The world has vaccines that can prevent most cases of Covid-19. It even has drugs that can help with the most serious symptoms of the disease. Now what it needs is a Tamiflu for SARS-CoV-2.
It would be a pill, exquisitely calibrated to target SARS-CoV-2, with tolerable side effects and a low-price tag. And it would work just as well as those antibody treatments that require an hourlong intravenous infusion, but it would come in a handy packet patient could take home.
“We’re looking for something I could give everyone in an urgent care setting who comes in with exposure or a positive test,” said Nathaniel Erdmann, an infectious disease specialist at the University of Alabama at Birmingham Hospital who treats Covid-19. “An easy, oral, safe drug.”
As simple as that sounds, the process of actually developing new antiviral treatments is overwhelmingly complicated, even outside of a pandemic. Things can go disastrously wrong at countless steps along the way, whether drugs are too weak to stop the viral spread or too sloppy to be safe. And SARS-CoV-2 is consistently evolving, meaning scientists have to outfox natural selection itself to stay ahead of the game.
The common cold is often caused by a coronavirus, after all. And, as scientists ruefully joke, after billions of dollars spent on research and development, there’s still no cure for that.
But in the case of Covid-19, it’s not for lack of trying. While the breathless search for a Covid-19 vaccine got most of the attention, the National Institutes of Health was running a sweeping parallel effort to find treatments for the disease itself.
Some drugs ended up being dead ends, like the malaria drug hydroxychloroquine, and some were unexpected successes, like the lifesaving steroid dexamethasone. Among the bright spots was Gilead Sciences’ remdesivir, an intravenous antiviral that proved to modestly reduce the length of hospitalization for patients with Covid-19. Likewise the antibody treatments from Eli Lilly and Regeneron, which helped keep high-risk patients out of the hospital.
Still missing, however, is what NIH Director Francis Collins called his “dream”: a highly effective pill that can be given immediately after diagnosis.
“It’s just a damn long pathway,” Collins said in an interview. First scientists have to find molecular vulnerability in a virus, and then comes the process of screening hundreds of thousands of would-be drugs to find the few that latch onto that target. Then medicinal chemists get to work on honing a Goldilocks molecule that balances power, specificity, and safety, and if everything goes well in the Petri dish, there’s still months of animal testing to do before a single human being can take a pill in a clinical trial.
“But I will tell you that this is an extremely high priority for Tony Fauci and Francis Collins and the Biden administration, to work with these companies to try to make sure that we speed this up,” Collins said. “Because this pandemic is going to be with us — even with great vaccines — and people are going to get sick.”
There is hope, even in the short term. Any day now, Merck is expected to present pivotal data on an oral treatment akin to remdesivir. Behind that is a treatment from Atea Pharmaceuticals, first developed for hepatitis C virus, which could have pivotal results in the coming months. Neither is purpose-built for the virus that causes Covid-19, but experts said the treatments could still tick many of the boxes of a hoped-for antiviral.
Perhaps most promising is a novel antiviral from Pfizer, a drug engineered specifically for the virus SARS-CoV-2 that entered its first clinical trial last month.
Scientists are crossing their fingers that each one demonstrates at least a marginal benefit, as the history of virology suggests the best bet for beating back Covid-19 will be a cocktail of treatments with complementary effects. But beyond the immediate crisis, experts hope society learns two key lessons: Antiviral development is really hard, and it’s even harder if you wait for a pandemic to start investing in it.
“We need to start thinking about biomedical research as essential infrastructure,” said Angela Rasmussen, a virologist at Georgetown University’s Center for Global Health Science and Security. “It reinforces that preparedness is not just about how prepared we are to innovate our way out of a crisis. It really does mean investing in drugs that may not have an obvious application when we’re developing them up front.”
How to make an antiviral
The fundamental problem, for drug hunters, is that viruses don’t fight fair.
As soon as SARS-CoV-2 takes hold, it begins using the body’s natural machinery to replicate itself. That gives the virus an edge. Scientists might spot scores of vulnerabilities in a virus, but the majority of them are sure to be shared by the host, making them unsafe targets to attack with a drug.
“If you look at the number of antivirals that exist compared to the number of antibiotics, there are so many fewer antivirals,” said Brianne Barker, a biology professor at Drew University who specializes in the body’s response to viral infection. “The reason for that is that viruses use our cells to reproduce, so you’re looking for a drug that hits some part of the viral reproduction without hurting our cells. And that’s not easy.”
