Brincidofovir

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Brincidofovir
Clinical data
Other namesCMX001; Cidofovir-HDP; hexadecyloxypropyl-cidofovir
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H52N3O7P
Molar mass561.701 g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCCCCCCOCCCOP(=O)(O)CO[C@H](CO)CN1C=CC(N)=NC1=O
  • InChI=1S/C27H52N3O7P/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-19-35-20-16-21-37-38(33,34)24-36-25(23-31)22-30-18-17-26(28)29-27(30)32/h17-18,25,31H,2-16,19-24H2,1H3,(H,33,34)(H2,28,29,32)/t25-/m0/s1
  • Key:WXJFKKQWPMNTIM-VWLOTQADSA-N

Brincidofovir (CMX001) is an experimental antiviral drug being developed by Chimerix of Durham, NC, for the treatment of cytomegalovirus, adenovirus, poxvirus, and ebolavirus infections.[2] Brincidofovir is a prodrug of cidofovir.[3] Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher intracellular and lower plasma concentrations of cidofovir, effectively increasing its activity against dsDNA viruses, as well as oral bioavailability.[4]

In animal trials the drug has shown activity against cytomegalovirus, adenoviruses, BK virus, poxviruses, and herpes simplex viruses.[3][5] It appears to have potential for the treatment of Ebola virus disease, which is somewhat paradoxical, as Ebola does not contain DNA.[6]

Adenovirus and cytomegalovirus

As of 2014, brincidofovir was in Phase III clinical trials for use in humans against cytomegalovirus and adenovirus, after testing for safety in over 1,000 human subjects,[7] and has received FDA Fast Track Designation for treatment of cytomegalovirus, adenovirus, and smallpox.[8] Chimerix announced in December 2015 that the Phase III trials for use of the drug in preventing cytomegalovirus infection in stem cell transplant patients had failed, and in February 2016 shut down two other late-stage trials for use of the drug in preventing infection after kidney transplants.

As of 2016, the company is planning on returning trials of the drug for use in stem cell transplant patients to Phase II, while continuing to advance a late-stage trial for use against adenovirus infections in patients suffering from weakened immune systems.[9]

Ebola

On October 6, 2014, Chimerix received an FDA authorization for emergency investigational new drug applications of brincidofovir for the treatment of Ebola virus disease. Brincidofovir was administered to the first patient diagnosed in the Ebola virus disease outbreak in the US in 2014.[8][10] The patient was given the drug starting six days after hospital admission when he was already critically ill; he died four days later.[11][12] Brincidofovir was also given to Ebola patient Ashoka Mukpo at the Nebraska Medical Center, who had developed the disease and then was pronounced Ebola-free and released from the Center on 22 October 2014.[13]

In October 2014, Chimerix reported it had been given approval by the FDA to start Phase 2 trials in patients infected with ebolaviruses for brincidofovir's safety, tolerability, and efficacy.[14] Organised by a team of scientists at the University of Oxford, including Peter Horby, Jake Dunning, Laura Merson and Trudie Lang,[15] a trial commenced during January 2015 in Liberia,[16] but was subsequently discontinued. Because of a lack of suitable subjects in Liberia, Oxford University and Médecins Sans Frontières planned to extend the trial to Sierra Leone, where there were still Ebola cases; but on the 30th of January 2015, the manufacturer decided to withdraw support for the trial and end discussion of future trials.[17][18]

Ethical considerations

Brincidofovir (CMX001) was the subject of widespread social media campaigning in 2014, which was then picked up by national news sources about a boy with an adenovirus infection following a bone marrow transplant.[19] The family requested legal access to the still-unapproved drug outside of any clinical trial, and Chimerix initially denied the request. After a short and intense media campaign, Chimerix got permission from the FDA to start a limited open-label trial which allowed the boy to receive the drug.[19] This media event sparked a debate on the ethics of using social media, the allocation of limited resources of a small company, and the emphasis on the individual over the group. The new use of any drug has the potential to interfere with the process to get the drug approved and widely marketed, through means such as consuming limited staff time that may be needed elsewhere – staff time that has the potential to save thousands of lives in the long-term, rather than one life now – overwhelming manufacturing capabilities, or by causing adverse effects or even death.[19] These adverse events are more likely during these programs, because the people seeking access are usually much sicker than most, and problems experienced by these people can result in an unfavorable and inaccurate perception of the drug's safety profile.[19] In this case, the boy recovered from the infection in 2014, and died in 2016 from complications of cancer.[20]

