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Current Indian Science

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ISSN (Print): 2210-299X
ISSN (Online): 2210-3007

Review Article

Fostemsavir: A Novel CD4 Attachment Inhibitor for Heavily Treated HIV-1 Patient

Author(s): Prince P. George, Ranjeet Kumar*, Manvi Sharma and Rojin G. Raj

Volume 1, 2023

Published on: 23 October, 2023

Article ID: e2210299X255078 Pages: 8

DOI: 10.2174/012210299X255078231011111629

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Abstract

Despite the evident success of antiretroviral therapy in recent years, many patients undergoing intense treatment still struggle to find a cure for their disease due to drug resistance or treatment failure. To solve this problem, new antiretroviral drug alternatives are required. The HIV-1 antiretroviral drug fostemsavir (GSK3684394, previously BMS-663068) is a first-in-class HIV-1 attachment inhibitor with a novel mechanism. After oral administration, fostemsavir gets converted into temsavir in the gastrointestinal lumen, which then attaches to the glycoprotein 120 surface subunit on HIV-1 and produces a conformational change that prevents it from adhering to CD4+ T cells of the host immune system, thereby preventing the virus from infecting other cells. Fostemsavir is indicated in heavily treated (HTE) patients with an ideal antiretroviral (ARV) regimen. The drug has shown significant tolerability, and no hepatic or renal dose adjustments were required. Fostemsavir can be used as an effective alternative in salvage therapy because of its favourable adverse effect profile and few drug interactions.

