Chloroquine May Fight Covid-19—and Silicon Valley’s Into ItWiredURL: https://www.wired.com/story/an-old-mala ... s-into-it/Category: Science
Published: March 19, 2020
Description: 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.
The Info War Over Chloroquine Has Slowed Covid-19 ScienceWiredURL: https://www.wired.com/story/the-info-wa ... 9-science/Category: Science
Published: May 1, 2020
Description: There’s been a lot of heat but not much light on whether the antimalarial drug helps coronavirus patients. That’s because we still need a big clinical trial.
On March 9, members of a team of infectious disease researchers based at the University of Minnesota found themselves with four free days. An HIV conference they were supposed to attend had been called off on account of the global pandemic, which gave the group an unusual moment of breathing space. “This was right when community spread was beginning to happen, and we realized it was going to be a problem,” says David Boulware, a physician and leader of the group. “We wanted to focus on prevention and early treatment. At the time, no one was really doing that.” Even then, research interest was circling around the decades-old antimalarial drugs chloroquine and its cousin, hydroxychloroquine. Silicon Valley hadn’t yet turned its disrupt-o-vision on the drugs, but they killed the SARS-CoV-2 virus in the lab, and a small, preliminary study in China seemed to suggest they worked in actual people too. Because physicians were already allowed to prescribe the drugs—for malaria and immune disorders like rheumatoid arthritis and lupus—they were starting to use it, Hail Mary–style, on Covid-19 patients in the hospital. It was, in short, worth a look. But not, in Boulware’s mind, for people so sick they were already hospitalized. “Late-stage severe disease, there’s a lot of things going on with the virus and the immune system. We realized six weeks ago hydroxychloroquine probably didn’t work then,” he says. But what about if it was prescribed early, to prevent people from getting the disease, or from getting very sick if they did? The team put together a plan for a double-blind, randomized, controlled trial—hydroxychloroquine versus a placebo. The US Food and Drug Administration gave them an Investigational New Drug approval to use the stuff in this new way. Just eight days after coming up with the idea, Boulware and his team enrolled the first subject into the trial, which is asking if the drug can help people in the early stages of Covid-19 infection and protect at-risk people such as health care workers and people taking care of infected family members. And then things got more complicated. The day before that first subject signed up, on March 16, SpaceX CEO Elon Musk tweeted about the drug, sparking interest among the crowd that wants to extend its life with metformin and blood from young people. Three days later, President Donald Trump said during a Covid-19 press briefing that he thought the drugs “could be something very, very incredible,” sparking a run on pharmacies. Whether someone believed the drugs worked against Covid-19 came to be a symbol of how they felt about the president. And all that happened without any real, solid scientific results. As of now, no one really knows if hydroxychloroquine and chloroquine help fight Covid-19. And an information war is hindering the struggle to find out. It’s not implausible that chloroquine could be helpful. As early as 2005, research showed that—in a laboratory mix of African green monkey cells, at least—it inhibits the virus that causes Severe Acute Respiratory Syndrome, SARS, a coronavirus related to the one that causes Covid-19. The drug kept cells from becoming infected and helped them fight off infection as well—a preventative and a therapy. Researchers even worked out its mechanism. A coronavirus anchors onto a cell via a specific docking port, a receptor called angiotensin-converting enzyme 2. Chloroquine seems to keep this ACE2 docking port from opening and also make the interior of cells less acidic, and so less friendly to the virus once it gets inside. Sounds good, right? So much so, in fact, that as The Washington Post reported, Oracle CEO Larry Ellison lobbied President Trump to build a national system for monitoring the drug. A family doctor in New York named Vladimir Zelenko started getting national attention for a series of videos he made touting the success of a protocol of his own devising against Covid-19, combining hydroxychloroquine, azithromycin, and zinc. Fox News picked up on the president’s early cheerleading, and started talking about the drugs as well. By the end of March, the president was tweeting that hydroxychloroquine in combination with the antibiotic azithromycin could be “a game changer.” The US Department of Health and Human Services started adding millions of doses of hydroxychloroquine to the Strategic National Stockpile of drugs for eventual distribution to states. The FDA issued an Emergency Use