青蒿素面臨抗藥性 抗擊瘧疾亟需新藥

China’s first Nobel Prize for physiology or medicine was 419 years in the making. Tu Youyou, an 85 year-old chemist, won last year’s prize for her work in the 1970s developing artemisinin as a malaria treatment.

中國獲得首個諾貝爾生理學或醫學獎(Nobel Prize)花了419年時間。去年，85歲的藥學家屠呦呦因在上世紀70年代開發用來治療瘧疾的青蒿素(artemisinin)贏得諾貝爾獎。

She had been alerted to the potential of artemisinin — an extract from the sweet wormwood plant — after scouring Chinese literature in search of traditional herbal remedies for the disease.

她在翻閱治療瘧疾的傳統中草藥文獻後注意到了青蒿素的潛在價值，青蒿素是從青蒿(Artemisia annua)中提煉出來的。

Records of sweet wormwood, or Artemisia annua, being used against malaria date back to at least 1596, when Li Shizhen, a Chinese medical scholar, suggested that it be given to patients as a tea.

用青蒿治療瘧疾的記錄至少可追溯到1596年，當時中國醫藥學家李時珍建議，患者應把青蒿代茶飲。

It is still one of the main weapons in the world’s armoury against the disease. Treatment courses of artemisinin-based combination therapies increased from 11m in 2005 to 392m in 2013 as global health authorities put the drug at the centre of their fight against the mosquito-borne scourge.

它仍是全球治療瘧疾的主要武器之一。基於青蒿素的綜合療法的療程從2005年的1100萬個增至2013年的3.92億個，全球醫療當局把這種藥物推到抗擊由蚊子傳播的瘧疾的風口浪尖。

Concern is growing, however, that four centuries after artemisinin’s first use, the parasites responsible for malaria may be starting to get the better of its ancient powers. Artemisinin-resistant strains were first detected eight years ago in western Cambodia. Cases have since been detected in Myanmar, Thailand, Vietnam and Laos.

然而，人們越來越擔心，在首次使用青蒿素4個世紀後，引發瘧疾的寄生蟲可能正開始戰勝古老力量。8年前，在柬埔寨西部首次發現了具有青蒿素抗藥性的菌株。隨後緬甸、泰國、越南和老撾也發現了類似的病例。

For global health leaders, the pattern is alarmingly similar to the way resistance to chloroquine, another malaria treatment, emerged in Southeast Asia in the 1950s and spread to Africa — where the large majority of cases occur.

對於全球公共衛生主管而言，這種現象與另一種抗瘧藥物氯奎(chloroquine)遭遇抗藥性的經歷有着驚人的相似性，上世紀50年代，氯奎抗藥性在東南亞出現，然後蔓延至非洲，大部分瘧疾病例出現在非洲。

“We see a little bit of history repeating itself,” says Thierry Diagana, head of the Novartis Institute for Tropical Diseases. “Artemisinin resistance has spread as far as the western border of Thailand and Cambodia. If it crosses into India it will become a much bigger challenge.”

“我們看到歷史正在重演，”諾華熱帶疾病研究所(Novartis Institute for Tropical Diseases)負責人蒂埃裏•迪亞賈納(Thierry Diagana)表示，“青蒿素抗藥性正蔓延到泰國和柬埔寨西部邊境。如果它越過邊境進入印度，那將變成一個嚴峻得多的挑戰。”

Novartis, the Swiss pharmaceuticals group, commercialised artemisinin combination therapy in the 1990s. The group is among the leaders in the hunt for new drugs to replace artemisinin as its efficacy fades.

上世紀90年代，瑞士製藥集團諾華將青蒿素綜合療法商業化。隨着青蒿素藥效減退，很多製藥公司正在尋找替代青蒿素的新藥，諾華是這項努力的領軍者之一。

In 2014, the Novartis unit led by Dr Diagana demonstrated the first clinical proof-of-concept — a clinical trial showing that a drug works — for a new malaria treatment. The compound, codenamed KAE 609, works by interfering with the sodium concentration in both of the two parasites that cause the majority of cases. Plasmodium vivax is common in Asia and South America, while the more virulent Plasmodium falciparum is most prevalent in Africa. Importantly, KAE 609 also worked in people with artemisinin-resistant strains in Southeast Asia.

2014年，由迪亞賈納博士領導的諾華熱帶疾病研究所展示了一種治療瘧疾的新藥的首次臨牀概念驗證（顯示藥物有效的臨牀試驗）。這種複方藥物的代號是KAE 609，它通過干擾引發大部分瘧疾病例的兩種寄生蟲體內的納濃度而起到治療作用。間日瘧原蟲(Plasmodium vivax)在亞洲和南美較爲普遍，而毒性更大的惡性瘧原蟲(Plasmodium falciparum)在非洲最爲普遍。重要的是，KAE 609對於東南亞那些攜帶青蒿素抗藥性菌株的人也有療效。

Proof-of-concept data are expected soon on a second Novartis compound, known as KAF 156. It has shown promise against drug-resistant strains of both parasites as well as a further unique advantage. Unlike artemisinin-based therapies, KAF 156 acts against the parasites while still in the asymptomatic “liver stage” of the disease, before it has spread into the blood stream.