[1]
WHO. HIV and AIDS. Available from:https://www.who.int/news-room/fact-sheets/detail/hiv-aids (accessed Nov. 11, 2022)
[2]
Hemelaar, J.; Elangovan, R.; Yun, J.; Dickson-Tetteh, L.; Fleminger, I.; Kirtley, S.; Williams, B.; Gouws-Williams, E.; Ghys, P.D.; Abimiku, A.G.; Agwale, S.; Archibald, C.; Avidor, B.; Barbás, M.G.; Barre-Sinoussi, F.; Barugahare, B.; Belabbes, E.H.; Bertagnolio, S.; Birx, D.; Bobkov, A.F.; Brandful, J.; Bredell, H.; Brennan, C.A.; Brooks, J.; Bruckova, M.; Buonaguro, L.; Buonaguro, F.; Buttò, S.; Buve, A.; Campbell, M.; Carr, J.; Carrera, A.; Carrillo, M.G.; Celum, C.; Chaplin, B.; Charles, M.; Chatzidimitriou, D.; Chen, Z.; Chijiwa, K.; Cooper, D.; Cunningham, P.; Dagnra, A.; de Gascun, C.F.; Del Amo, J.; Delgado, E.; Dietrich, U.; Dwyer, D.; Ellenberger, D.; Ensoli, B.; Essex, M.; Gao, F.; Fleury, H.; Fonjungo, P.N.; Foulongne, V.; Gadkari, D.A.; García, F.; Garsia, R.; Gershy-Damet, G.M.; Glynn, J.R.; Goodall, R.; Grossman, Z.; Lindenmeyer-Guimarães, M.; Hahn, B.; Hamers, R.L.; Hamouda, O.; Handema, R.; He, X.; Herbeck, J.; Ho, D.D.; Holguin, A.; Hosseinipour, M.; Hunt, G.; Ito, M.; Bel Hadj Kacem, M.A.; Kahle, E.; Kaleebu, P.K.; Kalish, M.; Kamarulzaman, A.; Kang, C.; Kanki, P.; Karamov, E.; Karasi, J-C.; Kayitenkore, K.; Kelleher, T.; Kitayaporn, D.; Kostrikis, L.G.; Kucherer, C.; Lara, C.; Leitner, T.; Liitsola, K.; Lingappa, J.; Linka, M.; Lorenzana de Rivera, I.; Lukashov, V.; Maayan, S.; Mayr, L.; McCutchan, F.; Meda, N.; Menu, E.; Mhalu, F.; Mloka, D.; Mokili, J.L.; Montes, B.; Mor, O.; Morgado, M.; Mosha, F.; Moussi, A.; Mullins, J.; Najera, R.; Nasr, M.; Ndembi, N.; Neilson, J.R.; Nerurkar, V.R.; Neuhann, F.; Nolte, C.; Novitsky, V.; Nyambi, P.; Ofner, M.; Paladin, F.J.; Papa, A.; Pape, J.; Parkin, N.; Parry, C.; Peeters, M.; Pelletier, A.; Pérez-Álvarez, L.; Pillay, D.; Pinto, A.; Quang, T.D.; Rademeyer, C.; Raikanikoda, F.; Rayfield, M.A.; Reynes, J-M.; Rinke de Wit, T.; Robbins, K.E.; Rolland, M.; Rousseau, C.; Salazar-Gonzales, J.; Salem, H.; Salminen, M.; Salomon, H.; Sandstrom, P.; Santiago, M.L.; Sarr, A.D.; Schroeder, B.; Segondy, M.; Selhorst, P.; Sempala, S.; Servais, J.; Shaik, A.; Shao, Y.; Slim, A.; Soares, M.A.; Songok, E.; Stewart, D.; Stokes, J.; Subbarao, S.; Sutthent, R.; Takehisa, J.; Tanuri, A.; Tee, K.K.; Thapa, K.; Thomson, M.; Tran, T.; Urassa, W.; Ushijima, H.; van de Perre, P.; van der Groen, G.; van Laethem, K.; van Oosterhout, J.; van Sighem, A.; van Wijngaerden, E.; Vandamme, A-M.; Vercauteren, J.; Vidal, N.; Wallace, L.; Williamson, C.; Wolday, D.; Xu, J.; Yang, C.; Zhang, L.; Zhang, R. Global and regional molecular epidemiology of HIV-1, 1990–2015: A systematic review, global survey, and trend analysis. Lancet Infect. Dis., 2019, 19(2), 143-155.
[http://dx.doi.org/10.1016/S1473-3099(18)30647-9] [PMID: 30509777]
[3]
NIH. What’s New in the Guidelines. Available from:https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new-guidelines (accessed Nov. 11, 2022)
[4]
Gulick, R.M.; Flexner, C. Long-acting HIV drugs for treatment and prevention. Annu. Rev. Med., 2019, 70(1), 137-150.
[http://dx.doi.org/10.1146/annurev-med-041217-013717] [PMID: 30355266]
[5]
Liang, G.; Zhang, Z.; Zhou, Y. Fostemsavir: A novel multidrug-resistant HIV-1 infection therapy. 2022. Available from:https://scholar.archive.org/work/bt26camiqrcnjc6rnplndqcycy/access/wayback/http://www.clausiuspress.com/conferences/LNMLS/BLSME%202022/Y0824.pdf (Accessed: Nov. 11, 2022)
[6]
Berruti, M.; Pincino, R.; Taramasso, L.; Di Biagio, A. Evaluating fostemsavir as a therapeutic option for patients with HIV. Expert Opin. Pharmacother., 2021, 22(12), 1539-1545.
[http://dx.doi.org/10.1080/14656566.2021.1937120] [PMID: 34125644]
[7]
Kozal, M.; Aberg, J.; Pialoux, G.; Cahn, P.; Thompson, M.; Molina, J.M.; Grinsztejn, B.; Diaz, R.; Castagna, A.; Kumar, P.; Latiff, G.; DeJesus, E.; Gummel, M.; Gartland, M.; Pierce, A.; Ackerman, P.; Llamoso, C.; Lataillade, M. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N. Engl. J. Med., 2020, 382(13), 1232-1243.
[http://dx.doi.org/10.1056/NEJMoa1902493] [PMID: 32212519]
[8]
ViiV Healthcare and Medicine Patent Pool statement on voluntary licences in enabling access to fostemsavir. Available from:https://viivhealthcare.com/hiv-news-and-media/news/company-statements/fostemsavir-voluntary-licences-statement/ (accessed Oct. 18, 2022)
