Taxpayers paid to develop remdesivir but will have no say when Gilead sets price

The drug that buoyed expectations for a coronavirus treatment and drew international attention for Gilead Sciences, remdesivir, started as a reject, an also-ran in the search for antiviral drugs. Its path to relevance did not begin until Robert Jordan cleared it.

A Gilead scientist at the time, Jordan convinced the company seven years ago to let him assemble a library of 1,000 castoff molecules in a search for medicines to treat emerging viruses. Many viral illnesses threaten human health but do not attract commercial interest, because they lack potential for huge drug sales.

"I kept asking them, 'Is this OK?' " said Jordan, who is now a vice president at a pharmaceutical start-up. "These don't represent a commercial opportunity but a public health opportunity. Gilead gave me their blessing to do this on the side."

To make progress, Gilead needed help from U.S. taxpayers. Lots of help. Three federal health agencies were deeply involved in remdesivir's development every step of the way, providing tens of millions of dollars of government research support. Now that big government role has set up a political showdown over pricing and access.

Despite the heavy subsidies, federal agencies have not asserted patent rights to Gilead's drug, potentially a blockbuster therapy worth billions of dollars. That means Gilead will have few constraints other than political pressure when it sets a price in coming weeks. Critics are urging the Trump administration to take a more aggressive approach.

"Without direct public investment and tax subsidies, this drug would apparently have remained in the scrap heap of unsuccessful drugs," Rep. Lloyd Doggett, D-Texas, chairman of the House Ways and Means health subcommittee, said this month. Doggett and Rep. Rosa DeLauro, D-Conn., have asked Health and Human Services Secretary Alex Azar for a detailed financial accounting of federal support for remdesivir's discovery and development.

The HIV-prevention advocacy group PrEP4All Collaboration, working with the Technology Law & Policy Clinic at New York University, released an analysis Monday that said the government, because it helped cull the drug from hundreds of compounds, probably has a legal right to claim it co-invented remdesivir. It contends that government scientists should have been listed as co-inventors on remdesivir patents because of their contributions. It says the Trump administration should be leveraging the government's involvement to ensure that the United States and other countries can get access at a low cost.

"Agencies can't just punt it over the fence to a pharmaceutical company and walk away," said James Krellenstein, a co-founder of PrEP4All. "For the federal government to just walk away from that responsibility is a dereliction of the public trust."

Two other nonprofit watchdog groups, Knowledge Ecology International and Public Citizen, also have documented the large taxpayer-funded contributions toward the drug. Public Citizen estimates public investment at a minimum of $70 million.

"Gilead did not make this drug alone. The public helped make it, and the public has a stake," said Peter Maybarduk, director of the access to medicines program at Public Citizen.

Gilead has acknowledged the large role of government agencies in remdesivir's development but said that the original compound was discovered by Gilead researchers years earlier and that the government has no potential patent rights to the drug. It has said it will spend up to $1 billion on remdesivir manufacturing and development in 2020 as it rapidly increases production and distribution around the world.

"We are focused on getting this treatment into the hands of as many patients as possible and making sure it is both accessible and affordable to patients in the United States and around the globe," company spokesman Ryan McKeel said in an email. "We take that responsibility to patients and families affected by covid-19 very seriously and we will work to make sure access is not an issue.

"Gilead researchers invented remdesivir more than a decade ago, identified its broad-spectrum antiviral activity, optimized the formulation of the product and scaled up the manufacturing process," McKeel said. "Although government funding was used to further characterize remdesivir's profile after its initial discovery, this did not result in the creation of the underlying intellectual property invented by Gilead."

The story of the drug's creation shows that Gilead would not be commercializing the drug if it were not for the extensive involvement of government scientists and agencies. The industry-government partnership crossed the finish line this month when the Food and Drug Administration issued an emergency use authorization clearing remdesivir to treat hospitalized patients with covid-19, the disease caused by the coronavirus.

Screening a huge number of chemicals for effective drugs is arduous work and often fails to produce a winner. In remdesivir's case, government researchers narrowed the search from 1,000 compounds to the chemical that would become remdesivir, confirmed its potency in laboratory tests, tested it in monkeys, and finally sponsored a pivotal clinical trial in humans.

