These drugs could treat COVID-19, but silver bullet might not be found

The journey of EIDD-2801, from laboratory to the mouth of a human, unfolded with head-snapping speed.

On March 23, a division of Emory University in Atlanta licensed the experimental drug to a Miami company owned by a wealthy hedge-fund manager and his wife. Just three weeks later, a pill was given to a person for the first time in a test of its safety, in Britain.

It marked the beginning of an accelerated testing regimen that will determine whether EIDD-2801 will emerge as a true weapon against SARS-CoV-2—or wind up as one of many hopeful bids in a field of long-shot treatments. If it works, the pill could be given to people as soon as they show symptoms of COVID-19, Wayne Holman, the founder of privately held Ridgeback Biotherapeutics, said in an interview. Holman has deep experience investing in drug companies and set up Ridgeback Bio with his wife, Wendy, in 2015.

Because it is a pill, Holman said, the Emory/Ridgeback drug has the potential to be even better than the most promising treatment in the pipeline, remdesivir, an intravenous drug made by Gilead Sciences. Remdesivir was the subject of heavy stock market speculation Thursday after a report on the news site STAT indicated the experimental drug showed positive results at a single clinical trial site, in Chicago.

“Imagine that person being treated at home, by mouth, on day three and being better and no longer spreading the virus. It cuts it short,” Holman said. “That is game-changing.”

“Imagine” is the most relevant word at this early stage of the drug’s development. But that sense of hope, and Ridgeback’s accelerated project, illustrate the frenzied pace at which governments, companies and academic researchers have opened the floodgates to testing numerous drugs—old, new and barely out of the lab—to combat the novel coronavirus and give seriously ill people a better shot at survival.

Call it the kitchen-sink approach to the pandemic. The roster of potential therapies includes new antivirals, older antivirals designed to fight HIV, anti-inflammatory drugs used for rheumatoid arthritis, stem cell therapies that could harness the immune system, antiparasitic drugs that treat malaria and head lice, and even treatments for erectile dysfunction.

None of them so far has offered the silver bullet the world is seeking, and expectations need to be tempered, according to specialists.

“It’s hard to speculate whether one is going to be a breakthrough. Very few treatments in medicine end up being breakthrough treatments. They provide incremental benefit over standard of care,” said James Cutrell, an infectious-disease specialist at the University of Texas Southwestern Medical Center, who surveyed the landscape of possible coronavirus treatments for a paper published this week in the Journal of the American Medical Association.

Unlike antibiotics, which are effective against numerous forms of bacteria, broad-spectrum antivirals have been difficult to develop because viruses are so varied in structure. Cutrell and his colleagues did not identify any clear front-runners in their survey of contenders. More definitive evidence, positive or negative, is expected to emerge within weeks for some of the drugs.

A potential scenario is that two drug treatments emerge, Cutrell said: one that helps curb the virus itself, to be taken in earlier phases of the disease, and another that helps combat an overly aggressive immune-system response that overtakes the bodies of some patients and destroys lung tissue in later stages.

Avalere Health, a consulting firm that advises pharmaceutical companies, is tracking over 100 different coronavirus treatment projects around the world. The first team to conduct successful, rigorously controlled clinical trials will be the winners, said Kelly George, a specialist in drug development at Avalere.

The age of the “magic bullet” medicine of the 20th century has given way to much harder problems like emerging viral threats in the 21st, she said.

“There’s a balance between, let’s get these drugs to as many people as we can, and let’s take the time to sit down and really find out if these drugs are working,” she said. “The speed of getting it into people, figuring out the safety and writing it up is going to have a huge impact on what we end up using.”

Here’s a rundown of the most widely discussed drugs in the treatment pipeline:

A leading antiviral

Many in the medical community view an experimental antiviral drug called remdesivir, manufactured by Gilead Sciences, as the best chance for a treatment. In tests in academic labs, in work sponsored by the federal government, it has been shown to block viral replication. A clutch of clinical trials are underway worldwide to test it in patients, and Gilead is distributing it to thousands of people on a “compassionate use” basis.

Remdesivir is considered a broad-spectrum antiviral, meaning it is believed to work against multiple types of virus. But it failed in a test against Ebola last year. Also, it has a big drawback: It is a liquid that must be given intravenously, which means people must go to a hospital or clinic on 10 consecutive days to be treated. Gilead, the National Institutes of Health and the World Health Organization are among those sponsoring multiple clinical trials, and preliminary results are expected within weeks.