[9]
ViiV healthcare submits new drug application to the FDA for fostemsavir, an investigational, first-in-class attachment inhibitor for the treatment of HIV in adults with few treatment options available. Available from:https://viivhealthcare.com/en-us/media-center/news/press-releases/2019/december/viiv-healthcare-submits-new-drug-application-to-the-fda-for-fost/ (accessed Nov. 10, 2022)
[10]
ViiV Healthcare receives Marketing Authorisation for Rukobia (fostemsavir), a first-in-class attachment inhibitor in combination with other antiretrovirals for the treatment of adults with multidrug-resistant HIV. Available from:https://viivhealthcare.com/hiv-news-and-media/news/press-releases/2021/february/viiv-healthcare-receives-marketing-authorisation-for-rukobia/ (accessed Oct. 16, 2022)
[11]
ViiV Healthcare announces positive CHMP opinion for Rukobia (fostemsavir), a first-in-class attachment inhibitor for the treatment of adults with multidrug-resistant HIV with few treatment options available. Available from:https://viivhealthcare.com/hiv-news-and-media/news/press-releases/2020/december/viiv-healthcare-announces-positive-chmp-opinion-for-rukobia/ (accessed Oct. 18, 2022)
[12]
Craft, B.M.; Baker, D.E. Fostemsavir. Hosp. Pharm., 2021, (Jan)
[http://dx.doi.org/10.1177/0018578720985433]
[13]
Hiryak, K.; Koren, D.E. Fostemsavir: A novel attachment inhibitor for patients with multidrug-resistant HIV-1 infection. Ann. Pharmacother., 2021, 55(6), 792-797.
[http://dx.doi.org/10.1177/1060028020962424] [PMID: 32964736]
[14]
Magee, M.; Slater, J.; Mannino, F.; Ackerman, P.; Llamoso, C.; Moore, K. Effect of renal and hepatic impairment on the pharmacokinetics of temsavir, the active moiety of fostemsavir. J. Clin. Pharmacol., 2021, 61(7), 939-953.
[http://dx.doi.org/10.1002/jcph.1810] [PMID: 33368327]
[15]
NIH. Antiretroviral medication Fostemsavir (FTR, Rukobia). Available from:https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv/fostemsavir (accessed Nov. 11, 2022)
[16]
Seval, N.; Frank, C.; Kozal, M. Fostemsavir for the treatment of HIV. Expert Rev. Anti Infect. Ther., 2021, 19(8), 961-966.
[http://dx.doi.org/10.1080/14787210.2021.1865801] [PMID: 33331202]
[17]
Meanwell, N.A.; Krystal, M.R.; Nowicka-Sans, B.; Langley, D.R.; Conlon, D.A.; Eastgate, M.D.; Grasela, D.M.; Timmins, P.; Wang, T.; Kadow, J.F. Inhibitors of HIV-1 attachment: The discovery and development of temsavir and its prodrug fostemsavir. J. Med. Chem., 2018, 61(1), 62-80.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01337] [PMID: 29271653]
[18]
Thompson, M.; Lalezari, J.P.; Kaplan, R.; Pinedo, Y.; Pena, O.A.S.; Cahn, P.; Stock, D.A.; Joshi, S.R.; Hanna, G.J.; Lataillade, M. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: Week 48 analysis of AI438011, a Phase IIb, randomized controlled trial. Antivir. Ther., 2017, 22(3), 215-223.
[http://dx.doi.org/10.3851/IMP3112] [PMID: 27922453]
[19]
Lataillade, M. Viral drug resistance through 48 Weeks, in a Phase 2b, randomized, controlled trial of the HIV-1 attachment inhibitor prodrug, fostemsavir. J. Acquir. Immune. Defic. Syndr., 2018, 77(3), 299-307.
[http://dx.doi.org/10.1097/QAI.0000000000001602]
[20]
Lalezari, J.P.; Latiff, G.H.; Brinson, C.; Echevarría, J.; Treviño-Pérez, S.; Bogner, J.R.; Thompson, M.; Fourie, J.; Sussmann Pena, O.A.; Mendo Urbina, F.C.; Martins, M.; Diaconescu, I.G.; Stock, D.A.; Joshi, S.R.; Hanna, G.J.; Lataillade, M. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. Lancet HIV, 2015, 2(10), e427-e437.
[http://dx.doi.org/10.1016/S2352-3018(15)00177-0] [PMID: 26423650]
[21]
Anderson, S.J.; Murray, M.; Cella, D.; Grossberg, R.; Hagins, D.; Towner, W.; Wang, M.; Clark, A.; Pierce, A.; Llamoso, C.; Ackerman, P.; Lataillade, M. Patient-reported outcomes in the phase III brighte trial of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals. Patient, 2022, 15(1), 131-143.
[http://dx.doi.org/10.1007/s40271-021-00534-y] [PMID: 34180035]
[22]
