The old malaria drug is getting used against the coronavirus. Tech enthusiasts are abuzz. One missing step: clinical trials.
THE CHATTER ABOUT a promising drug to fight Covid-19 started, as chatter often does (but science does not), on Twitter. A blockchain investor named James Todaro tweeted that an 85-year-old malaria drug called chloroquine was a potential treatment and preventative against the disease caused by the new coronavirus. Todaro linked to a Google doc he’d cowritten, explaining the idea.
Though nearly a dozen drugs to treat coronavirus are in clinical trials in China, just one—remdesivir, an antiviral that was in trials against Ebola and the coronavirus MERS—is in full-on trials in the US. Nothing has been approved by the Food and Drug Administration. So a promising drug would be great—and even better, chloroquine isn’t new. Its use dates back to World War II, and it’s derived from the bark of the chinchona tree, like quinine, a centuries-old antimalarial. That means the drug is now generic and is relatively cheap. Physicians understand it well, and they’re allowed to prescribe it for anything they want, not just malaria.
Todaro’s tweet got thousands of likes. The engineer/tech world picked up the idea. The widely-read blog Stratechery linked to Todaro’s Google document; Ben Thompson, the blog’s editor, wrote that he was “wholly unqualified to comment” but that the anecdotal evidence favored the idea. Echoing the document, Thompson wrote that the paper was written in consultation with Stanford Medical School, the University of Alabama at Birmingham medical school, and National Academy of Sciences researchers—none of which is exactly true. (More on that in a bit.) One of Todaro’s coauthors, a lawyer named Gregory Rigano, went on Fox News to talk about the concept. Tesla and SpaceX CEO Elon Musk tweeted about it, citing an explanatory YouTube video from a physician who’s been doing a series of coronavirus explainers. To be fair, Musk wasn’t all-in on the idea absent more data, though he wrote that he’d received a life-saving dose of chloroquine for malaria.
It’s the definition of “big if true.” Part of the story of Covid-19, of the coronavirus SARS-CoV-2, is that it is novel. Humans don’t have any immunity to it. There’s no vaccine, no drug approved to treat it. But if a drug did exist—if a cheap, easy drug can stave off the worst, ventilator-requiring, sometimes-fatal complications of coronavirus infection, or maybe prevent that infection in the first place, what are we all socially isolating for, like suckers?
That if—as the saying goes—is doing a lot of work. The Covid-19 pandemic is causing, reasonably, a worldwide freak-out as scientists and policymakers race to find solutions, not always competently or efficiently. It’s the kind of thing that rankles the engineer-disruptor mindset. Surely this must be an easily solved problem that’s primarily the fault of bureaucracy, regulation, and people who don’t understand science. And maybe the first two things are true. The third thing, though, is where the risks hide. Silicon Valley lionizes people who rush toward solutions and ignore problems; science is designed to find solutions by identifying those problems. The two approaches are often incompatible.
What happened here, specifically, is that Rigano sought Todaro out. Todaro’s tweet identified Rigano as being affiliated with Johns Hopkins; Rigano’s LinkedIn profile says he’s on leave from a masters degree program there in bioinformatics, and has been an advisor to a program at Stanford called SPARK, which does translational drug discovery—finding new uses and applications for approved drugs. “I have a very unique background at the crossroads of law and science,” Rigano tells me. “I have been working with large pharmaceutical companies, universities, biotechs, and nonprofits in the development of drugs and medical products.” He says those contacts told him about the use of chloroquine against Covid-19 in China and South Korea, so he started reading up on it.
(Johns Hopkins did not return a request for comment; a spokesperson for Stanford Medical School emails: “Stanford Medicine, including SPARK, wasn’t involved in the creation of the Google document, and we’ve requested that the author remove all references to us. In addition, Gregory Rigano is not an advisor with Stanford School of Medicine and no one at Stanford was involved in the study.“)
It turns out that people have been pitching chloroquine as an antiviral for years. In the early 1990s researchers proposed it as an adjunct to early protease inhibitor drugs to help treat HIV/AIDS. A team led by Stuart Nichol, the head of the Special Pathogens Unit at the Centers for Disease Control and Prevention, published a paper in 2005 saying that the drug was effective against primate cells infected with SARS, the first big respiratory coronavirus to affect humans. That’s an in vitro test, not live animals—just cells.
