Wikipedia

Maribavir

Maribavir, sold under the brand name Livtencity, is an antiviral medication that is used to treat post-transplant cytomegalovirus (CMV).[8][9] Maribavir is a cytomegalovirus pUL97 kinase inhibitor that works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.[9]

Maribavir
Clinical data
Trade namesLivtencity
Other names1263W94
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • (2S,3S,4R,5S)-2-[5,6-Dichloro-2-(propan-2-ylamino)benzimidazol-1-yl]-5-(hydroxymethyl)oxolane-3,4-diol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H19Cl2N3O4
Molar mass376.23 g·mol−1
3D model (JSmol)
  • CC(C)Nc1nc2cc(c(cc2n1[C@@H]3[C@H]([C@H]([C@@H](O3)CO)O)O)Cl)Cl
  • InChI=1S/C15H19Cl2N3O4/c1-6(2)18-15-19-9-3-7(16)8(17)4-10(9)20(15)14-13(23)12(22)11(5-21)24-14/h3-4,6,11-14,21-23H,5H2,1-2H3,(H,18,19)/t11-,12-,13-,14-/m0/s1 ☒N
  • Key:KJFBVJALEQWJBS-XUXIUFHCSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

The most common side effects include taste disturbance, nausea, diarrhea, vomiting and fatigue.[9]

Maribavir was approved for medical use in the United States in November 2021,[9][11] and in the European Union in November 2022.[10] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[12]

Medical uses

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In the United States, maribavir is indicated to treat people twelve years of age and older and weighing at least 35 kilograms (77 lb) with post-transplant cytomegalovirus infection/disease that does not respond (with or without genetic mutations that cause resistance) to available antiviral treatment for cytomegalovirus.[9]

In the European Union, maribavir is indicated for the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adults who have undergone a hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT).[10]

Adverse effects

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Adverse effects of maribavir include taste disturbances, nausea, and vomiting.[13]

Contraindications

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The cytomegalovirus pUL97 kinase activates ganciclovir and valganciclovir, so coadministration with these medications is not recommended because maribavir may reduce their antiviral activity.[9]

History

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Maribavir is licensed by ViroPharma from GlaxoSmithKline in 2003, for the prevention and treatment of human cytomegalovirus (HCMV) disease in hematopoietic stem cell/bone marrow transplant patients. The mechanism by which maribavir inhibits HCMV replication is by inhibition of an HCMV encoded protein kinase enzyme called UL97 or pUL97.[14][15] Maribavir showed promise in phase II clinical trials and was granted fast track status, but failed to meet study goals in a phase III trial.[16] However, the dosage used in the phase III trial may have been too low to be efficacious.[17]

A phase II study with maribavir demonstrated that prophylaxis with maribavir displayed strong antiviral activity, as measured by statistically significant reduction in the rate of reactivation of CMV in recipients of hematopoietic stem cell/bone marrow transplants.[18] In an intent-to-treat analysis of the first 100 days after the transplant, the number of subjects who required pre-emptive anti-CMV therapy was statistically significantly reduced with maribavir compared to placebo.[19]

ViroPharma conducted a phase III clinical study to evaluate the prophylactic use for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplant patients. In February 2009, ViroPharma announced that the phase III study failed to achieve its goal, showing no significant difference between maribavir and a placebo at reducing the rate at which CMV DNA levels were detected in patients.[20]

The safety and efficacy of maribavir were evaluated in a phase III, multicenter, open-label, active-controlled trial that compared maribavir with a treatment assigned by a researcher running the study, which could include one or two of the following antivirals used to treat cytomegalovirus: ganciclovir, valganciclovir, foscarnet, or cidofovir.[9] In the study, 352 transplant recipients with cytomegalovirus infections who did not respond (with or without resistance) to treatment randomly received maribavir or treatment assigned by a researcher for up to eight weeks.[9] The study compared the two groups' plasma cytomegalovirus DNA concentration levels at the end of the study's eighth week, with efficacy defined as having a level below what is measurable.[9] Of the 235 participants who received maribavir, 56% had levels of cytomegalovirus DNA below what was measurable versus 24% of the 117 participants who received an investigator-assigned treatment.[9]

The US Food and Drug Administration (FDA) granted the application for maribavir orphan drug, breakthrough therapy and priority review designations.[9][11][21][22][12] The FDA granted the approval of Livtencity to Takeda Pharmaceuticals Company Limited.[9][11]

Society and culture

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On 15 September 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Livtencity, intended for the treatment of cytomegalovirus (CMV) infection and/or disease that is refractory to one or more prior therapies.[23] The applicant for this medicinal product is Takeda Pharmaceuticals International AG Ireland Branch.[23] Maribavir was approved for medical use in the European Union in November 2022.[10][24]