預計諾華的第二種複方藥物（名爲KAF 156）的概念驗證數據將很快出爐。它有望抵禦兩種寄生蟲的抗藥菌株，並具有另一種獨特優勢。與基於青蒿素的療法不同，KAF 156可以在瘧疾的無症狀“肝臟期”、在疾病蔓延到血流之前殺滅寄生蟲。

This would enable it not only to treat sufferers at malaria’s earliest stage — the disease can remain dormant in the liver for months after infection — but also prevent them passing on the parasite to mosquitoes for further transmission.

這令其不僅能夠治療處於瘧疾最早期的患者（在感染後，這種疾病可以在肝臟中潛伏數月之久），而且還能阻止患者將這種寄生蟲傳遞到蚊子身上進一步傳播。

The positive early data must be replicated in larger studies if KAE 609 and KAF 156 are to satisfy regulators. Dr Diagana says Novartis aims to have at least one of them on the market by 2021.

要讓KAE 609和KAF 156獲得監管機構的批准，積極的早期數據必須在更大規模的研究中得到驗證。迪亞賈納博士表示，諾華計劃最遲在2021年至少向市場投放其中一種藥物。

The Novartis compounds are among the most promising of over 50 antimalarial products being developed in partnership with the Medicines for Malaria Venture (MMV). Donors including the Bill & Melinda Gates Foundation, the UK Department for International Development and the Wellcome Trust have pledged $865m to the non-profit organisation since it was set up in 1999.

諾華公司的這兩種複方藥物列在與“瘧疾藥品事業會”(Medicines for Malaria Venture，簡稱MMV)合作開發的50多種最有希望的瘧疾藥品中。自這家非盈利組織1999年成立以來，捐款者已捐款8.65億美元，包括比爾及梅琳達·蓋茨基金會(Bill & Melinda Gates Foundation)、英國國際發展部(UK Department for International Development)以及維康信託基金會(Wellcome Trust)。

However, that is small compared with the billions of dollars invested by the pharmaceuticals industry in more commercially attractive disease areas such as cancer, and progress is slow. It typically takes about 10 years to get a new drug from early stage development to market and less than 10 per cent of candidates make it all the way.

然而，與製藥行業投入癌症等更具商業吸引力的疾病領域的鉅額資金相比，這些捐贈規模較小，而且進展緩慢。一種新藥從初期研發到推向市場一般耗時10年左右，同時只有不到10%的候選新藥會成功推向市場。

The MMV is not relying solely on big pharmaceuticals groups. It has also awarded research grants for academics to pursue assets from its so-called Malaria Box of compounds that have shown potential against the disease but have lacked funding for development.

瘧疾藥品事業會並不單單依賴大型製藥公司。它還向學者們提供研究補助，支持他們研究所謂的“瘧疾信息庫”(Malaria Box)中的化合物，這些化合物已顯示出治療瘧疾的潛力，但缺乏開發資金。

Back in China, last year’s Nobel Prize for Ms Tu — she is neither a doctor nor professor — has stirred pride but also surprise that she received little previous recognition in her own country. The official Xinhua news agency said that the four-decade gap between her discovery and the award showed that “science is never about instant success.”

回到中國，去年頒給屠呦呦的諾貝爾獎（她既不是醫師也不是教授）激起了中國人的驕傲，但也讓人意外，因爲她之前在國內沒有得到什麼認可。官方的新華社表示，從發現青蒿素到獲得諾獎經歷了40年時間，表明科學不能急功近利。

The spread of artemisinin-resistant malaria is adding urgency to the search for a fresh generation of drugs. In her Nobel lecture in Stockholm in December, Ms Tu issued a “severe warning” over the looming threat to the drug she helped discover.

具有青蒿素抗藥性的瘧疾的蔓延給尋找新一代藥物增添了緊迫感。在去年12月在斯德哥爾摩諾貝爾獎頒獎典禮上演講時，屠呦呦對她幫助發現的這種藥物面臨的威脅發出了“嚴重警告”。

Dr Diagana says that Novartis and its partners are moving as fast as possible. “It’s a good time for malaria drug discovery,” he says. “But we need to make progress quickly so we can avoid another global failure like we had with chloroquine.”

迪亞賈納博士表示，諾華及其合作伙伴正儘快採取行動。“現在是發現治療瘧疾藥物的好時機，”他表示，“但我們需要快速取得進展，使我們能夠避免當年氯奎那樣的全球失敗。”