经历过SARS和MERS，这次疫情为何还没有抗病毒药物？

Even with highly effective vaccines, cases of COVID-19 are still happening in the U.S. More than 40,000 people a day are being diagnosed with the disease, based on a seven-day average of Johns Hopkins University data.

Many people remain hesitant about getting the shot, and breakthrough infections can occasionally occur in those who are vaccinated. Meanwhile, some countries don’t have enough vaccine doses. COVID-19 is likely here to stay—at least for the foreseeable future.

Drug developers and public health experts say what’s needed now is an easy-to-take treatment for COVID-19. A pill akin to Tamiflu—an antiviral for seasonal influenza—could prevent people with symptoms from getting worse and ending up in the hospital. Antibody drugs have been shown to do just that, but these drugs need to be given via an IV, making them difficult to deploy quickly to a large number of people. A pill would be far more convenient.

“Unless we can persuade enough people to agree to vaccination, we are going to need a second approach, and oral antivirals can give us that,” says Richard Plemper, a molecular virologist and biochemist at Georgia State University.

An antiviral pill for COVID-19 would work similarly to a course of antibiotics. Your doctor would prescribe a pack of pills, and you’d take one or two a day for five to seven days while you stay at home. The hope is that a pill would alleviate symptoms and help people bounce back from the infection faster. When Tamiflu is taken within 48 hours, it speeds recovery time by a day.

The search for a coronavirus pill has lagged behind the light-speed development of vaccines in part because antivirals haven’t gotten the same influx of cash from the federal government that COVID-19 vaccines have.

A handful of experimental pills are now being tested in clinical trials, and the next few months will reveal whether any of them are effective. At the forefront is a drug called molnupiravir, developed by Merck and Ridgeback Biotherapeutics. In preliminary results announced in March, the company said the pill was safe and significantly reduced viral loads in nonhospitalized adults. The companies are expected to release more data soon.

Pfizer, which developed one of the mRNA vaccines for COVID-19, is also testing an antiviral pill. CEO Albert Bourla told CNBC recently that the drug could be available by the end of the year.

Thwarting the virus

Beyond Tamiflu, antivirals are available to treat infections like HIV, herpes, and hepatitis B and C, but that’s a short list compared to the numerous antibiotics on the market for bacterial infections.

Drug developers say it’s because safe and effective antivirals are just trickier to make than antibiotics. Unlike bacteria, which are independent organisms that can reproduce on their own, viruses need to find a host in order to spread. Once a virus particle slips inside a host cell, it hijacks the cell’s machinery and starts churning out copies of itself. The new copies then travel throughout the body, infecting more cells.

All viruses need to keep replicating to continue the infection, so if you can block one of the steps in this replication process, then you can halt the infection. Antivirals don’t kill viruses outright; they just prevent the virus from replicating.

What’s tricky is targeting the virus during this process without also killing the cells where the virus resides. Antibiotics kill only bacterial cells, not human ones. But when developing antivirals, toxicity is always a concern.

“Finding the unique Achilles’ heel of the virus that we can exploit without affecting the host, that is really the major challenge for antiviral therapy,” Plemper says. Some do this by directly targeting a site on the virus. Others target human proteins that get commandeered in the viral replication process.

Another factor that makes antiviral development challenging is the timing of the drug. “Antiviral drugs need to be given very early, very rapidly after someone's been diagnosed,” says Lisa Gralinski, an assistant professor of epidemiology at the University of North Carolina at Chapel Hill, who’s been involved in lab tests of molnupiravir.

If the virus has already spread widely throughout the body, it can start inflicting serious damage. An antiviral can stop the virus, but it can’t reverse the damage that it’s already done to tissue. Patients have to be diagnosed quickly—within a few days of developing symptoms—making enrolling participants for clinical trials difficult. Many cases of COVID-19 are mild, and if patients aren’t very sick yet, they may not be motivated to volunteer for an experimental drug trial.

Currently, Gilead’s remdesivir is the only antiviral approved for COVID-19, and it’s given as an infusion to hospitalized patients. The drug hasn’t been shown to save lives, but it does shorten the recovery time for those who get better. But because of the unclear benefits, the World Health Organization has recommended against its use as a routine treatment. Gilead is looking to create an inhaled or pill version of remdesivir that patients could take at home.

If they work, antivirals could even be prescribed as a preventive measure to high-risk individuals exposed to COVID-19.

In the pipeline

Molnupiravir—originally invented at Emory University—got a head start in the antiviral race because researchers were already studying it against several viruses in the lab. Before the pandemic hit, Plemper had discovered that the drug inhibited influenza viruses, and researchers at the University of North Carolina at Chapel Hill found that it was effective against other coronaviruses like MERS and SARS.

“We had a strong inkling that it would work against SARS-CoV-2 because we already knew its mechanism of action,” Gralinski says.

Molnupiravir is a type of drug known as a nucleoside analog. It works by tricking the virus into making lots of mistakes, or mutations, in its genome when it replicates. The virus accumulates so many mutations that it can’t survive.

