In mid-November, an arthritis drug with a tricky name hit a pandemic milestone — then slipped back into relative obscurity.
The drug, baricitinib, was granted an emergency authorization by the Food and Drug Administration to treat a subset of hospitalized Covid-19 patients in combination with another medication, the antiviral remdesivir. It is one of only a handful of treatments to have earned the agency’s green light.
But baricitinib’s reception by the medical community has been lukewarm. It doesn’t work all that well, for one thing, and comes with side effects, such as blood clots. And at a cost of roughly $1,500 per patient, many doctors don’t know when it would make sense to use the drug, which might have overlapping roles with cheap and widely available steroids like dexamethasone.
In a clinical trial sponsored by the National Institutes of Health, hospitalized Covid-19 patients treated with baricitinib and remdesivir recovered one day faster than patients who had received remdesivir alone.
“I think it’s really a nothing burger,” said Dr. Ilan Schwartz, an infectious disease physician at the University of Alberta. “We’re talking about adding a drug that reduces the time to clinical improvement by one day, in a disease that takes weeks to recover.”
These results, which were announced through a series of news releases by drugmaker Eli Lilly, have yet to be published in a peer-reviewed scientific journal. Kristen Porter Basu, a spokeswoman for the company, wrote in an email that a “more detailed analysis” would be published “very soon.”
When an emergency authorization has been released but the data have not, doctors are caught “in a difficult place,” said Dr. Manuela Cernadas, a critical care physician at Brigham and Women’s Hospital in Boston. “It’s not entirely clear where this drug fits in our armamentarium of drugs we’re comfortable using.”
Baricitinib is a repurposed arthritis treatment that, like a steroid, dampens inflammation, which, in severe cases of Covid-19, can spiral out of control and destroy healthy tissues. The drug acts like a molecular muffler, preventing the cells from responding to alarm signals that could make the body’s immune response spiral out of control.
The N.I.H. trial was designed to test whether baricitinib could boost the benefits of remdesivir, now the standard of care for Covid-19 patients. Remdesivir by itself speeds recovery by several days. The researchers found that the addition of baricitinib clipped an additional day off a patient’s recovery time and kept a few extra people off ventilators. But these and other results largely failed to impress experts, many of whom said the drug would need to have far bigger benefits to outweigh its price tag and potential harms.
“It seems more incremental than blockbuster,” said Dr. Taison Bell, a critical care physician at the University of Virginia, who was involved in the clinical trial. Although Dr. Bell described baricitinib as a reasonable addition to the Covid treatment toolbox, and even deserving of an emergency approval, “I don’t think it’s a game changer,” he said.
Still, the findings were enough to convince the F.D.A., which issued an emergency authorization on Nov. 19. The drug is now allowed to be paired with remdesivir, but only to hospitalized patients who need supplemental oxygen, mechanical ventilation or other breathing support.
The agency’s limited clearance aligns with the subset of patients in the N.I.H. trial who benefited the most from the dual drug combo, said Dr. Andre Kalil, an infectious disease physician at the University of Nebraska Medical Center and one of the lead researchers on the trial.
But this same population of patients — people sick enough to need some form of breathing support — would also be great candidates for steroids like dexamethasone, said Dr. Phyllis Tien, an infectious disease physician at the University of California, San Francisco.
Dexamethasone, unlike baricitinib, has been shown in studies to curb mortality in severely sick Covid-19 patients. A generic drug, it’s also cheap, costing cents or dollars per day of treatment, and has for months been a part of the coronavirus treatment playbook.
“I’m asking myself, ‘Who would I think about using baricitinib in, over dexamethasone?’” Dr. Tien said.
But Dr. Boghuma Kabisen Titanji, an infectious disease physician at Emory University who pioneered early studies of baricitinib against the coronavirus, offered a more sobering perspective on dexamethasone. Steroids are “blunt knives,” she said, quashing inflammation on a broader scale than drugs like baricitinib do. That’s why steroids come with a host of unwanted side effects, including exacerbating conditions like diabetes or osteoporosis, she said.
The family of drugs that includes baricitinib, on the other hand, may offer more therapeutic precision, Dr. Titanji said. There’s also been some evidence that baricitinib might be able to block the coronavirus from entering cells.
Confused by the terms used about how to treat Covid-19? Let us help:
- ACE-2: A protein that sits on the surface of certain types of human cells. The coronavirus has to bind to ACE-2 in order to enter cells.
- Adverse event: A health problem that crops up in volunteers in a clinical trial of a vaccine or a drug. An adverse event isn’t always caused by the treatment tested in the trial.
- Antibody: A protein produced by the immune system that can attach to a pathogen such as the coronavirus and stop it from infecting cells.
