In late March, just as the COVID-19 pandemic was ramping up in the United States, David Fajgenbaum, a physician-scientist at the University of Pennsylvania, devised a 10-day challenge for his lab: they would sift through 1,000 recently published scientific papers documenting cases of the deadly virus from around the world, pluck out the names of any drugs used in an attempt to cure patients, and track the treatments and their outcomes in a database.
Before late 2019, no one had ever had to treat this exact disease before, which meant all treatments would be trial and error. Fajgenbaum, a pioneering researcher in the field of drug repurposing—which prioritizes finding novel uses for existing drugs, rather than arduously and expensively developing new ones for each new disease—knew that physicians around the world would be embarking on an experimental journey, the scale of which would be unprecedented. His intention was to briefly document the early days of this potentially illuminating free-for-all, as a sidebar to his primary field of research on a group of lymph node disorders called Castleman disease. But now, 11 months and 29,000 scientific papers later, he and his team of 22 are still going strong.
They're running a publicly accessible database called the CORONA Project (COvid19 Registry of Off-label & New Agents) that to date tracks 400 different COVID-19 treatments that have been tried somewhere in the world, along with the frequency of their use, and the outcomes.
"There's so many drugs being used all over the place, in different ways, with different outcomes," says Fajgenbaum. "We're trying to add some order to the madness."
20,000 people have accessed the registry—other physicians and researchers, those in the pharmaceutical industry, and even curious lay people—and the data are now being shared with the U.S. Food and Drug Administration in the hopes of launching large-scale trials that would lead to approving a constellation of treatment options for COVID-19 faster than any new drugs could come online.
"What David's group has done with the CORONA Project is on a scale that I don't think has ever been seen before," says Heather Stone, a health science policy analyst at the FDA who specializes in drug repurposing. She was not involved in establishing the project, but is now working with its data. "To collect and collate that information and make it openly accessible is a massive feat, and a huge benefit to the medical community," she says.
On a Personal Mission
In the science and medical world, Fajgenbaum lives a dual existence: he is both researcher and subject, physician and patient. In July 2010, when he was a healthy and physically fit 25-year-old finishing medical school, he began living through what would become a recurring, unprovoked, and overzealous immune response that repeatedly almost killed him.
His lymph nodes were inflamed; his liver, kidneys, and bone marrow were faltering; and he was dead tired all the time. At first his doctors mistook his mysterious illness for lymphoma, but his inflamed lymph nodes were merely a red herring. A month after his initial hospitalization, pathologists at Mayo Clinic finally diagnosed him with idiopathic multicentric Castleman disease—a particularly ruthless form of a class of lymph node disorders that doesn't just attack one part of the body, but many, and has no known cause. It's a rare diagnosis within an already rare set of disorders. Only about 1,500 Americans a year receive the same diagnosis.
Without many options for treatment, Fajgenbaum underwent recurring rounds of chemotherapy. Each time, the treatment would offer temporary respite from Castleman symptoms, but bring the full spate of chemotherapy side effects. And it wasn't a sustainable treatment for the long haul. Regularly dousing a person's cells in unmitigated toxicity was about as elegant a solution to Fajgenbaum's disease as bulldozing a house in response to a toaster fire. The fire might go out (though not necessarily), but the house would be destroyed.
A swirl of exasperation and doggedness finally propelled Fajgenbaum to take on a crucial question himself: Among all of the already FDA-approved drugs on the market, was there something out there, labeled for another use, that could beat back Castleman disease and that he could tolerate long-term? After months of research, he discovered the answer: sirolimus, a drug normally prescribed to patients receiving a kidney transplant, could be used to suppress his overactive immune system with few known side effects to boot.
Fajgenbaum became hellbent on devoting his practice and research to making similar breakthroughs for others. He founded the Castleman Disease Collaborative Network, to coordinate the research of others studying this bewildering disease, and directs a laboratory consumed with studying cytokine storms—out-of-control immune responses characterized by the body's release of cytokines, proteins that the immune system secretes and uses to communicate with and direct other cells.
