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Investigational

Fostemsavir  Audio icon

Other Names: BMS-663068, Fostemsavir tromethamine, prodrug of BMS-626529, prodrug of temsavir
Drug Class: Entry and Fusion Inhibitors
Registry Number: 864953-29-7 (CAS)
Company: Bristol-Myers Squibb
Phase of Development: IIb
Chemical Image:
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fostemsavir
fostemsavir
Molecular Weight: 583.4954
(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)
Patent Version Content

Pharmacology


Mechanism of Action: HIV-1 entry inhibitor. Fostemsavir (also known as BMS-663068) is a methyl phosphate prodrug of the small molecule inhibitor temsavir (also known as BMS-626529).3-5 Temsavir prevents viral entry by binding to the viral envelope gp120 and interfering with virus attachment to the host CD4 receptor.6

Half-life (T½): In a multiple-ascending-dose study of fostemsavir in HIV-infected participants, the average plasma half-life of temsavir was 3.2 to 4.5 hours (immediate-release formulation) and 7 to 14 hours (extended-release formulation [with or without ritonavir]).7

Metabolism/Elimination: Temsavir is metabolized via esterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation.8 In a single-dose study, urinary recovery of temsavir was less than 4%.7

Resistance: In an 8-day study of fostemsavir administered as monotherapy in treatment-experienced and treatment–naive HIV-1 patients infected with subtype B virus, fostemsavir did not appear to select for temsavir resistance. Virological nonresponse to fostemsavir was associated with low baseline susceptibility to temsavir and the presence of attachment inhibitor resistance mutations M426L or S375M. Other gp120 substitutions associated with reduced susceptibility to temsavir included M434I and M475I.9-11

In a Phase IIb study of fostemsavir versus atazanavir/ritonavir (ATV/r), each combined with tenofovir DF and raltegravir, response rates through 24 weeks for fostemsavir were similar to response rates for ATV/r in HIV-infected, treatment-experienced patients, regardless of baseline resistance, temsavir IC50, or baseline viral load. Emergent mutations in fostemsavir treatment failures were identified in 6 out of 200 patients at key positions known to confer reduced susceptibility to temsavir (M426L, M434K, and S375M/N). Key gp120 substitutions at baseline did not correlate with the incidence of virologic failure in fostemsavir-treated patients.12,13

The activity of temsavir against HIV that is resistant to various entry inhibitors was investigated in an in vitro study. No in vitro cross resistance between temsavir and other entry inhibitors (ibalizumab, enfuvirtide) was observed. Some maraviroc-resistant envelopes exhibited decreased susceptibility to temsavir; however, susceptibility to temsavir was shown to be independent from maraviroc resistance. This study also determined that the use of fostemsavir is unlikely to promote resistance via generation of CD4-independent virus.14

In vitro activity of temsavir has generally not been associated with tropism or subtype (with the exception of subtype AE and possibly group O).15



Dosing in Clinical Trials


Study Identifiers: AI438006; NCT0100981416
Phase: IIa
Study Purpose: Proof-of-concept monotherapy study evaluating the antiviral activity of temsavir, administered as the prodrug fostemsavir with or without ritonavir
Study Population: HIV-infected, treatment-naive or –experienced adults with clade B HIV-1
Dosing: Fostemsavir was administered orally under fed conditions over 8 days. Patients were randomized to one of the following five dosing regimens:

  • Fostemsavir 600 mg plus ritonavir 100 mg every 12 hours
  • Fostemsavir 1200 mg plus ritonavir 100 mg at bedtime
  • Fostemsavir 1200 mg plus ritonavir 100 mg every 12 hours
  • Fostemsavir 1200 mg every 12 hours plus ritonavir 100 mg every morning
  • Fostemsavir 1200 mg every 12 hours.3,16
(See references cited above for information on study results.)


Study Identifiers
: AI438011; NCT0138473417
Phase: IIb
Study Purpose: Dose-response safety and efficacy study of fostemsavir versus atazanavir/ritonavir (ATV/r)
Study Population: HIV-infected, treatment-experienced adults with HIV susceptibile to all study drugs
Dosing: Fostemsavir was administered orally over 24 weeks (primary endpoint) with long-term follow-up ongoing through 96 weeks. (A lead-in fostemsavir monotherapy sub-study was also conducted). Patients were randomized to one of four fostemsavir-dosing regimens or to ATV/r as follows:

  • Fostemsavir 400 mg twice daily in combination with raltegravir plus tenofovir DF
  • Fostemsavir 800 mg twice daily in combination with raltegravir plus tenofovir DF
  • Fostemsavir 600 mg once daily in combination with raltegravir plus tenofovir DF
  • Fostemsavir 1200 mg once daily in combination with raltegravir plus tenofovir DF
  • ATV/r 300/100 mg once daily in combination with raltegravir plus tenofovir DF17-19
(See references cited above for information on study results.)
 


