Tenofovir Alafenamide 2

- Oct 31, 2017 -

Other Names: GS-7340, TAF, TFV alafenamide, prodrug of tenofovir, tenofovir alafenamide fumarate

Drug Class: Nucleoside Reverse Transcriptase Inhibitors

Molecular Formula: C21 H29 N6 O5 P

Registry Number: 379270-37-8 (CAS)

Chemical Name: isopropyl (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

Chemical Class: Purine Nucleotides

Organization: Gilead Sciences, Inc. (The darunavir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose combination [FDC] is being developed by Janssen R&D Ireland.)

Phase of Development:

Two tenofovir alafenamide-containing FDC regimens are in Phase III development for HIV treatment: darunavir/cobicistat/emtricitabine/tenofovir alafenamide and bictegravir/emtricitabine/tenofovir alafenamide. The emtricitabine/tenofovir alafenamide FDC tablet (brand name: Descovy) is in Phase III development for HIV prevention.


The following 3 tenofovir alafenamide-containing FDC tablets are FDA-approved for HIV treatment: 1) elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (brand name: Genvoya), 2) emtricitabine/rilpivirine/tenofovir alafenamide (brand name: Odefsey), and 3) Descovy. As a stand-alone agent, tenofovir alafenamide (brand name: Vemlidy) is FDA-approved for chronic hepatitis B virus (HBV) infection treatment.



Chemical Image: (Click to enlarge)

 tenofovir alafenamide

tenofovir alafenamide


Molecular Weight: 476.4711


(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 ClinicalTrials.gov,3-5 and Gilead Sciences, Inc. press releases6-10)



Pharmacology



Mechanism of Action: Nucleotide reverse transcriptase inhibitor. Tenofovir alafenamide is a phosphonoamidate prodrug of the nucleotide analog tenofovir (TFV). Tenofovir alafenamide was designed to circulate systemically as the prodrug and undergo conversion to TFV intracellularly, achieving higher active metabolite concentrations in peripheral blood mononuclear cells and lower plasma TFV exposures than tenofovir disoproxil fumarate (tenofovir DF; TDF) does.11-13


Tenofovir alafenamide is predominantly metabolized intracellularly to TFV. This intracellular metabolism is primarily catalyzed by cathepsin A (CatA). Inside cells, tenofovir alafenamide is initially hydrolyzed to a partially stable metabolite, from which the phenol group is spontaneously released, forming a cell-impermeable tenofovir-alanine (TFV-Ala) intermediate. TFV-Ala is converted to parent TFV, which undergoes subsequent phosphorylations to yield the active tenofovir diphosphate (TFV-DP) metabolite.14-16 TFV-DP inhibits the activity of HIV reverse transcriptase by competing with natural substrates and causing DNA chain termination after being incorporated into viral DNA.17


Tenofovir alafenamide has also demonstrated in vitro and in vivo activity against HBV.10,18


Half-life (T?): The median terminal half-life of tenofovir alafenamide is 0.51 hours. The active metabolite, TFV-DP, has an intracellular half-life of 150 to 180 hours.19


Metabolism/Elimination: More than 80% of an oral dose of tenofovir alafenamide is metabolized. In vitro, tenofovir alafenamide is intracellularly metabolized to TFV by the CES1 enzyme (in hepatocytes) and by CatA (in PBMCs and macrophages). CYP3A-mediated metabolism of tenofovir alafenamide is minor. Following single-dose administration of radiolabeled tenofovir alafenamide, less than 1% of the dose is excreted in the urine and 31.7% of the dose excreted in feces.19


Resistance: In vitro, HIV-1 isolates with reduced susceptibility to tenofovir alafenamide have been selected, including virus with the K65R substitution (sometimes with S68N or L429I substitutions) and virus with the K70E substitution.19


The K65R and K70E TFV resistance substitutions can result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and TFV. HIV-1 containing multiple thymidine analog mutations (TAMs; M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R) showed resistance to tenofovir alafenamide in cell culture. In addition, multi-nucleoside resistant virus with a T69S double insertion mutation or with a Q151M mutation complex including K65R exhibited in vitro resistance to tenofovir alafenamide.19


In a Phase II study (NCT01565850) comparing the FDC tablet darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/COBI/FTC/TAF) versus cobicistat-boosted darunavir plus emtricitabine/tenofovir DF (DRV + COBI + FTC/TDF) in treatment-naive adults, 6 participants (5.8%) receiving DRV/COBI/FTC/TAF and 2 participants (4%) receiving DRV + COBI + FTC/TDF met criteria for resistance analysis because of virologic rebound through 48 weeks. However, no mutations associated with tenofovir DF, emtricitabine, or darunavir were detected in these participants.20,21


Additional information on HIV resistance mutations associated with tenofovir alafenamide use may be described in the following full prescribing labels: Genvoya, Odefsey, and Descovy.19,22,23




Clinical Trials



Tenofovir Alafenamide for HIV Treatment


Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (DRV/COBI/FTC/TAF)

Study Identifiers: GS-US-299-0102; NCT01565850

Sponsor: Gilead Sciences

Phase: II

Study Purpose: The purpose of this 48-week safety and efficacy study was to compare the single-tablet FDC regimen DRV/COBI/FTC/TAF versus DRV + COBI + FTC/TDF.

