Drugs

Tenofovir Alafenamide

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 Research & Development, LLC.) Phase of Development:

Tenofovir alafenamide is a component of the FDC darunavir/cobicistat/emtricitabine/tenofovir alafenamide currently being studied in Phase III trials for HIV treatment. An application for marketing approval of this product was submitted to the U.S. Food and Drug Administration (FDA). The emtricitabine/tenofovir alafenamide FDC (brand name: Descovy) is in Phase III development for HIV prevention.

Four tenofovir alafenamide-based FDCs are FDA-approved for HIV treatment: 1) elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (brand name: Genvoya), 2) emtricitabine/rilpivirine/tenofovir alafenamide (brand name: Odefsey), 3) Descovy, and 4) bictegravir/emtricitabine/tenofovir alafenamide (brand name: Biktarvy). As a stand-alone agent, tenofovir alafenamide (brand name: Vemlidy) is FDA-approved for chronic 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 Janssen press release,3 ClinicalTrials.gov,4,5 and Gilead Sciences, Inc. press releases6-10)

Pharmacology


Mechanism of Action: Nucleotide reverse transcriptase inhibitor. Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide analog tenofovir (TFV). TAF 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

TAF is predominantly metabolized intracellularly to TFV. This intracellular metabolism is primarily catalyzed by cathepsin A (CatA). Inside cells, TAF 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

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

Half-life (T½): The median terminal half-life of TAF 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 TAF is metabolized. In vitro, TAF is intracellularly metabolized to TFV by the CES1 enzyme (in hepatocytes) and by CatA (in PBMCs and macrophages). CYP3A-mediated metabolism of TAF is minor. Following single-dose administration of radiolabeled TAF, less than 1% of the dose is excreted in the urine and 31.7% of the dose is excreted in feces.19

Resistance: In vitro, HIV-1 isolates with reduced susceptibility to TAF 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) have shown resistance to TAF in cell culture. In addition, multi-nucleoside resistant virus with a T69S double insertion mutation or with a Q151M mutation complex including K65R has exhibited in vitro resistance to tenofovir alafenamide.19

In a Phase III trial (AMBER; NCT02431247) of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/COBI/FTC/TAF) versus darunavir/cobicistat (DRV/COBI) plus emtricitabine/tenofovir DF (FTC/TDF) in treatment-naive adults, Week 48 resistance analysis was available for 9 participants (n = 7 DRV/COBI/FTC/TAF; n = 2 control) who had experienced virologic failure. Among these 9 participants, no DRV, primary PI or NNRTI resistance associated mutations were detected. One participant in the DRV/COBI/FTC/TAF group who had K103N at screening developed the M184I/V mutation.20

In another Phase III trial (EMERALD; NCT02269917), investigators evaluated the safety and efficacy of switching from a boosted PI plus FTC/TDF regimen to DRV/COBI/FTC/TAF in treatment-experienced virologically suppressed adults with HIV. Week 48 resistance analysis was available for 3 participants (n = 2 DRV/COBI/FTC/TAF; n = 1 control) who had experienced virologic failure. Among these 3 participants, no DRV, primary PI, TFV, or FTC resistance associated mutations were detected.21

Additional information on HIV resistance mutations associated with TAF use may be described in the FDA full prescribing information for the following TAF-based FDCs: Genvoya, Odefsey, Descovy, and Biktarvy.19,22-24


Clinical Trials


Tenofovir alafenamide for HIV treatment

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (DRV/COBI/FTC/TAF)
In September 2017, a new drug application (NDA) for DRV/COBI/FTC/TAF for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older was submitted to FDA.3

Study Identifiers: AMBER; NCT02431247
Sponsor: Janssen Sciences Ireland UC
Phase: III
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the efficacy of DRV/COBI/FTC/TAF versus DRV/COBI plus FTC/TDF in treatment-naive adults with HIV.
Study Population:
  • Participants are treatment-naive adults with HIV.
  • Participants have HIV RNA ≥1,000 copies/mL at screening and CD4 counts >50 cells/mm3.
  • Participants are fully sensitive to DRV, TDF, and FTC based on genotypic testing.

