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Investigational

Fostemsavir  Audio icon

Other Names: BMS-663068, fostemsavir tromethamine, prodrug of BMS-626529, prodrug of temsavir
Drug Class: Entry Inhibitor
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)-
Company: Bristol-Myers Squibb
Phase of Development: III
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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 (attachment 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 48 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. Of the fostemsavir-treated participants who met resistance testing criteria and had a determinable HIV-1 gp120 genotype, 15 out of 40 had virus with greater than 3-fold increase in temsavir IC50 from baseline. Among these 15 participants, 10 were identified as having emergent substitutions  known to be associated with reduced susceptibility to temsavir. The substitutions were at positions M426, S375, and M434. Five out of the 15 participants achieved subsequent viral resuppression to less than 50 copies/mL, regardless of key gp120 substitutions present at baseline. The prescence of key gp120 substitutions (S375, M426, M434, and M475) at baseline did not correlate with the number of participants who had on-study resistance testing. Across the fostemsavir groups, 6 participants developed resistance to raltegravir.12

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.13

In vitro activity of temsavir has generally not been associated with tropism or subtype (with the exception of subtype AE and possibly group O).14



Dosing in Clinical Trials


Study Identifiers: AI438006; NCT0100981415
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.3,15

(See references cited above for information on study results.)

Study Identifiers: AI438011; NCT0138473416
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 DF16-20

(See references cited above for information on study results.)


Study Identifiers
: AI438-047; NCT0236250321
Phase: III
Study Purpose: Study to evaluate the safety and efficacy of fostemsavir in heavily treatment-experienced adults with multi-drug resistant HIV.
Study Population: HIV-infected, treatment-experienced adults with resistance, intolerability, and/or contraindications to at least 3 classes of ARVs. Participants are currently failing their current ARV regimen with HIV-1 RNA ≥400 copies/mL and have ≤2 classes of ARVs remaining to form a viable new ARV regimen.
Dosing: Participants will be assigned to either a randomized or non-randomized cohort. The assignment will be based on the number of fully active ARVs remaining to form a viable optimized background therapy (OBT) regimen for each participant. Participants who are able to receive ≥1 fully active approved ARV (but no more than 2) as part of their OBT starting from Day 9 onwards will be assigned to the randomized cohort. Participants without any fully active approved ARVs remaining may be enrolled to the non-randomized cohort.

 

  • Randomized Cohort
    • Blinded phase (Days 1-8): Participants will be randomly assigned to receive either fostemsavir 600 mg or placebo, each administered twice daily and orally, plus current failing ARV therapy.
    • Open-label phase (Day 9-Week 48 or longer): All participants will receive open-label fostemsavir 600 mg administered twice daily and orally plus OBT.
  • Non-Randomized Cohort
    • Starting on Day 1, participants will receive open-label fostemsavir 600 mg administered twice daily and orally plus OBT. (OBT may contain the investigational entry inhibitor ibalizumab.)21-23


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 the Phase IIb study (AI438011), no fostemsavir-related serious adverse events or adverse events leading to study discontinuation occurred through 48 weeks of treatment. Grade 2 to 4 adverse events occurred in 8.5% of fostemsavir-treated participants and in 29.4% of ATV/r-treated participants. No dose-related safety signals associated with the use of fostemsavir were reported, and no Grade 2 to 4 laboratory abnormality trends were identified.19 


Drug Interactions


Fostemsavir and temsavir are neither inducers nor inhibitors of major CYP enzymes; however, temsavir is metabolized in part by cytochrome P450 3A4 (CYP3A4). Dose adjustments are not necessary when fostemsavir is co-administered with the following antiretrovirals: tenofovir DF, atazanavir plus ritonavir, darunavir plus ritonavir with or without etravirine, etravirine alone, ritonavir alone, or raltegravir plus tenofovir DF. Dose modification is also not required when co-administering fostemsavir with rifabutin (given with or without ritonavir).8, 24

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. Co-administration of rifampin with fostemsavir is not recommended.24, 25


References



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  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 November 1, 2015.
  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 November 1, 2015.
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Last Reviewed: November 2, 2014

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