Drugs

Fostemsavir

Other Names: BMS-663068, FTR, GSK3684934, fostemsavir tromethamine, prodrug of BMS-626529, prodrug of GSK2616713, prodrug of temsavir Drug Class: gp120 Attachment Inhibitor
Molecular Formula: C25 H26 N7 O8 P
Registry Number: 864953-29-7 (CAS) Chemical Name: Piperazine, 1-benzoyl-4-((4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-((phosphonooxy)methyl)-1H-pyrrolo(2,3-c)pyridin-3-yl)oxoacetyl)- Chemical Class: Pyridines and derivatives Organization: ViiV Healthcare Phase of Development: Fostemsavir is in Phase 3 development for HIV treatment.

Chemical Image:

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fostemsavir

fostemsavir

Molecular Weight: 583.4954

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 DrugBank,3 and HIV Treatment Bulletin article4)

Pharmacology


Mechanism of Action: gp120 attachment inhibitor. Fostemsavir (FTR; GSK3684934) is a methyl phosphate prodrug of the small molecule inhibitor temsavir (TMR; GSK2616713).5–8 TMR prevents viral entry by binding to the viral envelope gp120 and interfering with virus attachment to the host CD4 receptor. Because TMR binds directly to the virus and not a host cell receptor, it is active against multiple HIV-1 populations regardless of viral tropism.8

Half-life (T½): In a multiple-ascending-dose study of FTR in participants with HIV, the average plasma half-life of TMR was 3.2 to 4.5 hours (immediate-release formulation) and 7 to 14 hours (extended-release formulation [with or without ritonavir]).9 In a single-dose study of FTR (solution) with or without ritonavir in healthy male participants, the half-life of TMR was 5 to 10 hours.10

Metabolism/Elimination: TMR is largely cleared by biotransformation, primarily via esterase-mediated hydrolysis and CYP450-mediated oxidation. UGT-mediated glucuronidation has a minor role in TMR metabolism.10,11 Following a single dose of FTR administered to healthy male participants, 44–51% of the dose was excreted in urine, 33% in feces, and 5% in bile.10

Resistance: In an 8-day study (NCT01009814) of FTR monotherapy in treatment-experienced and treatment–naive participants with subtype B HIV, FTR administration did not appear to select for high-level TMR resistance. Virological nonresponse to FTR was associated with low baseline susceptibility to TMR and the presence of attachment inhibitor resistance mutations M426L or S375M. Other gp120 substitutions associated with reduced susceptibility to TMR included M434I and M475I.12–14

A Phase 2b study (NCT01384734) investigated FTR versus atazanavir/ritonavir (ATV/r), each combined with tenofovir disoproxil fumarate (TDF) and raltegravir (RAL), in treatment-experienced adults. Results demonstrated that response rates through 48 weeks were similar across both study groups, and these response rates were not affected by baseline resistance. Treatment-emergent resistance was more common with FTR than with ATV/r. Among 44 FTR-treated participants who had available phenotype/genotype resistance data (PhenoSense GT assay), four participants had emergent resistance to RAL. Thirteen out of 29 FTR-treated participants who had evaluable phenotype testing (PhenoSense Entry) had virus with greater than 3-fold increase in TMR IC50 from baseline. Seven of the 13 participants were identified as having emergent gp120 substitutions – S375, M426, and M434 – known to be associated with reduced susceptibility to TMR. However, five of the 13 participants achieved subsequent viral resuppression to less than 50 copies/mL.15,16


