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Wednesday, March 29, 2023

Hydroxychloroquine Is Toast. Now Say Hi to Its 'Dirty' Cousin

There have been multiple funerals, by now, for hydroxychloroquine, a decades-old malaria drug that has been touted as a cure for Covid-19. Although US President Donald Trump once took the medicine as a prophylactic—and even now insists that it would be “the hottest thing going” if not for biased media coverage—hydroxychloroquine was a flop in clinical trials, and in June the US Food and Drug Administration revoked its emergency approval for use in fighting the pandemic. The proverbial nail in the coffin—which I helped hammer in—was the revelation that early research on the drug’s efficacy against Covid-19 had used the wrong type of cells. Now that rollercoaster may be starting on a second trip: New experiments on hamsters suggest that a close chemical cousin to hydroxychloroquine, called amodiaquine, might also hold some promise against the pandemic virus.


The surprising study became available on the preprint server bioRxiv on August 19. Its authors describe how they dosed a couple dozen hamsters with amodiaquine and then spritzed the rodents’ noses with the new coronavirus. The animals continued to receive amodiaquine for three more days, and then were checked against a control group that did not receive the drug. Hamsters treated with amodiaquine ended up with 70 percent less genetic material from the virus in their lungs. In a second study, the researchers started healthy hamsters on amodiaquine, then put them in a cage with others that were sick. Again they did much better than their control-group counterparts: Treated animals ended up with 90 percent less viral material in their lungs.

The researchers have submitted their paper for publication in a scientific journal, but it has not yet undergone formal review for errors by their scientific peers—and they stress that it’s a far leap from hamsters to humans. Amodiaquine is one of a smattering of drugs that have shown some efficacy against the pandemic virus in laboratory animals. But given its close connection to hydroxychloroquine, the emergence of this drug in particular as a candidate for further research could be quite significant. For many around the world, it could also be quite dangerous.

Amodiaquine was first synthesized in the mid-1940s, at a time when scientists were making artificial versions of the antimalarial compound quinine, which is found in the bark of the cinchona tree. (During World War II, supply chains for cinchona bark were compromised, so alternatives became important.) Amodiaquine’s molecular structure is very similar to those of chloroquine and hydroxychloroquine, the latter of which was discovered around the same time. During the 1970s, it was tested in owl monkeys, and then in human trials, and found to be an especially useful therapy for chloroquine-resistant strains of malaria.

But from a pharmaceutical point of view, there’s at least one major difference between these drugs. Benjamin tenOever, a microbiologist at the Icahn School of Medicine at Mount Sinai in New York and one of the authors of the new study, describes amodiaquine as being “dirtier” than its cousins. That means that its effects on cells are more spread out, hitting a greater variety of molecular targets. As biochemist Bryan Roth once told Nature, a dirty drug may be less like a “magic bullet” than a “magic shotgun.”

Still, after all the hype and then deflation over hydroxychloroquine, he didn’t see much reason to be excited for amodiaquine. Both drugs had been tested against a wide range of diseases such as Ebola, Zika and even Dengue virus, with mixed results. Amodiaquine, like hydroxychloroquine, showed promise against the original SARS virus and the related Middle East Respiratory Syndrome virus—though these experiments (like the early ones on hydroxychloroquine and Covid-19) were done using monkey kidney cells, which don’t offer a great model for what happens in the human lung. But in April, tenOever’s funders at the US Defense Advanced Research Projects Agency asked him to run the tests. “I was really reluctant to do it,” he says, “but we did eventually come to try.”

The first time tenOever and his collaborators gave the drug to hamsters in his lab, in early June, it offered considerable protection against the virus that causes Covid-19. “We thought, ‘Oh, OK, that was weird. Let’s do it again,’” tenOever says. They kept repeating it and seeing good results. The research team, which includes Donald Ingber of the Wyss Institute in Boston, had already shown that, in human lung cells, the drug reduces levels of a harmless virus engineered to carry the same spike protein as the pandemic one. “It works beautifully,” tenOever says.

Others are not as convinced by the results. "The surrogate virus is not the same," says Vincent Racaniello, a microbiologist at Columbia University in New York, referring to the human-lung-cell tests. Racaniello points to design limitations of the study such as this and says evidence is currently insufficient to warrant testing of amodiaquine in humans.

Notably, when other researchers have run hamster and human-lung-cell tests using hydroxychloroquine or chloroquine, they came up empty. Just to make sure, tenOever and his collaborators also ran a direct, head-to-head comparison of amodiaquine and hydroxychloroquine in hamsters, with a common control group. Amodiaquine reduced the amount of viral material. Hydroxycholorquine didn't. (The experiment did not measure differences in live virus.)