Jordan sent Gilead's screening library to the Centers for Disease Control and Prevention in Atlanta, and to Fort Detrick in Frederick, Maryland, home to the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). Scientists at both federal facilities study dangerous viruses in high-security biocontainment labs. The National Institutes of Health and academic labs in Tennessee and North Carolina that receive NIH grants also would play key roles studying the drug in mice.

Front-line government scientists who worked directly with Gilead on the drug described the heavy involvement of federal resources in the drug's development, though they said their concern at the time was not patents but speeding treatments in the battle against dangerous diseases, especially Ebola.

The former chief scientific officer at USAMRIID who supervised the development of remdesivir, Sina Bavari, said the team was working rapidly on a treatment for Ebola in 2014 and did not consider filing a patent application when the agency's scientists helped discover new uses of the drug and tested it in government monkeys. Bavari and other government scientists were co-authors of an article in the scientific journal Nature that described its discovery and successful tests in the government's rhesus monkeys.

Gilead contributed the drug and spent millions from its own budgets to hone the drug's formulation, said Bavari, who now runs his own consulting company. Deciding when to file a government patent in the case of industry partnerships presents a "tightrope" for public health agencies that want to maintain positive relationships with industry partners, Bavari said.

Many antiviral drugs are taken for a short time and given to relatively few people. They do not represent large markets, so government subsidies are used to keep corporations interested in pursuing treatments, he said.

"Without incentivizing some of these companies to stay attached to emerging disease, I think they will walk away, even after this one," he said. "In this situation [filing for a government patent] would have caused more harm with Gilead and not been worth it.

"The government's job is to make sure industry is successful, and if industry is successful, then we all benefit from it."

An Army lawyer said the Gilead drug did not meet the threshold of a government co-invention.

"Although USAMRIID performed extensive and critical screening and testing for Gilead, testing a compound and finding that it is indeed an effective antiviral compound does not qualify USAMRIID as a joint inventor of the compound," Leigh Callander, chief patent counsel for the U.S. Army Medical Research and Development Command, said in an email.

An independent organization that measures the cost-effectiveness of drugs said Gilead could be justified in charging up to $4,500 for a 10-day course of treatment for a single coronavirus patient. But advocates, citing a study by academic researchers on what it costs to make the drug, have said Gilead could break even by charging $1 per dose.

The Department of Health and Human Services, in response to emailed questions, said it was too early to discuss pricing of remdesivir but noted that the government has reimbursed hospitals and other providers for the costs of testing and treating people with no health insurance. For those with insurance, many insurance companies have waived patient co-payments for covid-19-related care and therapies, it said.

"The Trump Administration is committed to ensuring Americans have access to life-saving therapeutics and vaccines as we combat this pandemic," it said.

Gilead is donating the first 1.5 million doses to governments worldwide, which it said was enough for at least 140,000 patients through the end of May. More than half of that was targeted for U.S. patients. The drug is given intravenously in the hospital for five to 10 days. Gilead is investigating ways of making the drug in pill form, which could dramatically increase use - and sales - especially if the coronavirus lasts for years in the human population.

Because Gilead tackles viral targets, it has a long history of working closely with the CDC and the NIH to develop drugs for infectious diseases that other companies have shunned, especially HIV and hepatitis C. But Gilead's pricing and intellectual property practices have drawn public and congressional criticism.

The company received negative publicity for pricing its hepatitis C drug Sovaldi at $84,000 for a 12-week course of treatment in 2013. Last year, after a report in The Washington Post and congressional scrutiny, the Department of Justice filed a lawsuit to enforce a government patent on the HIV prevention Truvada for PrEP (pre-exposure prophylaxis) after Gilead refused to recognize its legitimacy. As that court fight is being waged, Gilead continues to charge more than $20,000 a year for Truvada for PrEP. It said last year that it would donate 2.4 million bottles per year of Truvada through 2030 to contribute to a government plan to combat HIV.

Still, like other pharmaceutical and biotechnology companies, behind the aggressive business and patent strategies are thousands of scientists who spend careers discovering and developing medicine to fight disease. Jordan said Gilead scientists volunteered to help him identify potential drugs in the company's library that could interfere with viral replication.

Remdesivir's parent compound GS-441524 was invented about 2009 when Gilead was looking for drugs to treat hepatitis C, according to Gilead.