An initial Gilead-sponsored study of outcomes in 53 seriously ill patients treated under compassionate use, published in the New England Journal of Medicine last week, showed that 13 percent of the patients died, while two-thirds improved. The STAT report Thursday cited a physician’s account of results at a single trial site in Chicago; the physician said only two people died out of 113 with severe disease. The site is part of a Gilead-sponsored clinical trial that does not have a placebo-controlled arm, which means caution is required in interpreting incomplete, anecdotal results.

Other antivirals

A number of other antiviral compounds are being tested against coronavirus. Emory University’s EIDD-2801 works in a similar fashion to remdesivir, but it has the advantage of coming in a pill form, so patients can take it themselves, said Holman, of Ridgeback. The drug’s development in academic labs has been sponsored by the federal government. It is just entering Phase 1 safety trials, to make sure it does not have excessively toxic effects on people, so proof of effectiveness is at least months away.

Some other antivirals being tested have already been approved to treat HIV, including AbbVie’sKaletra, which is a combination drug that did not show significant benefit against COVID-19 patients in a study in China.

An influenza drug that has been approved in Japan, Avigan, is being studied and reportedly has caught the interest of the White House, but is not approved for use in the United States. Its manufacturer, Fujifilm, announced that a Phase 2 trial is launching in the United States. Among the side effects are birth defects. Phase 2 clinical trials test a drug in a small group of patients to see if it is effective. In Phase 3, the drug is tested in a larger group of patients, and typically compared to placebo in an effort to definitively prove that it has a benefit.

Antiparasitic drugs

President Donald Trump has stoked expectations by repeatedly promoting the use of decades-old anti-malaria drugs—hydroxychloroquine and chloroquine—to treat the virus, despite a lack of strong evidence that they work, as well as a growing recognition of serious side effects, including the risk of a fatal cardiac arrhythmia. Hospitals and doctors in the United States have depleted supplies in the rush to try the generic drugs through “off-label” prescriptions.

The compounds have an anti-inflammatory effect and are used by lupus and rheumatoid arthritis patients. The Food and Drug Administration has issued an emergency-use authorization allowing them to be given to patients in hospitals. The WHO and several other organizations are conducting full clinical trials of the drugs to see if they work. The drugs are known as antiparasitics (malaria is a parasite, not a virus).

Another older antiparasitic drug receiving attention is Ivermectin, which is used to treat a variety of parasitic infections in humans and animals and has shown effectiveness in laboratories against coronavirus.

Biologic drugs that target virus

Biotechnology companies are growing living proteins called antibodies, developed from cells of people infected with the disease, that are designed to thwart the coronavirus. Vir Biotechnology, a San Francisco company, announced this month that it had partnered with GlaxoSmithKline to conduct Phase 2 trials within three to five months.

AbCellera, of Vancouver, has teamed with Indianapolis-based Eli Lilly to test hundreds of antibodies, the company said in a news release. Regeneron is screening hundreds of antibodies to determine their effects against the virus and has said human trials could begin in the summer.

Anti-inflammatory drugs

Therapies that reduce inflammation by controlling the immune system are another key category of drug being tested in coronavirus patients. The goal is to stop the immune system’s “cytokine storm” that destroys lung tissue and is the most common cause of death in people with severe cases of COVID-19.

Some drugs that are already on the market to treat rheumatoid arthritis and other inflammatory diseases are being tested in coronavirus patients. These include Roche’s Actemra, and Kevzara, a drug sold by Regeneron and Sanofi. AstraZeneca announced it is testing its blood cancer drug Calquence, which also targets immune cells, on coronavirus patients.

Stem-cell treatments

At least two companies, Mesoblast and Celularity, are investigating the use of stem cells to fight the excessive immune system response in covid-19 patients. Mesoblast said this month it has received FDA approval to begin human testing. Celularity is partnering with Maryland-based United Therapeutics.

Convalescent plasma

Blood plasma is being taken from people who have recovered from covid-19 and injected into the bodies of new patients. The hope is that the coronavirus antibodies developed in the recovered patient will neutralize the virus once they are introduced in the new patient. It is an old approach to infectious disease, and has been used over many decades against polio, measles, mumps and flu.

Boosting oxygen

Also being studied is nitric oxide, a gas that relaxes blood vessels, increasing the amount of oxygen being transferred to the blood and reducing the heart’s workload.The gas led to Viagra, an erectile dysfunction drug, after scientists discovered the molecule helps increase blood flow to the penis.

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