The US Food and Drug Administration (FDA) has approved Chimerix’s brincidofovir (BCV, Tembexa) 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 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 1 is the “first in human” testing, looking primarily for safety and toxicity. Phase 2 is dose-finding, looking for the best dose to treat a specific condition. The investigational drug is generally given to people who are relatively healthy otherwise (eg, have uncomplicated pneumonia). Phase 3 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 4, or post-marketing, studies are done, and continue to monitor for side effects. Rare side effects will often not appear until Phase 4, 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 too dangerous and too 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 expedites 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 lipid conjugate of cidofovir, a drug used to treat cytomegalovirus (CMV) in patients with AIDS. BCV is metabolized intracellularly and has less kidney toxicity than CMV. BCV completed phase 3 trials targeting adenovirus infections but did not show good efficacy or suppress CMV infections following hematopoietic cell transplant. GI side effects were common.
Dr Gigi Kwik Gronvall
Smallpox is a deadly disease killing about 30% of those infected and maiming many of its victims. Smallpox also used to be a leading cause of blindness, Gigi Kwik Gronvall, PhD, senior scholar, Johns Hopkins Center for Health Security, told Medscape Medical News. Natural smallpox was eliminated in 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 commented that “it was nice to see that some more naturally, relevant poxviruses were used as a standard instead” of using nonhuman 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) being 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 immunogenic but safer.
In regard to a role for brincidofovir, Gronvall told Medscape Medical News that, 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], 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.”
Gronvall has reported no relevant financial relationships.
Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone
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