29 日起,阿尔兹海默病患者可以凭医生处方,在全国各大专业药房买到“九期一”了。 From December 29 , patients with Alzheimer's disease can buy "Nine Phases One" in major professional pharmacies across the country with a doctor's prescription.

Taking the opportunity of a formal listing, some queries were answered.

Doubt 2: What is "conditional"?

30 亿美元,支持“九期一”上市后真实世界研究、国际多中心三期临床研究、扩大适应症研究和机制深入研究等。 Green Valley plans to invest US $ 3 billion in the future to support real-world research after the "nine-phase one" market launch, international multi-center third-phase clinical research, expanded indication research, and in-depth mechanism research. 2000 例轻、中度阿尔茨海默病患者为对象,在北美、欧盟、东欧、亚太等地区的 200 个临床中心开展 12 个月的双盲试验和 6 个月的开放试验,进一步深入验证“九期一”的临床价值。 Among them, the international multi-center phase III clinical study will target more than 2000 patients with mild to moderate Alzheimer's disease and conduct a 12 -month double-blind trial in 200 clinical centers in North America, the European Union, Eastern Europe, and the Asia-Pacific region. And 6 months of open trials, further in-depth verification of the clinical value of "nine phase one". 2024 年完成国际多中心临床试验,在 2025 年完成新药全球注册申报。 We will strive to complete the international multi-center clinical trial in 2024 and the global registration of new drugs in 2025 .

Response:

加拿大滑铁卢大学的流行病学家 Mark Oremus 说:“ ADAS-Cog 改善 2.54 分在临床上并不重要。我认为一项为期 36 周的研究时间太短,无法评估 AD 药物的中、长期疗效。”(《科学》杂志, 2019 11 5 日) Questioning: Mark Oremus , an epidemiologist at the University of Waterloo, Canada, said: " Improving ADAS-Cog by 2.54 points is not clinically important. I think a 36- week study is too short to evaluate the mid- to long-term value of AD drugs. Effect. "(Science , November 5 , 2019 )

The reason why we did not evenly distribute patients in clinical trials to three levels, one was because the clinical trial subjects were randomly assigned, and the other was that patients with moderate and moderately severe clinical trials have always been very rare. rare.

Doubt point 3: The test time is too short

GV-971 "Nine Phases One" is China's original new drug for the treatment of Alzheimer's disease, also known as mannut sodium capsule, code GV-971 . 11 月,国家药品监督管理局批准这个药“有条件上市”。 In November 2019 , the State Drug Administration approved the drug to be “conditionally marketed”. However, after that, Geng Meiyu and the R & D team began to face questions from domestic and foreign public opinion.

Xiao Shifu:

24 周到 36 周的数据太诡异了,发生了什么?” ADAS-Cog 是一个被广泛使用的认知能力测试指标,一般不会在轻度阿尔茨海默症患者中出现快速变化。 Questioning : " The data from 24 to 36 weeks is too weird, what happened?" ADAS-Cog is a widely used indicator of cognitive ability testing, and generally does not show rapid changes in patients with mild Alzheimer's disease. . "The persuasive power is not strong, if there is another cognitive scale to verify, it may be more reasonable." One person engaged in drug development commented. 2019 11 4 日) ("Southern Weekend", November 4 , 2019 )

Although this hypothesis was not first proposed by us, we have conducted substantial research on pharmacological mechanisms.

“国际同类试验都是设置两项大型三期临床试验,而该试验只有一个。”(新浪微博 @ 黄建平 J Questioning: "Two international large-scale clinical trials are set up in similar international trials, and there is only one trial." (Sina Weibo @ 黄建平 J )

图1

通俗地解释,药物能卖,但需要在一段时间内进行更多研究,以便药监局判断药物究竟是否靠谱。 Questioning: Explain in plain terms that drugs can be sold, but more research needs to be done within a period of time for the FDA to determine whether the drugs are reliable. 2019 11 4 日) ("Southern Weekend", November 4 , 2019 )

Doubt point five: The curve is abruptly weird

2700 多只老鼠做了试验,一共开展了 23 批试验,积累了 9 箱原始数据资料,互相佐证、补充、完善,最终发现,阿尔兹海默症不仅是大脑的神经退行性疾病,更是肠道菌群失衡导致全身系统混乱的免疫系统性疾病。 Since then, the research team has conducted experiments on more than 2,700 mice. A total of 23 batches of trials have been carried out . Nine boxes of raw data have been accumulated, which have been mutually corroborated, supplemented and improved. Eventually, they discovered that Alzheimer's disease is not only a neurodegenerative brain Sexual diseases are immune system diseases that cause the disorder of the whole system caused by imbalance of intestinal flora.