References

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  1. ^ a b "Livtencity". Therapeutic Goods Administration (TGA). 21 October 2022. Archived from the original on 5 February 2023. Retrieved 29 April 2023.
  2. ^ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ^ "LIVTENCITY (Takeda Pharmaceuticals Australia Pty Ltd)". Therapeutic Goods Administration (TGA). 11 November 2022. Archived from the original on 27 March 2023. Retrieved 29 April 2023.
  4. ^ "Therapeutic Goods (Poisons Standard—June 2024) Instrument 2024". Federal Register of Legislation. 30 May 2024. Retrieved 10 June 2024.
  5. ^ "Livtencity (Maribavir tablets) Product Monograph" (PDF). Health Canada. September 2022. Archived (PDF) from the original on 1 October 2022. Retrieved 29 April 2023.
  6. ^ "Livtencity Summary Basis of Decision". Health Canada. 23 October 2014. Archived from the original on 29 April 2023. Retrieved 10 March 2023.
  7. ^ "Details for: Livtencity". Health Canada. 25 October 2022. Archived from the original on 3 March 2024. Retrieved 3 March 2024.
  8. ^ a b "Livtencity- maribavir tablet, coated". DailyMed. Archived from the original on 19 December 2021. Retrieved 19 December 2021.
  9. ^ a b c d e f g h i j k l m "FDA Approves First Treatment for Common Type of Post-Transplant Infection that is Resistant to Other Drugs". U.S. Food and Drug Administration (FDA) (Press release). 23 November 2021. Archived from the original on 24 November 2021. Retrieved 23 November 2021.   This article incorporates text from this source, which is in the public domain.
  10. ^ a b c d "Livtencity EPAR". European Medicines Agency (EMA). 14 September 2022. Archived from the original on 26 November 2022. Retrieved 25 November 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. ^ a b c "Takeda's Livtencity (maribavir) Approved by U.S. FDA as the First and Only Treatment for People Ages 12 and Older with Post-Transplant Cytomegalovirus (CMV), Refractory (With or Without Genotypic Resistance) to Conventional Antiviral Therapies". Takeda (Press release). 23 November 2021. Archived from the original on 27 November 2021. Retrieved 26 November 2021.
  12. ^ a b Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023.   This article incorporates text from this source, which is in the public domain.
  13. ^ Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, et al. (June 2008). "Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study". Blood. 111 (11): 5403–5410. doi:10.1182/blood-2007-11-121558. PMC 5726327. PMID 18285548.
  14. ^ Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith III AA, Davis MG, et al. (August 2002). "Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action". Antimicrobial Agents and Chemotherapy. 46 (8): 2365–2372. doi:10.1128/aac.46.8.2365-2372.2002. PMC 127361. PMID 12121906.
  15. ^ Prichard MN (July 2009). "Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir". Reviews in Medical Virology. 19 (4): 215–229. doi:10.1002/rmv.615. PMC 3777615. PMID 19434630.
  16. ^ Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, et al. (April 2011). "Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial". The Lancet. Infectious Diseases. 11 (4): 284–292. doi:10.1016/S1473-3099(11)70024-X. PMID 21414843.
  17. ^ Snydman DR (April 2011). "Why did maribavir fail in stem-cell transplants?". The Lancet. Infectious Diseases. 11 (4): 255–257. doi:10.1016/S1473-3099(11)70033-0. PMID 21414844.
  18. ^ "Phase 2 Data Shows Maribavir Markedly Reduced Rate Of Cytomegalovirus Infection And Disease In Bone Marrow Transplant Patients" (Press release). ViroPharma. 30 August 2008. Archived from the original on 3 January 2009. Retrieved 25 November 2022 – via Medical News Today.
  19. ^ Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, et al. (June 2008). "Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study". Blood. 111 (11): 5403–5410. doi:10.1182/blood-2007-11-121558. PMC 5726327. PMID 18285548.
  20. ^ "ViroPharma:Maribavir Phase III Study Missed Goal;Shares Plunge". CNN. 12 February 2009. Archived from the original on 12 February 2009. Retrieved 25 November 2022.
  21. ^ "Maribavir Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 1 February 2007. Archived from the original on 27 November 2021. Retrieved 26 November 2021.
  22. ^ "Maribavir Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 7 June 2011. Archived from the original on 27 November 2021. Retrieved 26 November 2021.
  23. ^ a b "Livtencity: Pending EC decision". European Medicines Agency (EMA). 14 September 2022. Archived from the original on 19 September 2022. Retrieved 18 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  24. ^ "Livtencity Product information". Union Register of medicinal products. Archived from the original on 17 November 2022. Retrieved 3 March 2023.
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  • Clinical trial number NCT02931539 for "Efficacy and Safety Study of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir" at ClinicalTrials.gov
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