启明星 | 英矽智能全球首创TNIK抑制剂ISM001-055获2a期临床试验积极结果 | Bilingual

启明创投投资企业、由生成式人工智能（AI）驱动的临床阶段生物科技公司英矽智能宣布，其在研管线ISM001-055在一项2a期临床试验中取得了积极的初步研究结果。ISM001-055是一款“全球首创”（first-in-class）小分子抑制剂，由生成式AI驱动药物发现与设计过程，靶向TNIK（Traf2/NCK相互作用激酶）用于特发性肺纤维化（IPF）治疗。

此项研究不仅达到了主要研究终点，即药物的安全性验证，同时达到了次要研究终点，即初步疗效验证，在用力肺活量（FVC）这一评测IPF患者肺功能改善的重要指标上呈现出剂量依赖性的药效趋势。

此前，英矽智能于2024年3月在全球顶尖期刊Nature Biotechnology发表科研论文，详细介绍了利用人工智能平台发现治疗IPF的新颖靶点TNIK，以及随后利用生成化学平台设计ISM001-055分子的全过程。该论文还首次披露了该人工智能赋能发现的小分子药物的临床前数据，以及积极的0期微剂量人体试验和1期临床研究结果，展示了该分子改善IPF疾病的潜力。

这项针对ISM001-055开展的2a期临床研究（NCT05938920）是一项随机、双盲、安慰剂对照试验，在中国21个临床研究中心招募了71名IPF患者。患者被随机分配接受安慰剂、每日一次30mg、每日两次30mg或每日一次60mg，持续12周的用药观察。该临床试验于2023年4月启动患者招募工作，并于2024年8月完成最后一位受试者的随访。与此同时，一项ISM001-055的平行2a期试验（NCT05975983）正在美国进行，并已启动患者招募工作。

为期12周的研究初步结果表明，ISM001-055在所有剂量水平上均表现出良好的安全性。次要终点即主要通过FVC评测IPF患者肺功能改善方面，呈现出剂量依赖性的药效趋势，接受每日一次60mg用药的IPF患者，在FVC方面表现出最大改善。英矽智能计划在后续医学会议上发布该项研究的完整数据，并提交期刊开展同行审议并发表。

英矽智能创始人兼首席执行官Alex Zhavoronkov博士表示：“这项研究结果代表了人工智能驱动药物发现的一个关键里程碑，也是我迄今为止人生中的一个重要里程碑。虽然我们预期该药物是安全的，但并没有预料到在如此短的给药期后，看到明显的剂量依赖性疗效信号。IPF是一种非常多样化的疾病，很难见到患者FVC的改善，我们试图寻找在纤维化疾病和衰老中的共同生物学机制，最大限度地扩大创新TNIK抑制剂在适应症拓展方面的潜力。”

英矽智能联合首席执行官兼首席科学官任峰博士表示：“很高兴在三个月的治疗周期中看到ISM001-055针对特发性肺纤维化（IPF）的显著临床疗效。ISM001-055为人工智能驱动的药物发现提供了概念性验证。虽然这些数据还是初步的，但无疑非常令人鼓舞。我相信这一里程碑的实现既得益于我们专有生成式人工智能平台的能力，也归功于我们多学科研发团队的努力。我们将继续为全球患者获益而努力。”

在取得这项2a期试验的积极结果后，英矽智能计划与监管机构围绕ISM001-055的2b期研究设计展开讨论，旨在更长的给药期和更广的患者队列中，进一步研究ISM001-055对IPF的治疗潜力。

Insilico Medicine, a clinical-stage generative artificial intelligence (AI)-driven biotechnology company and our portfolio company, announced positive preliminary results from its Phase 2a clinical trial evaluating ISM001-055. ISM001-055 is a first-in-class small molecule targeting TNIK (Traf2- and Nck-interacting kinase) and was designed utilizing generative AI to treat idiopathic pulmonary fibrosis (IPF). The study met both its primary endpoint of safety and its secondary efficacy endpoints, demonstrating dose-dependent response in forced vital capacity (FVC), a critical measure of lung function in IPF patients.

Insilico Medicine's proprietary AI platform facilitated ISM001-055's target identification and molecular design. Its development was recently described in a March 2024 Nature Biotechnology paper, which detailed TNIK's identification as a novel therapeutic target in IPF and ISM001-055 subsequent design. This comprehensive paper showcased ISM001-055's preclinical evaluation and positive Phase 0 & Phase 1 clinical studies justifying this intervention's potential as a disease-modifying agent for IPF.

ISM001-055's Phase 2a study (NCT05938920) was a randomized, double-blind, placebo-controlled trial that enrolled 71 patients with IPF across 21 sites in China. Patients were randomized to receive either placebo, 30mg once daily (QD), 30mg twice daily (BID), or 60mg QD for 12 weeks. Patient enrollment was initiated in April 2023, and the last subject's follow-up visit was completed in August 2024. A parallel Phase 2a (NCT05975983) clinical trial in the U.S. is ongoing and actively enrolling patients.  

In this 12-week Phase 2a study, ISM001-055 met its primary endpoint of safety and tolerability across all dose levels. Positive results were also reported for the secondary efficacy endpoint, wherein a dose-dependent FVC improvement was observed. Patients receiving 60mg QD of ISM001-055 demonstrated the largest improvement in FVC. Complete topline data will be released at the upcoming medical conference and clinical trial results will be submitted for publication in a peer-reviewed journal.

"This study result represents a critical milestone in AI-powered drug discovery and in my life to date," said Alex Zhavoronkov, PhD, co-CEO of Insilico Medicine. "While we expected the drug to be safe, we did not expect to see such a clear dose-dependent efficacy signal after such a short dosing period. IPF is a very diverse disease and it is very rare to see improvement in FVC. With our novel TNIK inhibitor, we attempted to go after what we think is a common mechanism in fibrotic diseases and in aging to maximize indication expansion potential."

"I am excited to see that ISM001-055 demonstrated obvious clinical efficacy in IPF patients in only 3-months treatment. While preliminary, this clinical data is certainly encouraging, and provides the clinical validation of AI-powered drug R&D for both novel target and novel molecule," said Feng Ren, PhD, co-CEO and CSO of Insilico Medicine. "This is a significant milestone for Insilico Medicine and the AI driven drug discovery Industry. The milestone is achieved due to the contribution of both the capabilities of our proprietary generative AI platform and the efforts of our multidisciplinary R&D team. We will continue to fully commit to provide breakthrough solutions for the benefit of the patients globally."

Following the positive results from this Phase 2a trial, Insilico Medicine will engage regulatory authorities to discuss the design of a Phase 2b study. The company aims to explore extended treatment durations and larger patient cohorts to further investigate ISM001-055's therapeutic potential in IPF.