Xiao Shifu:

Europe and the United States have stipulated that two clinical trials are to be conducted in the third phase, and two identical clinical trials are used to confirm each other. 2007 年公布的《药品注册管理办法》,规定三期还是做一项临床试验。 According to the "Administrative Measures for the Registration of Drugs" promulgated in 2007 , China stipulates that the third phase is still a clinical trial. The next phase of global clinical trials to be done, if it is to be registered in Europe and the United States, is to do two clinical trials.

Copyright statement: All works marked “Source: China Science News, Science Net, Science News Magazine” on this website, reprinted on the website, please indicate the source and author at the top of the text, and may not make substantial changes to the content; WeChat public , Headline number and other new media platforms, please contact the authorization for reprinting. Email: shouquan@stimes.cn.

Response:

Geng Meiyu:

Li Jinhe, Vice President of Green Valley Pharmaceuticals and Global Chief Operating Officer:

Geng Meiyu, the inventor of the "Nine Phase One", academic director and researcher of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences:

Response:

3 个月,三期的研究时间是 6 个月,为了充分了解药物的临床效果,我们的二期临床持续了 6 个月,三期临床持续了 9 个月,完全超过了新药审批的要求。 In China, in the approval of new drugs, the phase II clinical research period is 3 months, and the phase III clinical research period is 6 months. In order to fully understand the clinical effect of the drug, our phase II clinical study lasted 6 months, and the phase III clinical It lasted 9 months and completely exceeded the requirements for new drug approval.

Response:

9 个月的时候也没看到效果,可能我们的临床也会延续到一年、两年,甚至更长。 Suppose we did not see the effect at 9 months, maybe our clinic will continue to one year, two years, or even longer.

Xiao Shifu, the lead investigator of the "nine-phase one" and three-phase clinical studies, and professor of mental health center of Shanghai Jiaotong University:

Doubt point 4: There is only one test

Speaking with more data is a powerful support for scientific discovery.

Doubtful point 1: academic misconduct

12 26 日,我们将报告提交上去了。 Fortunately, on December 26 , we submitted the report. Experimental results show that the drug does not pose any carcinogenic risk.

Response:

Questions with scientific basis are very important for scientific development. 30 亿美元用于进一步的科学研究,我们期待与更多的科学家合作开展研究,共同把药物的潜力开发出来,用科研行动揭示药物价值。 In the future, we will continue to invest 3 billion US dollars for further scientific research. We look forward to cooperating with more scientists to carry out research, jointly develop the potential of drugs, and use scientific research actions to reveal the value of drugs. If Mr. Rao Yi is interested in participating in intestinal flora research, we are also very welcome.

“今年中国科学院上海药物研究所的耿美玉研究员作为通讯作者的文章( Wang et al Cell Research 29:787-803 ),号称其发明的药物 GV-971 能够通过肠道菌群治疗小鼠的阿尔兹海默症。这篇文章,不造假是不可能的。”(饶毅, 2019 11 28 日) Questioning: "This year's article by researcher Geng Meiyu of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences as a corresponding author ( Wang et al Cell Research 29: 787-803 ) claims that his drug GV-971 can treat mice through the intestinal flora Alzheimer's disease. In this article, it is impossible to not fake. "(Rao Yi, November 28 , 2019 )

When we applied for approval, although the trial was completed, the information was not fully prepared. 104 周的致癌毒性报告提交上去,证明药物没有任何致癌风险,如果三个月之内交不了,就会取消我们的新药证书资格。 The State Food and Drug Administration required us to submit our rat 's carcinogenic toxicity report for 104 weeks within three months , demonstrating that the drug has no carcinogenic risk. If it cannot be delivered within three months, it will cancel our new drug certificate.

图2

0.4 0.5 分。 In the past, failed Alzheimer's drugs could basically only improve by 0.4 or 0.5 points. 2.54 分。 "Nine Phase One" has proven the effectiveness of the drug during the Phase III clinical trial, reaching 2.54 points. 9 个月的纯安慰剂双盲随机平行对照研究。 The drug is also the world's first 9 -month, double-blind, randomized, parallel, placebo-controlled study in the field of Alzheimer's disease drugs . 78% ,可以持续、明显改善患者的认知功能,且安全性好,不良事件发生率与安慰剂组相当。 The results of clinical trials show that the effective rate of the drug is 78% , which can continuously and significantly improve the cognitive function of patients, and the safety is good, and the incidence of adverse events is comparable to that of the placebo group.

Clinical trials are designed for mild, moderate, and severe patients. In fact, if you look at the experimental data of patients with mild (left), moderate (middle), and moderately heavy (right) alone, the difference between the improvement of the drug effect and the deterioration of the placebo effect does not occur at the same time (as shown in the figure above ). 50% 以上,所以影响了最终的数据结果。 However, the previously published data is based on the average of the three types of patients, and the proportion of mild patients in clinical trials accounts for more than 50% , so it affects the final data results.