Dosing: Treatment phase (blinded): Participants will receive either DRV/COBI/FTC/TAF (800/150/200/10 mg) or DRV/COBI (800/150 mg) + FTC/TDF (200/300 mg) once daily up to Week 48 (primary endpoint). Matching placebos will also be administered to each group.

After Week 48 (single-arm phase), participants in both groups will receive DRV/COBI/FTC/TAF up to Week 96. After Week 96 (roll-over phase), participants may continue receiving DRV/COBI/FTC/TAF.4,20

Selected Study Results:
Study Identifiers: EMERALD; NCT02269917
Sponsor: Janssen R&D Ireland
Phase: III
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the efficacy of switching from a regimen of a boosted PI plus FTC/TDF to DRV/COBI/FTC/TAF versus continuing on a boosted PI plus FTC/TDF in virologically suppressed adults.
Study Population:
  • Participants are treatment-experienced adults with HIV who have been receiving a stable ART regimen consisting of a boosted PI (DRV or atazanavir [ATV] with low-dose ritonavir [RTV] or COBI, or lopinavir with RTV) plus FTC/TDF for the 6 months prior to screening.
  • Participants are virologically suppressed with HIV RNA <50 copies/mL for at least 2 months prior to screening.
  • Participants have no history of virological failure on a DRV-based regimen and have no documented DRV resistance associated mutations.

Dosing: Treatment phase: Participants will be randomly assigned to either continue their current treatment of a boosted PI plus FTC/TDF or switch to DRV/COBI/FTC/TAF (800/150/200/10 mg) once daily for 48 weeks (primary endpoint).

After Week 48 (extension phase), participants in both groups will receive DRV/COBI/FTC/TAF. After Week 96, participants may continue receiving DRV/COBI/FTC/TAF until the drug becomes commercially available and if they are continuing to benefit from it.21,25

Selected Study Results:
Tenofovir alafenamide for HIV prevention

Emtricitabine/Tenofovir Alafenamide (FTC/TAF; Descovy)
Study Identifiers: DISCOVER; GS-US-412-2055; NCT02842086
Sponsor: Gilead Sciences
Phase: Phase III
Status: This study is ongoing, but not recruiting participants.
Purpose: The purpose of this study is to evaluate the safety and efficacy of FTC/TAF in preventing HIV infection in men and transgender women who have sex with men and are at high risk of sexual acquisition of HIV.
Study Population:
  • Participants are HIV-negative men and transgender women who have sex with men.
  • Participants are at high risk of sexual acquisition of HIV infection.

Dosing: Treatment phase: Participants will receive either FTC/TAF (200/25 mg) + FTC/TDF placebo or FTC/TDF (200/300 mg) + FTC/TAF placebo once daily for at least 96 weeks.

Open-label extension phase: After the treatment phase, participants may opt to continue on open label FTC/TAF treatment.5


Adverse Events


AMBER (NCT02431247):

In this Phase III study, 725 total treatment-naive participants were treated with either the study regimen DRV/COBI/FTC/TAF (n =362) or the control regimen DRV/COBI plus FTC/TDF (n = 363). There were few cases of serious adverse events (SAEs), Grade 3 or 4 AEs, or discontinuations because of an AE. There were no discontinuations attributed to bone, renal, or CNS AEs. AEs that were considered to be at least possibly related to the study drug occurred in 34.8% of participants receiving the study regimen and 41.6% of participants receiving control. Among AEs that were considered possibly drug-related, the most common were diarrhea (study group 8.6%; control group 11.0%), rash (study group 6.1%; control group 3.9%), and nausea (study group 5.5%; control group 9.9%). DRV/COBI/FTC/TAF had a more favorable renal and bone safety profile than control. The lipid profile was slightly better with control than with DRV/COBI/FTC/TAF, although there was no significant difference in total cholesterol/HDL-C ratio between the 2 groups.20,26

EMERALD (NCT02269917):

In this Phase III trial involving 1141 total treatment-experienced virologically suppressed adults, 763 participants switched to the study regimen DRV/COBI/FTC/TAF and 378 participants continued on their current regimen of a boosted PI plus FTC/TDF (control group). Overall, safety was comparable between groups, with 82% of participants in each group experiencing an AE. Frequencies of treatment discontinuations due to an AE, SAEs, and Grade 3 or 4 AEs were similar between both groups. Drug-related AEs, however, were significantly more common with DRV/COBI/FTC/TAF (18%) than with the control regimen (7%). One SAE (pancreatitis), which occurred in the study group, was considered to be possibly drug-related.21

