Let’s talk about artesunate.
This drug is now the standard, World Health Organization-recommended treatment for severe malaria. It was only in 2011 that it officially displaced the old treatment, quinine, which you may know better as the thing in tonic water that makes G&Ts delicious. Artesunate is one of a class of anti-malarials developed as part of Project 523, an effort launched by Chinese leaders Zhou Enlai and Mao Zedong in the middle of the Cultural Revolution as a favor to North Vietnamese leader Ho Chi Minh.
Ho was in the midst of a brutal guerrilla war with the Americans, and his soldiers were falling sick and dying of malaria at alarming rates. He wanted a better class of treatments, but his country, which had been fighting the Japanese, the French, South Vietnam, and the Americans for a quarter-century by that point, didn’t exactly have the manpower or money to develop them itself. So he asked his comrades in Beijing to help.
Tu Youyou, a chemist and expert on Chinese traditional medicine, led a team that combed through ancient medical guides for hints at compounds that could fight malaria. She found that Artemisia annua, a type of wormwood, was mentioned as fighting malaria in A Handbook of Prescriptions for Emergencies, written by the 4th-century traditional Chinese doctor Ge Hong (284-346). Tu’s team developed an extract from the plant (known as “artemisinin”) that they found effective in treating severe malaria cases. A whole class of treatments, known as “artemisinin derivatives,” comes out of this work. Tu would eventually win the 2015 Nobel Prize in Medicine for her achievements.
Liu Xu, a scientist at the Guilin Pharmaceutical Factory in southern China, attended a meeting in 1977 held by Project 523, and heard about artemisinin derivatives for the first time. He began experimenting in rodents and found that one specific derivative was up to seven times more effective than ordinary artemisinin against severe malaria. It could also be formulated as an intravenous treatment. It became known as artesunate.
The long road to treatment
But, as a new report from the research group Rethink Priorities written by analyst Bruce Tsai and Erin Braid details, that was just the start of the story. It took decades for Tu and Liu’s discoveries to translate into a change in the worldwide treatment of malaria, a disease that still kills over 600,000 people per year.
As late as 1998, Tsai and Braid write, “there was no particular interest in artesunate specifically.” A Cochrane review that year found that artemisinin derivatives generally were “no worse” than quinine at treating malaria. The main derivative tested at that point was artemether, which seemed a viable alternative to quinine, but not clearly superior.
So what changed? Tsai and Braid give primary credit to a series of randomized controlled trials (RCTs) funded by the Wellcome Trust, the British medical foundation. First a small 113-person study found lower mortality when intravenous artesunate was used than with quinine. While not statistically significant, this result was promising enough to prompt a much larger, multicountry study of 1,461 patients across India, Bangladesh, Myanmar, and Indonesia. It concluded that mortality with artesunate was 34.7 percent lower than with quinine, and also had fewer harmful side effects. A still larger study in nine African countries with 5,425 child patients also showed a huge advantage (22.5 percent lower mortality), and demonstrated that the results generalized outside of adults in South Asia.
At the same time, the Medicines for Malaria Venture, a nonprofit funded by foreign aid agencies and foundations, funded an RCT that found a lower-dose, cheaper regimen of artesunate was just as effective as a bigger dose. It also worked with Guilin, the pharma company where Liu had developed artesunate, to get “prequalified” by the WHO. Prequalification is a kind of quality check involving pharmaceutical factory inspections and other steps meant to signal to governments that prequalified products are safe and legitimate, and can greatly increase uptake.
Tsai, Braid, and the Rethink Priorities team estimate that the 2011 introduction of injectable artesunate has prevented at least 785,716 deaths so far. Projecting forward, it estimates the drug could save as many as 4 million lives total.
Philanthropic investment in drugs pays off in lives
The tale of artesunate is a wild story that jumps from the Vietnam War to 4th-century Chinese medicine to modern randomized trial-based medical research. Its main lesson, for me, is a simple one, widely known to experts on global health but probably underemphasized outside that world: we cannot rely on businesses alone to protect us from disease.
At each step in the artesunate story, the key funders and actors have been governments, foundations, and NGOs. Even Guilin, the pharmaceutical company that invented the drug, existed in the context of pre-reform China, where few enterprises were truly “private” and the state was heavily, heavily involved. (It still is, to a lesser extent, today.)
The delay in the drug’s rollout seems attributable in part to the lack of much commercial incentive to develop better malaria treatments, given how poor most people who get malaria are. If malaria was killing 190,000 Americans a year — which is the number of Nigerians who died from the disease in 2021 — I’d guess artesunate would have become a standard treatment within a couple years of discovery, not over three decades later. Americans would be able to pay for it, and pharma firms would rush to soak up that money.
Though maybe even that is too optimistic — a paper examining cancer drug trials from 1973 to 2011 in the United States found that drug companies systematically underinvested in research and development, and that proper investment would have led to patients living longer, cumulatively adding millions of years of additional life. The US invests heavily in health research through the National Institutes of Health and public universities. But there’s a strong case we should be doing still more.