Study Population: Participants were HIV-infected, treatment-naive adults who had HIV RNA ≥5,000 copies/mL and CD4 counts >50 cells/mm3. At screening, participants had HIV that was sensitive to DRV, TDF, and FTC, based on genotypic testing. 

Dosing: Treatments were administered orally and once daily. Participants were assigned to 1 of the following 2 groups:


DRV/COBI/FTC/TAF (800/150/200/10 mg) single-tablet regimen

DRV 800 mg (given as 2 400-mg tablets) + COBI 150 mg + FTC/TDF (200/300 mg)

Matching placebos were also administered to each group.20,21,24


Selected Study Results:


ICAAC, 2014 (presentation): 48 Week Study of the First PI-based Single Tablet-Regimen (STR) Darunavir/Cobicistat/Emtricitabine/ Tenofovir Alafenamide (D/C/F/TAF) vs. Darunavir (DRV) boosted by Cobicistat (COBI) and Emtricitabine/Tenofovir Disoproxil Fumarate (TVD) in HIV-Infected Treatment-Na?ve Adults

ICAAC, 2014 (abstract): 48 Week Study of the First PI-based Single Tablet-Regimen (STR) Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) vs. Cobicistat (COBI)-boosted Darunavir (DRV) and Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF) in Treatment-na?ve (TN) Adults

Phase III studies evaluating DRV/COBI/FTC/TAF are also being conducted.3,25


One of the Phase III studies (NCT02431247) will evaluate DRV/COBI/FTC/TAF versus DRV/COBI + FTC/TDF in treatment-naive adults.3

*This study is ongoing, but not recruiting participants.

 The other Phase III study (NCT02269917) will evaluate switching from a regimen of a boosted PI + FTC/TDF to DRV/COBI/FTC/TAF versus continuing on a boosted PI + FTC/TDF in virologically suppressed adults.25

*This study is ongoing, but not recruiting participants.

Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)


Several Phase III studies will be evaluating an FDC tablet containing BIC/FTC/TAF (50/200/25 mg). Bictegravir (also known as GS-9883) is an investigational INSTI that does not require boosting.4,26-29


Two of the Phase III studies will evaluate BIC/FTC/TAF in treatment-naive adults, with 1 study (NCT02607956) comparing BIC/FTC/TAF to dolutegravir (DTG) + FTC/TAF and the other study (NCT026007930) comparing BIC/FTC/TAF to abacavir/dolutegravir/lamivudine (ABC/DTG/3TC).4,27

*Both studies are ongoing, but not recruiting participants.

Two other Phase III studies (NCT02603107 and NCT02603120) involving virologically suppressed adults will evaluate the safety and efficacy of switching to a BIC/FTC/TAF FDC regimen from either 1) a regimen containing boosted atazanavir (ATV) or boosted DRV + either FTC/TDF or ABC/3TC or 2) a regimen consisting of ABC, DTG, and 3TC.28,29

*Both studies are ongoing, but not recruiting participants.

A Phase II/III study (NCT02881320) will investigate BIC/FTC/TAF in virologically suppressed children and adolescents.30

*This study is currently recruiting participants.

Tenofovir Alafenamide for HIV Prevention


Emtricitabine/Tenofovir Alafenamide (FTC/TAF; Descovy)

A Phase III study (NCT02842086) will evaluate the safety and effectiveness of FTC/TAF in preventing HIV infection in men who have sex with men and in transgender women who are at risk of acquiring HIV. FTC/TAF (200/25 mg) will be compared to FTC/TDF (200/300 mg).5  

*This study is currently recruiting participants.


Other prevention studies involving tenofovir alafenamide have also been undertaken.




Adverse Events



In Study GS-US-299-0102 (NCT01565850), most adverse events (AEs) were mild to moderate in severity. AEs occurring in at least 10% of participants in the DRV/COBI/FTC/TAF group included diarrhea, upper respiratory tract infection, fatigue, nausea, and rash. Two participants in each arm experienced an AE leading to study discontinuation: rash and substance dependence in the DRV/COBI/FTC/TAF arm and worsening diarrhea and proximal renal tubulopathy in the DRV + COBI + FTC/TDF arm. Participants in the DRV/COBI/FTC/TAF arm had significantly less increase in proximal tubular proteinuria and less reduction in estimated glomerular filtration rate (eGFR) when compared to participants in the DRV + COBI + FTC/TDF arm. Change in spine and hip bone mineral density (BMD) was significantly less with DRV/COBI/FTC/TAF than with DRV + COBI + FTC/TDF. No fractures were reported in either group.20,24


Other AEs associated with tenofovir alafenamide may be described in the following full prescribing labels: Genvoya, Odefsey, Descovy, and Vemlidy.19,22,23,31




Drug Interactions



Tenofovir alafenamide does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. Tenofovir alafenamide is a weak inhibitor of CYP3A in vitro. Tenofovir alafenamide is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3 and a weak inhibitor of both OCT1 and MATE1. Drugs that inhibit P-gp and/or BCRP may increase the absorption of tenofovir alafenamide, while drugs that induce P-gp activity may decrease the absorption of tenofovir alafenamide. Tenofovir alafenamide does not interact with renal transporters OAT1 or OAT3.32-34


Specific drug-drug interactions associated with tenofovir alafenamide may be described in the following full prescribing labels: Genvoya, Odefsey, Descovy, and Vemlidy.19,22,23,31


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