A higher purpose

更大的用處

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

專利保護期過后的藥品還有新用途，但需要更多的資金投入

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歲的英國人阿里斯塔爾身體突然抽搐，在經(jīng)過掃描設(shè)備檢查后，醫(yī)生告訴他了一個令人震驚的消息。他的腦袋里長了一個名叫膠質(zhì)母細胞瘤的腫瘤，這是一種手術(shù)無法治愈的腫瘤，他的時間所剩無多了。不久之后，他在報紙上讀到一篇文章，上面提到了一種廉價的雞尾酒療法，涉及的藥品都十分常見，這些藥品或多或少都有抗癌效果。報紙上的這位病人患有和他相同的疾病，這一療法的應(yīng)用成功緩解了這位病人的病情。負責治療阿里斯塔爾的醫(yī)生對此嗤之以鼻“我們管不了你。”

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.

多年來，阿里斯塔爾一直都在使用這種藥物治療模式，同時接受醫(yī)生的標準化治療。這種雞尾酒療法的提倡者是位于倫敦的“腫瘤護理診所”，它是一家私人診所，它建議這一療法的組成包括：他汀類（降膽固醇藥物）、二甲雙胍（用于治療2型糖尿病的藥物）強力霉素（一種抗生素）和甲苯咪唑（一種抗蟲蛀劑）。這個配方聽起來有點令人難以置信，但其實這些藥物都很安全，價格便宜，并且都是具有抗癌效果的常規(guī)藥物。盡管如此，這些藥物的標簽上從來沒說過他們可以治療膠質(zhì)母細胞瘤，或是任何相關(guān)的惡性腫瘤。

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.

臨床工作者對此并不是很感興趣。許多常見藥都具有再開發(fā)的潛能，但人們都還沒有意識到這一點。這些藥品曾經(jīng)只能針對某種特定的疾病，現(xiàn)在它們擁有了治療更多疾病的潛力。臭名昭著的晨間止吐藥“反應(yīng)?！爆F(xiàn)在可用于治療麻風病和某種血癌；一種痤瘡藥成為了某一白血病的有效治療方案；名藥“萬艾可”是曾經(jīng)治療心絞痛的失敗品。

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.

擴展藥物用途具有廣闊的應(yīng)用前景。布魯斯·布魯是美國慈善機構(gòu)“解藥觸手可及”的負責人，這是一家推廣“老藥新用”的組織。他表示，約9000種常用藥物都獲得了用途擴展的批準。Pan Pantziarka，另一家慈善組織，隸屬于美國抗癌基金會，他們發(fā)現(xiàn)約有260種非抗癌藥物表現(xiàn)出了抗癌特性，它們中有很多已經(jīng)過了專利保護期?？茖W界對于這些藥物展現(xiàn)出的興趣主要源于涉及動物實驗的前臨床研究，案例報告，小型的臨床試驗以及大型的觀察性研究。

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.

一些大范圍的篩查研究逐漸發(fā)現(xiàn)了許多藥物不為人所知的療效。美國醫(yī)學研究機構(gòu)國家衛(wèi)生局（NIH）在篩選了上千種批準藥物后發(fā)現(xiàn)，25種特定分子可能對耐藥菌起效。加利福尼亞生物醫(yī)藥研究所（CIBR），位于圣地亞哥市，它擁有一個囊括12000種藥品化合品的樣品庫，該機構(gòu)在這一樣品庫的基礎(chǔ)上測試其對于疾病引起的病原體的抑制作用。這一試驗產(chǎn)生了兩大成果：對肺結(jié)核患者應(yīng)用抗風濕藥金諾芬，以及在治療寄生蟲隱孢子蟲的藥品中加入氯苯吩嗪，一種治療麻風病的藥。

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.

專利期已過，廉價，并且允許流通，像這樣的藥品都有再開發(fā)的潛力，可以用來治療很多新的疾病。新分子實體藥物目前的測試費用約為百萬美元，加上各種各樣的安全性問題或毒理學問題，45%左右的藥物將會止步臨床實驗。改變藥物用途，同時擁有已獲得的安全認可，這樣可節(jié)省五至七年的藥品研發(fā)時間。藥品通過率也更高，并且有人估計“新用途藥”的造價僅為新藥的60%。

Multiple choice

多項選擇

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.

“老藥新用”這一概念吸引了越來越多人的目光，尤其在一些落后國家，這些藥物可以用來治療一些長期被人們忽視的疾病，一些疑難病，癌癥以及心理疾病。JAMA精神病協(xié)會在最近的一項研究中表示，他汀類，二甲雙胍和一些降壓藥在治療一些精神疾病，如精神分裂癥和狂躁型抑郁癥方面有很大的潛力。米諾環(huán)素，一種抗生素，目前已經(jīng)完成了治療自閉癥的試驗。Ammar Al-chalabi?是倫敦國王學院的一位神經(jīng)學家，他試圖擴展抗艾藥物阿巴卡韋的用途，他發(fā)現(xiàn)該藥物可以用來治療一些神經(jīng)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”.

然而問題總是存在的。Katherine Arline工作于一家專注罕見癌癥的生物科技公司，她表示，這些藥物的開發(fā)費用其實非常高，但是回報很低，所以很多公司都沒有進行相關(guān)臨床試驗的計劃。同時，公司一旦支付了這些藥品的測試費用和登記費用，沒有專利保護也會使這一計劃泡湯。一些人將這些專利期已過的藥物稱為“融資孤兒”。

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.

一種解決方案是想辦法改變這些“老藥”讓它們從新獲得專利保護。采用這一途徑的公司包括美國強生，他們?yōu)槁樽硭幙伤峁┝艘幌盗兄委熾y治型抑郁的證據(jù)。強生微調(diào)了這一藥物的分子結(jié)構(gòu)，使其成為一種可吸入藥品。藥品結(jié)構(gòu)重構(gòu)造假不菲，并且很有可能降低原來的治療效果。但是強生公司貌似能夠得到食品藥品管理局（FDA）的上市批準。

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.

多年以來，像可他命這種具有非常規(guī)用途的藥品基本上價格都十分昂貴并且難以獲得。因此在美國和歐洲多地，可他命的臨床應(yīng)用發(fā)展都受到一定程度的重視。英國牛津健康組織主要負責該藥品在英國的供應(yīng)，它是國家健康服務(wù)部（NHS）的下屬機構(gòu)。但對于可他命的抗抑郁用途，NHS還無法承擔其花費，相關(guān)患者若想要使用此藥，需要支付795歐元（1058美元）用于三次基本注射。強生公司研發(fā)的艾斯可他命的售價比可他命更加昂貴。

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.

很多因素阻礙了“老藥新用”的推廣步伐。Bloom先生表示，從他的經(jīng)驗來看，有三成至一半左右的病人都不愿意使用這類非常規(guī)用途藥品，甚至面對可能導致死亡的疾病時，他們也不愿意。而且就算醫(yī)生愿意嘗試，在實際操作中他們還是會擔心一些涉及到問責的法律問題，因為一旦出了差錯，醫(yī)生們就得負責。其他的一些爭論來自公共衛(wèi)生部門和保險業(yè)者，他們擔心這些藥品沒有治療某一疾病的資質(zhì)。