Step one in the antiviral-development process is clearing that hurdle again and again, in the lab, in animals, and in healthy human volunteers.
The next challenge relates to timing. The precise moment of viral infection starts a countdown clock as the virus gradually awakens the immune system, creating a narrow window of time after which an antiviral is likely useless.
“For most viral diseases, the acute ones, the disease is really caused by the host’s response to it,” Rasmussen said. “If that virus gets a foothold and sets off all of these abnormal host processes, the horse is already out of the barn, so to speak.”
For SARS-CoV-2, it can take anywhere from a few days to two weeks for those abnormal immune processes to kick in. That means any clinical trial for an antiviral requires a delicate design. Patients must have confirmed infections, but if they’re already experiencing serious symptoms of Covid-19, they might be too far along to benefit.
Once a would-be antiviral developer has solved the timing problem, then there’s the conundrum of choosing a dose. In normal circumstances, dosing is a precise science, studied in tiered, escalating studies designed to isolate the perfect amount of drug that can achieve a benefit at minimal risk.
In the immediacy of the pandemic, drug developers have understandably sped past some of that methodical work, making educated guesses in the spirit of emergency. That makes each antiviral trial a high-wire scientific act, said Craig Rayner, an executive at the drug development consultancy Certara who worked on Tamiflu. Choosing the right dose can determine not only whether a trial will succeed, but also the manufacturing, rollout, and final cost of the drug in question.
“For every milligram above what is considered optimal, you’re wasting it,” Rayner said. “And for every milligram below, you’re putting everything at risk, because the virus has a chance to be clever and evolve around it.”
That leads to the next hurdle in developing antivirals: Even if you succeed, one drug is never enough. Unless a given antiviral can block 100% of viral replication, in time, evolution is going to kick in.
“In any other aspect of pharma, you’d never need to have 100% efficacy,” Barker said. “But with antivirals, if you allow any replication at all, the virus is going to mutate around the drug.”
In the long-term, the best bet for controlling SARS-CoV-2 is widespread vaccination backed up by a combination antiviral treatment, experts said — a drug cocktail that targets multiple facets of the virus to minimize the risk of mutation.
But first, they need that Tamiflu.
The leading contenders
The first drug poised to check all the boxes of an ideal antiviral is molnupiravir, invented at the Emory Institute for Drug Development and developed by Merck and Ridgeback Biotherapeutics. The drug is what’s known as a nucleoside analog, designed to throw a wrench in the process of viral replication by tricking SARS-CoV-2 into corrupting its own genetic material.
Merck is enrolling about 3,000 patients, both hospitalized and not, in a Phase 2/3 trial that will determine whether molnupiravir can help clear SARS-CoV-2 from the body faster than placebo and keep patients out of the hospital. Data from the smaller Phase 2 portion are expected in the coming weeks, and experts are particularly focused on whether Merck’s drug can prevent patients with mild symptoms from developing severe Covid-19.
Behind Merck’s drug is a treatment from Atea Pharmaceuticals that builds on prior antiviral success. Atea’s drug, AT-527, targets an enzyme key to viral replication, a similar approach to Gilead Sciences’ curative treatments for hepatitis C. Later this year, Atea expects to have Phase 2 data on AT-527’s benefits for patients in and out of the hospital. The company is also planning a larger, Phase 3 study on outpatients.
Experts are hopeful that both drugs can make a difference. They’ve selected targets that are likely to minimize the risk of side effects, and they’ve designed studies that should determine whether they work in that key post-diagnosis window. However, some expressed concern that because neither treatment was specifically engineered for SARS-CoV-2, there remains a substantial risk that each will come up short. When it comes to repurposed antivirals, “theoretically they should work great,” Rasmussen said, “but in reality a lot of times they don’t.”
An antiviral from Pfizer, now in the earliest stages of human testing, could address that problem. Catchily named PF-07321332, Pfizer’s drug targets SARS-CoV-2’s backbone enzyme, the linchpin of the virus’s replication process. That enzyme, called 3CL, is one of two that are specific to all coronaviruses. That means if Pfizer can find the right dose, and run the right trials, it might have a treatment not just for SARS-CoV-2 but future pandemic viruses.
“What we might end up doing here is curing the common cold,” Collins said. “Then I wouldn’t have to listen to those jokes anymore”.