Nichol didn’t respond to a request for comment, but a CDC spokesperson emailed this: “CDC is aware of reports of various medications being administered for either treatment or prophylaxis for COVID-19, including those demonstrating in vitro activity against SARS-CoV- 2. At this time, it is important to ensure robust clinical data, gathered from clinical trials, are obtained quickly in order to make informed clinical decisions regarding the management of patients with COVID-19.”
At a World Health Organization press conference in February, a reporter from the fact-checking group Africa Check asked whether chloroquine was an option. Janet Diaz, head of clinical care for the World Health Organization Emergencies Program, answered that WHO was prioritizing a couple of other drugs in testing along with remdesivir, and acknowledged that Chinese researchers were working on even more. “For chloroquine, there is no proof that that is an effective treatment at this time,” Diaz said. “We recommend that therapeutics be tested under ethically approved clinical trials to show efficacy and safety.”
Chloroquine and an alternative version called hydroxychloroquine seem to work on viruses by inhibiting a process called glycosylation, a chemical transformation of the proteins in the virus’s outer shell that’s part of the infection process. Chinese researchers have initiated perhaps a half-dozen randomized trials of the two versions in humans and gotten at least some promising initial data.
With that data in mind, a French infectious disease researcher named Didier Raoult published a fast review of existing in vitro studies of chloroquine and hydroxychloroquine, and (along with some other researchers) has recommended not only spinning up research in humans but also starting to use the drugs clinically. (Raoult didn’t return a request for comment, but a publicist at the hospital where he works sent a link to a video in which Raoult presents data he says shows efficacy in a small group of actual humans. That data hasn’t been published or peer reviewed.)
Except for that video, which hadn’t come out yet, Rigano put all that together and got in touch with Todaro. “I essentially wrote the publication based on my interface with various Stanford researchers and others, and we developed this body of evidence and hardcore science,” Rigano says. “James, Dr. Todaro, was doing the best job, I thought, of anyone in the media, any doctor, any news outlet, anyone on Twitter, of covering coronavirus. I’d been following his research on other items, like decentralized computing, for several years.”
Todaro, who got an MD from Columbia and is now a bitcoin investor, was interested enough to collaborate on the document. “I added stuff that pertained more to the medical side of things, and gave a more, I guess, clinical feel to it,” Todaro says. “Something that Big Pharma is not going to like—it’s widely available, it’s pretty cheap, and it’s something that at least a million people are already on. It’s really got a lot of the aspects of something that can be rolled out quickly if the right clinical data is there.”
Todaro and Rigano together started talking to Raoult about the small study he was then preparing, and they also called a retired biochemist named Tom Broker. He was originally listed as the first author of the Google doc, his name followed by “(Stanford).” That’s where Broker got his PhD, in 1972, but Broker has been, for years, at the University of Alabama at Birmingham. His area of research is adenovirus and human papillomavirus, which have DNA as their genetic material, as opposed to the RNA inside coronaviruses. They’re pretty different.
Broker says he wasn’t involved in producing the Google doc and would never advocate the use of a drug without formal trials. Todaro and Rigano have since removed his name from it, at Broker’s request. “I neither contributed to, wrote any part of, nor had knowledge of this google.com document. I have never conducted research on RNA virus pathogens … I have no professional credentials or authority to suggest or recommend clinical trials or practices,” Broker wrote in an email. “Apparently I was inserted as a ‘gratuitous’ author, a practice that I have always avoided over my 53-year career. Moreover, I have never engaged any part of social media, privately or professionally. All of my scientific publications are processed through peer review. I suggest that you communicate with one of the actual authors.”
Asked about Broker’s statement, Todaro says that Broker just didn’t want to engage with the attention the idea and document were getting “I don’t personally know Tom Broker. My correspondence has been with Mr. Rigano,” Todaro says. “When we started getting inquiries from the press, my impression was, Mr. Broker got very overwhelmed by that.”
Rigano says that was his impression as well. “Dr. Broker is a scientist of the highest order. He’s not used to this type of media attention, so we kind of just have to proceed without him here,” Rigano says. “He’s not ready for the media, becoming a celebrity.”
The chloroquine document Todaro and Rigano wrote spread almost—sorry about this—virally. But even though some people are hyping this is a treatment, it still has not yet undergone a large-scale randomized control trial, the gold standard for evaluating whether a medical intervention like a drug actually works. Until that happens, most physicians and researchers would say that chloroquine can’t be any kind of magic bullet. “Many drugs, including chloroquine or hydroxychloroquine, work in cells in the lab against coronaviruses. Few drugs have been shown to work in an animal model,” says Matthew Frieman, a microbiologist who studies therapeutics against coronaviruses at the University of Maryland. What happens if you put the drugs into animals? No one knows yet. Probably nothing bad, because they’ve been used for decades. But maybe they don’t actually help a person fight off the virus.