Authorization telling physicians they could prescribe the drug to people hospitalized for Covid-19. (Many already were; it’s relatively cheap, already in the pharmacopeia, and they didn’t have anything else.) Demand for hydroxychloroquine spiked to such an extent that people who depend on it to treat their rheumatoid arthritis or lupus started to worry that they wouldn’t be able to get it. The evidence wasn’t as hot as the market. Unorthodox research methods and a seeming rush to publication, or even prepublication, muddied the situation. Early studies from an infectious disease researcher named Didier Raoult, director of the Research Unit in Infectious and Tropical Emergent Diseases in Marseille, seemed promising, albeit un-peer reviewed. On March 20, Raoult’s group published a second trial as a preprint and then in a peer-reviewed journal: a non-randomized, open-label trial. Instead of following the gold-standard protocol for testing drugs against diseases, the researchers simply gave Covid-19 patients the drugs and then monitored their viral counts, comparing them to Covid-19 patients elsewhere who didn’t get the drug. No placebo, no double-blinding. (Raoult has said in interviews that he doesn’t think randomization is necessary in infectious-disease drug research.) The larger research community and scientific watchdogs quickly tore into Raoult’s methodology. The data seemed sketchy to them—not every patient who died was accounted for, and the comparisons among the groups weren’t rigorous. Some of the math behind the statistical analysis didn’t work out. And the paper itself seemed to cruise through ethical gatekeeping and peer review too quickly. The publishers of the journal, the International Society of Antimicrobial Chemotherapy and Elsevier, would eventually issue a joint statement expressing “concern” with the research. “The French stuff was low quality in terms of evidence of whether this thing works or not,” says Walid Gellad, head of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. Of course, Raoult wasn’t the only scientist on the case. Chinese researchers had been studying chloroquine since early on in their experience with the pandemic. But few published results, it seems. According to one, a randomized controlled trial with 30 subjects in the early stages of Covid-19 infections published in the Journal of ZheJiang University, roughly the same number of people improved whether they were on the drug or not. Those who had taken hydroxychloroquine showed moderate benefits in terms of lung damage seen on a CT scan. “There was a small trial in China that showed it did have an effect—a randomized trial showing an effect in some measures, when given early,” Gellad says. Meanwhile, other clinical trials are spinning up. The World Health Organization’s Solidarity trial of Covid-19 treatments and the United Kingdom’s Recovery trial both include tests of hydroxychloroquine. Around the world, nearly 150 are either underway or set to begin soon. As that global race to investigate the drug began, though, it hit what looked like speed bumps. In late April, a preprint—no peer review—detailed results for 368 people treated for Covid-19 in Veterans Affairs hospitals with hydroxychloroquine, hydroxychloroquine and azithromycin, or none of the above. The drug didn’t reduce the risk of being put on a ventilator, and it slightly increased the chances people would eventually die of the disease. Suggestive, and not in a good way. And then the results of a Brazilian trial of chloroquine in people hospitalized with severe Covid-19 seemed to sap even more momentum. A safety committee actually stopped that randomized, double-blind study early. Nearly 40 percent of the people receiving a very high dose of chloroquine had died, and many showed a heart problem called QT interval prolongation, a known side effect of the drug and one potentially made worse when it’s used in combination with azithromycin. On April 24, the FDA issued a new statement—a Drug Safety Communication—warning that physicians shouldn’t prescribe the drugs to people outside a hospital or trial. The FDA had also received more “adverse event” reports on the drugs, primarily related to heart problems. “While we are unable to offer more specifics on the small number of cases we have reviewed at this time, we will continue to investigate the risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and will share any additional information or analysis publicly as we’re able,” the statement read. Sounds bad, right? Except … again, the research wasn’t clear. The VA study was retrospective, and small. That Brazilian study was only of very sick people, exactly the group that big studies like Boulware’s and the international trials planned to exclude on the grounds that they’re probably too sick to help. (Or, perhaps more importantly, it would be too hard for researchers to disaggregate the effects of the drugs from everything else going on in those people’s bodies.) And that high dose of