Adverse Events


The most common adverse events associated with fostemsavir in a Phase IIa trial (AI438006) were headache and rash. All doses were generally well tolerated, with no deaths, serious adverse events, or study discontinuations due to adverse events. There were no clinically relevant effects on electrocardiogram (ECG), laboratory values, vital signs, or physical exams.6

In a Phase IIb study, AI438011, no fostemsavir-related serious adverse events or adverse events leading to study discontinuation occurred. No safety signals associated with the use of fostemsavir were reported, and no Grade 2 to 4 adverse event or laboratory abnormality trends were identified.19 


Drug Interactions


Fostemsavir and temsavir are neither inducers nor inhibitors of major CYP enzymes. Dose adjustments are not necessary when fostemsavir is co-administered with tenofovir DF.8 

Temsaivr is a P-glycoprotein (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 temsavir area under the curve (AUC) and maximum concentration (Cmax) by 82% and 76%, respectively.20


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/864953-29-7. Last accessed on September 23, 2014.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on September 23, 2014.
  3. 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 Oct 1;206(7):1002-11. Available at: http://jid.oxfordjournals.org/content/206/7/1002.long. Last accessed on September 23, 2014.
  4. 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: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Paper 518. Available at: http://retroconference.org/2011/Abstracts/41587.htm. Last accessed on May 20, 2013.
  5. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/701213-36-7. Last accessed on September 23, 2014.
  6. Nettles R, Schurmann D, Zhu L, et al. Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068: A Potentially First-in-class Oral HIV Attachment Inhibitor. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Paper 49. Available at: http://retroconference.org/2011/Abstracts/41942.htm. Last accessed on May 20, 2013.
  7. 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. Accessed March 20, 2013. Available at: http://www.natap.org/2011/Pharm/Pharm_05.htm. Last accessed on September 23, 2014.
  8. 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: 13th International Workshop on Clinical Pharmacology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract P_13. Available at: http://regist2.virology-education.com/abstractbook/2012_3.pdf. Last accessed on September 23, 2014.
  9. 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. J Acquir Immune Defic Syndr. 2013 Sep 1;64(1):7-15. Available at: http://www.natap.org/2013/HIV/Prediction_of_Virological_Response_and_Assessment.3.pdf. Last accessed on September 23, 2014.
  10. 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 Mar;69(3):573-81. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24128669. Last accessed on September 23, 2014.
  11. 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. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=8ed08ff3-8b0b-4cda-b481-30a670282653. Last accessed on September 23, 2014.
  12. Lataillade M, Zhou N, Joshi S, et al. HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Primary Week 24 Analysis of Emergent Drug Resistance. Abstract presented at: International Workshop on Antiviral Drug Resistance; June 3-7, 2014; Berlin, Germany. Abstract 21. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=45f04284-16aa-414f-bf02-fafc1f71ad75. Last accessed on September 23, 2014.
  13. Lataillade M, Zhou N, Joshi S, et al. HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Primary Week 24 Analysis of Emergent Drug Resistance. International Workshop on Antiviral Drug Resistance; June 3-7, 2014; Berlin, Germany. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/ResisWksp/ResisWksp_08.htm. Last accessed on September 23, 2014.
  14. Li Z, Zhou N, Sun Y, et al. Activity of the HIV-1 attachment inhibitor BMS-626529 against HIV-1 envelopes resistant to other entry inhibitors. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE015. Available at: http://pag.aids2012.org/abstracts.aspx?aid=5714. Last accessed on September 23, 2014.
  15. Nowicka-Sans B, Gong YF, McAuliffe B, et al.  In Vitro Antiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068. Antimicrob Agents Chemother. 2012 Jul;56(7):3498-507. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393465/. Last accessed on September 23, 2014.
  16. Bristol-Myers Squibb. 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. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01009814. Last accessed on September 23, 2014.
  17. Bristol-Myers Squibb. 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. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01384734. Last accessed on September 23, 2014.
  18. Lalezari J, Latiff GH, Brinson C, et al. Attachment Inhibitor Prodrug BMS-663068 in ARV-Experienced Subjects: Week 24 Analysis. Abstract presented at: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6 2014; Boston, MA. Abstract 86. Available at: http://croi2014.org/sites/default/files/uploads/CROI2014_Final_Abstracts.pdf. Last accessed on September 23, 2014.
  19. Lalezari J, Latiff GH, Brinson C, et al. HIV-1 Attachment Inhibitor Prodrug BMS-663068 in ARV-Experienced Subjects: Week 24 Analysis. 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6 2014; Boston, MA. Levin: HIV-1 Attachment Inhibitor Prodrug in ARV-Experienced Subjects: Week 24 Analysis; Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/CROI/croi_26.htm. Last accessed on September 23, 2014.
  20. 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. Available at: http://regist2.virology-education.com/abstractbook/2013_3.pdf. Last accessed on September 23, 2014.
 


Last Reviewed: September 23, 2014

Last Updated: September 23, 2014


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