In 2013, Jordan - who now works at Meissa Vaccines, a California start-up - included GS-441524 in the set of samples he sent to CDC scientist Michael Lo in Atlanta for testing against Nipah virus, a bat-borne disease found in parts of Asia. The compound showed promise not just against Nipah but also as a broad-spectrum antiviral. It interfered with virus RNA and stopped replication.

Lo "had a collection of human virus in the freezer and asked, 'Do you mind if we try it against filovirus, Ebola?' " Jordan said. By that time, an Ebola outbreak had begun in West Africa, and labs around the world were scrambling to respond.

In 2014, Lo said he was examining a readout from the CDC's laboratory tests of the compound showing that the drug had a strong effect against Ebola virus in lab containers.

"It was a very exciting moment," Lo said. "We were the first to really identify that this compound had promise against Ebola."

Lo said questions about government patents were not discussed at the time and said such decisions were "above my pay grade." The CDC did not respond to a question about whether it considered filing a patent for the work of Lo and other CDC scientists.

Jordan also had sent the library to another agency with advanced capabilities to develop drugs for virus: USAMRIID, the lead unit for biological defense research in the U.S. military. Bavari said government scientists rapidly got to work conducting virus screening on trays of 384 chemical samples at a time. Bavari estimated that up to 15 government scientists at USAMRIID worked on the program.

GS-441524 stood out for its potent activity against Ebola virus, Bavari said.

"We started communicating back and forth with CDC and repeated the test. They had similar data," he said. "It definitely was a breakthrough."

Jordan said he went back to his superiors at Gilead with the laboratory data from CDC and USAMRIID screening tests as the Ebola outbreak in West Africa continued. The company's interest in proceeding with a rapid development program was strong, he said.

"That launched a significant effort at Gilead to focus a lot of resources to developing this compound as quickly as possible and getting into patients as quickly as possible," he said.

Gilead's chemists in California took a crucial step toward making the compound work in animals and people: They turned the parent molecule into a prodrug, which means it is activated after it enters the body, and tweaked the compound further to make it more potent once it gets inside cells, Jordan and Bavari said. The result was GS-5734, later named remdesivir.

The next step by the government provided another vital milestone: Remdesivir was tested in government monkeys infected with Ebola at USAMRIID. When given within three days of infection to monkeys, the drug showed 100% efficacy against Ebola, the researchers found.

In humans, the drug was being tested by Gilead in healthy volunteers for safety by 2015, and the next year NIH tested it in Ebola survivors in West Africa. The NIH sponsored the next major step, a clinical trial in humans infected with Ebola in the Congo in 2018 and 2019. The drug performed worse than two other drugs and its use was stopped in the trial, but that did not stop federally sponsored research.

Researchers at Vanderbilt University and the University of North Carolina, with funding from an NIH-funded Antiviral Drug Discovery and Development Center (AD3C), studied how remdesivir performed against emerging diseases called severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

In addition to distributing grants and funding clinical trials, the NIH also has taken a direct interest in remdesivir. In a key federal animal trial that gave federal investigators greater confidence in the drug, the National Institute of Allergy and Infectious Diseases tested the drug as a MERS prevention in government monkeys at the Rocky Mountain Laboratories in Hamilton, Montana. The results, published this year, showed that monkeys given the drug did not get sick and had low volumes of virus in their lungs.

Once the coronavirus pandemic struck, the World Health Organization identified remdesivir as among the most promising potential treatments for the disease - raising hope for rapid help for sick patients.

The finish line came within sight with uncommon speed. NIAID sponsored a fast-paced clinical trial of remdesivir in more than 1,000 SARS-CoV-2 patients that began in February. (SARS-CoV-2 is the technical name for the novel coronavirus.) NIAID director Anthony Fauci - a top adviser to President Donald Trump's coronavirus task force - announced partial, top-line results from the White House on April 29: The drug shortened hospital stays by four days and reduced mortality from 11.6% to 8%, which was not considered a significant reduction in death, Fauci said.

Fauci said the results were modest. But, lacking any other treatments, he proclaimed the drug the "standard of care" for hospitalized coronavirus patients. Full results of the trial have not been released, and many questions about the drug's effectiveness remain unanswered.

But Jordan, the former Gilead researcher who pulled the parent molecule out of the company's library of compounds seven years ago, said he was happy with the results.

“I was very excited about that. This isn’t a home run. It’s clinical evidence that you can improve outcomes with an antiviral,” he said. “The fact that we can do something to this disease, that’s a great start.”