速研发过程，为高质量药物的诞生提供更多机会。在英矽智能，ISM8969的适应症拓展研究正在进行中，我们希望看到更多AI驱动的概念验证案例。”

As the first line against microbial infections or endogenous cellular damage in our body, the innate immune system utilizes NLRs (NOD-like receptors) to sense the molecules triggering microbial infection and damage, thus ensuring the proper immune response function. In the NLRs family, NLRP3 is the most characterized member, and its overactivation can lead to excessive production of pro-inflammatory cytokines and chemokines, driving pathological processes in various inflammatory diseases.

CAMBRIDGE, Mass., Dec 10, 2024 --- Insilico Medicine (“Insilico”), a clinical-stage generative artificial intelligence (AI)-driven drug discovery company, today announced the nomination of ISM8969, an orally available NLRP3 inhibitor as pre-clinical candidate. Powered by Insilico’s proprietary Pharma.AI platform, the BBB (blood-brain barrier) penetrable molecule was designed as a potential treatment of various inflammation-related diseases, including gout flare, asthma, Crohn’s disease, Alzheimer’s disease and epilepsy.

NLRP3 (NOD-like receptor family pyrin domain containing 3) is essential for identifying microbial infections and damage, which forms a multimolecular complex known as the inflammasome to trigger an innate immune cascade upon activation. By inhibiting NLRP3, it is possible to modulate the inflammatory response, so as to prevent tissue damage, leading to the suppression of IL-1β and IL-18 release, as well as a reduction in pyroptotic cell death. However, no current FDA-approved drugs specifically target NLRP3, calling for further research in the area.

“The need of patients has been driving our portfolio management decisions, and chronic diseases including inflammation-related disorders have attracted our attention with the massive population worldwide,” says Feng Ren, PhD, Co-CEO and Chief Scientific Officer of Insilico Medicine. “We are thrilled to take another step forward in the area of inflammation disease intervention. Leveraging our AI-driven platform has already demonstrated promising results, and we look forward to utilizing AI better for the benefit of patients.”

In preclinical evaluation studies, ISM8969 exhibited a balanced druggability profile, with promising in vitro activity and safety, favorable in vivo PK/PD (pharmacokinetic/pharmacodynamic) profile, as well as efficacy against inflammation in multiple mouse disease models, including acute inflammatory disease and chronic disease models.

Unlike certain peripheral-restricted candidates currently in the clinical stage also targeting NLRP3, ISM8969 has a desired BBB penetrable property, enabling the drug candidate to cross the natural protective membrane between CNS (central nervous system) and the blood stream, and providing the possibility to treat neuroinflammation-related diseases. The Insilico research and development team is working on the evaluation of ISM8969 in various neurological disease models.

“Chronic inflammation is closely linked to aging and a host of other serious health conditions, attaching even more importance to the fight against it,” says Alex Zhavoronkov, PhD, founder and CEO of Insilico Medicine. “It is exciting to see that AI has been accelerating the R&D process, giving more opportunities for a better shot at high-quality drugs. At Insilico, indication expansion research is ongoing for ISM8969, and we hope to see more proof-of-concept cases coming with the power of AI.”

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 21 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.