While social distancing and flattening the curve are the initial strategies to reduce the spread of SARS-CoV-2 — the clinical name for the novel coronavirus — the production of vaccines and treatments be crucial over the longer term, especially if the virus mounts a resurgence in the fall. But the scientific, medical and manufacturing demands are much more challenging than the stock market’s exuberant reaction might indicate.
The surge was based on a videotaped comments by a University of Chicago Medicine researcher leading a local trial site for Gilead’s experimental drug remdesivir. The video was obtained by the news site STAT. Of 113 patients who were severely ill with covid-19, the disease caused by the novel coronavirus, only two people treated with the drug died, and most got better quickly, the researcher said. It was not disclosed how many were on ventilators before they improved.
University of Chicago Medicine is one of dozens of sites listed by Gilead on clinicaltrials.gov as for the company’s remdesivir study, with the 6,000 patients grouped into four categories of disease severity and dosing. The worldwide trial is ongoing, with preliminary results not expected until next month.
“Drawing any conclusions at this point is premature and scientifically unsound,” University of Chicago Medicine said in a statement.
There is no placebo arm in the trial, meaning Gilead is not testing the drug, which is administered intravenously, against dummy doses in patients. A placebo-controlled study, considered the gold standard of clinical trials, would allow it to definitively measure how well the drug works.
Still, clues continued to accumulate that remdesivir could work. The National Institutes of Health reported Friday that its own study of 12 infected monkeys, six treated with the drug and six untreated, showed the treated group in better health after seven days.
Just a week before, in a Gilead-sponsored study of 54 patients that was peer-reviewed and published in the New England Journal of Medicine, researchers reported that seven patients died, or 13 percent. The NEJM study was based on observations of patients receiving the drug under “compassionate use.” It also did not have a set of patients receiving a placebo for comparison.
Developing real proof that the drug works will take weeks, if not months, experts say, although the Food and Drug Administration has already allowed one set of drugs — anti-malarials touted by President Trump — to be administered under an emergency use authorization, despite a lack of sound evidence of effectiveness.
Even if the FDA gives a rapid green light, manufacturing bottlenecks could produce more delays; Gilead said last week it has 1.5 million doses, enough for 140,000 patients. Worldwide demand would far exceed that supply initially, and Gilead has said it is laying plans to produce more of the drug in the event it works and is approved.
Gilead sought to downplay the leaked results from Chicago on Friday, but did not say when preliminary results or peer-reviewed analysis would be available. It indicated it would be analyzing trial results over the next month.
“The totality of the data need to be analyzed to draw any conclusions from the trial," said Gilead spokesman Ryan McKeel. “Anecdotal reports, while encouraging, do not provide the statistical power necessary to determine the safety and efficacy profile of remdesivir as a treatment for covid-19."
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, even after showing promise in monkeys. Also, it has a big drawback: It is a liquid given intravenously, which means people must go to a hospital or clinic on 10 consecutive days to be treated. In addition to Gilead, the National Institutes of Health and the World Health Organization are sponsoring multiple clinical trials of the drug.
Remdesivir has been deemed by the WHO as the most promising of dozens of experimental treatments in the pipeline to tackle coronavirus. 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 magic 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 (JAMA).
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. The first team to conduct successful, rigorously controlled clinical trials will be the winners, said Kelly L. 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.”
Another early-stage, early-state antiviral drug is EIDD-2801. Its journey 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 remdesivir.
“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.
Like remdesivir, EIDD-2801′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’s Kaletra, 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. Among the side effects are birth defects. Its manufacturer, Fujifilm, announced that a Phase 2 trial is launching in the United States. 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 a placebo in an effort to definitively prove that it has a benefit.
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 FDA 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 has shown effectiveness in laboratories against coronavirus.
In another approach, 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 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.
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.
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.
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.