Effective treatments for COVID-19 are tough to develop, but this pill is raising hopes

It took medical science barely a year to produce a variety of highly effective vaccines to prevent infection with the virus that is threatening humankind.

But come up with COVID-19 therapies? Not so much, despite vast global investment in the quest.

The United States has fully approved only a single drug, the antiviral remdesivir, and it is far from a miracle cure. It can shorten recovery time for hospitalized COVID-19 patients, but it doesn’t appear to save lives.

Experts point to a fundamental reason for the lack of specific, effective COVID-19 treatments: Viruses, unlike bacteria, are hard to stop without doing serious collateral damage to the human host.

Still, there is cautious optimism that molnupiravir, an experimental compound originally studied as an influenza treatment, might fight the novel coronavirus — and maybe other viruses as well. The developers, Merck and Ridgeback Pharmaceuticals, are expected to announce detailed results from midstage clinical trials within weeks.

“Molnupiravir might be unusually potent and broad acting,” said Derek Lowe, a pharmaceutical chemist who writes the popular drug discovery blog In the Pipeline. “Another unusual thing: It seems to have a very low tendency” to make the virus mutate to become resistant.

Before getting into virology, here’s a quick review of the COVID-19 therapeutic landscape.

Although remdesivir is the only approved drug, several “monoclonal antibodies” — synthetic versions of the body’s own disease-fighting antibodies — have received emergency authorization and have raised hopes for keeping high-risk patients out of the hospital. But these drugs, which must be given intravenously, pose logistical and medical quandaries, and have shown modest benefits. That said, just this week Eli Lilly announced that its new combination of monoclonal antibodies dramatically reduced hospitalizations and deaths in a clinical trial.

» READ MORE: Monoclonal antibody drugs raise hopes for keeping high-risk COVID-19 patients out of the hospital. But it’s complicated.

Dexamethasone, a venerable, generic steroid that tamps down inflammation, is the only drug previously shown to improve outcomes for severely ill, hospitalized COVID-19 patients. In those who develop blood clots, anticoagulants also help.

Repurposed drugs that were touted early in the pandemic — including malaria medicines, a head lice treatment, and HIV antivirals — have proven ineffective or even harmful in treating COVID-19. Convalescent plasma, a century-old approach that uses recovered patients’ antibody-laden blood plasma, has been mired in political controversy and fallen from favor as careful studies have undercut early hype.

Meanwhile, thousands of other long shots — everything from antidepressants to Zithromax, an antibiotic — are in COVID-19 clinical trials around the world, in hopes that using existing drugs would reduce the time and cost of drug development.

“It’s desperation. The drugs are on the shelves, so let’s try them,” Lowe, the chemist and blogger, said in an interview. “But most of the trials are too small to see an effect, so the conclusion is: ‘We learned someone needs to run a real trial.’“

The pandemic, he said, has driven the drug-research world “into headless-chicken mode.”

Nobel Prize winner Peter Medawar famously called viruses “a piece of bad news wrapped up in protein.”

Viruses are so tiny and structurally simple that they can’t reproduce on their own. Like a cellular parasite, a virus must latch onto a host’s cell, break in, and hijack the cell’s molecular machinery to make copies of itself. Then these copies break out and infect more cells.

Antiviral drugs work by blocking a step in the viral replication process. But it is no easy feat.

“Antiviral designers face a challenge: how to stop the virus without damaging the inner workings of healthy cells, too,” science journalist Amber Dance explained in Scientific American.

“In general,” Lowe said, “there aren’t that many effective antiviral drugs, and the ones we have are extremely concentrated in two areas: HIV and hepatitis C. Those have been extensively, painstakingly developed against specific viral targets” in those particular diseases.

In contrast, bacteria are single-celled organisms that carry their own molecular equipment for reproduction. Antibiotics can attack the microbes in ways that don’t disrupt healthy cells. Antibiotics can kill bacteria directly by, say, rupturing their cell walls, or indirectly by blocking their nutrients so they can’t multiply. Another plus: Many antibiotics work against a spectrum of disease-causing bacteria — although the germs are constantly mutating to find ways to resist the drugs.

Another obstacle to effective antivirals is that they generally must be used early in the course of the disease, before the infection takes off and the virus becomes uncontrollable.

The newish antiviral flu drug Xofluza works by preventing the virus from copying itself, while decades-old Tamiflu keeps the virus from exiting cells and spreading within the body. Both drugs should be given within 48 hours of the first symptoms — before many people even realize they have the flu. And even then, the effect is small; recovery is shortened by about a day.

“The faster you can take the [antiviral] drug, the more you can limit the virus’ ability to spread,” University of North Carolina virologist Mark Heise said in the Scientific American article.

One proven way to foil viruses involves messing up their ability to assemble copies of their genetic code, which is made up of building blocks called nucleotides. Viruses often have unique molecules, called polymerases, to do the assembly job.

To trick the virus, the antiviral compound masquerades as a nucleotide. The polymerase inserts the drug into the genetic code, then the drug derails the assembly process. The herpes drug acyclovir, for example, keeps the virus from adding more nucleotides.

Remdesivir also mimics a nucleotide to slip into the viral code. But this gambit doesn’t always work. Remdesivir was tested and failed against the Ebola virus, which causes a deadly hemorrhagic fever.

Coronaviruses are particularly challenging because they have a protein that acts as an editor. If a nucleotide mimic tries to sneak in, the editor protein cuts it out.

Molnupiravir, the drug being developed by Merck and Ridgeback, gets around this by exploiting the fact that, even with editing mechanisms, viruses are prone to make errors, because now and then, those mutations give it a survival advantage.

Molnupiravir works by pushing the polymerase “into making so many errors that the end result can’t even produce a competent virus,” Lowe wrote in his blog. The technical name is “an error catastrophe.”

Fortunately, studies have shown molnupiravir triggers this catastrophe in the genetic code of the virus, but not the host. Antiviral compounds similar to molnupiravir have not been so lucky. They “are notorious for wiping out in human trials due to toxicity in the liver, kidneys, and other organs,” Lowe wrote.

So far, the data on molnupiravir, while preliminary, are encouraging. In lab and animal studies, it was active against a range of viruses, including Ebola and influenza. It blocked infection and spread of the coronavirus in ferrets, according to a study published in December. It had a reassuring safety profile in initial human tests. And last week, the developers announced a tantalizing hint of effectiveness from a midstage clinical trial: After five days of treatment, COVID-19 patients on the drug had no virus in their nasal swabs, while 76% of patients on placebo still had detectable virus.

If molnupiravir pans out, it would have the added advantage of being a pill — not an intravenous drug that must be given in a medical facility, like monoclonal antibodies or remdesivir. And while vaccination is the key to ending this pandemic, the whole world now recognizes the importance of preparedness.

“I really have hopes that molnupiravir will be ready for the next coronavirus that attacks us,” Lowe said.