In the spring of 2020, when cytokine storms emerged as a hallmark of the most severe and deadly cases of COVID-19, Fajgenbaum's ears perked up. Although SARS-CoV-2 itself was novel, Fajgenbaum already had almost a decade of experience battling the most severe biological forces it brought. Only this time, he thought, it might actually be easier to pinpoint a treatment—unlike Castleman disease, which has no known cause, at least here a virus was clearly the instigator.
"Because [a drug] looks promising, we need to do a well-designed, large randomized controlled trial to really investigate whether this drug works or not ... We don't use that to say, 'You should take it.'"
Thinking Beyond COVID
The week of March 13, when the World Health Organization declared COVID-19 a pandemic, Fajgenbaum found himself hoping that someone would make the same connection and apply the research to COVID. "Then like a minute later I was like, 'Why am I hoping that someone, somewhere, either follows our footsteps, or has a similar background to us? Maybe we just need to do it," he says. And the CORONA Project was born—first as a 10-day exercise, and later as the robust, interactive tool it now is.
All of the 400 treatments in the CORONA database are examples of repurposed drugs, or off-label uses: physicians are prescribing drugs to treat COVID that have been approved for a different disease. There are no bonafide COVID treatments, only inferences. The goal for people like Fajgenbaum and Stone is to identify potential treatments for further study and eventual official approval, so that physicians can treat the disease with a playbook in hand. When it works, drug repurposing opens up a way to move quickly: A range of treatments could be available to patients within just a few years of a totally new virus entering our reality compared with the 12 - 19 years new drug development takes.
"Companies for many decades have explored the use of their products for not just a single indication but often for many indications," says Stone. "'Supplemental approvals' are all essentially examples of drug repurposing, we just didn't call it that. The challenge, I think, is to explore those opportunities more comprehensively and systematically to really try to understand the full breadth of potential activity of any drug or molecule."
The left column shows the path of a repurposed drug, and on the right is the path of a newly discovered and developed drug.
Cures Within Reach
In Fajgenbaum's primary work, promising drugs stand out easily. For a disease like Castleman, where improvement almost never occurs on its own, any improvement that follows a treatment can pretty clearly be attributed to that treatment. But Fajgenbaum says tracking COVID outcomes is less straightforward since "the vast majority of people will get better, whether they take steroids or they take Skittles." That's why the intent of the database is to identify promising treatments only to generate hypotheses and fruitful clinical trials, not to offer full-throated treatment recommendations. Within the registry, Fajgenbaum considers a drug promising if it's being used in humans, not just in lab animals, and a significant proportion of cases report patient improvement.
"It's that sort of combination of rock-solid randomized controlled trial data, plus anecdotal retrospective data, that we combine to say, 'Wow, this drug looks more promising than another,'" says Fajgenbaum. "Because it looks promising, we need to do a well-designed, large randomized controlled trial to really investigate whether this drug works or not ... We don't use that to say, 'You should take it.'"
Experts say that the search for repurposed drugs to treat COVID could have implications for rare diseases in general. Rare diseases, of which Castleman is one, affect 400 million people around the world. 95% of them don't have a tailor-made, FDA-approved drug treatment. Developing one is a lengthy and often prohibitively expensive process. If only a dozen people will benefit from and buy a drug, it's not often worth it to pharmaceutical companies to spend millions of dollars making them. On occasion when they do, however, that overhead shows up in the price tag: the top 10 most expensive drugs in the world are all for rare diseases, often making them inaccessible to patients. Identifying new clinical uses for drugs that already exist is critical for opening a trap door out of a cycle that prioritizes profits over health outcomes.
"COVID is an interesting case where it's demonstrated that when the scientific and medical community really focuses all of its efforts and talents on a single problem, a solution can be identified and in a much faster time period than has ever historically been the case," says Stone. "I certainly wish it hadn't taken a pandemic to do that, but I think it does have lessons for the future in terms of our ability to accomplish things that we might have previously not thought were possible"—for example, mainstreaming the idea of drug repurposing as a treatment tool, even long after the pandemic subsides.