Select Clinical Trials


Study Identifiers: AI438-006; NCT01009814
Sponsor: ViiV Healthcare
Phase: 2a
Status: This study has been completed.
Study Purpose: AI438-006 was an open-label proof-of-concept monotherapy study that evaluated the antiviral activity of TMR, administered as the prodrug FTR, with or without ritonavir (RTV).
Study Population:
  • Participants were treatment-naive (defined as not having received ART for ≥1 week) or treatment-experienced adults with subtype B HIV-1. All participants were off all ART for at least 8 weeks prior to study entry.
  • Participants had HIV RNA ≥5,000 copies/mL and CD4 counts ≥200 cells/mm3.5,17
Selected Study Results:
Study Identifiers: AI438-011; NCT01384734
Sponsor: ViiV Healthcare
Phase: 2b
Status: This study has been completed.
Study Purpose: AI438-011 was a dose-response safety and efficacy study of FTR versus ATV/r.
Study Population:
  • Participants were treatment-experienced adults with HIV that were susceptible to all study drugs.
  • Participants had less than 1 week of previous exposure to INSTIs.
  • Participants had HIV RNA ≥1,000 copies/mL and CD4 counts >50 cells/mm3.15,18
Selected Study Results:
Study Identifiers: BRIGHTE; AI438-047; NCT02362503
Phase: 3
Sponsor: ViiV Healthcare
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of the BRIGHTE study is to evaluate the safety and efficacy of FTR in heavily treatment-experienced adults with multidrug-resistant HIV.
Study Population:
  • Participants are highly treatment-experienced adults with resistance, intolerability, and/or contraindications to at least three classes of ARVs.
  • Participants are failing their current ARV regimen, with HIV-1 RNA ≥400 copies/mL.
  • Participants in the randomized cohort have less than two classes of ARVs remaining (at least one fully active agent per class) and are unable to form a viable new ARV regimen.
  • Participants in the non-randomized cohort have no remaining ARV classes and no fully active agents available.19,20
Selected Study Results:


Adverse Events


AI438-006 study (NCT01009814):
In this Phase 2a trial (n = 50), 78% of participants experienced at least one adverse event (AE), and 66% of participants experienced at least one treatment-related AE. All AEs were of mild or moderate intensity. The most common treatment-related AEs were headache, rash, and micturition urgency, the majority of which were of Grade 1 intensity. No deaths, serious adverse events (SAEs), or study discontinuations due to an AE were reported. There were no clinically relevant effects on ECG, laboratory values, vital signs, or physical exams.5,17

AI438-011 study (NCT01384734):
Cumulative safety results from this Phase 2b study found that among 251 treated participants (n = 200 FTR; n = 51 ATV/r), 93% of FTR participants and 98% of ATV/r participants experienced at least one AE. Grade 2 to 4 treatment-related AEs, Grade 3 to 4 AEs, and AEs leading to discontinuation occurred in a higher percentage of participants receiving ATV/r than in participants receiving FTR. No participants receiving FTR discontinued the study because of an FTR-related AE. Treatment-related SAEs occurred in one participant receiving FTR and in two participants receiving ARV/r. The most common drug-related AEs in the FTR groups were headache (6%) and nausea (5%).21

BRIGHTE (NCT02362503):
This Phase 3 study evaluated 371 total participants. A safety analysis at Week 96 found that 94% of participants experienced at least one AE. Grade 2 to 4 treatment-related AEs occurred in 21% of participants and included nausea, diarrhea, headache, IRIS, vomiting, fatigue, and asthenia. Seven percent of participants experienced an AE that resulted in study discontinuation. SAEs, of which pneumonia was the most common, occurred in 38% of participants. Twelve participants (3%) had a treatment-related SAE. Twenty-nine participants (8%) died during the study, with the majority of deaths resulting from AIDS-related events or acute infections.22


Drug Interactions


TMR is neither an inducer nor inhibitor of major CYP or UGT enzymes; however, TMR is metabolized in part by cytochrome CYP3A4. TMR is also a P-gp and BCRP substrate. TMR and/or its metabolites inhibit BCRP, OATP1B1, and OATP1B3.23

Dose adjustments are not necessary when FTR is coadministered with currently approved ARV drugs across all classes. Dose modifications are also not required when coadministering FTR with any of the following: drugs that increase gastric pH (such as famotidine), strong CYP3A inhibitors (such as ritonavir and cobicistat), moderate CYP3A inducers (such as rifabutin and etravirine), and opioid dependence therapy (methadone and buprenorphine).23

