Clinical trials could get monkeypox drug to desperate patients, but U.S. efforts lag
On a sultry Tuesday evening in New York City, Luke Brown excitedly opened a newly delivered bottle of black-and-orange pills, popped his first dose in his mouth, and washed it down with root beer.
Having contracted monkeypox this month, the lanky, bespectacled 29-year-old project manager had been suffering from what he called “the most severe pain of my life” for over a week before he finally was able to obtain a course of antivirals — a treatment he hoped would soon clear up his lesions and alleviate his suffering.
For Brown, this was cause for celebration. But it was also a sobering moment for him to reflect on how, to gain access to this medication, he had to leverage high degrees of personal privilege, medical literacy and self-advocacy that he said he was guiltily aware most people at risk for monkeypox probably lack. Because to join the fortunate few who have obtained this prized medication, called TPOXX, he had to navigate what he characterized as the exasperatingly byzantine maze of the medical and public health system.
“Here we are in the epicenter of an outbreak primarily affecting gay men in the city,” Brown said of his hometown, New York, which as of Thursday had 778 confirmed monkeypox cases out of 2,593 nationwide. “The city that of anywhere in the world should have the most impressive and robust infrastructure to respond to the health care needs of gay men. And at every level it has fallen flat on its face.”
Like many of his fellow gay and bisexual men — a demographic that comprises the vast majority monkeypox cases in the global outbreak that has ballooned to 15,848 cases — Brown said he has grown increasingly appalled and infuriated by the nation’s response to a virus spreading so swiftly that many epidemiologists now believe will likely become endemic in the U.S. and around the world.
Supply of the antiviral is not the problem; there are 1.7 million courses in the nation’s Strategic National Stockpile, according to Dennis Hruby, chief scientific officer of the U.S. pharmaceutical company SIGA, TPOXX’s manufacturer. But the drug, also known as tecovirimat, is not approved by the Food and Drug Administration to treat monkeypox as it is by regulators in the United Kingdom and the European Union; the drug is approved only for smallpox in the U.S.
This is bad news for the Americans with monkeypox who like Brown suffer from excruciating physical pain or other severe outcomes from the infection and who are desperate for treatment to speed their healing. They, and the health care providers who care for them, are up against the U.S. regulatory system.
Even as the Centers for Disease Control and Prevention continues to reduce the red tape that impedes TPOXX access, announcing new changes Friday, public health experts pointed to a complementary means of leveraging the drug’s potential power to alleviate suffering: large clinical trials of the antiviral as a monkeypox treatment.
Plans for such trials are already in advanced stages in Canada, the U.K. and the European Union, according to Hruby. The National Institutes of Health is also planning one in the Democratic Republic of the Congo. But the federal agency’s efforts to launch such research in the U.S. are only in the earliest planning stages.
“This points to a persistent issue we saw during Covid,” said James Krellenstein, a public-health activist and cofounder of the activist group PrEP4All, “where the United Kingdom and European researchers were really able to mount much quicker clinical studies than the United States was.”
Excessive barriers to prescribing
In addition to Brown, NBC News spoke with a dozen people who have taken TPOXX, all of whom suffered from extreme pain before starting the antiviral. They generally reported that within a few days of treatment, their monkeypox symptoms — the pain in particular — began to ease, much to their relief. Most reported no bothersome side effects, or, in one case at least, not bad enough to discontinue treatment. While they all acknowledged that they could not be certain how the course of the disease might have unfolded had they not taken the drug, they generally believed it had been effective for them.
The FDA approved TPOXX as a treatment for smallpox in 2018 based on studies that had infected rabbits with rabbitpox and nonhuman primates with monkeypox. (Smallpox and monkeypox are close viral relatives, so treatments for one are expected to work for the other.) Researchers had to rely on these proxy models of similar viruses because there is no smallpox to investigate, as the virus has been eradicated; and even if there were, it would be unethical to study such a lethal pathogen in humans.
The data indicating the drug is safe for humans comes from a study of 449 healthy people.
Typically, physicians may use their own judgment to prescribe medications off label for purposes other than those for which they were granted explicit FDA approval.
But given the lack of research on TPOXX’s efficacy in humans, federal health regulations dictate that health care providers may only prescribe the drug for monkeypox through a compassionate-use system overseen by the CDC. Physicians such as Dr. Marshall Glesby, an infectious disease specialist at Weill Cornell Medicine in New York City, said that these strict rules are excessive, including the need to review a more than 100-page treatment-protocol document to qualify as a TPOXX prescriber and to thoroughly document each case.
Such burdens sharply limit the number of health care providers who are willing and able to prescribe TPOXX, according to clinicians who have gained such authority.
“It’s a cumbersome process,” said Dr. Anu Hazra, a physician at Howard Brown Health in Chicago who recently began prescribing the treatment.
“Because we don’t yet know how well this drug is going to work for monkeypox patients,” said Dr. Jennifer McQuiston, who leads the CDC’s monkeypox response, “it is important to ensure we have some data from patients who use it, so we can better understand the risks and benefits and ultimately help other people as well.”
Responding to health care providers’ recent complaints about the TPOXX compassionate-use system, the CDC has, for example, made optional previous requirements that clinicians submit photographs of patients’ monkeypox lesions and ship viral specimens to the agency.
In a July 15 letter to the heads of various federal health agencies, PrEP4All and the nonprofit Partners in Health called on the CDC and FDA to end all restrictions on TPOXX’s use and to allow health care providers to freely prescribe it for monkeypox.
