Maribavir: Difference between revisions

{{Short description |Antiviral drug}}

{{Use dmy dates|date=December 2021}}

{{Infobox drug

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| verifiedrevid = 450846483

| image = Maribavir.svg

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<!-- Clinical data -->

| tradename = Livtencity

| Drugs.com = {{drugs.com|monograph|maribavir}}

| MedlinePlus =

| DailyMedID = Maribavir

| pregnancy_AU = D

| pregnancy_AU_comment = <ref name="Livtencity APMDS" /><ref>{{cite web | title=Updates to the Prescribing Medicines in Pregnancy database | website=Therapeutic Goods Administration (TGA) | date=21 December 2022 | url=https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database | access-date=2 January 2023 | archive-date=3 April 2022 | archive-url=https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database | url-status=live }}</ref>

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| routes_of_administration = [[Oral administration|By mouth]]

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| ATC_prefix = J05

| ATC_suffix = AX10

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<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref name="Livtencity APMDS">{{cite web | title=Livtencity | website=Therapeutic Goods Administration (TGA) | date=21 October 2022 | url=https://www.tga.gov.au/resources/auspmd/livtencity | access-date=29 April 2023 | archive-date=5 February 2023 | archive-url=https://web.archive.org/web/20230205203443/https://www.tga.gov.au/resources/auspmd/livtencity | url-status=live }}</ref><ref>{{cite web | title=LIVTENCITY (Takeda Pharmaceuticals Australia Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=11 November 2022 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/livtencity-takeda-pharmaceuticals-australia-pty-ltd | access-date=29 April 2023 | archive-date=27 March 2023 | archive-url=https://web.archive.org/web/20230327062506/https://www.tga.gov.au/resources/prescription-medicines-registrations/livtencity-takeda-pharmaceuticals-australia-pty-ltd | url-status=live }}</ref><ref>{{cite web | title=Therapeutic Goods (Poisons Standard—June 2024) Instrument 2024 | website=Federal Register of Legislation | date=30 May 2024 | url=https://www.legislation.gov.au/F2024L00589/asmade/text | access-date=10 June 2024}}</ref>

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title = Livtencity (Maribavir tablets) Product Monograph | website=[[Health Canada]] | date = September 2022 | url = https://pdf.hres.ca/dpd_pm/00067349.PDF | access-date = 29 April 2023 | archive-date = 1 October 2022 | archive-url = https://web.archive.org/web/20221001051134/https://pdf.hres.ca/dpd_pm/00067349.PDF | url-status = live }}</ref><ref>{{cite web | title=Livtencity Summary Basis of Decision | website=[[Health Canada]] | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00625&lang=en | access-date=10 March 2023 | archive-date=29 April 2023 | archive-url=https://web.archive.org/web/20230429042815/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00625&lang=en | url-status=live }}</ref><ref>{{cite web | title=Details for: Livtencity | website=[[Health Canada]] | date=25 October 2022 | url=https://dhpp.hpfb-dgpsa.ca/dhpp/resource/101989 | access-date=3 March 2024 | archive-date=3 March 2024 | archive-url=https://web.archive.org/web/20240303064142/https://dhpp.hpfb-dgpsa.ca/dhpp/resource/101989 | url-status=live }}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Livtencity FDA label">{{cite web | title=Livtencity- maribavir tablet, coated | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c94fc2c5-e840-4f18-b7d8-d5eacb26d3a0 | access-date=19 December 2021 | archive-date=19 December 2021 | archive-url=https://web.archive.org/web/20211219212750/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c94fc2c5-e840-4f18-b7d8-d5eacb26d3a0 | url-status=live }}</ref><ref name="FDA PR 20211123" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Livtencity EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

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| CAS_number_Ref = {{cascite|correct|??}}

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| DrugBank = DB06234

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 413807

| KEGG_Ref =

| KEGG = D04859

| ChEBI_Ref =

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| ChEMBL_Ref =

| ChEMBL = 515408

| NIAID_ChemDB = 070966

| PDB_ligand =

| synonyms = 1263W94

<!-- Chemical and physical data -->

| IUPAC_name = (2''S'',3''S'',4''R'',5''S'')-2-[5,6-Dichloro-2-(propan-2-ylamino)benzimidazol-1-yl]-5-(hydroxymethyl)oxolane-3,4-diol

| C=15 | H=19 | Cl=2 | N=3 | O=4

| SMILES = CC(C)Nc1nc2cc(c(cc2n1[C@@H]3[C@H]([C@H]([C@@H](O3)CO)O)O)Cl)Cl

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = KJFBVJALEQWJBS-XUXIUFHCSA-N

