15/10/2021
Scientist behind Merck's Covid pill: We need to watch out for resistance
Jason Mast
Editor
When Mark Denison awoke this month to learn that another one of the drugs from his lab had proven effective against Covid-19, two thoughts rushed through his mind.
“I was so excited to hear that it had this potential,” he said. “And then I thought: Our resistance work is more important than ever.”
Denison, 66, is arguably the scientist most responsible for molnupiravir, the pill Merck announced last week cut the risk of hospitalization or death in newly diagnosed Covid-19 patients by 50%. It came to his Vanderbilt lab alongside another molecule known as 3a — or, as it was later rechristened, remdesivir — in the years after the 2012 MERS outbreak, as Denison worked to identify drugs that could be deployed in the event of another deadly coronavirus spillover.
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Mark Denison
Molnupiravir was arguably a bigger advance than remdesivir was at the beginning of the pandemic. Public health officials had waited 20 months for a pill they could give to save the most at-risk patients. The news was instantly heralded as a pandemic “game-changer,” and Merck on Monday applied for emergency use authorization.
But caveats emerged almost as quickly. Some scientists were concerned about the drug’s mutagenicity, i.e. its potential to induce mutations in human DNA, like cigarette smoke or radiation. Others were concerned about how quickly you’d have to get the drug to patients. A report out of India days later suggested the drug did little in patients who had progressed to “moderate” disease.
Denison, though, mostly feared that the virus could eventually find a way around the little brown pill.
“Coronaviruses can adapt to anything,” he said.
Resistance
Denison would know; he’s been studying coronaviruses for longer than nearly anyone on the planet. His first published academic paper, in 1986, was on coronaviruses and for decades before the pandemic, he ran a lab that charted the wily contours of a viral family most of the world regarded as a minor nuisance. For a while, he believes he might’ve been the only fully funded coronavirus antiviral lab in the world.
On the morning Merck announced its Phase III data, Denison’s star researcher, Laura Stevens, was suited up in Tyvek at their BSL-3 facility at 6 am for work. Denison identified molnupiravir’s potential against coronaviruses, but the actual development for Covid-19 — animal studies, clinical trials, manufacturing, etc. — was variously done by a nonprofit at Emory, the tiny startup Ridgeback Bio, and Merck.
Stevens and the rest of Denison’s lab have been focused on predicting whether and how SARS-CoV-2 can develop resistance to therapies, assaulting the virus with a battery of different attacks and seeing how it evolves in response.
The resistance that concerns Denison, though, is different than the resistance that thwarted early treatments for HIV or hepatitis C. Those infections need to be hit with multi-pronged attacks because they can easily mutate around virtually any single attack. SARS-CoV-2 is far less devious.
Where the virus has been able to evolve, it’s been to avoid monoclonal antibodies that are directed against the virus’ spike protein, the hook it uses to grab onto human cells. But the spike protein is ultimately just a tool for the virus. Molnupiravir throws a wrench in a part of the virus far more essential, one it can’t easily change: the enzyme it uses to make copies of its genetic code.
This enzyme, known as RNA polymerase, is virtually identical across most coronaviruses. Denison compares it to a Mercedes engine finely engineered over decades. One part out of place and it can’t run.
Robert Shafer
“The polymerase enzyme is very conserved, much more so than the spike,” said Bob Shafer, an infectious disease physician at Stanford. “I think the risk of resistance for this is not high.”
Denison said his own experiments back that up: In the lab, coronaviruses have great difficulty getting around molnupiravir or remdesivir. And when they do, it tends to come at a cost. They become weaker, less able to infect and spread.
So why care about resistance at all? The drug’s danger stems from the same quality that makes it so important: accessibility. Previous Covid-19 treatments have been infused or injected by medical professionals. Everyone received the full dose.
With a pill taken eight times per day over five days at home, many patients will likely take only a few pills and then stop when they start feeling better. The next time a family member has the sniffles, they might then reach for the leftover doses, whether or not they get a Covid-19 diagnosis.
And, as when patients skip or unnecessarily take antibiotic doses, that will create the perfect conditions for resistance.