A Confounding Virus
The FDA declined to comment on what drugs it was fast-tracking for trials, but Fajgenbaum says that based on the CORONA Project's data, which includes data from smaller trials that have already taken place, he feels there are three drugs that seem the most clearly and broadly promising for large-scale studies. Among them are dexamethasone, which is a steroid with anti-inflammatory effects, and baricitinib, a rheumatoid arthritis drug, both of which have enabled the sickest COVID-19 patients to bounce back by suppressing their immune systems. The third most clearly promising drug is heparin, a blood thinner, which a recent trial showed to be most helpful when administered at a full dose, more so than at a small, preventative dose. (On the flipside, Fajgenbaum says "it's a little sad" that in the database you can see hydroxychloroquine is still the most-prescribed drug being tried as a COVID treatment around the world, despite over the summer being debunked widely as an effective treatment, and continuously since then.)
One of the confounding attributes of SARS-CoV-2 is its ability to cause such a huge spectrum of outcomes. It's unlikely a silver bullet treatment will emerge under that reality, so the database also helps surface drugs that seem most promising for a specific population. Fluvoxamine, a selective serotonin reuptake inhibitor used to treat obsessive compulsive disorder, showed promise in the recovery of outpatients—those who were sick, but not severely enough to be hospitalized. Tocilizumab, which was actually developed for Castleman disease, the disease Fajgenbaum is managing, was initially written off as a COVID treatment because it failed to benefit large portions of hospitalized patients, but now seems to be effective if used on intensive care unit patients within 24 hours of admission—these are some of the sickest patients with the highest risk of dying.
Other than fluvoxamine, most of the drugs labeled as promising do skew toward targeting hospitalized patients, more than outpatients. One reason, Fajgenbaum says, is that "if you're in a hospital it's very easy to give you a drug and to track you, and there are very objective measurements as to whether you die, you progress to a ventilator, etc." Tracking outpatients is far more difficult, especially when folks have been routinely asked to stay home, quarantine, and free up hospital resources if they're experiencing only mild symptoms.
But the other reason for the skew is because COVID is very unlike most other diseases in terms of the human immune response the virus triggers. For example, if oncology treatments show some benefit to people with the highest risk of dying, then they usually work extremely well if administered in the earlier stages of a cancer diagnosis. Across many diseases, this dialing backward is a standard approach to identifying promising treatments. With COVID, all of that reasoning has proven moot.
As we've seen over the last year, COVID cases often start as asymptomatic, and remain that way for days, indicating the body is mounting an incredibly weak immune response initially. Then, between days five and 14, as if trying to make up for lost time, the immune system overcompensates by launching a major inflammatory response, which in the sickest patient can lead to the type of cytokine storms that helped Fajgenbaum realize his years of Castleman research might be useful during this public health crisis. Because of this phased response, you can't apply the same treatment logic to all cases.
"In COVID, drugs that work late tend to not work if given early, and drugs that work early tend to not work if given late," says Fajgenbaum. "Generally this … is not a commonplace thing for a virus."
"There are drugs that are literally sitting in every single hospital pharmacy in the country that, if a study shows it's effective, can be deployed that evening to patients on a massive scale."
This see-sawing necessitates tracking a constellation of drugs that might work for different stages of the disease as a patient moves from the weak immune response stage into the overzealous immune response.
"COVID is difficult, compared to other diseases, because there are so many different levels of disease severity, and recovery at different rates," says Stone, the FDA researcher. "That makes it hard to see the patterns or signals and it makes it very important to collect very, very large numbers of cases in order to really reliably identify signals."
This particular moment in the pandemic feels like a massive tipping point, or the instant a tiny pinprick of light finally appeared at the end of the tunnel: several vaccines are already here, with more on the way imminently. In the U.S., more than 65 million doses of the vaccine have been administered, and positive COVID cases are finally falling back to levels not seen since October. On the hopeful surface, it might seem a strange moment to be preparing to launch trials that will validate treatments for a virus it seems the U.S. may finally be beating back. But at best, Americans are still months away from reaching herd immunity through vaccination, and new circulating variants may threaten to upend our fragile progress.
