Merck’s Little Brown Pill Could Transform the Fight Against Covid
The antiviral drug molnupiravir, still in clinical trials, would give doctors an important new treatment and a weapon against coronaviruses and future pandemics
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Molnupiravir SOURCE: MERCK |
The story of what might become the next major breakthrough in Covid-19 treatment starts on a hotel hallway floor in January 2020, months before you were worried about the virus, weeks before you likely knew it existed. A scientist and a business executive were at a health-care conference in San Francisco, hatching a plan to get a promising drug out of academia and into research trials for regulatory approval. George Painter, president of the Emory Institute for Drug Development, and Wendy Holman, chief executive officer of Ridgeback Biotherapeutics, had met at the Handlery Union Square Hotel to discuss a compound Painter had started developing with funding from the National Institutes of Health. They got so enthusiastic about the possibilities that their meeting ran long and a group of lawyers kicked them out of their room. So they continued on the hall floor, hours after they’d started.
Painter and Holman weren’t talking about targeting Covid at the time. The disease and the coronavirus that causes it, SARS-CoV-2, weren’t major concerns at the J.P. Morgan-run conference, where handshakes and cocktail parties with hundreds of guests were still the norm. Rather, Painter was hoping his drug, molnupiravir, could get more funding to speed up flu studies. Holman was eager to see if it worked on Ebola. That’s the thing about molnupiravir: Many scientists think it could be a broad-spectrum antiviral, effective against a range of threats.
A few days later, Holman arrived in Atlanta to see the labs at Emory and pore through the early data. As she and Painter hashed out the terms of a deal in which Ridgeback would buy the drug and start studying its safety and efficacy in people, Covid was seeping into the public consciousness. By the time Ridgeback announced its acquisition of molnupiravir, on March 19, the world had shut down, and it was clear which threat the drug needed to be tested on right away. Clinical trials for the pill kicked off in April. The next month, Merck & Co., which has a deep history of public-health development work, including on HIV and Ebola, struck a deal to buy rights to molnupiravir from Ridgeback and start the types of large-scale trials that could get it authorized by regulators. Those began in the fall.
Even as vaccines are rolling out worldwide, the coronavirus and its mutations still pose a major health threat. Not everyone who’s eligible for a shot will agree to get one. The hundreds of thousands of people who continue to contract Covid each day have few treatment options. There’s no simple, inexpensive pill that can prevent those at the earliest stages of infection from later needing to be hospitalized. The monoclonal antibody therapies that doctors now have available for those most at risk of getting severely ill need to be administered by infusions at specialized medical centers. And for those who do become hospitalized, the antiviral remdesivir, from Gilead Sciences Inc., speeds recovery, but hasn’t been shown to reduce deaths.
Drugmakers see an opportunity to add to the arsenal of potential therapies. There are 246 antivirals in development, according to the Biotechnology Innovation Organization, an industry trade group. And companies as big as Pfizer Inc. and as little-known as Veru Inc. are testing them in pill form. Merck’s molnupiravir is among the furthest along. Its developers hope the pills can be prescribed widely to anyone who gets sick. Think Tamiflu for Covid.
The hurdle, beyond ensuring the drug works, is making sure it’s safe. Developers of antivirals have been dealing with the thorny issues they pose for decades. Should Merck succeed in demonstrating that molnupiravir is effective and free of serious side effects, it could be a boon to the company, and to society, for many years to come.
Viruses are uniquely difficult to attack with drugs. They hijack human cells and set up machinery to churn out copies of themselves, creating a challenge: destroying the virus without harming the cells. Success, when it comes, can be fleeting, because viruses mutate to survive.
The first antiviral approved in the U.S. was idoxuridine, a herpes treatment regulators green-lit in 1963, generations after the discovery of antibiotics. It’s among a widely used class of drugs called nucleoside analogues—synthetic versions of nucleosides, critical building blocks of DNA and its counterpart, RNA, the messenger molecule that delivers instructions to a cell’s protein-making factories. Nucleoside analogues prevent viruses from replicating, or from replicating effectively, inside cells.
Concerns that idoxuridine was toxic to the heart led it to be recommended only for topical use—the sort of hurdle that kept antiviral drug development slow. The AIDS crisis of the 1980s invigorated the field. “Until HIV came along, there were precious few antivirals,” says Saye Khoo, a professor of pharmacology and therapeutics at the University of Liverpool. Rising death rates and the public outcry about the virus prompted companies and governments to pour millions of dollars into an area that hadn’t seen that kind of investment before.
The breakthroughs were meaningful. Khoo says scientists discovered that some people appeared to have a natural resistance to getting HIV—they lacked a receptor allowing the virus to enter cells—leading to a new class of drugs. They also realized that antivirals would need to be adaptable enough to deal with mutations, and that potent combination therapies involving multiple drugs could prevent the evolution and spread of drug resistance. At the same time, some of the new treatments had serious side effects, including anemia and liver problems, pushing drugmakers to continually improve upon their treatments.
