Approval granted earlier this month by Japan’s regulatory agency for the antiviral drug tecovirimat – also known as TPOXX – for the treatment of mpox and its two cousins, smallpox and cowpox, has baffled some scientists, after studies have shown it doesn’t work.
There is currently no treatment for mpox, and tecovirimat initially looked promising, having prevented death in monkeys given lethal doses of mpox and smallpox virus, reports Science.
The European Union and the United Kingdom both approved it in 2022, after an earlier epidemic of mpox in men who have sex with men (MSM). At the time, the drug had been shown to be safe in humans, but no efficacy data existed.
And until recently mpox was a rare disease limited to remote African villages, which made large, placebo-controlled trials difficult.
But in the past six months, two such studies have definitively shown tecovirimat doesn’t work in people infected with either of the two clades of mpox virus.
“To approve it now is very confusing,” said Jason Zucker, an infectious disease specialist at Columbia University who co-led one of the trials, the Study of Tecovirimat for Human Mpox (STOMP), which enrolled mostly MSM in the United States, Japan, Latin America, South Africa and Thailand.
“I am very curious to read studies used by Japanese (regulators) to approve it,” added epidemiologist Placide Mbala of the Democratic Republic of the Congo’s (DRC) National Institute of Biomedical Research, who helped run the other trial – PALM007.
That study, in the DRC, tested the drug in children as well as adults and also found no benefit.
It’s unclear what moved Japan’s Pharmaceuticals and Medical Devices Agency to approve the drug in the face of negative data.
The agency told Science it “does not answer any questions regarding specific products”.
In a press release, the drug’s manufacturer, SIGA Technologies, said Japan’s decision was based on favourable results from 15 clinical trials that together enrolled 800 people – although all were healthy volunteers, meaning those trials could only measure safety and how the body processes the drug, not efficacy.
SIGA told Science the agency also considered the PALM007 results, but the STOMP results “were not available at the time of their review”.
The findings from PALM007 and STOMP could cause the European drug agencies to reverse their decision. And some argue they should even lead the US Food and Drug Administration (FDA) to revisit a 2018 approval of the drug against smallpox, a potential bioterror threat, because the mechanism of action is the same for both viruses (FDA has not approved the drug for mpox).
Tecovirimat blocks the interaction between cellular proteins and a surface protein common to orthopoxviruses, which in turn disrupts the formation of new virus particles and prevents their release.
The studies showing it works in monkeys led to FDA’s smallpox approval. Because smallpox was eradicated four decades ago, the agency relied on the Animal Rule, which allows for the approval of drugs against national security threats when efficacy trials are unethical or unfeasible. (Adopted after 9/11, the rule has also been used to approve countermeasures against the plague, anthrax and several nerve gases.)
By now the US Government has invested more than $600m in 1.5m doses of tecovirimat for the country’s Strategic National Stockpile. The European Medicines Agency (EMA) and the UK’s Medicines & Healthcare products Regulatory Agency (MHRA) followed with their 2022 approvals of the drug for the three poxviruses under “exceptional circumstances”.
But the drug fell flat in the real world. In PALM007, which enrolled 600 people, skin did not heal any faster in people getting the drug, the National Institute of Allergy and Infectious Diseases (NIAID) announced last August. Mortality was 1.7% whether people got the drug or the placebo. PALM007 also showed no impact on virus levels in blood, lesions and the throat.
STOMP’s results, revealed by NIAID in December 2024, were more dire still. The drug again failed to shorten the time for lesions to heal, and the lack of efficacy was so clear that NIAID pulled the plug on the study when it had enrolled 75% of the targeted 719 participants. “This is pretty convincing evidence that when used alone, it’s not going to be efficacious,” said study chair Timothy Wilkin, an infectious disease clinician at the University of California-San Diego.
But in an August 2024 statement about PALM007, SIGA CEO Diem Nguyen said the company was “highly encouraged” by the results and claimed some preliminary analyses of the trial data suggest tecovirimat “offers potential benefit” to patients with severe disease and those who sought treatment early.
NIAID biostatistician Lori Dodd discounted those hints. “(The) observed differences were small and did not satisfy standard criteria for statistical significance,” she said.
The reasoning behind regulatory approvals is often difficult to understand, said John Rizk, who is working on a PhD in pharmacology at the University of Maryland and co-authored a November 2024 report in Drugs on mpox therapeutics and vaccines and their regulatory status. Still, he said: “This Japan approval was a shocker to me.”
In Europe, a risk-management plan made public when the drug was greenlighted said EMA would review its decision after new studies, including STOMP, reported results. Marco Cavaleri, who heads EMA’s office of biological health threats and vaccines, said the agency “will scrutinise” the data from both trials and an ongoing trial in Brazil, Switzerland and Argentina.
As for Japan’s approval, “it looks a bit strange at this point,” Cavaleri said, and given the new results, he “would have had a problem” with recommending approval of the drug today.
MHRA told Science it annually reviews all drug authorisations made under the “exceptional circumstances” provision. Rizk said the European agencies should at least issue a “dear doctor” letter to notify clinicians about the PALM007 and STOMP findings.
What the new data mean for tecovirimat as a smallpox treatment is unclear. In a statement sent to Science, the FDA notes the drug’s failure to speed healing in the mpox trials does not mean it will be ineffective against smallpox. If the drug ever is used to treat smallpox in humans, FDA will try to obtain data from studies.
SIGA told Science the monkey studies suggest it will work in smallpox because they “accurately recapitulate” how it causes disease and kills people.
But Wilkin said the FDA should reconsider its approval for smallpox. “We felt that we needed a therapy in case there was a bioterrorist attack,” he said. “But I would not feel comfortable counting on its efficacy.”
See more from MedicalBrief archives:
Mpox drug SAE only in compromised patients – CDC study
Lessons – and mysteries – from fast-disappearing mpox
Hope for Africa as WHO approves first mpox vaccine