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 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 IIb study (NCT01384734) investigated FTR versus atazanavir/ritonavir (ATV/r), each combined with tenofovir DF (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
: AI438-006; NCT01009814
: ViiV Healthcare
: This study has been completed.
: 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).
Selected Study Results
- 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
: AI438-011; NCT01384734
: ViiV Healthcare
: This study has been completed.
: AI438-011 was a dose-response safety and efficacy study of FTR versus ATV/r.
Selected Study Results
- 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
: BRIGHTE; AI438-047; NCT02362503
: ViiV Healthcare
: This study is ongoing, but not recruiting participants.
: The purpose of the BRIGHTE study is to evaluate the safety and efficacy of FTR in heavily treatment-experienced adults with multidrug-resistant HIV.
Selected Study Results
- 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
AI438-006 study (NCT01009814)
In this Phase IIa 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)
Results from this Phase IIb study found that among 251 treated participants, no FTR-related SAEs or AEs leading to study discontinuation occurred through 96 weeks of treatment. Grade 2 to 4 treatment-related AEs occurred in 8.5% of FTR-treated participants and in 37.0% of ATV/r-treated participants. No dose-related safety signals associated with the use of FTR were reported, and no Grade 3 to 4 laboratory abnormality trends were identified. The most common AE reported in the FTR groups was headache, the majority of which were Grade 1. Headache occurred in 16% of FTR-treated participants and in 10% of ATV/r-treated participants.8,15,21
This Phase III study evaluated 371 total participants. A safety analysis at Week 24 found that 91% of participants experienced at least one AE (mostly Grade 1 to 2). Grade 2 to 4 treatment-related AEs occurred in 18% of participants and included nausea, diarrhea, headache, vomiting, fatigue, and asthenia. Six percent of participants experienced an AE that resulted in study discontinuation. SAEs, of which pneumonia was the most common, occurred in 30% of participants. Nine participants (2%) had a treatment-related SAE. Seventeen participants (5%) died during the study, with the majority of deaths resulting from AIDS/IRIS-related events.19,20,22
FTR and TMR are neither inducers nor inhibitors of major CYP enzymes; however, TMR is metabolized in part by cytochrome CYP3A4. Dose adjustments are not necessary when FTR is coadministered with the following ARVs: TDF, ATV/r, darunavir plus ritonavir (DRV/r) with or without etravirine (ETR), ETR alone, RTV alone, or RAL plus TDF. Dose modification is also not required when coadministering FTR with rifabutin (given with or without RTV).11,23
TMR is a P-gp substrate. In a one-sequence, one-way-interaction study in 15 healthy participants, rifampin (a P-gp and CYP3A inducer) was shown to significantly reduce TMR AUC and Cmax by 82% and 76%, respectively. Coadministration of rifampin with FTR is not recommended.23,24
In vitro, TMR inhibits OATP1B1, OATP1B3, and BCRP, indicating the possibility of drug-drug interactions between TMR and statins. In a study of multiple doses of FTR with rosuvastatin (an OATP and BCRP substrate), FTR was found to increase rosuvastatin Cmax by 78% and AUC[INF] by 69% when compared to rosuvastatin administered alone. These data suggest that dose adjustment of certain statins may be required when coadministered with FTR.25
In a Phase I study evaluating the effects of FTR on the pharmacokinetics of methadone or buprenorphine/norbuprenorphine in participants without HIV or HBV, FTR increased methadone exposures by 9% to 15% and increased buprenorphine/norbuprenorphine exposures by 24% to 39%. Dose adjustments are unnecessary when methadone and buprenorphine are coadministered with FTR.26
The impact of FTR coadministered with a combined oral contraceptive containing norethindrone (NE) and ethinyl estradiol (EE) was evaluated in healthy female participants. FTR coadministration increased EE exposure by 40% but did not affect NE exposure. These results suggest that FTR, when given without a pharmacoenhancer, may be coadministered with a combined oral contraceptive containing NE and 30 µg or less of EE.27
- United States National Library of Medicine. ChemIDplus Advanced: Fostemsavir. https://chem.nlm.nih.gov/chemidplus/rn/864953-29-7. Accessed January 29, 2019.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed January 29, 2019.
