Tecovirimat and the treatment of monkeypox – past, present and future considerations

In 1988, the human immunodeficiency virus (HIV) spread rapidly around the world, disproportionately devastating certain communities, particularly gay, bisexual, and other men who have sex with men. Even after promising new pharmacological therapies have been developed, approval processes for their use in humans have been slow. Led by the AIDS Coalition to Unleash Power (ACT UP) and other advocacy groups, federal scientists and policymakers have worked with affected people to find a way forward that balances two ethical imperatives: respecting the right of people with the disease to access potentially beneficial treatment and serious treatment. It supports the responsibility of health and public health communities to ensure that treatment is safe and effective. The result was an improved regulatory process designed to speed access and expedite approval of drugs that treat serious illness.

Now, 34 years later, we find ourselves in a strikingly similar situation. An unprecedented epidemic of monkeypox has occurred that now disproportionately affects men who have sex with men in many countries where the disease is not endemic, including the United States. Although not as life-threatening as HIV, monkeypox can cause serious complications, including eye involvement, soft tissue superinfection, and anogenital complications.1 In the current situation, available for clinical use under the expanded access protocol (https://www.cdc.gov/poxvirus/monkeypox/clinicians/obtaining-tecovirimat.html) – there is a fast-acting drug – tecovirimat to solve monkeypox and improve outcomes that raises the same conundrum: how to manage compassionate access to a drug whose safety and efficacy have not been established in humans. Because smallpox and monkeypox are caused by the same virus, it is important to understand the basis for its approval by the US Food and Drug Administration (FDA) to better understand the role tecovirimat plays in our response to monkeypox outbreaks. for the treatment of smallpox and remaining knowledge gaps.

Tecovirimat is an antiviral drug approved for the treatment of smallpox under the so-called “Animal Rule.”two This pathway allows drugs to be approved for serious or life-threatening conditions when conducting efficacy studies in humans is unethical and field trials to investigate the effectiveness of the drug or biological product are not possible. Under the Animal Rule, efficacy is established based on adequate and well-controlled studies in animal models of the human disease or condition of interest; People’s safety should be assessed.

Because smallpox is an eradicated disease and efficacy studies in humans are neither ethical nor feasible, the animal rule was the only regulatory pathway for product approval to treat smallpox. Smallpox is a serious and dangerous human disease caused by the variola virus, which belongs to the orthopoxvirus family of viruses. Animal studies using variola virus, including nonhuman primate models, are not consistently reproducible and require unnaturally high viral challenge doses; In addition, variola virus infection in animals does not resemble smallpox in humans. In addition, variola virus research presents significant feasibility challenges because virus-related research is limited to the two most comprehensive laboratories located in the United States and Russia.

Therefore, the efficacy of teclorimate in the treatment of smallpox was established and the drug was approved based on studies in animal models of the relevant orthopoxviruses—namely, nonhuman primates infected with monkeypox virus and rabbits infected with rabbitpox virus. In these studies, survival rates were significantly higher among animals receiving teclorimate than those receiving placebo. Human safety was evaluated by evaluating adverse reactions in healthy volunteers who received the drug. The recommended dose of teclorimat for the treatment of smallpox in humans was determined by comparing plasma concentrations of the drug in healthy volunteers with concentrations in animal models at doses that have been shown to be fully effective against monkeypox and rabbitpox. The recommended duration of therapy in humans is based on the results of studies conducted in animals and healthy humans.

Unlike smallpox, monkeypox remains endemic in some parts of the world (primarily West and Central Africa) and researchers can develop ethical and feasible clinical trials. Although there are case reports of the use of tecoirimat to treat patients with monkeypox and other nonvariola orthopoxvirus infections, these data are insufficient to demonstrate efficacy. Animal studies can be influential,3 however, efficacy observed in animals does not always translate directly to efficacy observed in humans in subsequent clinical trials.4 The safety data for tecovirimate can be obtained from people with monkeypox rather than from healthy volunteers. Thus, research in humans with monkeypox is necessary and possible.

To this end, and prior to the onset of the current outbreak, the National Institutes of Health (NIH) began planning a randomized, controlled trial (RCT) to evaluate the safety and efficacy of the drug in the Democratic Republic of the Congo (DRC). in the treatment of monkeypox. However, the current worldwide outbreak involves a different strain of monkeypox virus that generally causes monkeypox infection in CKD and some of the clinical manifestations of the current outbreak (severe disease with significant anogenital and oral mucosal involvement) and affected populations. this time (men who have sex with men) differs from countries where monkeypox is endemic.1 Therefore, the NIH is currently developing a US-based RCT to evaluate the safety and efficacy of tecovirimat for the treatment of monkeypox. The trial will be conducted by the AIDS Clinical Trials Group, a research network established in the late 1980s to rapidly assess the safety and effectiveness of antiretroviral drugs for HIV infection. We expect that these trials will provide the information needed to inform clinical and regulatory decisions in the United States.

We understand that monkeypox can cause severe disease and that tecurimate has demonstrated efficacy in animal models of monkeypox and an acceptable safety profile in healthy humans. Therefore, in RCT development, the Centers for Disease Control and Prevention (CDC) and the FDA worked together to streamline the expanded access process by reducing paperwork and data collection.5 and we will continue to refine these mechanisms with input from health care providers using this process. In parallel, we believe that a US RCT remains important to determine whether tecoxiramit is a safe and effective treatment for monkeypox, especially given the clinical presentation of the disease in the current outbreak. As with antiretrovirals for HIV in the 1980s, without RCT data, we cannot know whether tecurimate benefits, harms, or has no effect on people with monkeypox. CDC, FDA, and NIH will continue to work together to ensure access to data for compassionate use, with appropriate evaluation of safety and efficacy in RCTs.

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