"In the meantime, there are drugs that are literally sitting in every single hospital pharmacy in the country that, if a study shows it's effective, can be deployed that evening to patients on a massive scale. It wouldn't have to be newly produced, it wouldn't have to be shipped, it's literally there already," says Fajgenbaum. "The idea that you can save a lot of lives by finding things that are just already there I think is really compelling, given how many people are going to die over these next few months."
Even after that, not everyone can or will be vaccinated, and, as the Wall Street Journal recently reported, "The pathogen will circulate for years, or even decades, leaving society to coexist with Covid-19 much as it does with other endemic diseases like flu, measles, and HIV." Neither vaccines, personal behavior, or treatments alone is a panacea against the virus, but together they might be.
"It's important to explore all avenues in this public health emergency, and drug repurposing can continue to play a role as the pandemic continues and evolves," says Stone. "I think COVID variants in particular are a big concern at the moment, and therefore continuing to investigate new therapeutics, even as the vaccines roll out, will continue to be a priority."
In November 2020, messenger RNA catapulted into the public consciousness when the first COVID-19 vaccines were authorized for emergency use. Around the same time, an equally groundbreaking yet relatively unheralded application of mRNA technology was taking place at a London hospital.
Over the past two decades, there's been increasing interest in harnessing mRNA — molecules present in all of our cells that act like digital tape recorders, copying instructions from DNA in the cell nucleus and carrying them to the protein-making structures — to create a whole new class of therapeutics.
Scientists realized that artificial mRNA, designed in the lab, could be used to instruct our cells to produce certain antibodies, turning our bodies into vaccine-making factories, or to recognize and attack tumors. More recently, researchers recognized that mRNA could also be used to make another groundbreaking technology far more accessible to more patients: gene editing. The gene-editing tool CRISPR has generated plenty of hype for its potential to cure inherited diseases. But delivering CRISPR to the body is complicated and costly.
"Most gene editing involves taking cells out of the patient, treating them and then giving them back, which is an extremely expensive process," explains Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the COVID-19 vaccines.
But last November, a Massachusetts-based biotech company called Intellia Therapeutics showed it was possible to use mRNA to make the CRISPR system inside the body, eliminating the need to extract cells out of the body and edit them in a lab. Just as mRNA can instruct our cells to produce antibodies against a viral infection, it can also teach them to produce the two molecular components that make up CRISPR — a guide molecule and a cutting protein — to snip out a problem gene.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies."
In Intellia's London-based clinical trial, the company applied this for the first time in a patient with a rare inherited liver disease known as hereditary transthyretin amyloidosis with polyneuropathy. The disease causes a toxic protein to build up in a person's organs and is typically fatal. In a company press release, Intellia's president and CEO John Leonard swiftly declared that its mRNA-based CRISPR therapy could usher in a "new era of potential genome editing cures."
Weissman predicts that turning CRISPR into an affordable therapy will become the next major frontier for mRNA over the coming decade. His lab is currently working on an mRNA-based CRISPR treatment for sickle cell disease. More than 300,000 babies are born with sickle cell every year, mainly in lower income nations.
"There is a FDA-approved cure, but it involves taking the bone marrow out of the person, and then giving it back which is prohibitively expensive," he says. It also requires a patient to have a matched bone marrow done. "We give an intravenous injection of mRNA lipid nanoparticles that target CRISPR to the bone marrow stem cells in the patient, which is easy, and much less expensive."
Meanwhile, the overwhelming success of the COVID-19 vaccines has focused attention on other ways of using mRNA to bolster the immune system against threats ranging from other infectious diseases to cancer.
