Drugs

Fostemsavir

Other Names: BMS-663068, GSK3684934, fostemsavir tromethamine, prodrug of BMS-626529, prodrug of GSK2616713, 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)- Organization: ViiV Healthcare Phase of Development: III

Chemical Image:

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fostemsavir

fostemsavir

Molecular Weight: 583.4954

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and GlaxoSmithKline press release3)

Pharmacology


Mechanism of Action: HIV-1 entry inhibitor (attachment inhibitor). Fostemsavir (GSK3684934; formerly BMS-663068) is a methyl phosphate prodrug of the small molecule inhibitor temsavir (GSK2616713; formerly BMS-626529).4-7 Temsavir prevents viral entry by binding to the viral envelope gp120 and interfering with virus attachment to the host CD4 receptor. Because temsavir binds directly to the virus and not a host cell receptor, it is active against multiple HIV-1 populations regardless of viral tropism.7

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]).8

Metabolism/Elimination: Temsavir is metabolized via esterase-mediated hydrolysis and CYP450-mediated oxidation.9 In a single-dose study, urinary recovery of temsavir was less than 4%.8

Resistance: In an 8-day study of fostemsavir monotherapy in treatment-experienced and treatment–naive participants infected with subtype B virus, fostemsavir administration did not appear to select for high-level 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.10-12

In a Phase IIb study (NCT01384734) of fostemsavir versus atazanavir/ritonavir (ATV/r), each combined with tenofovir DF (TDF) and raltegravir (RAL), 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 RAL.13,14

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 and 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.15

In vitro activity of temsavir has generally not been associated with viral tropism or subtype (with the exception of subtype AE and possibly group O).16



Clinical Trials


Study Identifiers: AI438-006; NCT01009814
Sponsor: Bristol-Myers Squibb
Phase: IIa
Study Purpose: AI438-006 was an open-label proof-of-concept monotherapy study that evaluated the antiviral activity of temsavir, administered as the prodrug fostemsavir, with or without ritonavir (RTV).
Study Population:

  • Participants were HIV-infected, treatment-naive (defined as no receipt of ART for ≥1 week) or –experienced adults with subtype B HIV-1 and 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.

Dosing: Fostemsavir was administered orally under fed conditions over 8 days. Participants were randomized to 1 of the following 5 dosing regimens:

  • Fostemsavir 600 mg plus RTV 100 mg every 12 hours
  • Fostemsavir 1200 mg plus RTV 100 mg at bedtime
  • Fostemsavir 1200 mg plus RTV 100 mg every 12 hours
  • Fostemsavir 1200 mg every 12 hours plus RTV 100 mg every morning
  • Fostemsavir 1200 mg every 12 hours.4,17

Selected Study Results:

Study Identifiers: AI438-011; NCT01384734
Sponsor: Bristol-Myers Squibb
Phase: IIb
Study Purpose: AI438-011 was a dose-response safety and efficacy study of fostemsavir versus ATV/r.
Study Population:

  • Participants were HIV-infected, treatment-experienced adults with HIV susceptibile 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.

Dosing: AI438-011 consisted of a lead-in fostemsavir monotherapy substudy and a main study. During the main study, fostemsavir (blinded) and ATV/r (open-label) were administered orally over 24 weeks (primary endpoint). After Week 24, all groups received open-label dosing. Through the first 48 weeks, participants were randomized to 1 of 4 fostemsavir-dosing regimens or to ATV/r as follows:

  • Fostemsavir 400 mg twice daily in combination with RAL plus TDF
  • Fostemsavir 800 mg twice daily in combination with RAL plus TDF
  • Fostemsavir 600 mg once daily in combination with RAL plus TDF
  • Fostemsavir 1200 mg once daily in combination with RAL plus TDF
  • ATV/r 300/100 mg once daily in combination with RAL plus TDF.

After Week 48, all participants in the fostemsavir dosing groups received fostemsavir 1200 mg once daily in combination with RAL plus TDF. Participants in the control group continued to receive ATV/r 300/100 mg once daily in combination with RAL plus TDF. Long-term follow-up lasted through 96 weeks.7,14,18-21

Selected Study Results:

Study Identifiers: AI438-047; NCT02362503
Phase: III
Sponsor: Bristol-Myers Squibb
Study Purpose: The purpose of the AI438-047 study is to evaluate the safety and efficacy of fostemsavir in heavily treatment-experienced adults with multi-drug resistant HIV.
Study Population:

  • Participants are 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. All doses of fostemsavir will be administered orally. 

  • Randomized Cohort
    • Blinded phase (Days 1-8): Participants will be randomly assigned to receive either fostemsavir 600 mg or placebo, each administered twice daily, 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 plus OBT.
  • Non-Randomized Cohort
    • Starting on Day 1, participants will receive open-label fostemsavir 600 mg administered twice daily plus OBT. (OBT may contain the investigational entry inhibitor ibalizumab.)22-24

* This study is currently recruiting participants.


Adverse Events


In the Phase IIa AI438-006 study (NCT01009814) involving 50 enrolled participants, 78% of participants experienced at least 1 adverse event (AE), and 66% of participants experienced at least 1 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 electrocardiogram (ECG), laboratory values, vital signs, or physical exams.4,17

In the Phase IIb AI438-011 study (NCT01384734) involving 251 treated participants, no fostemsavir-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 fostemsavir-treated participants and in 37.0% of ATV/r-treated participants. No dose-related safety signals associated with the use of fostemsavir were reported, and no Grade 3 to 4 laboratory abnormality trends were identified. The most common AE reported in the fostemsavir groups was headache, the majority of which were Grade 1. Headache occurred in 16% of fostemsavir-treated participants and in 10% of ATV/r-treated participants.7,14,20 
 


Drug Interactions


Fostemsavir and temsavir are neither inducers nor inhibitors of major CYP enzymes; however, temsavir is metabolized in part by cytochrome CYP3A4. Dose adjustments are not necessary when fostemsavir is coadministered with the following antiretrovirals: 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 fostemsavir with rifabutin (given with or without RTV).9,25

Temsaivr 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 temsavir area under the curve (AUC) and maximum concentration (Cmax) by 82% and 76%, respectively. Coadministration of rifampin with fostemsavir is not recommended.25,26

In vitro, temsavir inhibits OATP1B1, OATP1B3, and BCRP, indicating the possibility of drug-drug interactions between temsavir and statins. In a study of multiple doses of fostemsavir with rosuvastatin (an OATP and BCRP substrate), fostemsavir was found to increase rosuvastatin Cmax by 78% and AUC[INF] by 69% when compared to rosuvastatin administered alone. These data suggest that dose adjustement of certain statins may be required when coadministered with fostemsavir.27

 


References


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Last Reviewed: November 21, 2016