We need a new Artesunate - the miracle drug fades

TLDR: After artesunate rose from an obscure Chinese herb to be the lynchpin of malaria treatment, increasing resistance means we might need a fresh miracle.
 

Back in 2010 I visited Uganda for the first time, a wide eyed medical intern in the Idyllic Kisiizi rural hospital. In my last week malaria struck me down, but there was a problem – a nationwide shortage meant that no adult artesunate doses remained. Through an awkward mix of white privilege and Ugandan hospitality, I was handed the last four children’s doses to make up one adult dose. Even in my fever dream, I pondered the fate of those 4 kids who would miss out because of me…

Act 1 – The Origin

In the midst of the Vietnam war, a fierce arms race was afoot. But not for a killer – for a life saver. Troops died from more than just bullets, bombs and shrapnel – a nefarious killer roamed, and the drugs of the day weren’t good enough. “The incidence (of malaria) in some combat units..., approached 350 per 1,000 per year”. Chloroquine and quinine took too long to cure malaria and side effects were rough. Resistance to quinine was on the rise, “14 days proved inadequate to effect a radical cure, and there was a 70 to 90 percent rate of recrudescence within a month.” Soldiers might not die of malaria but could be out of action for weeks.

Both sides set their best scientists to the race. The Americans discovered that if you added an extra drug pyrimethamine, cure rates were higher and recovery was quicker -a useful development but hardly a game changer. The Chinese though had a secret weapon.

I’m proud that EAs lobby to normalise “challenge studies” as a quicker way to find cures than laborious multi-year RCTs. China's Tu Youyou was putting them to great use to help the North Vietnamese cause. Armed with malaria infected mosquitos and 2,000 traditional herbs, she wondered whether there was any merit in thousands of years of traditional Chinese medicine. After culling the initial list of 2000 to the 380 most promising herbs, she started infecting and treating mice. Only one herb actually worked for malaria, but that one was enough. She then volunteered to be the first human subject.

As much as nature cruelly dealt us the malaria parasite, nature also gifted us our two best cures. “Quinine” bark was discovered to have antimalarial properties perhaps 2,000 years ago and has been refined over the centuries. And Youyou’s jackpot? The humble Artemisin "Wormwood" plant – an almost absurdly effective malaria cure with barely any side effects.

Act 2  - The Deadly Delay

After Youyou’s discovery, the Artemisin timeline would ideally have gone something like this.

1973 – Discovery
1975 – Randomised trials in Asia and Africa
1978 – Production increases
1980 – Artesunate takes over Qunine as the drug of choice and we all rejoice!

INSTEAD the timeline went

1973 – Discovery
1981 - Discovery Presented to WHO
.......
…….
…….
1996 - Trials in African and Asia show artemisin derivatives no worse than Quinine
1998 – Cochrane review shows artemisin derivatives no worse than Quinine
2003 – Small RCT shows artesunate “as effective as quinine” for severe malaria 
2005 - SEAQUAMAT study in Southeast Asia shows clear mortality reduction in adults
2010 - AQUAMAT study in Africa shows even larger mortality reduction in children
2011 - WHO finally recommends injectable Artesunate as first line for severe malaria

What caused this long, tragic delay isn’t clear, but we do know that the Chinese didn’t broadcast their miracle to the world, while the West also didn’t show enough interest despite being aware of the drug. 

Even the 2005 East Asian based “SEAQUAMAT” study which showed a 34% mortality reduction over quinine didn’t stimulate immediate uptake. We instead insisted on another “AQUAMAT" study in African Children which completed another 5-years-of-wasted-lives later. In 2011 The West finally woke up, a chilling 38 years after Youyou’s discovery. In 2015, 42 years after her stroke of genius we finally gave Tu Youyou the Nobel prize she deserved, though she remains a relatively little known and celebrated Nobel winner.

Rethink priorities calculated that Artemisin derivatives might have saved 2 million lives ^[1] in the 10 years between 2012 and 2022. Does this mean that at least 5 million more could  have been saved had we not delayed for 30 years between 1980 and 2010? 

Only 10 years after we heroically co-ordinated to eradicate smallpox, through a combination of Chinese Protectionism, Western skepticism and perhaps just apathy, we missed the artemisinin boat and allowed untold unnecessary suffering. We humans are capable of both incredible good and unfathomable folly.

Act 3 - The Miracle

But despite this delay, the miracle stands – and miracle is hardly  too strong a word. Artesunate clears those pesky parasites more than twice as quickly as quinine. Every African doctor has seen kids seizing, unconscious, gasping for air brought back from the brink less than an hour after the magic injection. I’m not sure there’s any antimicrobial drug which illicits a more breathaking recovery ^[2]

 
White, N. The parasite clearance curve. Malar J 10, 278 (2011). 
 

As Artemisinin comes from a plant ramping up production wasn’t easy, we needed thousands of acres of plants. Back in 2010 when I stole the last children's doses, we still couldn’t produce enough artemisinin to treat all 10 million malaria cases every year. Through artificial synthesis, we now produce enough artemisinin to treat every malaria case in the world.

Act 4 - The Wormwood wilts?

In 2025 artemesin’s flower has begun to wilt. Resistance first emerged in South-East Asia before spreading to Africa. Artesunate still works, but takes longer to clear the parasites and the drug’s power wanes. We’ve now reached a tipping point where for the first time, normal artemisin doses don’t always cure malaria.

As we speak, in combination with other medication artesunate still cures over 99.9% of malaria cases - if a little slower than before. But we don’t know when that will become  99%, then only 90% at which point we’ll need alternatives. We have stop-gap measures. Some suggest longer medication courses, rotating our dual therapies, or even adding a 3rd drug to the treatment cocktail – a blunt and expensive instrument but ont that could buy us another 10 years.

Combined with climate change, increasing resistance to LLINs and reduced international funding, this emerging resistance might even be a small part of why malaria progress has stalled over the last 5 years.

                                                         The wormwood wilts…

Act 5 - A fresh miracle?

One might argue that this is all window dressing to the perfect malaria vaccine, yet that panacea still feels distant. Current vaccines might with perfect implementation at best halve malaria mortality. But unless we see another breakthrough soon, If we don’t find a new drug  we might even have to run back to the substandard quinine.

I sure hope we’re turning over every leaf both literally and digitally. Perhaps we’ll round out the botanical trifecta with a cloud forest cure. Or maybe through “AlphaMal” we’ll synthetically AI-our-way out of this pickle. While Bill Gates bets 400 million on a TB vaccine and OpenPhil and partners 100 million on lead elimination, perhaps we need to future proof ourselves from the unthinkable - that malaria treatment could soon be far less effective. 

Encouraging work is on the go. A Swiss outfit "Medicines for malaria venture" leads the way with funding from 10 National Aid bodies (USAID is still listed on their website...) and you guessed it - the Gates Foundation. Two new medications with the catchy names SJ733 and MED6-189 ^[3] show promise but are unproven. While we pump billions into malaria vaccines, maybe we should shuffle a few hundred million more towards a new cure as well?

We might just need a fresh miracle.

1. ^{^}

   I think they might be overstating this a little, but regardless Artesunate has saved LOTS of lives

2. ^{^}

   Outside of infectious disease injecting glucose for low blood sugar and naloxone for opiod overdose are even more impressive

3. ^{^}

   Inspired by a compound from a marine sponge!