- DrugBank. Fostemsavir. https://www.drugbank.ca/drugs/DB11796. Accessed January 29, 2019.
- Collins S and Clayden P, eds. HIV pipeline 2018: new drugs in development. HIV Treatment Bulletin. 2018 Jul; 19(1) Suppl: 1-29. HIV Treatment Bulletin. http://i-base.info/htb/wp-content/uploads/2018/07/PIPELINE-2018-full-version.pdf. Accessed January 29, 2019.
- 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 January 29, 2019.
- 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 January 29, 2019.
- United States National Library of Medicine. ChemIDplus Advanced: Temsavir. https://chem.nlm.nih.gov/chemidplus/rn/701213-36-7. Accessed January 29, 2019.
- 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 January 29, 2019.
- 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 January 29, 2019.
- 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 January 29, 2019.
- 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 January 29, 2019.
- 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 January 29, 2019.
- 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 January 29, 2019.
- 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
- 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 January 29, 2019.
- 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
- 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 January 29, 2019.
- 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
- 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 January 29, 2019.
- 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 January 29, 2019.
- Granados-Reyes ER, Sloan L, Ernst J, et al. HIV-1 attachment inhibitor prodrug BMS-663068 in antiretroviral-experienced subjects: Week 96 subgroup analysis. International Congress of Drug Therapy in HIV Infection (HIV Glasgow); October 23-26, 2016; Glasgow, UK. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. http://www.natap.org/2016/GLASGOW/GLASGOW_28.htm. Accessed January 29, 2019.
- Lataillade M. Phase 3 study of fostemsavir in heavily treatment experienced HIV-1 infected subjects: Day 8 and Week 24 primary efficacy and safety results (BRIGHTE study, formerly AI438-047). Abstract presented at: European AIDS Clinical Society (EACS) Conference; October 25-27, 2017; Milan, Italy. Abstract PS8/5. http://resourcelibrary.eacs.cyim.com/?mediaId=34870. Accessed January 29, 2019.
- Adamczyk R, Griffies A, Ravindran P, et al. HIV-1 attachment inhibitor prodrug BMS-663068: interactions with rifabutin, with or without ritonavir, in healthy subjects. International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; July 19-23, 2015; Vancouver, Canada. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2015. http://www.natap.org/2015/IAS/IAS_64.htm. Accessed January 29, 2019.
- Hruska M, Anderson J, Bedford B, et al. The effect of rifampin on the pharmacokinetics of the HIV-1 attachment inhibitor prodrug BMS-663068 in healthy subjects. Abstract presented at: 14th International Workshop on Clinical Pharmacology of HIV Therapy; April 22-24, 2013; Amsterdam, The Netherlands. Abstract P_05. http://regist2.virology-education.com/abstractbook/2013_3.pdf. Accessed January 29, 2019.
- Landry I, Vakkalagadda B, Lubin S, et al. HIV-1 attachment inhibitor prodrug BMS-663068: PK assessment with rosuvastatin. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. http://www.croiconference.org/sessions/hiv-1-attachment-inhibitor-prodrug-bms-663068-pk-assessment-rosuvastatin. Accessed January 29, 2019.
- Sevinsky H, Magee M, Ackerman P, et al. The effect of fostemsavir on methadone and buprenorphine pharmacokinetics. Abstract presented at: International AIDS Society (IAS) Conference on HIV Science; July 23-26, 2017; Paris, France. Abstract MOPEB0338. http://programme.ias2017.org/Abstract/Abstract/3300. Accessed January 29, 2019.
- Magee M, Sevinsky H, Ackerman P, et al. The effect of fostemsavir on the pharmacokinetics of a combined oral contraceptive (OC) containing ethinyl estradiol (EE) and norethindrone (NE) in healthy female subjects. Poster presented at: International AIDS Society (IAS) Conference on HIV Science; July 23-26, 2017; Paris, France. Poster MOPEB0339. http://programme.ias2017.org//PAGMaterial/eposters/3312.pdf. Accessed January 29, 2019.
Last Reviewed: January 29, 2019