Last year, Miami-based Ridgeback Biotherapeutics licensed molnupiravir—then called EIDD-2801—for initial human safety trials. The company is now collaborating with Merck on larger studies to test the pill in both hospitalized and nonhospitalized COVID-19 patients. Last month, the companies stopped the trial of molnupiravir in hospitalized patients, saying that those individuals are unlikely to benefit from the drug.

Meanwhile, Atea Pharmaceuticals is also repurposing an antiviral. Its pill, called AT-527, was originally developed for the hepatitis C virus. Last month the company launched a Phase III trial to test the drug in 1,400 nonhospitalized patients with mild to moderate COVID-19.

Pfizer is taking a more tailored approach with its pill. In March of last year, the company formed a team to design a molecule to specifically fight SARS-CoV-2, says Charlotte Allerton, head of medicinal design at Pfizer. By July, the team had identified a promising molecule that it dubbed PF-07321332.

The drug blocks viral replication by binding to a viral enzyme called a protease. Known as protease inhibitors, these drugs have been effective at treating other viruses, such as HIV and hepatitis C, both alone and in combination with other antivirals.

This March, Pfizer began an early-stage trial to test the safety of the drug in healthy adults. Allerton says the company plans to recruit COVID-19 patients for efficacy studies by summer.

Since it acts directly on the virus, one concern with a protease inhibitor is that SARS-CoV-2 could become resistant to the drug if the targeted part of the virus mutates. Allerton says her team is tracking SARS-CoV-2 variants to look for mutations in the protease that could potentially make the drug less effective.

“While there are low levels of mutations reported, we're not currently expecting them to cause any issue in terms of the antiviral efficacy of our molecule,” she says.

Small biotech firms Selva Therapeutics and Clear Creek Bio are developing pills that may be able to evade drug resistance because they act on host cells rather than the virus. Selva’s drug, which it licensed from the University of California, San Diego, inhibits an enzyme found in human lungs and other cells to block viral entry. Clear Creek’s drug brequinar, which it acquired a few years ago from Bristol Myers Squibb, inhibits an enzyme that starves the virus of its ability to steal genetic material from the host cell, which it needs for replication.

“What really struck us when the pandemic emerged was the idea that this could be resistance resistant,” says Vikram Sheel Kumar, cofounder and CEO of Clear Creek Bio, which is based in Cambridge, Mass. The company began a mid-stage trial of brequinar in nonhospitalized patients in November.

Beyond COVID-19

Most available antivirals work only against a specific virus. But there’s hope for experimental drugs known as broad-spectrum antivirals, like molnupiravir, to be used against a wide range of viruses. Scientists see these drugs as the holy grail of antivirals because of their potential to treat future viruses that emerge. After all, SARS-CoV-2 is the third coronavirus outbreak in the past 20 years, and hundreds more coronaviruses are known to be circulating in bats and other animals.

“We don't want to imagine that possible fourth one coming, but it would be smart to be prepared for it and plan in advance,” Gralinski says. “If we have these broadly acting drugs available, or even ones that are most of the way through development and are ready for future testing, hopefully we could avoid another pandemic.”

A major reason why there were no antivirals ready to go when the COVID-19 pandemic hit was because no drugs for SARS or MERS had ever been developed. When those outbreaks were contained quickly, drug and vaccine development came to a virtual halt.

Whether COVID-19 antivirals will ever make it to the masses will depend on investment from the federal government and private industry. Operation Warp Speed provided an infusion of $18 billion into medical countermeasures against the pandemic, but the vast majority of that money went toward vaccine development. The Trump administration program didn’t invest in new antivirals.

In April 2020, the National Institutes of Health did launch an effort called Accelerating COVID-19 Therapeutic Interventions and Vaccines, or ACTIV, but that program has mostly focused on repurposing existing antivirals, not discovering new ones.

Ted Daley, CEO and cofounder of Selva Therapeutics in San Diego, says more investment in antivirals is needed to speed these drugs to patients.

“There’s certainly a common public health interest in supporting the development efforts of drugs that not only address the current public health crisis that we're in but could also be a tool in the arsenal next time one of these viruses pops up,” he says.

And Big Pharma has had little interest in developing antivirals beyond chronic infections like HIV. Most respiratory viruses cause mild illness, and infections clear up within a few days. The economics of antivirals for short-lived infections didn’t make sense.

“They want to make drugs for diabetes. They want to make drugs for hypertension. They want to make things that you will need forever, not something that you need for five days,” says Elizabeth Duke, an infectious disease physician and researcher at the Fred Hutchinson Cancer Research Center in Seattle who’s overseeing a trial there of molnupiravir.

But Duke thinks COVID-19 could be a turning point for the pharmaceutical industry. The pandemic has shown that respiratory viruses can be far more deadly than the flu or common cold. Even with effective vaccines, SARS-CoV-2 is likely here to stay. But antivirals could help reduce the virus from a deadly menace to a manageable infection that we could largely fight at home.