During this era, the U.S. government also started to boost its pandemic preparedness, with an emphasis on guarding against bioterrorism. President Bill Clinton, alarmed after reading the Richard Preston novel The Cobra Event, in which a terrorist unleashes a virus that causes a fictional ailment called brainpox, convened a group of cabinet members and scientists in April 1998 to assess such threats. That led to the formation of what’s now called the Strategic National Stockpile, whose objective was to have enough emergency medicines and materials to deploy within 12 hours of an official request in times of crisis. Following the Sept. 11 and anthrax attacks of 2001, the Bush administration directed the stockpile to procure products such as smallpox vaccines. Then, in 2006, Congress authorized the formation of the Biomedical Advanced Research and Development Authority, or Barda, to help develop treatments and vaccines for public-health threats.
Pharma’s next major advance in antivirals came in 2013, a $1,000-per-pill hepatitis C cure produced by Gilead. The company was roundly criticized for setting so high a price for such a widely used drug. It was the usual risk-reward problem: If pharma companies can’t command prices that allow them to profit from the drugs, they aren’t likely to invest in them.
When they do invest, they have much more incentive to focus on chronic diseases than acute ones, which entail inherently shorter treatment—and revenue—windows. “If you look at what drugs have been developed against viruses, you have HIV, you have hep C, you have herpes. Those are all chronic infections. That means longer-term therapy,” says Ashley Brown, an associate professor at the Institute for Therapeutic Innovation at the University of Florida’s medical school. “For these acute viral infections like dengue, West Nile, chikungunya, you don’t have anything to treat with.” Doctors were also left scrambling when the two prior coronavirus pandemic threats—severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS)—emerged, in 2003 and 2012, respectively. Even for influenza, there are only four approved antiviral drugs recommended by the Centers for Disease Control and Prevention.
Barda might have helped fill the breach in antiviral drug research, but almost from the beginning it didn’t get the funding it needed to support a robust pipeline. The U.S. government’s focus on bioterrorism in some ways overshadowed the threat of infectious disease outbreaks. “There has not been as focused a strategy of investment in developing antivirals for pandemics,” says Phillip Gomez, who established a production program for potential HIV, SARS, and Ebola vaccines at the National Institute of Allergy and Infectious Diseases (Niaid) in the early 2000s before returning to the private sector.
Barda was also limited because the kinds of drugs that might be most useful in preparing for a pandemic—broad-spectrum compounds that fight multiple viruses—are particularly difficult to develop. “The whole field has been littered with casualties, candidates that never worked,” says Robin Robinson, director of Barda from 2008 to 2016. Even if a given formulation succeeds in stymieing the replication of one virus, that doesn’t mean it will work on another. That’s because viruses have different ways of replicating, he explains. So, rather than put money toward what Robinson calls a “moonshot,” the U.S. government has taken a more targeted approach, funding antivirals tailored to specific viruses rather than for a number of them. And getting enough money to do that has always been an issue. “Every time we have a big emergency in the United States in the last 75 years, we do a great job afterwards, and it dissipates four or five years after that, when the funding runs out,” Robinson says.
Without the government spending billions of dollars on potential pandemic drugs, a handful of academic centers were left doing much of the research work, until something proved promising enough that a biotech or a pharma company stepped in to pay for large-scale trials. Put bluntly, “pharma has an attention deficit disorder,” says Ali Munawar, founder of two early-stage antiviral drug companies, one of which was bought by Johnson & Johnson. “I think it is the reward issue,” he adds. “You cannot predict when the next pandemic is going to hit. That uncertainty is difficult to plan for.” Drugmakers’ lack of interest in developing antivirals for infectious diseases created what’s known as the valley of death, where promising discoveries land because no major pharma company steps in.
Once in a while, though, an opportunity arises.
The chemical compound on which molnupiravir is based—C9H13N3O6, or N4-hydroxycytidine—has been known for decades. Like idoxuridine, the herpes drug, it’s a nucleoside analogue. It interferes in replication, preventing a threat from causing severe infection. Molnupiravir doesn’t stop the virus from replicating, though; instead, the drug introduces errors into the virus’s RNA that are then replicated until it’s defunct.
With antivirals such as this, “basically you’re going to put a piece of sand in the gears and hope it stops the impact of the virus,” says Gomez, the former Niaid scientist. But, he adds, stopping the virus by creating errors in the genetic code or through other means can come with unintended consequences. “You don’t know where the sand might end up in the other parts of the body.” A company called Pharmasset Inc. (a hepatitis C drugmaker Gilead bought in 2011) investigated molnupiravir’s main ingredient around the turn of the century, but it abandoned development over concerns that it was mutagenic, meaning it could lead to birth defects.
