As Omicron spread looms, oral antivirals appear to be one of the best defenses — now we just need more
Thursday, December 2, 2021
Source: Endpoints News
After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.
“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”
So, what about small molecules and antivirals? Specifically, Merck’s molnupiravir and Pfizer’s proposed Paxlovid — how would they fare against Omicron?
According to several virologists and experts Endpoints spoke with, those two should maintain their effectiveness against the new variant, equipping public health officials in the US and other countries where the drugs are likely to become available with new weapons against the virus.
That’s because these proposed antivirals do not target the spike protein. The two pills, along with most other antivirals in development, go after different targets. Molnupiravir goes after RNA polymerase, interfering with viral replication. And Pfizer’s small molecule goes after the viral protease.
These drugs have attracted significant attention because they would be the first treatments approved in oral form, expanding access to the only currently available treatment for newly diagnosed Covid-19 patients: monoclonal antibodies that are available only through IV infusion and, in rare cases, injection. It would also work to evade manufacturing difficulties that affected antibodies, especially when Delta ran amok in the US earlier this year.
Merck announced in October that, in a large trial, molnupiravir reduced the risk of hospitalizations by 50% when given within 5 days of symptom onset, although an updated analysis last week found it to be only 30% effective. Pfizer’s Paxlovid claims an 89% reduction in risk of hospitalization or death related to Covid-19 when given within three days of symptom onset.
Although a committee of FDA advisors raised potential safety questions for molnupiravir, particularly in pregnant women, they gave the drug a narrow endorsement in a 13-10 adcomm vote, and Pfizer requested an EUA from the FDA in mid-November, which is still pending.
The US government has ordered 1.7 million doses for molnupiravir and 10 million doses of Paxlovid. Both companies have signed deals with a UN-backed nonprofit so the drug can be manufactured in low income countries, although access in middle-income countries remains unclear. Merck has also licensed its pill to eight Indian manufactures for generic production abroad.
“The hope would be that these antiviral pills … come online, so that when people are diagnosed, they can get a prescription, take a pill once or twice a day for five days with one of these two medications,” said Matt Hall, who runs a preclinical research group at the National Center for Advancing Translational Sciences, “and it should be effective in preventing things like severe symptoms of hospitalization and death.”
According to Benjamin tenOever, director of the Virology Institute of New York University, there is still a lot that remains unknown about Omicron — yet what we do know indicates that these drugs should remain effective against the new variant. The proteins the antivirals targets aren’t “mutated in any way,” he said.
“So there’s no reason to believe that either of those drugs would be any different now than they would be in the trials,” tenOever said, referencing molnupiravir and the Fujifilm antiviral favipiravir. “And the same is true for nelfinavir and [the Pfizer drug].”
And it’s unlikely mutations would arise. A virus being able to mutate the protease and the polymerase — the targets for Pfizer and Merck’s drug — is “a very high evolutionary bar to overcome,” tenOever said. And that’s because of their essential roles in viral replications.
Other scientists agreed with his assessment.
“They should retain effectiveness,” Kathleen Neuzil, director at the Center for Vaccine Development and Global Health at the University of Maryland, said in an email.
But that said, there is a need to develop more antivirals, Hall said. Although it would be difficult for the virus to mutate around these drugs, resistance could arise as they become more commonly used.
“We need to make sure we have a number of antivirals available against SARS-CoV-2 in anticipation of that,” he said.
To that effect, there are several Phase III studies being conducted on other drugs, including fluvoxamine, a cheap SSRI that is usually prescribed for OCD and depression. Unlike Merck’s and Pfizer’s molecules, fluvoxamine — made back in the ’80s by Abbott Laboratories and approved by the FDA in the mid-90s — does not go after the virus.
According to David Boulware, a University of Minnesota physician who helped run one of the fluvoxamine studies, the drug just might be as effective as molnupiravir. He cited the TOGETHER trial in Brazil, which was an 11-site trial involving more than 1300 patients.
“And they say a 30% reduction in ER visits and hospitalizations,” Boulware said. “And so, basically about the same effect as with the molnupiravir — and it’s only a $5 medicine.”
Even with all of these in mind, new antivirals and effectiveness against the variant do not ultimately mean much if doses are not given out early enough to those who need it.
Data on the new antivirals show peak effectiveness when given within 5 days of symptom onset, so both accurate and timely tests are needed. But patients have rarely gotten tested quickly during the pandemic — either because of personal unwillingness or because of the availability of tests — making it difficult to get people medicines in time.
“That’s one of the problems with antivirals — is that there is probably a decreasing effect over time. Clearly, earlier therapy is better,” Boulware said. “It’s kind of the experience that, by the time you get to day 10, you technically qualify, but you’re probably not having very much benefit.”