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 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 GlaxoSmithKline press release,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

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

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.11-13

In a Phase IIb study (NCT01384734) of FTR versus atazanavir/ritonavir (ATV/r), each combined with tenofovir DF (TDF) and raltegravir (RAL), in treatment-experienced adults, response rates through 48 weeks were similar across both study groups. These response rates were not affected by baseline resistance, TMR IC50, or viral load. Among 40 FTR-treated participants who had successful resistance testing, 15 had virus with greater than 3-fold increase in TMR IC50 from baseline. Among these 15 participants, 10 were identified as having emergent substitutions (M426, S375, and M434) known to be associated with reduced susceptibility to TMR. Five out of the 15 participants achieved subsequent viral resuppression to less than 50 copies/mL, regardless of key gp120 substitutions present at baseline. There was no correlation between the presence of key gp120 substitutions (S375, M426, M434, and M475) at baseline and the number of participants who had resistance testing. Across the FTR groups, 6 participants developed resistance to RAL.14,15

An in vitro study explored TMR’s activity against HIV that is resistant to various entry inhibitors. No in vitro cross resistance between TMR and other entry inhibitors (ibalizumab and enfuvirtide) was observed. Some maraviroc-resistant envelopes exhibited decreased susceptibility to TMR; however, susceptibility to TMR was shown to be independent from maraviroc resistance. This study also determined that resistance via generation of CD4-independent virus is unlikely with FTR.16

In vitro activity of TMR has generally not been associated with viral tropism or subtype (with the exception of subtype AE and possibly group O).17


Clinical Trials


Study Identifiers: AI438-006; NCT01009814
Sponsor: ViiV Healthcare
Phase: IIa
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 recieved 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.

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

  • FTR 600 mg plus RTV 100 mg every 12 hours
  • FTR 1200 mg plus RTV 100 mg at bedtime
  • FTR 1200 mg plus RTV 100 mg every 12 hours
  • FTR 1200 mg every 12 hours plus RTV 100 mg every morning
  • FTR 1200 mg every 12 hours.5,18
Selected Study Results:
Study Identifiers: AI438-011; NCT01384734
Sponsor: ViiV Healthcare
Phase: IIb
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 was 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 FTR monotherapy substudy and a main study. During the main study, FTR (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 FTR-dosing regimens or to ATV/r as follows:
  • FTR 400 mg twice daily in combination with RAL + TDF
  • FTR 800 mg twice daily in combination with RAL + TDF
  • FTR 600 mg once daily in combination with RAL + TDF
  • FTR 1,200 mg once daily in combination with RAL + TDF
  • ATV/r 300/100 mg once daily in combination with RAL + TDF

After Week 48, all participants in the FTR dosing groups received FTR 1,200 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.8,15,19-22

Selected Study Results:
Study Identifiers: BRIGHTE; AI438-047; NCT02362503
Phase: III
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 3 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 2 classes of ARVs remaining (at least 1 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.
Dosing: Participants will be assigned to either a randomized or non-randomized cohort. All doses of FTR will be administered orally.
  • Randomized Cohort
    • Blinded phase (Days 1-8): Participants will be randomly assigned to receive either FTR 600 mg or placebo, each administered twice daily, plus current failing ARV therapy.
    • Open-label phase (Day 9-Week 96 or longer): All participants will receive open-label FTR 600 mg administered twice daily plus optimized background therapy (OBT).
  • Non-Randomized Cohort
    • Starting on Day 1, participants will receive open-label FTR 600 mg administered twice daily plus OBT. (OBT may contain investigational agents.) Treatment will continue through Week 96 or longer.23-25
Selected Study Results:


Adverse Events


AI438-006 study (NCT01009814):
In this Phase IIa trial (n = 50), 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 ECG, laboratory values, vital signs, or physical exams.5,18

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

BRIGHTE (NCT02362503):
This Phase III study evaluated 371 total participants. A safety analysis at Week 24 found that 91% of participants experienced at least 1 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.23-25


Drug Interactions


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).10,26

TMR is a P-gp substrate. In a 1-sequence, 1-way-interaction study in 15 healthy participants, rifampin (a P-gp and CYP3A inducer) was shown to significantly reduce TMR area under the curve (AUC) and maximum concentration (Cmax) by 82% and 76%, respectively. Coadministration of rifampin with FTR is not recommended.26,27

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 adjustement of certain statins may be required when coadministered with FTR.28

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 unncessary when methadone and buprenorphine are coadministered with FTR.29

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 effect 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.30


References


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Last Reviewed: December 11, 2017