As supplies of vaccines against monkeypox remain constrained and the number of people contracting the disease continues to mount, physicians and researchers are looking to the drug tecovirimat for relief. In animals infected with monkeypox, the antiviral has been shown to lower the amount of virus in their bodies and reduce the number of fluid-filled ‘pox’ lesions forming on their skin.

Efficacy data in humans, however, are much more limited, making some researchers and regulatory agencies hesitant about authorizing tecovirimat’s widespread use. But people with monkeypox — in particular those with severe disease, which can cause extreme pain, scarring and, in rare cases, death — are pleading for access to the drug.

Clinical trials of the drug are starting up now, but results are still months away. Nature spoke to infectious-disease specialists to understand how tecovirimat works, and what data are still needed to assess whether it is effective against monkeypox in humans.

What is tecovirimat, and how does it work?

After the 2001 anthrax attacks in the United States, in which letters laced with spores of the lethal bacterium were sent to media organizations and politicians, the US National Institute of Allergy and Infectious Disease in Bethesda, Maryland, received a funding boost to develop treatments against pathogens with the potential to be used as bioweapons. Biosecurity officials were especially worried about smallpox, which can kill about 30% of the people who are infected. Although the disease was eradicated more than 40 years ago, the concern was that smallpox virus could be accidentally released from, or weaponized by, laboratories around the world where samples are still kept.

The influx of cash helped to give rise to tecovirimat. The antiviral works by preventing orthopoxviruses, such as smallpox, from creating a certain protein. Once this type of virus hijacks a host cell and replicates, the newly-formed viruses use this protein to escape from the infected cell and spread to other cells. By blocking the virus from making the protein, tecovirimat “essentially traps the virus inside infected cells”, leaving the immune system’s antibodies and T-cells to take care of the situation, says Dennis Hruby, chief scientific officer at SIGA Technologies, the New York City-based pharmaceutical firm that makes tecovirimat.

Researchers designed the antiviral with smallpox in mind, Hruby says. But because it targets a protein that other orthopoxviruses, including the monkeypox virus, use, scientists think the drug could also tame monkeypox.

Is there any evidence that tecovirimat works against monkeypox?

A 2018 trial in about 450 people, 90 of whom received a placebo, showed that the drug is safe and has few side effects. But demonstrating its efficacy against orthopoxviruses in humans has been less explored.

When the US Food and Drug Administration (FDA) considered approving the drug for smallpox in 2018, the agency acknowledged that it wouldn’t be feasible or ethical to test the drug by infecting people with that virus or any other orthopoxvirus. Instead, the FDA granted an exception to allow SIGA to use efficacy data from animal studies.

Researchers tested tecovirimat on non-human primates infected with the monkeypox virus and rabbits infected with the rabbitpox virus. In both cases, animals that received the antiviral four days after infection had a much higher chance of survival, developed fewer lesions and had a lower viral load compared with those that received a placebo.

The ongoing global monkeypox outbreak has so far provided only anecdotal evidence of tecovirimat’s effectiveness in people, says Daniel McQuillen, president of the Infectious Diseases Society of America, based in Arlington, Virginia. A couple of observational studies2,3 in a handful of people with monkeypox found that new lesions stopped forming within one day after physicians administered tecovirimat. And a study that administered the drug to 14 people in the Central African Republic, where a more deadly strain of the virus has been circulating for decades, found that participants' viral load dropped significantly within four days, according to a draft manuscript Nature has seen. These studies do not establish drug efficacy, as they did not have a control group for comparing results.

Physicians worldwide have had a hard time accessing tecovirimat. Why?

The European Union and the United Kingdom have approved tecovirimat for monkeypox using the same animal studies reviewed by the FDA, which has eased access to the drug in some countries. However, SIGA has so far taken orders from only 11 countries, including the United States and Canada, says Holly Stevens, a spokesperson for the company. (Stevens declined to disclose the other countries.) That means access to the drug is still extremely limited — and notably so in parts of Central and West Africa, where monkeypox has been spreading for decades and has caused the most deaths.

In the United States, the FDA hasn’t authorized tecovirimat’s use against monkeypox because, the agency says, the disease hasn’t been eradicated and therefore it is still possible to test the drug in humans. This means that US physicians can access the drug, deemed experimental for monkeypox, only by requesting special permission through the US Centers for Disease Control and Prevention (CDC). This red tape has put many physicians off prescribing tecovirimat, even though the country has a stockpile of 1.7 million courses — mainly intended for use against smallpox.

The paperwork required is an enormous burden for clinicians who have to juggle patients, says Amesh Adalja, an infectious-disease specialist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. The CDC recently made some of the forms optional and has allowed physicians to submit them after administering the drug to people. It is also working with the FDA to further tweak the process, says Scott Pauley, a CDC spokesperson.

The FDA finds itself in a “tricky position”, McQuillen says. The agency was criticized during the COVID-19 pandemic when it authorized the emergency use of drugs such as hydroxychloroquine and they turned out not to be effective. Making tecovirimat completely accessible could hinder clinical trials to determine the drug’s efficacy, because people might not want to enrol if there’s a chance they will receive a placebo, he says. The FDA did not respond to Nature’s queries.

What data are now being collected, and what do scientists still want to know?

The first randomized controlled trials are being set up in Canada, the Democratic Republic of the Congo, the United Kingdom and the United States; clinicians have begun enroling participants in the UK trial, and the others hope to begin soon.

Hruby says that researchers plan to enrol people with mild cases of monkeypox. If they are hospitalized, participants will have the opportunity to receive the drug, even if they were part of the placebo group. He adds that he expects to see the first data in a matter of months.

Apart from these efficacy trials, it would be helpful to test whether the drug can also prevent infection by administering it prophylactically, either before exposure to the monkeypox virus or within days of a person finding out they have been exposed, says Jessica Justman, an infectious-disease physician at Columbia University in New York City. With HIV, using antivirals prophylactically has been very effective in protecting against the virus — and that strategy might work for monkeypox too, she says.

In some countries, clinicians have been trialling the use of smallpox vaccines, which are thought to be effective against monkeypox, by offering them soon after a person has been exposed to the monkeypox virus. But the most common vaccine offered is given in two doses and takes six weeks after the first one to reach peak efficacy, meaning that using vaccines post-exposure might not be very effective. This is a situation in which a proven antiviral, which would probably take effect much faster than vaccines, could come in handy, Justman says.

More information about how the antiviral works in humans is desperately needed, McQuillen says, although he acknowledges the difficult task ahead. “We’re trying to figure out if a drug works in an outbreak that’s expanding exponentially and that we want to stop at the same time,” he says.

This article is reproduced with permission and was first published on August 25 2022.