With hospitals bracing for a possible fall and winter surge in cases of the novel coronavirus, the pharmaceutical toolbox for physicians to treat covid-19 is seriously restricted.
And those limited options have helped remdesivir move to launch commercially in record time, even though it’s a modestly beneficial drug with little evidence it improves survival. The government is poised to end its control of distribution of the drug after Sept. 30, a spokeswoman for the Department of Health and Human Services said last week, pushing it into normal drug distribution channels. And Gilead, the drugmaker, has taken more steps on its application for full, fast-track Food and Drug Administration approval, which could further expand its use.
But for doctors and researchers, clinical studies have reinforced questions about the effectiveness of the drug and who is best suited to receive it. The most conclusive evidence shows it reduces hospital stays from 15 to 11 days but does not significantly reduce the odds of dying of the coronavirus. And advocates are also questioning whether Gilead’s $3,120 price per course of treatment is justified, based on its modest benefits and previous taxpayer investments. Remdesivir was developed in partnership with government agencies and at least $70 million from U.S. taxpayers.
“The drug clearly has some kind of benefit, but it’s really not clear how great of a benefit it is. Everyone is waiting for better mortality data,” said Walid Gellad, a physician and director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh Department of Medicine. “The pricing is based on this drug that has a huge impact, and it’s turning out that it does not have a huge impact.”
Still, he added, “If you looked at the data and asked yourself, would I want to be on it — most people would say yes.”
And yet remdesivir is having commercial success. Shortages that marked its fast-paced rollout last spring and over the summer have eased, with an increase in manufacturing and a decrease in hospitalizations nationally.
The FDA agreed with the company’s request to start using its Nordic-sounding brand name, Veklury, and the company is on track to make more than $9 billion on the drug in 2020 and 2021, at the $3,120 price endorsed by the Trump administration, according to an estimate by a Credit Suisse investment analyst.
Gilead has not released specific sales forecasts for remdesivir and declined to outline plans for distribution after Sept. 30. It said it did not plan on changing its price for a five-day course of treatment. Government hospitals pay a discounted rate of about $2,340. The company defended the cost-effectiveness of the drug.
“The bottom line is that clinical data demonstrate that patients taking Veklury (remdesivir) recover four days faster than those taking placebo, and Veklury costs less than a one-day hospital stay, resulting in immediate savings to the health care system,” said company spokesman Chris Ridley in an email.
Physicians have been waiting for months for full results to be published from a National Institutes of Health randomized clinical trial, the trial that spurred the FDA on May 1 to grant an emergency use authorization for its use in severely ill hospitalized patients. An NIH spokeswoman said the eagerly awaited full results are expected to be published within a few weeks.
The FDA in August expanded its emergency use authorization to apply to any hospitalized patient, based in part on a less rigorous study sponsored by Gilead. That study, which did not compare the drug to a placebo, said people with less-severe covid-19 had better clinical status, such as being released from the hospital or not requiring oxygen, after five days of treatment. A puzzling twist was that patients who received 10 days of treatment were no better than patients not receiving the drug. The study added a sobering qualifier: The results were of “uncertain clinical importance.”
Despite such limitations, clinicians and hospitals say there are few other alternatives to treat coronavirus patients in the months ahead.
“We don’t have enough tools in our clinical toolbox to fight covid,” said Heather Pierce, senior director for science policy and regulatory counsel at the Association of American Medical Colleges, which represents academic medical centers around the country.
She cited flattening demand for remdesivir even as Gilead’s production surge has curbed shortages: “If it prevented people from dying, there would be a different demand.”
Hydroxychloroquine, an anti-malaria drug President Trump touted in March and April, won an emergency authorization from the FDA that proved to be premature. Clinical trials showed it did not work, and FDA withdrew the authorization in June.
An older, generic steroid medication, dexamethasone, has been shown in rigorous, placebo-controlled trials to reduce death by a third in patients on ventilators. It is being widely used in intensive care units, often in tandem with remdesivir.
