更大的用处

A higher purpose

更大的用处

Many off-patent drugs have promising new uses; but more incentive is needed to invest in them

专利保护期过后的药品还有新用途，但需要更多的资金投入

Towards the end of 2014 a 66-year-old British man named Alistair had a seizure. A scan revealed shocking news. He had an inoperable brain tumor—a glioblastoma—that was likely to kill him in a few years. Soon afterwards, he read a newspaper article suggesting that a cocktail of cheap, everyday drugs, chosen for their anti-cancer effects, had helped a patient with the same disease. His doctors were unimpressed but said: “We can’t stop you.”

2014年年末，66岁的英国人阿里斯塔尔身体突然抽搐，在经过扫描设备检查后，医生告诉他了一个令人震惊的消息。他的脑袋里长了一个名叫胶质母细胞瘤的肿瘤，这是一种手术无法治愈的肿瘤，他的时间所剩无多了。不久之后，他在报纸上读到一篇文章，上面提到了一种廉价的鸡尾酒疗法，涉及的药品都十分常见，这些药品或多或少都有抗癌效果。报纸上的这位病人患有和他相同的疾病，这一疗法的应用成功缓解了这位病人的病情。负责治疗阿里斯塔尔的医生对此嗤之以鼻“我们管不了你。”

Four years on Alistair is still taking this drug regimen alongside the “standard-of- care” treatment. The drug cocktail is prescribed by Care Oncology, a private clinic in London, which recommends a statin (a cholesterol-lowering drug), metformin (used to treat type-2 diabetes), doxycycline (an antibiotic) and mebendazole (an anti-worming agent). These may sound radical, but are actually safe, cheap, generic medicines with evidence of some anti-cancer effects. Nonetheless, their labels do not say they treat glioblastoma—nor any other cancer for that matter.

多年来，阿里斯塔尔一直都在使用这种药物治疗模式，同时接受医生的标准化治疗。这种鸡尾酒疗法的提倡者是位于伦敦的“肿瘤护理诊所”，它是一家私人诊所，它建议这一疗法的组成包括：他汀类（降胆固醇药物）、二甲双胍（用于治疗2型糖尿病的药物）强力霉素（一种抗生素）和甲苯咪唑（一种抗虫蛀剂）。这个配方听起来有点令人难以置信，但其实这些药物都很安全，价格便宜，并且都是具有抗癌效果的常规药物。尽管如此，这些药物的标签上从来没说过他们可以治疗胶质母细胞瘤，或是任何相关的恶性肿瘤。

This lack of clinical interest is not unusual. There is a huge untapped medicine chest of generic drugs with unexploited uses. Originally approved for one disease, these drugs went off-patent and now show promise in other diseases. Thalidomide, a morning-sickness drug forever linked with scandal and disaster, found new uses in leprosy and a blood cancer. An acne medicine is now part of an effective treatment for a form of leukaemia. Viagra, famously, came from failed work in angina.

临床工作者对此并不是很感兴趣。许多常见药都具有再开发的潜能，但人们都还没有意识到这一点。这些药品曾经只能针对某种特定的疾病，现在它们拥有了治疗更多疾病的潜力。臭名昭著的晨间止吐药“反应停”现在可用于治疗麻风病和某种血癌；一种痤疮药成为了某一白血病的有效治疗方案；名药“万艾可”是曾经治疗心绞痛的失败品。

The scale of the opportunity for “drug repurposing” is vast. Bruce Bloom, boss of Cures Within Reach, an American repurposing charity, says 9,000 generic drugs have been approved. Pan Pantziarka, of the Anticancer Fund, another charity, says his group has found evidence in almost 260 non-cancer drugs of anti-cancer activity. Most have lost patent protection. The science that has piqued interest in these drugs comes from pre-clinical lab work in animals, case reports, small clinical trials and large-scale observational studies.

扩展药物用途具有广阔的应用前景。布鲁斯·布鲁是美国慈善机构“解药触手可及”的负责人，这是一家推广“老药新用”的组织。他表示，约9000种常用药物都获得了用途扩展的批准。Pan Pantziarka，另一家慈善组织，隶属于美国抗癌基金会，他们发现约有260种非抗癌药物表现出了抗癌特性，它们中有很多已经过了专利保护期。科学界对于这些药物展现出的兴趣主要源于涉及动物实验的前临床研究，案例报告，小型的临床试验以及大型的观察性研究。

Increasingly, large-scale screening studies are plucking options from oblivion. After screening thousands of approved drugs, the National Institutes of Health (nih), an American research agency, identified 25 molecules that might fight drug- resistant bacteria, half of which are already approved drugs. The California Institute for Biomedical Research in San Diego has a library of 12,000 drug compounds it is testing against disease-causing pathogens. Two drugs are in trials as a result: an anti- rheumatic treatment called auranofin for tuberculosis; and clofazimine, a leprosy drug, to treat the parasite cryptosporidium.

一些大范围的筛查研究逐渐发现了许多药物不为人所知的疗效。美国医学研究机构国家卫生局（NIH）在筛选了上千种批准药物后发现，25种特定分子可能对耐药菌起效。加利福尼亚生物医药研究所（CIBR），位于圣地亚哥市，它拥有一个囊括12000种药品化合品的样品库，该机构在这一样品库的基础上测试其对于疾病引起的病原体的抑制作用。这一试验产生了两大成果：对肺结核患者应用抗风湿药金诺芬，以及在治疗寄生虫隐孢子虫的药品中加入氯苯吩嗪，一种治疗麻风病的药。

Drugs like these—off-patent, cheap and already approved—are relatively quick to develop to treat new diseases. New molecular entities can cost hundreds of millions of dollars to test, and safety and toxicity problems mean that 45% of drugs fail clinical trials. Repurposed drugs, with well-established safety profiles, can save about five to seven years in development time. Approval rates are higher, and some think overall costs are 60% of those of new drugs.