Chloraquine’s action, Frieman says, “has been known for some time for other coronaviruses but never developed as a tested therapeutic in humans. There is reason to believe that will change now, along with other therapeutics that have efficacy in the lab.” That’s because the new coronavirus is encouraging research to pick up again on just about anything that has ever shown any effect on coronaviruses, and some new ideas too.
Rigano says he and Todaro are now spinning up their own clinical trials, though it isn’t clear how they intend to collect or present the data. They’re hoping to have clinicians enroll as subjects, and they’d then prescribe hydroxychloroquine to themselves as they treat patients with Covid-19. When asked what the control group would be—case-matched physicians who didn’t take the drug, perhaps?—Rigano had a couple of ideas. “You can use historical controls, the rate of medical doctors being infected that were not on hydroxychloroquine regularly. And if there are doctors that would like to participate in the study that would like to not take hydroxychloroquine, they would also be excellent controls,” Rigano says. “Ethically speaking, we don’t want anyone to contract this virus. It’s really a wonderful design.”
Rigano says he’s talking to staff at four Australian hospitals about spinning up a bigger, randomized trial after the one with volunteer physicians is underway.
Rigano and Todaro know that a Google doc shared over Twitter isn’t the way science typically gets done. But they say there’s no time to waste, that the pandemic is moving too fast for traditional science. “That would take months,” Todaro says. “I’d hate to bank on things we would find in months, or a vaccine that comes out in mid to late 2021.”
They’re not the only ones with those worries, of course. The latest model from Imperial College London of Covid-19’s progress lays out a worst worst-case scenario that involves millions of deaths, or social distancing and sheltering in place across the planet for more than a year. Social distance might give hospitals a better chance to accommodate and treat the sick, but unsheltering means the disease just comes back. The only things that would shift those outcomes are vaccines or drugs.
Chloroquine and hydroxychloroquine aren’t the only candidates. There’s a protease inhibitor called camostat mesylate that a team of German scientists says works against the mechanism that SARS-CoV-2 uses to attach to the cells it infects. Virologists are pitching nucleoside analog inhibitors—remdesivir is one of these—that screw up the virus’ ability to replicate its RNA. Trials are actually going on—in China—on drugs like darunavir and cobicistat and interferon. And that doesn’t even get into the world of monoclonal antibodies that amp up a person’s own immune system to fight the virus. It’s good that all these things are in the works, and chloroquine’s relatively easy access does make it attractive … but no one knows which of these things is going to help people with Covid-19. All of them have side effects, to greater or lesser extents. Even chloroquine, well known and well tolerated, can cause nausea, heart palpitations, and—at the most extreme—eye damage and hallucinations.
Here’s the even deeper irony: Physicians are already using chloroquine anyway, because there’s nothing else yet. President Donald Trump actually mentioned it in a press conference on Thursday, praising the fact that it’s already approved by the FDA, albeit, again, not specifically for Covid-19. “It’s show—encouraging, very, very encouraging early results,” Trump said. “And we’re going to be able to make that drug available almost immediately.”
Not only is it already available, as it has been for almost a century, but Covid-19 patients are already getting it. Montefiore Medical Center in New York has already started seeing the surge of Covid-19 patients that public health experts have been warning about. The hospital is participating in the remdesivir trial and is giving Covid-19 patients chloroquine. “All of our patients get put on chloroquine, as well as on antiretrovirals. We’re using Kaletra. Different places are using different antiretrovirals,” says Liise-anne Pirofski, chief of infectious diseases at Albert Einstein College of Medicine and Montefiore. “Everybody gets that, unless they have some contraindication.”
And, according to Axios, the pharmaceutical company Bayer is getting ready to donate some large amount of the drug to the US—unclear what agency, though Axios cites an anonymous source at the Department of Health and Human Services—for use against Covid-19.
So it’s entirely possible that the disruptors are right about chloroquine, but wrong about how to prove it. Right now, in the midst of a crisis, they’re on the same page as the front-line practitioners facing a tsunami of sick people and nowhere near enough ventilators to keep them all breathing. Chloroquine has a chance of helping; the doctors are hoping it’ll do no harm.