Sunil Parikh, a malaria researcher at the Yale School of Public Health who is part of a separate group running lab tests of amodiaquine against Covid-19, notes that the hamsters in the new study were all given the drug one day before exposure to the pandemic virus. As a result, there’s no way to know what might happen when the medicine is given to an animal that’s already sick. “The hamster model results are impressive for demonstrating potential prophylactic activity but doesn’t help to show any potential for treatment,” Parikh says.

The results of the new study intrigue Isaac Bogoch, a Toronto General Hospital Research Institute clinical investigator, who specializes in infectious diseases. “I think it’s totally interesting,” he says. “But if the result of this is people hoarding amodiaquine and self-medicating with this and having doctors claim that they’ve found a cure, obviously that’s the wrong answer, and we’ve sort of been there and done that already.”

The hydroxychloroquine debacle underscores the profound dangers of hyping a drug in the absence of clinical trial data—not just for the people who might receive a useless drug with possible side effects, but for anyone who needs that drug for other reasons. As the US government bought up stores of hydroxychloroquine for use in the pandemic, and the number of prescriptions for it went through the roof as rumors spread about its potential use in the pandemic, patients who had been relying on it for years to treat ailments like lupus started running short. (This past spring, one in three lupus patients said they had difficulty obtaining their pills.) With amodiaquine, the same stockpiling behavior could be even more disastrous. It’s used in the second-most common combination treatment for malaria, a disease that claims the lives of almost half a million people every year, the majority of whom are children in Africa under the age of five.


“If we have a situation with amodiaquine like we had with hydroxychloroquine stockpiling then it’s going to have a huge effect on countries to have the required treatments for malaria, and potentially have a huge impact in increasing malaria mortality,” says Peter Olumese, a medical officer at the World Health Organization’s Global Malaria Programme. Amodiaquine is also given to healthy children in order to prevent malaria infection during the rainy season in countries such as Nigeria and Chad. In these situations, the drug is usually given for three days per month. Last year, 20 million children received the drug.

There’s one more complication in the fact that amodiaquine is not currently available in the US. Research in the 1980s documented liver damage among chronic users for malaria prevention; and there were also signs that when it accumulates at high doses, the drug can cause heart rhythm abnormalities. Parikh says that complicates any potential use of amodiaquine as a preventative drug against Covid-19. “Prophylactic trials are quite challenging, and when amodiaquine was used as a prophylactic in travelers in the West, it was pulled for toxicity,” he says.

But global health policymakers stress that the children who receive amodiaquine in malaria-prone regions do not take it continuously and are therefore not at risk for these side effects. “It has remained a crucial drug,” says Anders Björkman, a professor of infectious diseases at the Karolinska Institute in Stockholm who has studied malaria for more than three decades.

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The stakes were never quite this high for hydroxychloroquine. Although that drug is almost always introduced in news articles (including this one) as an antimalarial, it’s not widely used as such. Chloroquine, on the other hand, was for many years the star of the antimalarial drug arsenal; with amodiaquine becoming a vital substitute when chloroquine-resistance spread. Olumese explains that the small structural differences between amodiaquine and chloroquine are consequential in this regard. “Some of these chemical entities, just the positioning of maybe one molecule or something can completely change how the drug reacts and how resistance develops,” he says.

To be clear, these positive results for amodiaquine have no bearing whatsoever on the use of hydroxychloroquine for treating Covid-19. That drug is no more promising today than it was last week, and those who try to argue otherwise are simply wrong. So far they’ve been wooing the puffed-up stepsisters—and Cinderella hasn't even arrived at the ball.

Of course it's way too early to presume a fairytale ending for amodiaquine. Global health experts, in particular, warn against the dangers of creating too much hype around the drug’s potential effects against the pandemic virus. “This is all speculation. All bets should be off,” says George Jagoe of the Medicines for Malaria Venture, a Geneva-based public-private partnership to accelerate the development of new antimalarial drugs. “Everyone should be holding their breath,” he adds. If amodiaquine falters in follow-up trials for treating Covid-19, the scientific community “could end up in a very awkward place.”

The inkling of hope offered by this new study will be a test to see if we’ve learned our lesson. Even tenOever is reserving judgement until more evidence becomes available. “It’s so bizarre,” he told me. “I’m in this really weird world where I see this data that’s truly the most relevant thing I could ever be doing in my life and I’m not sure if it’s good news or bad news. It’s either extraordinary or nothing.”

Updated, 8/21/2020, 5:35 pm EST:
An earlier version of this story incorrectly stated that the experiments on hamsters were carried out before the ones using human lung cells.

Photographs: Alex Wong/Getty Images; Soumyabrata Roy/NurPhoto/Getty Images; Brian Ongoro/AFP/Getty Images

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