Painter dusted off the chemical structure of molnupiravir years ago. Prompted by a concern raised by the Defense Threat Reduction Agency, a unit of the U.S. Department of Defense, he was looking for a countermeasure against weaponized Venezuelan equine encephalitis, the stuff of Cobra Event-level nightmares. A chemist who holds 45 patents, some for hepatitis B and HIV antiviral drugs in use today, Painter has made a career of bridging the gap between academic drug discovery and the biotech and pharma industries that get treatments across the finish line. He took the chemical structure that Pharmasset had once studied and screened it against a wide range of viruses, including SARS and MERS. In late 2016 he made it possible to use in pill form by modifying that chemical structure into a “prodrug,” which meant the compound would break down in the body, allowing the part that interferes with viral replication to be properly absorbed into the bloodstream.
After his initial research, Painter settled on influenza, an ever-present threat, as molnupiravir’s first target and prepared to launch an NIH-funded safety trial in early 2020. He also applied for funding from Barda but didn’t get it. Rick Bright, then the agency’s director, later noted in a whistleblower complaint about the Trump administration’s pandemic response that, though his supervisor at the Department of Health and Human Services was excited about molnupiravir and wanted to fund it, Bright had been reluctant to invest when it was first presented to him in the fall of 2019. Other nucleoside analogues had caused birth defects in animals, and he wanted more safety data before signing off.
That’s where Holman came in. Her story is unusual for biotech. She’d worked in finance for more than 15 years, developing experience with the health-care industry before deciding she wanted to get into drug development for diseases with few existing treatment options. Her husband, Wayne, is a doctor and former health-care specialist at a division of Steven Cohen’s SAC Capital Advisors. Wayne’s hedge fund, Ridgeback Capital (an homage to the family dog, a Rhodesian Ridgeback named Coco), invested in major drug companies such as BioMarin Pharmaceutical Inc. and Celgene Corp. before he co-founded Ridgeback Biotherapeutics with Wendy in 2015. She became the biotech’s CEO and face.
Ridgeback Bio is best known for developing an approved Ebola treatment, Ebanga, which had its own wild journey. The centers where it was tested in Congo got caught up in violence and burned down during trials, as dedicated staffers saved patient records. (Holman has lately been working out how to transport the drug to parts of the country experiencing renewed outbreaks.) Her interest in molnupiravir stemmed from wanting to find new Ebola treatments.
As soon as she and Painter realized the urgency of the Covid crisis, they redirected their molnupiravir research toward SARS-CoV-2. She used her connections to track down the CEO of Labcorp—the company was busy making desperately needed Covid tests, but it also has a clinical trials business—to help her secure a facility in the U.K. for early-stage safety studies. “We came in and funded that because if we had waited around for the flu Phase I to happen, it would’ve taken six months to a year,” Holman says of those early studies of the drug.
Before the scale of the pandemic sank in, Ridgeback had invested enough in production to pay for 1 million treatment courses. “Then we started really thinking about it and thought, ‘If this is really needed and this can really work in this, that’s not enough drug,’ ” Holman says. “I did everything—there’s not a friend I didn’t call or a colleague I didn’t beg from.”
Her quest for more capacity made Merck a natural fit. The deal the companies struck last May involved a direct payment to Ridgeback for the drug and an agreement for a share of the profits if it’s approved. Ridgeback also kept a hand in development, running some trials seeking to further the research while Merck handled the large-scale ones. “The reason to partner with Merck,” she says, was to “make sure that there was enough drug around for the world.”
Merck could use a big win. In recent years it’s grown heavily dependent on a single cancer drug and a declining diabetes franchise. It was also late to the Covid vaccine race, and the two candidates it tested failed in human trials, relegating the company to the unglamorous work of manufacturing the competition’s shots.
After reaching the deal with Ridgeback, Merck launched Phase II/III trials aimed at enrolling almost 3,000 patients in the U.S., Colombia, Israel, Russia, and elsewhere. With millions of people contracting Covid worldwide, the company’s chief of research at the time, Roger Perlmutter, says he would “look at the enrollment in our trials twice a day,” checking in constantly about the pace of recruitment in hopes of bringing molnupiravir to market in record time. (Perlmutter has since retired from Merck.)
The company is studying a variety of dosages, keeping a close eye on side effects, and monitoring a range of disease progressions, including following up to learn whether patients at different stages of Covid end up hospitalized, suffer an adverse event, or die. It’s also looking at whether or not molnupiravir reduces viral load—a measure of virus particles concentrated in the body after a person becomes infected. These studies could form the backbone of an emergency-use authorization submission with regulators.