Friday, the CDC announced further revisions to the compassionate-use system, including plans to reduce the 100-plus-page document to under 50; pare back the number of reports physicians must fill out about each patient from six to two; and to permit virtual appointments.
“We have reduced the data we need down to the most critical pieces,” McQuiston said “and have worked to make using this drug simpler, in order to ensure doctors can get the drug to patients who need it.”
Dr. Jason Zucker, an infectious disease specialist at Columbia University Department of Medicine whose team has prescribed the antiviral to 45 patients, said that the U.S. should launch a large randomized clinical trial including people with mild monkeypox disease. If anyone in the placebo arm should progress to severe disease, he proposed, they could be switched into a parallel compassionate-use group. This would not only address the crucial question of the drug’s efficacy but also expand access to treatment while also collecting data on people receiving it in a much more rigorous and organized fashion than he said occurs through the current system.
Jumping through hoops to get TPOXX
Luke Brown said that he first tried to gain access to TPOXX through his primary care provider, who submitted the request to New York City’s health department. The request was denied on the grounds that his case wasn’t serious enough. But then he began to suffer pain so severe all he could do was pace around his apartment for hours; even then, his physician delayed in resubmitting the request. So the well-connected Brown tapped into his contacts on social media and finally found someone who linked him to a local doctor with prescribing authority.
“It’s infuriating,” he said of the hoops he had to jump through to obtain the drug.
“I had to fight for the TPOXX meds,” said an online content creator known as Boomer Banks, also a New Yorker, about what he said was a maddening ordeal finding someone at the city’s health department who could help him access the treatment. “I had no privilege to leverage, just my mouth,” said Banks, who did want to use his real name used to protect his privacy. “I’m a brown immigrant, 42-year-old HIV-positive sex worker with no insurance. I didn’t take ‘no’ as an answer.”
Under current CDC guidelines, TPOXX is reserved for those with severe disease, including those who are hospitalized or at high risk of a severe outcome because, for example, they are immunocompromised. Those suffering from a common symptom of the virus, intense anorectal or genital pain, qualify for TPOXX, Zucker said.
Brooklyn resident Sebastian Kohn, 39, who had a particularly severe case of monkeypox, said that days after he started TPOXX, the difference in his anorectal pain was “night and day.”
“I can wash myself without wanting to cry,” Kohn said.
Where is the U.S.-based clinical trial?
Asked about the NIH’s plans to back a U.S.-based clinical trial of TPOXX, Judith Hewitt, deputy director of the Office of Biodefense, Research Resources and Translational Research at the National Institute of Allergy and Infectious Diseases, said that “it’s super early days” for such plans.
“There are now just beginning to be discussions about a trial in people living with HIV or at risk of HIV,” she said.
In an email, Dr. Judith Currier, a professor of medicine at the UCLA Division of Infectious Diseases and the chair of a major HIV-related clinical trial network funded by the NIH, confirmed that a trial is being discussed. “I think the holdup is identifying the funding for this work.”
“Money is obviously the real issue here,” Hewitt said. “And so people are scrambling to do what we can do with the resources at hand.” She said the agency is debating whether, for example, to fund a study examining whether a lower dose of the Jynneos vaccine would be highly effective against monkeypox. “So that’s within the same treatment area. But then we’re still up to our eyeballs in Covid.”
Krellenstein, the activist, said, “It’s bizarre, given that we have such large supply in the strategic national stockpile and TPOXX was approved without any human efficacy data, that there weren’t ready-to-go plans for actually doing a U.S. clinical study in the event that we needed to use it.”
According to SIGA’s Hruby, the company might not even look to U.S.trial data on TPOXX to submit to the FDA. Instead, they might rely on the combined findings of the trials already primed to launch in other nations, along with safety data from compassionate-use programs worldwide.
As for how long before the company would submit the drug for FDA approval, Hruby wouldn’t speculate.
“These things always take longer than expected, especially when working with large teams,” Hruby said.
Even on a drug given priority review, the FDA typically takes six months to reach a decision.
TPOXX could help blunt monkeypox’s impact
If approved, TPOXX would offer a future in which the antiviral complements widespread vaccination among at-risk individuals to mitigate monkeypox’s impact on public health, experts said.
The virus could be treated at the very first sign of symptoms, and possibly even during the asymptomatic incubation period if testing technology advances to permit detection at that stage. Such early medical intervention would not only prevent pain and suffering, but would also very likely block transmission of the virus by shortening or eliminating the disease’s infectious period.
Treatment could also save people from the personal and financial hardship of isolating at home for what can be weeks of illness with monkeypox that’s left to resolve on its own.
What’s more, TPOXX could be used as post-exposure prophylaxis among people exposed to monkeypox, either among unvaccinated people or those who cannot be vaccinated, such as the immunocompromised, according to Columbia’s Zucker.
The U.S. Army Medical Research and Development Command does have an established study to assess such a preventive use of this drug. And while a listing of the trial indicates participants must be Department of Defense–affiliated personnel, according to Hruby, there actually is no such restriction.
Friday morning, Luke Brown said his pain had begun to subside and he was watching in wonder as his lesions were steadily sinking back into his skin — “like magic.”
Reflecting on the ordeal monkeypox has been for him, he said it had inspired him to become a public-health activist.
“I’m resolved to see that no one suffers like I did, because no one needs to,” he said.
Anticipating that the U.S. monkeypox outbreak will only continue to expand, he said, “We are just at a crest of avoidable pain unless access to this drug becomes easier.”