the drug? It was really high—600 mg twice a day for people in the high-dose arm of the trial, and on the low-dose arm 450 mg twice a day on the first day and then once thereafter. That’s compared to a recommended 400 mg twice a day for one day and then once thereafter in US protocols. “What’s being used in the US is much more like the low-dose arm, and there are no issues,” Gellad says. “The high-dose arm had people with other risk factors. It doesn’t tell us much about the way it’s going to be used in the US.” As for the FDA’s caution? “I think what’s happened is there’s been a lot of promotion of this drug as a cure-all by politicians and by the media. And, parenthetically, at the same time there’s been a lot of unnecessary vilification of the drugs,” Gellad says. “The reality is, there’s a ton of uncertainty … My guess is the FDA wanted to pull back on the idea that the government was promoting the use of this drug, not pushing this therapy but being very responsible, using it in clinical trials.” The FDA wanted to remind primary care physicians that while they were allowed to prescribe these drugs off-label, they had real side effects—and that some people who don’t have Covid-19 infections really need them for other reasons. “We understand that health care professionals are looking for every possible treatment option for their patients, and we want to ensure we’re providing them with the appropriate information needed for them to make the best medical decisions,” FDA commissioner Stephen Hahn said via press release. “While clinical trials are ongoing to determine the safety and effectiveness of these drugs for Covid-19, there are known side effects of these medications that should be considered.” The agency also didn’t want to step on ongoing research. Yet the ongoing back-and-forth about safety and efficacy has done exactly that. As soon as the drug hit the Strategic National Stockpile and started making its way to state hoards and the medicine cabinets of the worried well, “our enrollment started to tank,” Boulware says. Remember, being in a randomized controlled trial means you have a good chance of being in the placebo group—of not getting the drug. Trials aren’t meant to treat people; they’re meant to advance science. With so much positive spin, Boulware says, people figured: “Hey, it clearly works. Why would you be in a randomized controlled trial?” A clinical trial might not help each person, but it does help everyone; without them, no one can know if the drugs actually work. Boulware’s group has 1,200 people enrolled already, but they need 180 more. And he’s having a hell of a time getting them signed up. So far, Boulware says, no one in the study has had any safety issues remotely like what the Brazilians experienced—probably because of the lower dose. Yet the fights over hydroxychloroquine continue, on the internet and in real life. If the drug works, some partisans argue, it’s wrong to delay its widespread use by waiting for results; if it doesn’t, it’s wrong to even try it on people. “The social media perspective is: About half of people think it’s an unethical trial because it clearly works, and the other half thinks it's clearly dangerous and we shouldn’t do it,” Boulware says. “We’re just trying to get the answer. Having a solid study design and having the actual answer is really important for both the country and the world, and that’s our goal.” Meanwhile, though, it’s important to remember that nobody actually knows that answer. The Silicon Valley adherents insisting that the problem with the negative results thus far is that researchers tested the wrong kind of people, or used the wrong dose, or didn’t use zinc—they don’t have the data that can say whether any of that is true. The people saying that hydroxychloroquine is clearly unsafe, or that it can’t possibly work? They don’t have that data, either. Nobody does. The studies aren’t finished. “It’s going to be May 1, and we still don’t know if it works. It’s a giant failure,” Gellad says. “We should have had an answer. All you need is a randomized controlled placebo trial with 1,000 patients, and we’d know.” The president’s unjustified early enthusiasm for hydroxychloroquine (and his equally unjustified apparent abandonment of the idea) didn’t translate into a centralized, rapid-response study to determine the actual truth. The National Institutes of Health didn’t spin one up until the first week of April, a month after Boulware launched his. “Ideally, you would think, this is a national emergency and there would be coordination centrally, at the federal government level,” Boulware says. “The UK put together a nationwide trial for treatment. We weren’t able to do that.” But if we were? Imagine the satisfaction of knowing a true fact—of being able to help sick people, or knowing that hydroxychloroquine doesn’t help and being able to move on. Imagine, if you can, being able to decisively win a fight on Twitter.
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