“Ultimately, it depends on not the virus or the drug,” Denison said. “It depends on human beings.”
So what to do about it?
Denison has spent years theorizing about how to overcome potential resistance for a coronavirus pill. In an ideal world, he imagines a potent three-pronged attack.
Protease inhibitors — molecules that block one of the key steps SARS-CoV-2 uses to fuse itself with a cell — like the one Pfizer is developing are the most effective weapons at stopping coronaviruses in the lab, Denison said.
He would mix one of those with an oral form of remdesivir and molnupiravir. (Molnupiravir and remdesivir hit the same enzyme but in different ways, making them potentially synergistic.)
Practically, though, if Pfizer’s drug proves effective, there will be limited supply of both drugs and the best use from a public health perspective will be to give it separately.
And, he said, you would need clinical trials to find the best combinations. It took years before doctors figured out which antibiotics to use together.
“The risk of resistance doesn’t rise that high if you use it in the first 5 to 10 days, in the appropriate patients,” he said.
The other big fear
Pfizer’s treatment, which is due to read out in the coming months, could have another advantage. It doesn’t come with the same concerns around mutagenicity.
The coronavirus’ polymerase works by grabbing nucleosides in its environment and stringing them together to form the RNA at the virus’ center, its genetic code. Molnupiravir acts as a decoy. The virus grabs it instead of one of the nucelosides, until eventually it’s overwhelmed with mutations, a process called, alternatively, “lethal mutagenicity” and “error catastrophe.”
But human cells can also grab the decoy when trying to copy DNA, sparking fears that it could lead to birth defects or cancer. Those fears initially led the US government to punt on funding the drug in winter 2020. And last week, Emory chemist Raymond Schinazi, one of the first scientists to study the drug in the early 2000s, warned against using it in pregnant women.
Shafer and Denison agreed those risks have to be taken seriously.
“I don’t think it’s going to be something like Tamiflu or acyclovir,” Shafer said, referring to the common flu and herpes antivirals. “Drugs where you don’t think twice about taking or prescribing them.”
But not, they said, too seriously. The main measure researchers at Duke used to test the mutagenicity risk was by exposing certain mammalian cell lines to the drug for 32 days straight, a far cry from real-world conditions, where a patient would have exposure for five days.
And lots of daily activities expose you to mutagens.
“The goal there was provocative, the goal there was to create the circumstances that would maximally be able to detect whether it could affect DNA, and the data suggest it could,” Denison said. But “what does that mean? Does that mean it’s worse than the fact I walk to work every day without sunscreen on?”
Actually measuring the risk would be a colossal undertaking, sprawling well beyond the pandemic, they said. You would need to give the drug to people and then fellow for them for years, seeing whether there was a difference in cancer rates and mortality between those who once took the drug and those who didn’t.
In the meantime, it’s clear that for patients who are at high-risk and unvaccinated, or haven’t had a good response to the vaccine, the pill can substantially reduce your likelihood of winding up in a hospital or a morgue.
“These are questions that should not be posed as: This drug should never be used in humans,” he said. “But it’s something that you’d say, ‘Well, how might we best study it?'”
Delivery
Getting the drug to high-risk patients will still be a major logistical challenge, limiting its impact both in the US and around the world.
Reports last week that Indian drugmakers’ trials had found no “significant efficacy” on “moderate” patients appeared to throw cold water on the pill’s potential. But the Indian companies defined moderate broadly — an oxygen level between 90% and 93%, which would likely be classified as “severe” in the US.
And the news came as little surprise to virologists, who had long known you need to start treatment right after the infection begins. For the Merck trial, patients had to have started showing symptoms within the previous five days to enroll.
“The later you wait, the less chance a direct-acting antiviral drug is going to have any impact at all,” said Robert Garry, a virologist at Tulane.
Denison put it more bluntly: Wait a few days and you might as well pour the drug on a person’s head.
It’s why, he said, it’s important to get pills to patients ASAP and to keep developing new drugs so a hospital can have effective options for those who don’t get them in time, or who don’t respond to the pill.
“It’s a one-two punch,” he said.