The practicality of mRNA vaccines – relatively small quantities are required to induce an antibody response – coupled with their adaptable design, mean companies like Moderna are now targeting pathogens like Zika, chikungunya and cytomegalovirus, or CMV, which previously considered commercially unviable for vaccine developers. This is because outbreaks have been relatively sporadic, and these viruses mainly affect people in low-income nations who can't afford to pay premium prices for a vaccine. But mRNA technology means that jabs could be produced on a flexible basis, when required, at relatively low cost.
Other scientists suggest that mRNA could even provide a means of developing a universal influenza vaccine, a goal that's long been the Holy Grail for vaccinologists around the world.
"The mRNA technology allows you to pick out bits of the virus that you want to induce immunity to," says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech that's developing mRNA-based vaccines for malaria and HIV, as well as various forms of cancer. "This means you can get the immune system primed to the bits of the virus that don't vary so much between strains. So you could actually have a single vaccine that protects against a whole raft of different variants of the same virus, offering more universal coverage."
Before mRNA became synonymous with vaccines, its biggest potential was for cancer treatments. BioNTech, the German biotech company that collaborated with Pfizer to develop the first authorized COVID-19 vaccine, was initially founded to utilize mRNA for personalized cancer treatments, and the company remains interested in cancers ranging from melanoma to breast cancer.
One of the major hurdles in treating cancer has been the fact that tumors can look very different from one person to the next. It's why conventional approaches, such as chemotherapy or radiation, don't work for every patient. But weaponizing mRNA against cancer primes the immune cells with the tumor's specific genetic sequence, training the patient's body to attack their own unique type of cancer.
"It means you're able to think about personalizing cancer treatments down to specific subgroups of patients," says Mulqueen. "For example, eTheRNA are developing a renal cell carcinoma treatment which will be targeted at around 20% of these patients, who have specific tumor types. We're hoping to take that to human trials next year, but the challenge is trying to identify the right patients for the treatment at an early stage."
Repairing Damaged mRNA
While hopes are high that mRNA could usher in new cancer treatments and make CRISPR more accessible, a growing number of companies are also exploring an alternative to gene editing, known as RNA editing.
In genetic disorders, the mRNA in certain cells is impaired due to a rogue gene defect, and so the body ceases to produce a particular vital protein. Instead of permanently deleting the problem gene with CRISPR, the idea behind RNA editing is to inject small pieces of synthetic mRNA to repair the existing mRNA. Scientists think this approach will allow normal protein production to resume.
Over the past few years, this approach has gathered momentum, as some researchers have recognized that it holds certain key advantages over CRISPR. Companies from Belgium to Japan are now looking at RNA editing to treat all kinds of disorders, from Huntingdon's disease, to amyotrophic lateral sclerosis, or ALS, and certain types of cancer.
"With RNA editing, you don't need to make any changes to the DNA," explains Daniel de Boer, CEO of Dutch biotech ProQR, which is looking to treat rare genetic disorders that cause blindness. "Changes to the DNA are permanent, so if something goes wrong, that may not be desirable. With RNA editing, it's a temporary change, so we dose patients with our drugs once or twice a year."
Last month, ProQR reported a landmark case study, in which a patient with a rare form of blindness called Leber congenital amaurosis, which affects the retina at the back of the eye, recovered vision after three months of treatment.
"We have seen that this RNA therapy restores vision in people that were completely blind for a year or so," says de Boer. "They were able to see again, to read again. We think there are a large number of other genetic diseases we could go after with this technology. There are thousands of different mutations that can lead to blindness, and we think this technology can target approximately 25% of them."
Ultimately, there's likely to be a role for both RNA editing and CRISPR, depending on the disease. "I think CRISPR is ideally suited for illnesses where you would like to permanently correct a genetic defect," says Joshua Rosenthal of the Marine Biology Laboratory in Chicago. "Whereas RNA editing could be used to treat things like pain, where you might want to reset a neural circuit temporarily over a shorter period of time."
Much of this research has been accelerated by the COVID-19 pandemic, which has played a major role in bringing mRNA to the forefront of people's minds as a therapeutic.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies," says Mulqueen. "In the future, I would not be surprised if many of the top pharma products are mRNA derived."
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.