“If you are a patient in the hospital with covid-19, your physician is going to want to give you remdesivir,” said Evan Seigerman, the Credit Suisse analyst who is tracking the drug’s progress and predicted up to $4.5 billion in sales in 2020 and up to $5 billion in 2021. After that, sales may decline with advent of a vaccine and possible new treatments such as monoclonal antibodies. “Remdesivir is the therapeutic of choice at the moment,” he said.
Gilead CEO Daniel O’Day said in June the company could have charged more for remdesivir, considering that cutting hospital stays by four days would save hospitals $12,000 on average. But the price tag for a course of treatment triggered outrage among congressional and state government critics who cited a study that said the company could break even by charging less than $1 per vial.
Gilead disputed the study and pushed back on criticism of its price.
“It is inaccurate to suggest that developing and manufacturing a complicated investigational drug like Veklury, for which we have invested significant resources over the last 10 years, relies on raw materials sourced from around the world, involves multiple chemical reactions and requires sterile manufacturing facilities, is 93 cents,” said the company spokesman, Ridley.
Gilead invented the molecule that would become remdesivir during a search for treatments for hepatitis C a decade ago. In 2013, the company included it in a library of 1,000 molecules it provided to the Centers for Disease Control and Prevention and the U.S. Army Medical Research Institute of Infectious Diseases, which were searching for antivirals to target infectious diseases. The government scientists discovered in laboratory tests that remdesivir was effective against Ebola virus, but it did not work well in a clinical trial in Africa. Its potential against coronaviruses including Middle East respiratory syndrome (MERS) and sudden acute respiratory syndrome (SARS) remained strong.
When the SARS-CoV-2 outbreak began this year, NIH quickly fielded a placebo-controlled clinical trial. Once early results arrived in late April, Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, declared the drug a “modest” weapon against the disease but said it would be the standard of care.
Citing the taxpayer investment in the drug, a bipartisan group of 11 state treasurers said in a Sept. 16 letter to O’Day that Gilead’s price “suggest an opportunistic attempt to remarket an old drug at prices that are disconnected from economic reality.”
Attorneys general from 34 states and territories urged the Department of Health and Human Services in August to exercise “march-in” rights and license the drug to a different manufacturer because of supply shortages and a price that would “impede access to treatment in the U.S. and further strain state budgets.”
Gilead initially donated about 120,000 treatment courses for the United States through June. Then it signed an agreement with the Department of Health and Human services to sell another 500,000 treatment courses through the end of September, the pact that is about to expire. The company has said in all it aims to produce 2 million treatment courses in 2020.
“Remdesivir is not the answer to the epidemic. It’s going to play a role in helping a few people,” said Mark Siedner, an infectious-disease clinician and researcher at Massachusetts General Hospital. “Is it going to help us in lockdowns, school closures and cancellation of football seasons? Absolutely not.”
Although the FDA’s updated authorization permits it to be used for any hospitalized patient, including those who do not need supplemental oxygen, Mass General is still limiting it to those who need oxygen, Siedner said. There are many hospitalized patients who do not require oxygen who are likely to get better without the drug, and are discharged within five days, he said. In cases where remdesivir is given and the coronavirus continues to progress, then patients receive dexamethasone, he said.
The only other authorized treatment is convalescent plasma. Trump pushed regulators aggressively to approve the treatment and then overstated its benefits after the pressure was successful, a move that triggered a backlash and only served to highlight the lack of robust evidence that it works.
"We don’t know if we are conferring benefit onto patients by giving them convalescent plasma, said Claudia Cohn, director of the Blood Bank Laboratory at the University of Minnesota Medical Center, which is not providing plasma to patients unless they are part of a clinical trial. She said scientists are urging former coronavirus patients who were severely ill to donate their plasma for ongoing research because they have the highest levels of antibodies in their blood.
Heading into a possible winter surge in cases, specialists said distancing measures, hand-washing and masks will still be the most effective means of saving lives.
“We haven’t identified a game-changing agent or a magic bullet that cures a substantial number of people,” said James Cutrell, an infectious-disease specialist at University of Texas Southwestern Medical Center who co-wrote a paper on treatment options.
Cutrell said doctors are hungry for treatments that can be given in a pill form or with a simple injection to people who have not been hospitalized: “There’s still a great clinical need for effective outpatient treatments.”