The most common AEs included nasopharyngitis (study group 11%; control group 10%), upper respiratory tract infection (study group 11%; control group 10%), and diarrhea (study group 8%; control group 4%). Diarrhea and osteopenia were the most common drug-related AEs. Overall, DRV/COBI/FTC/TAF had an improved renal and bone safety profile compared with the control regimen. Smaller increases from baseline to Week 48 for fasting total cholesterol and LDL were seen in the control group than in the study group; however, there were no clinically relevant differences between groups in total cholesterol/HDL-C ratio.21

Other AEs associated with TAF may be described in the following full prescribing labels: Genvoya, Odefsey, Descovy, Vemlidy, and Biktarvy.19,22-24,27


Drug Interactions


At clinically relevant concentrations, TAF does not have inhibitory effects on the following transporters and enzymes: P-gp, BCRP (drug transporters); OAT1B1, OAT1B3, OCT1, BSEP (hepatic transporters); OAT1, OAT3, OCT2, MATE1 (renal transporters); or CYP, including CYP3A, and UGT1A1 (enzymes). TAF is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that inhibit P-gp and BCRP may increase the absorption of TAF and result in increased plasma concentrations of TAF, while drugs that induce P-gp activity may decrease the absorption of TAF leading to decreased plasma concentrations of TAF.22,24

Specific drug-drug interactions associated with TAF may be described in the following full prescribing labels: Genvoya, Odefsey, Descovy, Vemlidy, and Biktarvy.19,22-24,27


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/379270-37-8. Last accessed on February 21, 2018.
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  3. Janssen: Press Release, dated September 27, 2017. Janssen submits new drug application to U.S. Food and Drug Administration for the first darunavir-based single tablet regimen for the treatment of HIV-1. Available at: http://www.janssen.com/janssen-submits-new-drug-application-us-food-and-drug-administration-first-darunavir-based-single. Last accessed on February 21, 2018. [Archived at WebCite]
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  5. Gilead Sciences. A Phase 3, randomized, double-blind study to evaluate the safety and efficacy of emtricitabine and tenofovir alafenamide (F/TAF) fixed-dose combination once daily for pre-exposure prophylaxis in men and transgender women who have sex with men and are at risk of HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 20, 2016. NLM Identifier: NCT02842086. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02842086. Last accessed on February 21, 2018.
  6. Gilead: Press Release, dated February 7, 2018. U.S. Food and Drug Administration approves Gilead’s Biktarvy® (bictegravir, emtricitabine, tenofovir alafenamide) for treatment of HIV-1 infection. Available at: http://www.gilead.com/news/press-releases/2018/2/us-food-and-drug-administration-approves-gileads-biktarvy-bictegravir-emtricitabine-tenofovir-alafenamide-for-treatment-of-hiv1-infection. Last accessed on February 21, 2018. [Archived at WebCite]
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  8. Gilead: Press Release, dated March 1, 2016. U.S. Food and Drug Administration approves Gilead’s second TAF-based single tablet regimen Odefsey® (emtricitabine, rilpivirine, tenofovir alafenamide) for the treatment of HIV-1 infection. Available at: http://www.gilead.com/news/press-releases/2016/3/us-food-and-drug-administration-approves-gileads-second-tafbased-single-tablet-regimen-odefsey-emtricitabine-rilpivirine-tenofovir-alafenamide-for-the-treatment-of-hiv1-infection. Last accessed on February 21, 2018. [Archived at WebCite]
  9. Gilead: Press Release, dated April 4, 2016. U.S. Food and Drug Administration approves Descovy® (emtricitabine, tenofovir alafenamide), Gilead’s third TAF-based HIV therapy. Available at: http://www.gilead.com/news/press-releases/2016/4/us-food-and-drug-administration-approves-descovy-emtricitabine-tenofovir-alafenamide-gileads-third-tafbased-hiv-therapy. Last accessed on February 21, 2018. [Archived at WebCite]
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Last Reviewed: February 21, 2018