瑞士，星期四，2020年4月30日1:10 PM 欧洲中部时间*
作为全球首家发现COVID-19精准病因和病理1的AI生物医药公司，我们致力于公益发布Demiurge的COVID-19科学发现并公开验证Demiurge的COVID-19临床预测。
虽然基于2020年1月发布的同情用药数据2和体外实验数据3，全球专家普遍认为瑞德西韦(remdesivir)是COVID-19的最佳候选治疗方案，但是基于Demiurge的精准病理模型，我们在2020年2月23日公布的一个与大多数专家意见相反的临床预测：
“瑞德西韦作为目前在临床试验中的治疗药物，不会直接影响宿主细胞中的PI3K通路。瑞德西韦在用药过程中具有显著减少细胞内病毒复制的临床益处，但它也会诱导COVID-19潜伏于宿主细胞中。对于有中度至重度症状的COVID-19患者，瑞德西韦停药之后具有诱发细胞内病毒复制反弹的临床风险。”4
数据验证
2020年4月29日，全球第一个针对COVID-19重症患者的临床试验结果“针对COVID-19成年重症患者的瑞德西韦用药：一项随机，双盲，安慰剂对照，多中心临床试验”5发表于《柳叶刀》。该试验的临床方案设计、主要临床终点和入组排除标准都极为严谨。该试验最终分析了236名入组的COVID-19重症患者的相关临床数据。
由于瑞德西韦的作用机制是通过抑制病毒RNA复制酶来降低新冠病毒（SARS-CoV-2）在宿主细胞内的自我复制，因此瑞德西韦作为治疗COVID-19的效力在很大程度上取决于其抑制病毒载量的效力。因此，该试验在治疗日（第1、3、5、7和10天）和非治疗日（第14、21和28天）均收集了全部236名入组重症患者的多部位的病毒采样，并用定量PCR技术评估瑞德西韦对病毒载量的影响5:
如上图3所示5，虽然采集病毒样本的部位不同，瑞德西韦治疗组在停药之后的病毒载量与安慰剂组相比有显著的反弹（第21天和第28天），而瑞德西韦治疗组在用药期间的病毒载量与安慰剂组相比有数值上的降低（第5天和第7天）。
如上图S6所示5，虽然入组用药前的病程不同，瑞德西韦治疗组在停药之后的病毒载量与安慰剂组相比有显著的反弹（第21天和第28天），而瑞德西韦治疗组在用药期间的病毒载量与安慰剂组相比有数值上的降低（第5天和第7天）。
因此，这项大规模的临床试验数据已经验证了我们基于精准病理模型做出的与主流观点相反的临床预测——即瑞德西韦是在用药期间能够抑制病毒复制，但停药后导致病毒载量反弹的非特效药。
这个关键性临床试验的验证进一步表明，对于缺少临床数据和开发时间的新型疾病，基于AI的疾病建模和临床预测与传统方法相比，可提供更好的预测能力和解释能力。
治疗方案原则
做为体外细胞研究中展现出最强抗病毒功效的明星候选药物，瑞德西韦并未能在人类患者中显示出具有临床意义的抗病毒功效。一方面这样的结果令人失望，但另一方面这也给人警醒：瑞德西韦仅仅抑制病毒复制的作用机制，对于新冠病毒平衡病毒复制和病毒传播的生存机制来说，没有做到对症下药。正如我们自2020年3月7日6以来基于精准病理模型所预测和发表的那样：
“SARS-CoV-2与世界上迄今已知的所有其他病毒都有根本不同。” 1
“新冠病毒采用独特的无偏向性生存策略，平衡病毒复制与病毒扩散之间的差异，这与其他通常会彼此取舍的病毒形成鲜明的对比。” 1
“因此， 必须严谨合理地设计COVID-19的治疗方法，针对SARS-CoV-2平衡病毒复制和病毒扩散的无偏向性生存策略，对COVID-19的特效治疗方案也必须同时抑制病毒复制和调节免疫反应。” 1
因此，尽快发现同时抑制病毒复制和调节免疫反应的COVID-19特效治疗方案和长效疫苗可能是终结COVID-19大流行的唯一有效手段。
Demiurge是全球第一家基于精准病因和病理模型发现了COVID-19完整的预防和治疗方法的公司：
1. 伊立替康+依托泊苷作为危重症患者的特殊治疗方法（正在开展二期临床试验NCT04356690）
2. PI3K抑制剂可作为中重度患者的治疗方法（正在进行体外细胞研究）
3. 针对健康人群的广谱疫苗的非S病毒蛋白最佳靶标（正在进行前期开发）
参考文献:
1. Lovetrue, B. The AI-Discovered Aetiology of COVID-19 and Rationale of the Irinotecan+Etoposide Combination Therapy for Critically Ill COVID-19 Patients. (2020). doi:10.20944/PREPRINTS202003.0341.V1
2. Holshue, M. L. et al. First case of 2019 novel coronavirus in the United States. N. Engl. J. Med. 382, 929–936 (2020).
3. Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 30, 269–271 (2020).
4. Demiurge AI Discovers the Clinical Benefits and Risks of Remdesivir, Chloroquine, and PI3K inhibitors against 2019 Novel Coronavirus (COVID-19) - English. Available at: https://www.demiurge.technology/blog/demiurge-ai-discovers-the-clinical-benefits-and-risks-of-remdesivir. (Accessed: 30th April 2020)
5. Wang, Y. et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 0, (2020).
6. Demiurge AI Discovers the Complete Aetiology of COVID-19 and the Optimal Treatment Strategy for COVID-19 - English. Available at: https://www.demiurge.technology/blog/demiurge-ai-discovers-the-complete-aetiology-of-covid-19-and-the-optimal. (Accessed: 30th April 2020)
关于Demiurge Technologies AG
Demiurge Technologies是一家以研究为基础的AI技术与生物医药公司，致力于将公开的海量生命科学数据转换为精确疾病模型。Demiurge创新地建立了利用全球医药三期临床试验结果预测的准确性来验证并改良精准疾病模型的科学进化闭环。同时Demiurge 致力于将精准疾病模型发现的创新药物进行商业化开发。 Demiurge于2016年开始运营，总部位于瑞士。
AI已成为一种新型强大的技术方法，它可以帮助人类更深入地了解疾病和更快地发现药物。但AI必须经过严格的测试，在公众的监督下证明其价值。Demiurge已经完成了90多个三期临床试验结果的预测，实现了大于80%的准确率。同时，我们在推特（Twitter）上邀请公众参与见证我们对正在进行中的全球新药三期临床试验结果的预测（@DemiurgeTech）。
因此，我们在这里基于AI提出了COVID-19的完整致病机理和最佳治疗方案的科学假设，并公开邀请世界各地验证。Demiurge敦促大众在任何相关临床数据公布之前，不应将任何COVID-19候选治疗方案等同于COVID-19的治疗药物擅自使用。
* 本文译自于2020年4月30日发布的英文通告“Clinically Validated Pathology-based AI Prediction of Remdesivir-specific Post-treatment Rebound of SARS-CoV-2” 中英文通告的最终解释以英文为准。
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