In early March, results came in from a smaller study Ridgeback conducted of 202 nonhospitalized adults with Covid. Chief Medical Officer Wendy Painter, George’s wife, was listed as the lead author on findings from the study that were presented at one virtual conference. Some patients with detectable levels of virus particles saw them reduced after five days on the drug, with no major safety concerns. It was a good sign, but the study wasn’t comprehensive enough to determine efficacy on its own. “There’s a signal, there’s no denying that, but the numbers are so small that to say this is the ‘next antiviral,’ we need to be cautious of that,” says Adarsh Bhimraj, head of neurologic infectious disease at the Cleveland Clinic.
Data from Merck’s Phase II/III trials is expected in late March. Scientists are eager to find out if a reduction in viral load translates to better Covid outcomes. “We think that the more you lower the virus, the more likely it is to be beneficial,” says Rajesh Ghandi, an infectious disease physician and professor at Harvard Medical School. “We’ll also look to see, does it affect people’s clinical severity?” One reason Merck is studying molnupiravir in earlier-stage patients as well as later-stage, hospitalized ones is that interfering in viral replication might not make much difference in someone who’s already had Covid a while.
Then there’s the question of safety, which has resurfaced since Bright’s concerns first emerged. This March, researchers working out of the University of North Carolina at Chapel Hill presented a study of the drug’s main ingredient at the same infectious disease conference where Ridgeback presented its data. The UNC researchers said, based on their assays, that molnupiravir’s use should be limited to those likely to get the greatest benefits, “due to the unknown long term risks associated with systemic exposure to a DNA mutagen.”
Merck declined to comment on the UNC research. But given the class of drugs, “you do worry,” says Nicholas Kartsonis, senior vice president for clinical research for infectious diseases and vaccines at the company. “You want to make sure it doesn’t cause genetic mutations.” Merck has done studies in the lab, in rodents and in humans, and the data look clean, he says. What gives him the most confidence is a pair of two distinct assays looking at the drug’s capacity to alter DNA in living organisms. Here, molnupiravir was studied at higher doses and for longer periods than would be given to humans. The totality of data indicates it’s not mutagenic, Kartsonis says, “but I need that efficacy data to help confirm it’s not just a sugar pill.”
Some scientists say that, because the drug is only intended for use twice a day for five days, its potential to cause damage is limited. And Bright himself has changed his tune. “Any concern I had about an academic group or a small startup trying to move too quickly, those were softened when Merck got involved,” he says, adding that he trusts the drugmaker to do the right safety studies. “Merck, more so than many other companies, has terminated projects because the data didn’t look right.” Umer Raffat, a pharma analyst at investment firm Evercore ISI, says that while “big names in virology” have raised concerns about the risk profile of the drug, Merck is “very conservative,” and the early data don’t suggest the drug is mutagenic.
“There’s always a little bit of tension around these issues of, well, is the drug going to work or not?” says Robert Shafer, a Stanford medical school professor who specializes in infectious diseases. Data on how much molnupiravir reduces viral load, what effect this has on Covid, and what side effects it has “will definitely influence how widely a drug like this will be used,” Shafer says. “If there were remaining concerns, you’d probably use it in really limited circumstances to prevent Covid in high-risk patients. If accumulating data suggests it doesn’t have off-target effects, you might use it in lower-risk persons.”
For Merck, this could be the billion-dollar question. “It could be a $1 billion or $10 billion product,” depending on how the data turns out, says Mara Goldstein, an analyst at Mizuho Securities Co. Merck is considering studying molnupiravir as a preventive treatment, to be deployed after a person is exposed but before they’ve fallen ill. That would allow the drug to be deployed even more broadly in the fight against Covid.
If the drug proves safe and effective, Merck says it’s ready to go, with the capacity to make as many as 100 million molnupiravir pills, enough to treat 10 million people, by the end of the year. Down the road, the drug could even be an asset beyond the fight against Covid. Painter says it’s shown promise against a number of RNA viruses, not just SARS-CoV-2, which would mean it could help governments prepare for the next pandemic. “You never know what the next one is going to be,” says Brown, of the University of Florida. “Back when Zika happened, I was also looking at a lot of these drugs against Zika. Everything was Ebola, and then Zika. We have to kind of get ahead of it as opposed to trying to catch up.”
Timothy Sheahan, an assistant epidemiology professor at the University of North Carolina who worked with Painter on some of the early research into molnupiravir and played a role in Gilead’s remdesivir, thinks that, as soon as a year or two from now, there will be far more antivirals than there are today. “I’m predicting it will be unrecognizable,” he says. “The things that we will have at our disposal if another coronavirus emerges will be black-and-white compared to what we have today.” Molnupiravir, should it succeed, could be just the beginning.
