The last time the world needed an antiviral medicine as quickly as possible, Daria Hazuda, vice president of infectious disease and vaccine discovery research at Merck, answered the call. Around 150,000 Americans were infected with HIV each year when rates peaked in the mid-1980s, and by the year 2000 nearly 500,000 people had died of AIDS in the U.S. Hazuda’s research at the time focused on HIV’s ability to insert its genetic material into the human genome. Her lab developed a novel way to target that process with a drug called raltegravir, which was approved for use in 2007 and is still used today.
Now, she hopes to develop a drug for COVID-19 — at a substantially faster pace.
While most of the world’s attention is currently laser focused on getting vaccines to more people to stem the spread of the coronavirus, there’s also significant pressure on scientists to find a cure.
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Doctors have some medications they can use to treat the effects of COVID-19, but developing a drug that targets the virus itself is a complex and costly procedure. More than a year into the pandemic only one antiviral treatment — remdesivir — is currently recommended for use in the U.S., and experts say it is not nearly effective enough.
“Vaccine manufacturers are making next generation vaccines to try and stay one step ahead, but it is unpredictable. So you need other interventions to address the potential evolution of the virus,” Hazuda said.
She and her team, along with researchers at Miami-based Ridgeback Biotherapeutics, worked seven days a week in the spring of 2020 to find a possible treatment for COVID-19 and prepare for the clinical trials necessary to prove its safety and effectiveness. Their drug, molnupiravir, is one of two powerful medicines to treat COVID-19 that are nearing the end of clinical testing.
“The day started really early and ended really late at night,” Hazuda said. “But there was a tremendous sense of mission. Everybody wanted to help even though they were exhausted. There was so much we all had to do.”
Scientists are hopeful that new drugs designed to stop the virus’ deadly reproduction could reduce hospitalizations and deaths from COVID-19. The drugs offer hope and a contingency plan for unvaccinated individuals, particularly in low-income countries lagging far behind in the race to vaccinate.
Chasing a moving target
Viruses mutate constantly, making it challenging to find a medicine that will not just work, but continue to work as the virus morphs. Mutations can change the shape of viruses’ proteins and thereby make them resistant to drugs. The hunt for effective antivirals is largely a hunt for a “conserved target,” such as a protein that rarely changes its shape even as the virus mutates.
Since scientists shared the sequenced genome of the novel coronavirus in January 2020 — detailing the specific genetic information and proteins of the virus — researchers have worked at breakneck speed to find a targeted medicine.
Hazuda’s experience with HIV and Hepatitis C helped her team quickly rule out targets in the SARS-CoV-2 structure that were likely to change as the virus mutated and focus instead on “very highly conserved targets to minimize the potential of developing resistance,” she said.
Antiviral medications often target a virus during the process of replication, when it uses our cells’ resources to make copies of itself — leading to cell damage and the release of more virus.
By early March of last year, Hazuda had narrowed her search to compounds aimed at proteins that could copy the virus’s genetic material. Her team came across a pre-clinical publication from an Emory University scientist on molnupiravir, a compound initially developed for influenza and other viruses. Research suggested the compoundcould make it harder for the virus to replicate itself by interrupting the RNA polymerase enzyme, which acts like a copy machine for the viral genome. In various academic labs, molnupiravir has demonstrated activity against flu and many different types of coronavirus, including MERS and the common cold.
“We were very interested in finding an agent that would have the potential to be not only active against CoV-2, but potential future outbreaks or pandemics caused by other coronaviruses,” Hazuda said.
Because Ridgeback Biotherapeutics had the rights to molnupiravir, Merck began collaborating with the smaller pharmaceutical company to test the safety of the compound and prepare it for clinical studies.
The idea is that molnupiravir could be taken as an oral pill by symptomatic patients who test positive for COVID-19, before their illness is severe enough to require going to a hospital. The hope is that it can stop the virus in its tracks, before it can replicate uncontrollably and cause a person to become more sick.
One phase 2 clinical study showed that molnupiravir is unlikely to significantly change the illness of those people who are hospitalized with COVID-19, but Hazuda is hopeful that phase 3 trials — expected to conclude by the end of the year — will demonstrate its effectiveness as a treatment that can be used outside of the hospital for people with mild to moderate cases.
Adolfo Garcia-Sastre, the director of the Global Health and Emerging Pathogens Institute at Icahn School of Medicine at Mount Sinai, also spent the spring of 2020 looking for a medication that could thwart the coronavirus’ lifecycle, but at a different stage. He sought a drug that influences the human proteins that the virus uses to build its components.
Because viruses hijack human cells and use their proteins (called factors) and other materials for their own purpose, identifying the factors they rely on can be a first step toward halting their actions.
Garcia-Sastre’s collaborators at the Quantitative Biosciences Institute at the University of California, San Francisco, identified more than 300 human factors most likely to make an impact on viral replication. Then, his lab tested around 90 drugs that are known to affect these factors. They landed on plitidepsin, an injectable medicine developed by Spain’s PharmaMar and used in patients with multiple myeloma, a type of blood cancer. It was shown to interfere with the function of a human factor called eEF1A, which the virus uses in the assembly of its proteins.