Strong CYP3A inducers can significantly reduce plasma concentrations of TMR; therefore, the coadministration of FTR with strong CYP3A inducers (such as rifampin) is contraindiated. Due to TMR inhibition of OATP1B1 and OATP1B3 and the potential for increased grazoprevir plasma concentrations, the coadministration of FTR with elbasvir/grazoprevir is contraindicated.23

Dose modifications of certain statins (excluding pravastatin) may be necessary when FTR is administrered with certain statins.23

When coadministering FTR with estrogen-based therapies (such as oral contraceptives), the ethinyl estradiol (EE) dose should be 30 µg or less.23

FTR should be used with caution when given with drugs that are known to prolong the QT interval.23


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Fostemsavir. https://chem.nlm.nih.gov/chemidplus/rn/864953-29-7. Accessed November 1, 2019
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed November 1, 2019
  3. DrugBank. Fostemsavir. https://www.drugbank.ca/drugs/DB11796. Accessed November 1, 2019
  4. Collins S and Clayden P, eds. HIV pipeline 2019: new drugs in development. HIV Treatment Bulletin. 2019 Jul; 20(1) Suppl: 1-10. HIV Treatment Bulletin. http://i-base.info/htb/wp-content/uploads/2019/07/PIPELINE-2019-FINAL-full-version.pdf. Accessed November 1, 2019
  5. Nettles RE, Schürmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Infect Dis. 2012;206(7). https://academic.oup.com/jid/article/206/7/1002/805849. Accessed November 1, 2019
  6. Nowicka-Sans B, Gong Y-F, Ho H-T, et al. Antiviral activity of a new small molecule HIV-1 attachment inhibitor, BMS-626529, the parent of BMS-663068. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Paper 518. https://web.archive.org/web/20110727215207/http://retroconference.org/2011/Abstracts/41587.htm. Accessed November 1, 2019
  7. United States National Library of Medicine. ChemIDplus Advanced: Temsavir. https://chem.nlm.nih.gov/chemidplus/rn/701213-36-7. Accessed November 1, 2019
  8. Llamoso C, Bogner JR, Afonina L, et al. HIV-1 attachment inhibitor prodrug BMS-663068 in antiretroviral-experienced subjects: Week 96 safety analysis. International Congress of Drug Therapy in HIV Infection (HIV Glasgow); October 23-26, 2016; Glasgow, UK. http://natap.org/2016/GLASGOW/GLASGOW_32.htm. Accessed November 1, 2019
  9. Mascolini M. Levels of novel HIV attachment inhibitor with or without ritonavir. Conference Reports for National AIDS Treatment Advocacy Project (NATAP): 12th International Workshop on Clinical Pharmacology of HIV Therapy; April 13-15, 2011; Miami, FL. http://www.natap.org/2011/Pharm/Pharm_05.htm. Accessed November 1, 2019
  10. Gorycki P, Magee M, Ackerman P, et al. Pharmacokinetics, metabolism and excretion of radiolabeled fostemsavir administered with or without ritonavir in healthy male subjects.19th International Workshop on Clinical Pharmacology of Antiviral Therapy; May 22-24, 2018; Baltimore, MD. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2018. http://www.natap.org/2018/Pharm/Pharm_18.htm. Accessed November 1, 2019
  11. Zhu L, Hwang C, Shah V, et al. No clinically significant drug interaction when BMS-663068, a novel HIV-1 attachment inhibitor, is coadministered with tenofovir disoproxil fumarate. Abstract presented at: International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract P_13. http://regist2.virology-education.com/abstractbook/2012_3.pdf. Accessed November 1, 2019
  12. Zhou N, Nowicka-Sans B, McAuliffe B, et al. Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068. J Antimicrob Chemother. 2014;69(3). https://www.ncbi.nlm.nih.gov/pubmed/24128669. Accessed November 1, 2019