| density =

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'''Maribavir''', sold under the brand name '''Livtencity''', is an [[antiviral medication]] that is used to treat post-transplant [[cytomegalovirus]] (CMV).<ref name="Livtencity FDA label" /><ref name="FDA PR 20211123">{{cite press release | title=FDA Approves First Treatment for Common Type of Post-Transplant Infection that is Resistant to Other Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | date=23 November 2021 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-common-type-post-transplant-infection-resistant-other-drugs | access-date=23 November 2021 | archive-date=24 November 2021 | archive-url=https://web.archive.org/web/20211124015049/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-common-type-post-transplant-infection-resistant-other-drugs | url-status=live }} {{PD-notice}}</ref> Maribavir is a cytomegalovirus pUL97 kinase inhibitor that works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.<ref name="FDA PR 20211123" />

The most common side effects include taste disturbance, nausea, diarrhea, vomiting and fatigue.<ref name="FDA PR 20211123" />

Maribavir was approved for medical use in the United States in November 2021,<ref name="FDA PR 20211123" /><ref name="Takeda PR">{{cite press release | title=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 | website=Takeda | date=23 November 2021 | url=https://www.takeda.com/newsroom/newsreleases/2021/takeda-livtencity-maribavir-approved-by-us-fda/ | access-date=26 November 2021 | archive-date=27 November 2021 | archive-url=https://web.archive.org/web/20211127043919/https://www.takeda.com/newsroom/newsreleases/2021/takeda-livtencity-maribavir-approved-by-us-fda/ | url-status=live }}</ref> and in the European Union in November 2022.<ref name="Livtencity EPAR" /> The US [[Food and Drug Administration]] (FDA) considers it to be a [[first-in-class medication]].<ref name="New Drug Therapy Approvals 2021">{{cite report | title=Advancing Health Through Innovation: New Drug Therapy Approvals 2021 | website=U.S. [[Food and Drug Administration]] (FDA) | date=13 May 2022 | url=https://www.fda.gov/media/155227/download | format=PDF | access-date=22 January 2023 | archive-date=6 December 2022 | archive-url=https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download | url-status=live }} {{PD-notice}}</ref>

== Medical uses ==

In the United States, maribavir is [[Indication (medicine)|indicated]] to treat people twelve years of age and older and weighing at least {{convert|35|kg|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.<ref name="FDA PR 20211123" />

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 [[Organ transplantation|solid organ transplant]] (SOT).<ref name="Livtencity EPAR" />

== Adverse effects ==

Adverse effects of maribavir include taste disturbances, nausea, and vomiting.<ref>{{cite journal | vauthors = Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, Alangaden GJ, Chemaly RF, Petersen F, Chao N, Klein J, Sprague K, Villano SA, Boeckh M | display-authors = 6 | title = Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study | journal = Blood | volume = 111 | issue = 11 | pages = 5403–5410 | date = June 2008 | pmid = 18285548 | pmc = 5726327 | doi = 10.1182/blood-2007-11-121558 }}</ref>

== Contraindications ==

The cytomegalovirus pUL97 kinase activates [[ganciclovir]] and [[valganciclovir]], so coadministration with these medications is not recommended because maribavir may reduce their antiviral activity.<ref name="FDA PR 20211123" />

== History ==

Maribavir is licensed by [[ViroPharma]] from [[GlaxoSmithKline]] in 2003, for the [[Prophylaxis|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]].<ref>{{cite journal | vauthors = Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith III AA, Davis MG, Talarico CL, Miller WH, Ferris R, Dornsife RE, Stanat SC, Drach JC, Townsend LB, Koszalka GW | display-authors = 6 | title = Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 8 | pages = 2365–2372 | date = August 2002 | pmid = 12121906 | pmc = 127361 | doi = 10.1128/aac.46.8.2365-2372.2002 }}</ref><ref>{{cite journal | vauthors = Prichard MN | title = Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir | journal = Reviews in Medical Virology | volume = 19 | issue = 4 | pages = 215–229 | date = July 2009 | pmid = 19434630 | pmc = 3777615 | doi = 10.1002/rmv.615 }}</ref> Maribavir showed promise in [[clinical trial#Phase II|phase II]] clinical trials and was granted [[FDA Fast Track Development Program|fast track]] status, but failed to meet study goals in a phase III trial.<ref>{{cite journal | vauthors = Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, Young JA, Rodriguez T, Maertens J, Schmitt M, Einsele H, Ferrant A, Lipton JH, Villano SA, Chen H, Boeckh M | display-authors = 6 | title = Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial | journal = The Lancet. Infectious Diseases | volume = 11 | issue = 4 | pages = 284–292 | date = April 2011 | pmid = 21414843 | doi = 10.1016/S1473-3099(11)70024-X }}</ref> However, the dosage used in the phase III trial may have been too low to be efficacious.<ref>{{cite journal | vauthors = Snydman DR | title = Why did maribavir fail in stem-cell transplants? | journal = The Lancet. Infectious Diseases | volume = 11 | issue = 4 | pages = 255–257 | date = April 2011 | pmid = 21414844 | doi = 10.1016/S1473-3099(11)70033-0 }}</ref>

