June 10, 2021 -- The FDA has approved a new drug to treat smallpox. Fearful of a possible bioweapon attack, the United States has been steadily preparing a defense through BARDA, the Biomedical Advanced Research and Development Authority.
Tecovirimat was the first drug for smallpox, approved in 2018. The FDA granted the new drug, brincidofovir, or BCV, fast track status and orphan drug designations in 2018. The new approval came under the FDA's Animal Rule.
Drug testing usually goes through several phases prior to approval. First, there is preclinical testing in test tubes and animal models. Phase I is the "first in human" testing, looking primarily for safety and toxicity. Phase II is where researchers look for the best dose to treat a specific condition. The drug being tested is generally given to people who are relatively healthy otherwise.
Phase III broadens the population that receives the drug, including older people and those with underlying diseases (like diabetes or mild kidney disease). After this, the pharmaceutical company seeks FDA approval. Then phase IV, or post-marketing, studies are done, continuing to monitor for side effects. Rare side effects will often not appear until Phase IV, which is why drugs are sometimes recalled after initial approval.
But that's not how it worked for brincidofovir. The Animal Rule recognizes that some investigational treatments cannot be tested for a specific indication in people. This happens for infections where it is dangerous and unethical to expose people to an agent. Smallpox is one such infection; plague is another. Levaquin and Cipro, two quinolone antibiotics, are approved and often used for various infections but required this specific approval under the FDA's Animal Rule for use against plague.
BCV also received priority review, fast track, and orphan drug designations. The first two mean that the FDA believes the drug is likely to provide a significant advantage over current therapy. This speeds approval. An orphan drug designation is intended to support the development of drugs for rare diseases, but it has been abused by a number of pharmaceutical companies because the status is lucrative.
BCV is neither a new nor unknown drug. It is a version of a drug used to treat certain patients with AIDS.
Smallpox is a deadly disease that kills about 30% of those infected and maims many of its victims. Smallpox also used to be a leading cause of blindness, Gigi Kwik Gronvall, PhD, senior scholar atJohns Hopkins Center for Health Security, says. Natural smallpox was eliminated in the 1979, but both the United States and Russia (and perhaps other countries) have maintained stocks of the virus that could be used as bioterrorism.
Related to BCV's pre-approval studies, Gronvall says that "it was nice to see that some more naturally, relevant poxviruses were used as a standard instead" of using primates. The current studies used rabbitpox and mousepox (ectromelia virus) models, which have, she said, "a lot of relatedness to human smallpox" and are more like a natural infection.
The major defense against smallpox has been an old vaccine (ACAM2000) which has been stockpiled for emergency use. Routine administration of that vaccine was discontinued in the 1970s because it had so many side effects. There is a newer vaccine, modified vaccinia Ankara or MVA, which is less effective but safer.
That’s one reason brincidofovir is important, Gronvall says. In the event of a smallpox attack, "if you are not able to give somebody a vaccine within a few days of exposure, they're not going to benefit from the vaccine. So, having a treatment is important."
Gronvall concluded: "It's another success for BARDA that, with not as much resources [due to COVID-19], they were able ... to get this approved. That should be something we think about more in the future, especially with new advances in vaccine technologies and how that could be applied to some of the bioterrorism agents."
In biodefense labs, she added, "There are populations of people who actually do work with some of these agents and some of these vaccines would be very helpful for them. And so maybe I'm hopeful that ... BARDA can take this up."