Why Did the FDA Approve Tembexa, a Medication to Treat Smallpox?

In June 2021, the FDA approved Tembexa (brincidofovir) to treat smallpox. You may be wondering why a medication would be approved for an eradicated disease. However, this isn’t the first time the FDA has approved a smallpox medication. The first smallpox treatment was approved in 2018 — almost 40 years after the World Health Organization (WHO) declared the disease eradicated. 

Tembexa was approved as part of a medical countermeasure response. This is to ensure that treatment is available in the event the virus is ever used to attack Americans. The smallpox virus — along with anthrax and Ebola — is just one of many bioterrorism agents and diseases that are part of our bioterrorism preparedness. In other words, we’re proactively developing vaccines and treatments to protect us against potential threats.

Here we’ll cover why Tembexa was approved, how it works and was tested, and what else is being done to help protect Americans from potential bioweapon attacks.

What is smallpox?

Before it was eradicated in 1980, smallpox was a disease that had been around for a long time — at least 3,000 years. The expansion of trade and exploration resulted in smallpox outbreaks across the globe.

It was a contagious infection caused by the variola virus, which is part of the Orthopoxvirus group that includes a few other viruses that can cause disease in humans. 

People with smallpox disease would often get a fever and rash lesions that resulted in widespread scarring (known as “pockmarks”) all over their bodies. If the rash spread to the face, there was a risk of eye sores (called corneal ulcers). Although rare, the eye sores could lead to blindness.

Other serious complications included:

• Brain inflammation (encephalitis)

• Bone infections (osteomyelitis)

• Male infertility

• Pregnancy issues (e.g., stillbirth)

About 30% of people with the disease didn’t survive. And if they did recover, they were often left with severely disfiguring scars.

Does smallpox still exist?

Thanks to the smallpox vaccine, naturally occurring smallpox no longer exists. The last smallpox outbreak happened over 70 years ago, and the last known case was in 1977. 

It’s important to note that the smallpox vaccine paved the way for vaccine development. It was the first successful vaccine to be developed — and the first to lead to a disease being eradicated.

Today, the virus that causes smallpox only exists in two labs for research purposes — the Centers for Disease Control and Prevention (CDC) and the Russian State Centre for Research on Virology and Biotechnology.

Do people still get vaccinated against smallpox?

Due to smallpox being eradicated, we are no longer routinely vaccinated against the disease. Routine smallpox vaccinations stopped in the early 1970s. 

However, smallpox vaccines still exist. And, according to the CDC, there are enough doses available in the national stockpile to vaccinate all Americans in the event an outbreak occurs.

What is Tembexa?

Tembexa is an oral medication approved to treat smallpox disease in adults and children. It received the FDA’s priority review, fast track, and orphan drug designations, meaning that its review and approval were expedited as a rare disease treatment. 

If it’s ever needed, Tembexa will be available as a tablet and oral suspension. It’s taken as two doses — one week apart.

How does it work?

Tembexa is an antiviral medication that works against the variola virus. It’s considered to be a prodrug. This means that it’s broken down into its active form once it’s inside your body. 

Tembexa’s active form is cidofovir, a medication used to treat cytomegalovirus (CMV) — a viral infection that typically affects people with weakened immune systems. 

In this case, Tembexa is made of cidofovir that’s linked with lipid (fat) molecules to help it enter your cells. Once inside the cell, it’s activated to work against the virus by preventing it from replicating.

Was Tembexa tested on humans?

Determining efficacy in humans can be tricky for medical countermeasures. To make sure that a medication works against a disease, study participants would need to be infected with the germ. Obviously, this wouldn’t be an ethical practice.

That’s why the FDA will sometimes approve medications based on the Animal Rule, which allows for well-controlled animal studies to be used for determining efficacy instead of human trials. However, the medication’s safety is still tested in humans.

Efficacy in animals

Tembexa’s efficacy was tested in rabbits and mice that were infected with orthopoxviruses that are animal-specific — rabbitpox and mousepox — and are closely related to the variola virus. Additionally, lab tests have shown that the medication can stop variola virus growth. 

But it’s important to note that even though animal study and laboratory findings suggest that Tembexa could work against smallpox disease in humans, we don’t know that for sure since it hasn’t been confirmed.

Safety in humans

The medication’s safety was studied in both children and adults — but not as smallpox treatment. Instead, it was studied in stem cell transplant recipients who were taking it for CMV infection prevention.

Common side effects in both children and adults included:

• Nausea

• Vomiting

• Diarrhea

• Stomach pain

Like many medications, there can be some serious side effects. This includes a higher risk of death if the medication is taken for a longer period than indicated and changes in liver lab tests. 

Additionally, animal studies suggest that it can cause irreversible male infertility and that it’s a potential carcinogen (cancer-causing substance). And while this seems concerning, keep in mind that smallpox disease has been found to cause male infertility on its own.

Why did the FDA approve a smallpox medication?

Ever since smallpox disease was eradicated and routine vaccinations were stopped decades ago, there’s been an ongoing concern that the variola virus could be used to harm Americans. That’s why efforts have been made — both in developing treatments and securing vaccines — to protect us if that were to happen.

And while this might seem scary, there is no known immediate smallpox threat to the country. However, it’s best to be prepared. This latest approval is just one component needed in case of an emergency. 

Other public health response activities, like vaccination strategies, training, and communication, are also critical in preparing for and containing a biological threat. Additionally, smallpox treatments and vaccines are part of the Strategic National Stockpile to ensure that enough supplies are available in the event of a smallpox outbreak. 

Has this happened before?

Yes. The FDA approved TPOXX (tecovirimat) as the first smallpox treatment in 2018. Like Tembexa, it was also approved under the FDA’s Animal Rule, but it was also the first product to receive the Material Threat Medical Countermeasure priority review voucher. This means that there were additional incentives in place — like funding and liability protection — since the medication treats a potential biological threat. 

Why trust our experts?

Written by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

Our editorial standards

Meet our experts