- Antiviral drug: A drug that interferes with a virus’s ability to replicate inside cells. The first approved drug for Covid-19 in the United States, remdesivir, is an antiviral.
- Approval, licensure and emergency use authorization: Drugs, vaccines and medical devices cannot be sold in the United States without gaining approval from the Food and Drug Administration, also known as licensure. After a company submits the results of clinical trials to the F.D.A. for consideration, the agency decides whether the product is safe and effective, a process that generally takes many months. If the country is facing an emergency — like a pandemic — a company may apply instead for an emergency use authorization, which can be granted considerably faster.
- Compassionate use: A term used to describe treatments that are given to seriously ill people despite not yet being approved by the Food and Drug Administration for that use.
- Cytokine storm: A hyperactive response from the immune system that can lead to massive amounts of inflammation and tissue damage. Cytokine storms may be responsible for many of the severe cases of Covid-19, and a number of researchers are testing drugs that might be able to quiet them.
- Interferon: A molecule made by the immune system. Certain types of interferons can unleash inflammation in the body, while others tamp it down. Yet other types can spur cells to strengthen their defenses against viruses. Researchers are exploring whether treatments of synthetic interferons can help people fight off the coronavirus.
- Monoclonal antibodies: Monoclonal antibodies, created in a laboratory, mimic the natural antibodies produced by the immune system. A number of companies have developed these treatments for Covid-19. President Trump received Regeneron’s antibody treatment shortly after he was diagnosed with the disease.
- Phase 1, 2, and 3 trials: Clinical trials typically take place in three stages. Phase 1 trials usually involve a few dozen people and are designed to observe whether a vaccine or drug is safe. Phase 2 trials, involving hundreds of people, allow researchers to try out different doses and gather more measurements about the vaccine’s effects on the immune system. Phase 3 trials, involving thousands or tens of thousands of volunteers, determine the safety and efficacy of the vaccine or drug by waiting to see how many people are protected from the disease it’s designed to fight.
- Placebo: A substance that has no therapeutic effect, often used in a clinical trial. To see if a vaccine can prevent Covid-19, for example, researchers may inject the vaccine into half of their volunteers, while the other half get a placebo of salt water. They can then compare how many people in each group get infected.
- Post-market surveillance: The monitoring that takes place after a vaccine or drug has been approved and is regularly prescribed by doctors. This typically confirms that the treatment is safe. On rare occasions, it detects side effects in certain groups of people that were missed during clinical trials.
- Preclinical research: Studies that take place before the start of a clinical trial, typically involving experiments where a treatment is tested on cells or in animals.
- Trial protocol: A series of procedures to be carried out during a clinical trial.
- Retrospective study: A study that analyzes data collected in the past to assess how effective a treatment is. Retrospective studies can offer useful insights, but are not as definitive as randomized clinical trials.
- Spike protein: A protein that sits on the surface of coronaviruses. The spike protein binds to the ACE-2 receptor on human cells using a region called the receptor-binding domain (R.B.D.). Once the protein attaches, the virus can enter the cell. Many vaccines and monoclonal antibody treatments are designed to attach to the spike.
- Standard of care: A treatment accepted by medical experts as a proper way to treat a certain type of disease. Once a standard of care emerges for a disease, any new experimental treatments are typically tested against it, rather than against a placebo.
Still, baricitinib comes with its own problems, such as raising the risk of blood clots — already an issue in many cases of Covid-19. “That does give you pause,” Dr. Cernadas said.
Both baricitinib and dexamethasone also blunt immune function, increasing the likelihood that other viruses or bacteria might infiltrate the bodies of the people they’re used in. But of the two, dexamethasone is “the devil you know,” said Dr. Lauren Henderson, a pediatric rheumatologist at Boston Children’s Hospital. “I would probably not turn to baricitinib as a first line.”
Dr. Tien and other experts echoed this sentiment, saying they would be likely to choose dexamethasone over baricitinib when treating someone with a serious case of Covid-19, unless there was an obvious reason their patient might respond poorly to steroids.
A head-to-head comparison between baricitinib and dexamethasone might clarify which patients would be better off taking one drug over another. At the end of November, the N.I.H. announced a trial that will compare outcomes between hospitalized Covid-19 patients who receive either a combination of remdesivir and dexamethasone, or a combination of remdesivir and baricitinib. But Dr. Schwartz and others raised ethical concerns about this trial, which he said would by definition deprive some patients of a lifesaving steroid therapy.
Eli Lilly is also running a trial to study the effects of baricitinib on its own in hospitalized patients. In this study, which isn’t likely to finish until next summer, all participants will receive dexamethasone.