Lataillade, M.; Lalezari, J.P.; Kozal, M.; Aberg, J.A.; Pialoux, G.; Cahn, P.; Thompson, M.; Molina, J.M.; Moreno, S.; Grinsztejn, B.; Diaz, R.S.; Castagna, A.; Kumar, P.N.; Latiff, G.H.; De Jesus, E.; Wang, M.; Chabria, S.; Gartland, M.; Pierce, A.; Ackerman, P.; Llamoso, C. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: Week 96 results of the phase 3 BRIGHTE study. Lancet HIV, 2020, 7(11), e740-e751.
[http://dx.doi.org/10.1016/S2352-3018(20)30240-X] [PMID: 33128903]
[23]
Chen, B. Molecular mechanism of HIV-1 entry. Trends Microbiol., 2019, 27(10), 878-891.
[http://dx.doi.org/10.1016/j.tim.2019.06.002] [PMID: 31262533]
[24]
German Advisory Committee Blood (Arbeitskreis Blut), Subgroup ‘Assessment of Pathogens Transmissible by Blood’. Human Immunodeficiency Virus (HIV). Transfus. Med. Hemother., 2016, 43(3), 203-222.
[http://dx.doi.org/10.1159/000445852] [PMID: 27403093]
[25]
Pu, J.; Wang, Q.; Xu, W.; Lu, L.; Jiang, S. Development of protein- and peptide-based HIV entry inhibitors targeting gp120 or gp41. Viruses, 2019, 11(8), 705.
[http://dx.doi.org/10.3390/v11080705]
[26]
Sarkar, A. Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer. Nat. Commun., 2018, 9(1), 1-14.
[http://dx.doi.org/10.1038/s41467-018-04272-y]
[27]
Brelot, A.; Chakrabarti, L.A. CCR5 revisited: How mechanisms of HIV entry govern AIDS pathogenesis. J. Mol. Biol., 2018, 430(17), 2557-2589.
[http://dx.doi.org/10.1016/j.jmb.2018.06.027] [PMID: 29932942]
[28]
Gartland, M.; Cahn, P.; DeJesus, E.; Diaz, R.S.; Grossberg, R.; Kozal, M.; Kumar, P.; Molina, J.M.; Mendo Urbina, F.; Wang, M.; Du, F.; Chabria, S.; Clark, A.; Garside, L.; Krystal, M.; Mannino, F.; Pierce, A.; Ackerman, P.; Lataillade, M. Week 96 genotypic and phenotypic results of the fostemsavir phase 3 BRIGHTE study in heavily treatment-experienced adults living with multidrug-resistant HIV-1. Antimicrob. Agents Chemother., 2022, 66(6), e01751-21.
[http://dx.doi.org/10.1128/aac.01751-21] [PMID: 35502922]
[29]
Najjar, A.; Najjar, A.; Karaman, R. Newly developed prodrugs and prodrugs in development; an insight of the recent years. Molecules, 2020, 25(7), 884.
[http://dx.doi.org/10.3390/molecules25040884]
[30]
Gravatt, L.A.H.; Leibrand, C.R.; Patel, S.; McRae, M. New drugs in the pipeline for the treatment of HIV: A review. Curr. Infect. Dis. Reports, 2017, 19(11), 1-9.
[http://dx.doi.org/10.1007/s11908-017-0601-x]
[31]
NIH. Fostemsavir - Patient. Available from:https://clinicalinfo.hiv.gov/en/drugs/fostemsavir/patient (accessed Nov. 11, 2022)
[32]
Cahn, P.; Fink, V.; Patterson, P. Fostemsavir. Curr. Opin. HIV AIDS, 2018, 13(4), 341-345.
[http://dx.doi.org/10.1097/COH.0000000000000469] [PMID: 29771694]
[33]
Nettles, R.E.; Schürmann, D.; Zhu, L.; Stonier, M.; Huang, S.P.; Chang, I.; Chien, C.; Krystal, M.; Wind-Rotolo, M.; Ray, N.; Hanna, G.J.; Bertz, R.; Grasela, D. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J. Infect. Dis., 2012, 206(7), 1002-1011.
[http://dx.doi.org/10.1093/infdis/jis432] [PMID: 22896665]
[34]
Highlights of prescribing information These highlights do not include all the information needed to use RUKOBIA safely and effectively. See full prescribing information for RUKOBIA. Available from:https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Rukobia/pdf/RUKOBIA-PI-PIL.PDF (Accessed: Aug. 27, 2023)
[35]
Lataillade, M.; Ackerman, P.; Schoofs, T.; Clark, A.; Kozal, M. Fostemsavir in heavily treatment-experienced individuals living with HIV-1: Insights from the phase 3 brighte study. J. AIDS HIV Treat., 2021, 3(2), 31-36.
[http://dx.doi.org/10.33696/AIDS.3.019]
[36]
Fostemsavir tromethamine. Am. J. Health Syst. Pharm., 2020, 77(23), 1924-1927.
[http://dx.doi.org/10.1093/ajhp/zxaa294] [PMID: 32936234]
[37]
Prévost, J. Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir. bioRxiv, 2023, 2023, 537181.
[http://dx.doi.org/10.1101/2023.04.17.537181]
[38]
Gartland, M.; Zhou, N.; Stewart, E.; Pierce, A.; Clark, A.; Ackerman, P.; Llamoso, C.; Lataillade, M.; Krystal, M. Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense® Entry assay. J. Antimicrob. Chemother., 2021, 76(3), 648-652.
[http://dx.doi.org/10.1093/jac/dkaa474] [PMID: 33241285]
[39]
Lai, Y.T. Small molecule HIV-1 attachment inhibitors: Discovery, mode of action and structural basis of inhibition. Viruses, 2021, 13(5), 843.
[http://dx.doi.org/10.3390/v13050843]

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