Brincidofovir: Clinical Research and Therapeutic Applications
Brincidofovir is an antiviral medication that has been the subject of extensive research for its potential to treat a variety of severe viral infections. While it has shown promise in animal models and specific off-label uses, its journey through human clinical trials has been marked by significant challenges regarding efficacy and safety.
The drug is primarily investigated for its activity against DNA viruses, including cytomegalovirus (CMV), adenovirus, and poxvirus, as well as the ebolavirus. Notably, it has been utilized off-label for the treatment of monkeypox.
[ไม่มีภาพประกอบ]Key Facts
- Investigated for CMV, adenovirus, poxvirus, and ebolavirus infections.
- Used off-label for monkeypox treatment.
- Phase III trials for CMV and adenovirus prophylaxis failed to show efficacy.
- Associated with higher all-cause mortality (15.5%) and serious adverse events (57.1%) compared to placebo in certain CMV trials.
- FDA emergency authorization was granted for Ebola treatment in 2014, though subsequent trials were discontinued.
- Demonstrated activity in animal models against BK virus and herpes simplex viruses.
Clinical Trials for Adenovirus and Cytomegalovirus
By 2014, brincidofovir had entered Phase III clinical trials to evaluate its effectiveness against cytomegalovirus and adenovirus in humans. Initial safety data from a database of 1,000 patients initially supported the progression into these later stages.
However, the results were disappointing. In December 2015, Chimerix announced that Phase III trials aimed at preventing CMV infection in stem cell transplant patients had failed. This was followed in February 2016 by the shutdown of two late-stage trials focused on preventing infections after kidney transplants.
The lack of efficacy led to the drug remaining unapproved by the FDA for these specific uses. Data from the CMV prophylaxis trial in stem cell transplant patients revealed a 15.5% all-cause mortality rate at week 24, compared to 10.1% in the placebo group. Furthermore, serious adverse events were significantly higher in the brincidofovir group (57.1%) than in the placebo group (37.6%). Consequently, Chimerix discontinued the expanded access program and clinical trials for adenovirus treatment by May 9, 2019.
Investigation into Ebola Virus Disease
Following cell culture model studies by the Centers for Disease Control and Prevention (CDC), the FDA granted Chimerix emergency investigational new drug authorization for brincidofovir to treat Ebola virus disease on October 6, 2014.
The drug was administered to the first patient diagnosed with Ebola in the United States in 2014. However, the patient was already critically ill, receiving the drug six days after admission, and passed away four days later. Another patient, Ashoka Mukpo, received the drug at the Nebraska Medical Center and was later pronounced Ebola-free and released on October 22, 2014.
While the FDA approved Phase 2 trials to assess safety, tolerability, and efficacy, the practical application faced hurdles. A trial led by University of Oxford scientists—including Peter Horby, Jake Dunning, Laura Merson, and Trudie Lang—began in Liberia in January 2015 but was discontinued due to a lack of suitable subjects. Despite plans to extend the trial to Sierra Leone with Médecins Sans Frontières, the manufacturer withdrew support and ended discussions for future trials on January 30, 2015.
Animal Model Findings
In laboratory settings, brincidofovir has demonstrated activity against a broad spectrum of viruses in animal trials, including cytomegalovirus, adenoviruses, BK virus, poxviruses, and herpes simplex viruses.
Interestingly, the drug also showed potential for treating Ebola virus disease. This is considered paradoxical because ebolaviruses are RNA viruses, whereas the other viruses brincidofovir targets are DNA viruses.
| Target Virus | Status/Outcome | Key Finding |
|---|---|---|
| Cytomegalovirus (CMV) | Failed Phase III | Higher mortality and adverse events than placebo. |
| Adenovirus | Discontinued | Lack of efficacy; expanded access program ended 2019. |
| Ebolavirus | Discontinued | Emergency use authorized; Phase 2 trials withdrawn. |
| Poxvirus | Off-label use | Used for monkeypox treatment. |
| BK/Herpes Simplex | Animal Trials | Demonstrated antiviral activity. |
Frequently Asked Questions
Is brincidofovir FDA approved for CMV or adenovirus?
No, brincidofovir is not FDA approved for these infections due to a lack of efficacy demonstrated in clinical trials.
Why were the CMV prophylaxis trials stopped?
The trials were stopped because the drug failed to prevent infection and was associated with a higher rate of all-cause mortality and serious adverse events compared to the placebo group.
How was brincidofovir used during the Ebola outbreak?
It was used under an FDA emergency investigational new drug authorization for critically ill patients, though formal Phase 2 trials were eventually withdrawn by the manufacturer.
What is the paradoxical finding regarding brincidofovir and Ebola?
The paradox lies in the fact that brincidofovir typically targets DNA viruses, yet it showed potential activity against the ebolavirus, which is an RNA virus.
Has brincidofovir been used for any other poxviruses?
Yes, it has been used off-label for the treatment of monkeypox.