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Brincidofovir

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Brincidofovir
Clinical data
Other namesCMX001; Cidofovir-HDP; hexadecyloxypropyl-cidofovir
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H52N3O7P
Molar mass561.70 g/mol g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCCCCCCOCCCOP(=O)(CO[C@@H](CN1C=CC(=NC1=O)N)CO)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, smallpox, 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, smallpox, and herpes simplex viruses.[3][5] Preliminary in vitro tests have also shown it to have potential for the treatment of Ebola virus disease, which is somewhat paradoxical, as Ebola is not a DNA virus.[6]

Brincidofovir is currently in Phase III clinical trials for use in humans against cytomegalovirus and adenovirus, after testing for safety in over 1000 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. 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]

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] A trial commenced during January 2015 in Liberia,[15] 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.[16][17]

Ethical considerations

Brincidofovir (CMX001) was the subject of widespread social media campaigning which was then picked up by national news sources when a young boy with an adenovirus infection following a bone marrow transplant was denied compassionate use of the drug.[18] Chimerix quickly got permission to start a limited Phase III trial which allowed the use of the drug for this patient but also sparked a debate on the ethics of use of social media, the allocation of limited resources of a small company, and the emphasis on the individual over the group. The new use of the drug had the potential to interfere with the process to get the drug approved and widely marketed.

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."[19]

See also

  • BCX4430
  • Favipiravir
  • FGI-106
  • JK-05
  • Lamivudine
  • TKM-Ebola
  • ZMapp
  • Kern, ER; Hartline, C; Harden, E; Keith, K; Rodriguez, N; Beadle, JR; Hostetler, KY (2002). "Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir". Antimicrob. Agents Chemother. 46: 991–5. doi:10.1128/aac.46.4.991-995.2002. PMC 127114. PMID 11897580.

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; Rose, M; Painter, W; O'Mahony, R; Almond, M; Painter, G (2010). "Development of CMX001 for the treatment of poxvirus infections". Viruses. 2 (12): 2740–2762. doi:10.3390/v2122740.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ a b "Brincidofovir (CMX001)". Chimerix.
  4. ^ "Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses". Expert Rev Anti Infect Ther. 12 (10): 1171–8. October 2014. doi:10.1586/14787210.2014.948847.
  5. ^ Quenelle, Debra C.; Lampert, Bernhardt; Collins, Deborah J.; Rice, Terri L.; Painter, George R.; Kern, Earl R. (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.
  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. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  9. ^ Vinluan, Frank. "After Failed Trial, Chimerix Shuts Down Two More Phase 3 Tests". Exome. Retrieved 7 June 2016.
  10. ^ "Dallas Ebola Patient Receives Experimental Drug". The Huffington Post. 6 October 2014. Retrieved 8 October 2014.
  11. ^ "Thomas Duncan, the Texas Ebola patient, has died". Washington Post. Retrieved 8 October 2014.
  12. ^ Dallas Ebola patient waited nearly a week for experimental drug; family claims bias
  13. ^ "http://www.nbcnews.com/storyline/ebola-virus-outbreak/young-healthy-how-nbc-news-freelancer-ashoka-mukpo-survived-ebola-n231681". {{cite web}}: External link in |title= (help); Missing or empty |url= (help)"Ebola Patient Slightly Improved: Father "Cautiously Optimistic"". Nebraska Medical Center. 10 October 2014.
  14. ^ Chimerix to Conduct Ebola Drug Trial: Drug Company Gets FDA Approval to Start Trial Immediately in Infected Patients
  15. ^ "Trials of untested Ebola drugs begin in West Africa". Reuters. Retrieved 6 January 2015.
  16. ^ "Chimerix Ends Brincidofovir Ebola Trials To Focus On Adenovirus And CMV". Forbes. Retrieved 31 January 2015.
  17. ^ http://www.msf.org/article/ebola-drug-trial-liberia-halted
  18. ^ Chimerix CEO Out In Wake Of Josh Hardy Compassionate Use Media Frenzy, Forbes, April 10, 2014
  19. ^ "WHO - Ethical considerations for use of unregistered interventions for Ebola virus disease". Retrieved 8 October 2014.
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