  13. Zhou N, Ray N, Healy M, et al. Genotypic and phenotypic correlates of virological response to the attachment inhibitor BMS-626529 in a short-term monotherapy study with its prodrug BMS-663068. Abstract presented at: International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies; June 5-9, 2012; Sitges, Spain. Abstract 6. http://www.intmedpress.com/serveFile.cfm?sUID=8ed08ff3-8b0b-4cda-b481-30a670282653. Accessed November 1, 2019
  14. Ray N, Hwang C, Healy MD, et al. Prediction of virological response and assessment of resistance emergence to the HIV-1 attachment inhibitor BMS-626529 during 8-Day monotherapy with its prodrug BMS-663068. JAIDS J Acquir Immune Defic Syndr. 2013;64(1):7. doi:10.1097/QAI.0b013e31829726f3
  15. ViiV Healthcare. A Phase IIb randomized, controlled, partially-blinded trial to investigate safety, efficacy and dose-response of BMS-663068 in treatment-experienced HIV-1 subjects, followed by an open-label period on the recommended dose. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 23, 2011. NLM Identifier: NCT01384734. https://clinicaltrials.gov/ct2/show/NCT01384734. Accessed November 1, 2019
  16. Lataillade M, Zhou N, Joshi SR, et al. 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 1999. 2018;77(3):299-307. doi:10.1097/QAI.0000000000001602
  17. ViiV Healthcare. Randomized, open label, multiple-dose study to evaluate the pharmacodynamics, safety and pharmacokinetics of BMS-663068 in HIV-1 infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 6, 2009. NLM Identifier: NCT01009814. https://clinicaltrials.gov/ct2/show/NCT01009814. Accessed November 1, 2019
  18. Lalezari JP, Latiff GH, Brinson C, et al. 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. doi:10.1016/S2352-3018(15)00177-0
  19. ViiV Healthcare. A multi-arm Phase 3 randomized placebo controlled double blind clinical trial to investigate the efficacy and safety of BMS-663068 in heavily treatment experienced subjects infected with multi-drug resistant HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 9, 2015. NLM Identifier: NCT02362503. https://clinicaltrials.gov/ct2/show/NCT02362503. Accessed November 1, 2019
  20. Kozal M, Aberg J, Pialoux G, et al. Phase 3 study of fostemsavir in heavily treatment-experienced HIV-1-infected participants: Day 8 and Week 24 primary efficacy and safety results (BRIGHTE study, formerly 205888/AI438-047). European AIDS Conference; October 25-27, 2017; Milan, Italy. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2017. http://www.natap.org/2017/EACS/EACS_34.htm. Accessed November 1, 2019
  21. Thompson M, Urbina FM, Latiff G, et al. Long-term safety and efficacy of fostemsavir in treatment-experienced participants living with HIV-1. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2019; Seattle, WA. Poster 483. https://www.croiconference.org/sites/default/files/posters-2019/1430_Thompson_0483.pdf. Accessed November 1, 2019
  22. Lataillade M, Lalezari J, Aberg J, et al. Week 96 safety and efficacy of the novel HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced participants infected with multi-drug-resistant HIV-1 (BRIGHTE study). Slides presented at: International AIDS Society (IAS) Conference on HIV Science; July 21-24, 2019; Mexico City, Mexico. http://programme.ias2019.org/PAGMaterial/PPT/1166_3381/IAS%20Brighte%20Week%2096%20oral_with%20link%20for%20sharing.pptx. Accessed November 1, 2019
  23. Moore KP, Mageau AS, Magee M, et al. Fostemsavir drug-drug interaction profile, an attachment inhibitor and oral prodrug of temsavir, for heavily treatment-experienced HIV-1 infected patients. Poster presented at: ID Week; October 2-6, 2019; Washington DC. Mascolini: fostemsavir interaction study flags strong CYP3A inducers, statins, oral contraceptives; Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2019. http://www.natap.org/2019/IDWeek/IDWeek_30.htm. Accessed November 1, 2019


Last Reviewed: November 1, 2019