Brincidofovir is one of several experimental drugs administered to a small number of patients to treat Ebola virus disease during the 2014 outbreak. The WHO published a report on the ethics of using unregistered interventions to treat Ebola, where they concluded that "In the particular context of the current Ebola outbreak in West Africa, it is ethically acceptable to offer unproven interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans as potential treatment or prevention."[21]

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ Lanier R, Trost L, Tippin T, Lampert B, Robertson A, Foster S, et al. (December 2010). "Development of CMX001 for the Treatment of Poxvirus Infections". Viruses. 2 (12): 2740–2762. doi:10.3390/v2122740. PMC 3077800. PMID 21499452.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ a b "Brincidofovir (CMX001)". Chimerix. Archived from the original on 2014-03-20.
  4. ^ Florescu DF, Keck MA (October 2014). "Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses". Expert Review of Anti-Infective Therapy. 12 (10): 1171–8. doi:10.1586/14787210.2014.948847. PMID 25120093.
  5. ^ Quenelle DC, Lampert B, Collins DJ, Rice TL, Painter GR, Kern ER (November 2010). "Efficacy of CMX001 against herpes simplex virus infections in mice and correlations with drug distribution studies". The Journal of Infectious Diseases. 202 (10): 1492–9. doi:10.1086/656717. PMC 2957530. PMID 20923374.
  6. ^ David Kroll (7 October 2014). "Chimerix's Brincidofovir Given To Dallas, Nebraska Ebola Patients". forbes.com.
  7. ^ "Brincidofovor for Ebola". Chimerix. Archived from the original on 2014-10-09.
  8. ^ a b "Chimerix Announces Emergency Investigational New Drug Applications for Brincidofovir Authorized by FDA for Patients With Ebola Virus Disease". Archived from the original on 6 October 2014. Retrieved 8 October 2014.
  9. ^ Vinluan, Frank (2016-02-22). "After Failed Trial, Chimerix Shuts Down Two More Phase 3 Tests". Exome. Retrieved 7 June 2016. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  10. ^ Almendrala, Anna (6 October 2014). "Dallas Ebola Patient Receives Experimental Drug". The Huffington Post. Retrieved 8 October 2014. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  11. ^ Berman, Mark; Brown, DeNeen L. (8 October 2014). "Thomas Duncan, the Texas Ebola patient, has died". Washington Post. Retrieved 8 October 2014. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  12. ^ Cohen, Elizabeth (October 7, 2014). "Dallas Ebola patient waited nearly a week for experimental drug; family claims bias". CNN. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  13. ^ Wilson, Tyler (2014-10-22). "Young and Healthy: How NBC News Freelancer Ashoka Mukpo Survived Ebola". NBC News. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  14. ^ Loftus, Peter (16 October 2014). "Chimerix to Conduct Ebola Drug Trial: Drug Company Gets FDA Approval to Start Trial Immediately in Infected Patients". The Wall Street Journal. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  15. ^ Boseley, Sarah (2015-02-17). "Ebola: the race to find a cure". The Guardian. ISSN 0261-3077. Retrieved 2020-03-16. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  16. ^ Giahyue, James Harding (6 January 2015). "Trials of untested Ebola drugs begin in West Africa". Reuters. Retrieved 6 January 2015. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  17. ^ "Chimerix Ends Brincidofovir Ebola Trials To Focus On Adenovirus And CMV". Forbes. Retrieved 31 January 2015.
  18. ^ "Ebola drug trial in Liberia halted". Médecins Sans Frontières. 3 February 2015.
  19. ^ a b c d Darrow JJ, Sarpatwari A, Avorn J, Kesselheim AS (January 2015). "Practical, legal, and ethical issues in expanded access to investigational drugs". The New England Journal of Medicine. 372 (3): 279–86. doi:10.1056/nejmhle1409465. PMID 25587952.
  20. ^ "Josh Hardy, Va. Boy Who Inspired Social Media Campaign, Dies". NBC4 Washington. 22 October 2016. Retrieved 2018-05-21.
  21. ^ Report of an advisory panel to WHO. "Ethical considerations for use of unregistered interventions for Ebola virus disease". Retrieved 8 October 2014.

Further reading

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