专利期已过，廉价，并且允许流通，像这样的药品都有再开发的潜力，可以用来治疗很多新的疾病。新分子实体药物目前的测试费用约为百万美元，加上各种各样的安全性问题或毒理学问题，45%左右的药物将会止步临床实验。改变药物用途，同时拥有已获得的安全认可，这样可节省五至七年的药品研发时间。药品通过率也更高，并且有人估计“新用途药”的造价仅为新药的60%。

Multiple choice

多项选择

Interest in drug repurposing has been rising, particularly for medicines that could treat neglected diseases in poor countries, and rare diseases, cancer and mental health. A recent study in JAMA Psychiatry said that statins, metformin and blood- pressure drugs had potential for treating mental illnesses such as schizophrenia and bipolar disorder. Minocycline, an antibiotic, is already being tested as a treatment for autism. Ammar Al-Chalabi, a neurologist at Kings College, London, wants to repurpose Triumeq, an hiv drug, to fight motor neurone disease.

“老药新用”这一概念吸引了越来越多人的目光，尤其在一些落后国家，这些药物可以用来治疗一些长期被人们忽视的疾病，一些疑难病，癌症以及心理疾病。JAMA精神病协会在最近的一项研究中表示，他汀类，二甲双胍和一些降压药在治疗一些精神疾病，如精神分裂症和狂躁型抑郁症方面有很大的潜力。米诺环素，一种抗生素，目前已经完成了治疗自闭症的试验。Ammar Al-chalabi 是伦敦国王学院的一位神经学家，他试图扩展抗艾药物阿巴卡韦的用途，他发现该药物可以用来治疗一些神经元疾病。

There is a problem, however. Katherine Arline of Shepherd Therapeutics, a biotech firm that works in rare cancers, says that, because the costs are high and may not be recouped, firms have little incentive to run clinical trials on generic drugs. Once the costs of testing and registering have been paid, the lack of patent protection means that any firm can make the drug. Some describe generics as “financial orphans”.

然而问题总是存在的。Katherine Arline工作于一家专注罕见癌症的生物科技公司，她表示，这些药物的开发费用其实非常高，但是回报很低，所以很多公司都没有进行相关临床试验的计划。同时，公司一旦支付了这些药品的测试费用和登记费用，没有专利保护也会使这一计划泡汤。一些人将这些专利期已过的药物称为“融资孤儿”。

One approach is to change the generic drug to create something patentable. This is how the American drug firm, Johnson & Johnson (j&j), approached ketamine, an anaesthetic with a stack of evidence to support its use in treatment-resistant depression. j&j tweaked the molecule to create a variant that could also be inhaled. Reformulation is costly and risks reducing the efficacy of the drug. But j&j seems likely to receive approval from the Food and Drug Administration, the fda.

一种解决方案是想办法改变这些“老药”让它们从新获得专利保护。采用这一途径的公司包括美国强生，他们为麻醉药可他命提供了一系列治疗难治型抑郁的证据。强生微调了这一药物的分子结构，使其成为一种可吸入药品。药品结构重构造假不菲，并且很有可能降低原来的治疗效果。但是强生公司貌似能够得到食品药品管理局（FDA）的上市批准。

For years, like many off-label medicines, ketamine has been a valuable but hard-to-obtain therapy. This has driven the growth of ketamine clinics in America and Europe. In Britain Oxford Health, a unit within the National Health Service (nhs), will provide it. But the nhs as a whole does not cover it because it is not approved for this use, so patients must pay £795 ($1,058) for three infusions; j&j’s esketamine is likely to be far more costly.

多年以来，像可他命这种具有非常规用途的药品基本上价格都十分昂贵并且难以获得。因此在美国和欧洲多地，可他命的临床应用发展都受到一定程度的重视。英国牛津健康组织主要负责该药品在英国的供应，它是国家健康服务部（NHS）的下属机构。但对于可他命的抗抑郁用途，NHS还无法承担其花费，相关患者若想要使用此药，需要支付795欧元（1058美元）用于三次基本注射。强生公司研发的艾斯可他命的售价比可他命更加昂贵。

Several issues dog reusing generic medicines in new indications. Mr Bloom says that, in his experience, between one-third and a half of patients are loath to use drugs outside the current standard of care—even if they have a disease they know is going to kill them. And even if doctors might be willing in principle to prescribe an off-la- bel drug, many feel unable to do so because of worries about their legal liability should something go wrong. Or there may be disputes over whether public health services or insurers will pay for drugs that have not been approved for that disease.

很多因素阻碍了“老药新用”的推广步伐。Bloom先生表示，从他的经验来看，有三成至一半左右的病人都不愿意使用这类非常规用途药品，甚至面对可能导致死亡的疾病时，他们也不愿意。而且就算医生愿意尝试，在实际操作中他们还是会担心一些涉及到问责的法律问题，因为一旦出了差错，医生们就得负责。其他的一些争论来自公共卫生部门和保险业者，他们担心这些药品没有治疗某一疾病的资质。