So far, plitidepsin seems to overcome some of the difficulties in finding a drug that targets virus replication. One is that often their effectiveness in the lab or in animal testing doesn’t carry over to humans. Another is toxicity: The concentrations required can cause undesired effects in human cells. Plitidepsin passed the critical phase 1 clinical trial conducted in Spain, showing that toxicity is not a barrier to use. The ongoing phase 3 clinical trial will show whether plitidepsin decreased days of hospitalization for COVID-19 patients.
The study, expected to be completed in August, will compare plitidepsin’s effectiveness to remdesivir, the current standard of care, which also works by inhibiting replication and can shorten hospitalization for COVID-19 patients by four days, on average. Where remdesivir has fallen short on decreasing the deadliness of the virus, Garcia-Sastre hopes plitidepsin will demonstrate live-saving potential.
The cost of discovery
While doctors have blood thinners and steroids to treat the symptoms of a raging COVID-19 illness, developing a new medicine that specifically targets the virus itself can take many years, explained Bhaven Sampat, an economist and associate professor at the Department of Health Policy and Management at the Mailman School of Public Health at Columbia University.
By repurposing an existing medicine and using already-developed compounds, both Garcia-Sastre and Hazuda shaved precious time off the drug development process. Piggybacking off already identified candidates also helps sidestep some of the cost spent on basic research.
“That’s particularly useful because you don’t have to reinvent the wheel in a way,” Sampat said.
Remdesivir, so far the only antiviral approved for COVID-19, benefited from the same leg up. Developed nearly a decade ago and shown effective against other coronaviruses including Ebola, SARS and MERS, it was fast tracked for use against COVID-19 and greenlit by the FDA in October 2020.
Another existing drug, ivermectin, may also have potential against SARS-CoV-2. A May meta-analysis suggests it could speed recovery and reduce mortality from COVID-19. The idea is controversial; some experts are unconvinced while proponents are eager to put it to use as a cheap, effective treatment. The anti-parasitic, developed by Merck in the 1980s, is no longer under patent. The company has contended there is not sufficient evidence for its use against COVID. Merck declined to respond to PBS NewHour’s request for comment.
Developing a new drug oftentimes costs more than $1 billion dollars, a financial and technological burden typically shared by federally and grant-supported research labs (often at universities), which do basic research to identify drug candidates, and pharmaceutical companies, which bring medicines through expensive clinical trials to market.
The National Institutes of Health is responsible for administering $41.7 billion annually for medical research with an additional $4.9 billion allotted for COVID-19 research. But the percent of the U.S. government’s budget dedicated to scientific research and development hit a 60-year low in 2019.
Meanwhile, private entities, such as pharmaceutical companies, have greatly increased their spending on research. “Public and private sectors play complementary but usually distinct roles,” said Sampat, who studies NIH funding.
The country’s vulnerability during this pandemic has boosted interest in recommitting to basic research in the form of increased federal spending. Biden’s administration proposed budget increases of 20 percent or more for the NIH, Centers for Disease Control, and the National Science Foundation, which could help support future discovery and protect against the next pandemic.
Public funding more often is directed at basic research that enables the development of treatments for rare diseases or diseases of which little is known. Pharma companies tend to put most of their R&D budgets into medicines that will be widely used and turn a profit. Both entities consider protection against future pandemics.
Over the course of the pandemic, the development of a treatment has had to compete with vaccine development for limited funding. “I’m not saying we should have spent less on vaccines — I think we should have spent just a lot more on therapies. And I think there’s still time to do so,” said Sampat.
Money isn’t the only crucial resource subject to competing priorities. Deciding where to direct the limited pool of people eligible to enroll in clinical trials requires oversight from federal regulating bodies, such as the FDA and NIH. Leaders must be aware of all of the possibile medicine candidates to help promote work on the most promising ones.
“I think the NIH could have done more of that,” Sampat said. “The coordination point is central. It’s as important, if not more important, than the funding point. It was kind of like the wild, wild west out there, and that’s a problem.”
If funding and clinical trial participants are directed towards a medicine — such as hydroxychloroquine — that does not yield results, that limits the pace at which other drugs can be studied.
There is much to be learned about how best to accelerate the process of drug development so that we are better prepared to face the next pandemic. But figuring out how to evaluate the effectiveness of funding of research and development is difficult; scientific discovery builds upon itself and it is hard to know the importance of new knowledge until it can be put to use, sometimes in unexpected ways. “To attribute the outcomes we care about for these investments, it’s a very, very tricky thing and something that Congress, economists and others have struggled with for 60 or 70 years,” Sampat said.
If plitidepsin or molnupiravir doesn’t make it out of clinical trials successfully, both Hazuda and Garcia-Sastre are sure that their work will not be in vain. Perhaps the drugs can lead researchers in the right direction for treating COVID, or provide a jumping off point for the next great medical need. Because molnupiravir has shown activity against strains of coronavirus that cause the common cold, it may be studied for this purpose in the future or other viruses entirely.
“If it doesn’t work, why doesn’t it work?” Garcia-Sastre said. “Can we learn something for why it’s not working that will help us to get better?”