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 transplant]]s.<ref>{{cite press release | title=Phase 2 Data Shows Maribavir Markedly Reduced Rate Of Cytomegalovirus Infection And Disease In Bone Marrow Transplant Patients | publisher=ViroPharma | via=Medical News Today | date=30 August 2008 | url=http://www.medicalnewstoday.com/articles/109557.php | archive-url=https://web.archive.org/web/20090103195326/http://www.medicalnewstoday.com/articles/109557.php | archive-date=3 January 2009 | url-status=dead | access-date=25 November 2022}}</ref> 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.<ref>{{cite journal | vauthors = Winston DJ, Young JA, Pullarkat V, Papanicolaou GA, Vij R, Vance E, Alangaden GJ, Chemaly RF, Petersen F, Chao N, Klein J, Sprague K, Villano SA, Boeckh M | display-authors = 6 | title = Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study | journal = Blood | volume = 111 | issue = 11 | pages = 5403–5410 | date = June 2008 | pmid = 18285548 | pmc = 5726327 | doi = 10.1182/blood-2007-11-121558 }}</ref>

ViroPharma conducted a [[clinical trial#Phase III|phase III]] clinical study to evaluate the [[Prophylaxis|prophylactic]] use for the prevention of cytomegalovirus disease in recipients of [[tissue engineering|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.<ref>{{cite news | title=ViroPharma:Maribavir Phase III Study Missed Goal;Shares Plunge | website=CNN | date=12 February 2009 | url=http://money.cnn.com/news/newsfeeds/articles/djf500/200902091012DOWJONESDJONLINE000320_FORTUNE5.htm | archive-url=https://web.archive.org/web/20090212134018/http://money.cnn.com/news/newsfeeds/articles/djf500/200902091012DOWJONESDJONLINE000320_FORTUNE5.htm | archive-date=12 February 2009 | url-status=dead | access-date=25 November 2022}}</ref>

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]].<ref name="FDA PR 20211123" /> 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.<ref name="FDA PR 20211123" /> 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.<ref name="FDA PR 20211123" /> 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.<ref name="FDA PR 20211123" />

The US [[Food and Drug Administration]] (FDA) granted the application for maribavir [[orphan drug]], [[breakthrough therapy]] and [[priority review]] designations.<ref name="FDA PR 20211123" /><ref name="Takeda PR" /><ref>{{cite web | title=Maribavir Orphan Drug Designations and Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=1 February 2007 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=229906 | access-date=26 November 2021 | archive-date=27 November 2021 | archive-url=https://web.archive.org/web/20211127043920/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=229906 | url-status=live }}</ref><ref>{{cite web | title=Maribavir Orphan Drug Designations and Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=7 June 2011 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=332210 | access-date=26 November 2021 | archive-date=27 November 2021 | archive-url=https://web.archive.org/web/20211127043919/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=332210 | url-status=live }}</ref><ref name="New Drug Therapy Approvals 2021" /> The FDA granted the approval of Livtencity to Takeda Pharmaceuticals Company Limited.<ref name="FDA PR 20211123" /><ref name="Takeda PR" />

== Society and culture ==

=== Legal status ===

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.<ref name="Livtencity: Pending EC decision" /> The applicant for this medicinal product is Takeda Pharmaceuticals International AG Ireland Branch.<ref name="Livtencity: Pending EC decision">{{cite web | title=Livtencity: Pending EC decision | website=[[European Medicines Agency]] (EMA) | date=14 September 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/livtencity | access-date=18 September 2022 | archive-date=19 September 2022 | archive-url=https://web.archive.org/web/20220919055110/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/livtencity | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Maribavir was approved for medical use in the European Union in November 2022.<ref name="Livtencity EPAR">{{cite web | title=Livtencity EPAR | website=[[European Medicines Agency]] (EMA) | date=14 September 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/livtencity | access-date=25 November 2022 | archive-date=26 November 2022 | archive-url=https://web.archive.org/web/20221126054101/https://www.ema.europa.eu/en/medicines/human/EPAR/livtencity | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref>{{cite web | title=Livtencity Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1672.htm | access-date=3 March 2023 | archive-date=17 November 2022 | archive-url=https://web.archive.org/web/20221117235140/https://ec.europa.eu/health/documents/community-register/html/h1672.htm | url-status=live }}</ref>

== References ==

== External links ==

* {{ClinicalTrialsGov|NCT02931539|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}}

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