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Tenofovir alafenamide - Gilead Sciences

Drug Profile

Tenofovir alafenamide - Gilead Sciences

Alternative Names: GS-7340; GS-7340-02; GS-7340-03; TAF; Tenofovir alafenamide fumarate; Vemlidy

Latest Information Update: 13 Jul 2021

At a glance

  • Originator Gilead Sciences
  • Developer Gilead Sciences; University Hospital Inselspital; University of California
  • Class Amines; Antivirals; Phosphorus compounds; Propionates; Purines; Small molecules
  • Mechanism of Action Nucleotide reverse transcriptase inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - HIV infections
  • New Molecular Entity No

Highest Development Phases

  • Marketed Hepatitis B
  • Phase III HIV-1 infections
  • Phase II HIV infections

Most Recent Events

  • 01 Jul 2021 Phase-II clinical trials in Hepatitis B (Combination therapy) in New Zealand (PO) (NCT04891770)
  • 03 Jun 2021 Updated safety and efficacy data from a phase II trial in Hepatitis B presented at the the International Liver Congress 2021 (ILC-2021)
  • 21 May 2021 Gilead Sciences in collaboration with Vir Biotechnology plans a phase IIa trial for chronic Hepatitis B (Combination therapy) in July 2021 (NCT04891770) (PO, tablet)

Development Overview

Introduction

Tenofovir alafenamide is an isopropylalaninyl phenyl ester prodrug of the nucleotide analogue tenofovir [see AdisInsight drug profile 800005710] and a nucleotide reverse transcriptase inhibitor, in development with Gilead Sciences in the US for the treatment of HIV-1 and hepatitis B (HBV) infections. Tenofovir has poor oral bioavailability and cellular permeability. Tenofovir alafenamide is designed to be orally bioavailable, stable in prodrug form in plasma and to be selectively metabolised within target cells to tenofovir. Clinical development for HIV-1 and hepatitis B infection is underway in several countries worldwide. Tenofovir alafenamide has been approved in the EU, Canada, China, Japan, Iceland, Liechtenstein and Norway and launched in the US and Taiwan for the treatment of hepatitis B.

In addition to its development as monotherapy, tenofovir alafenamide is also being developed as part of fixed dose combinations with other antiviral drugs [see Adis Insight drug profile 800035274, 800035548, 800040899].

Company Agreements

In December 2014, Gilead Sciences entered into a non-exclusive licensing agreement with Mylan Laboratories Limited for manufacturing and distribution of tenofovir alafenamide as a single agent and in combination with other drugs [see Adis Insight drug profiles 800040899, 800035548], for the treatment of HIV-1 infections, in 112 developing countries. Under the terms of the agreement, following approval by US FDA, Mylan will receive a technology transfer from Gilead for manufacturing of low-cost versions of the products [1] .

In September 2014, Medicines Patent Pool entered into a sub-licensing agreement with Aurobindo, Cipla, Desano, Emcure, Hetero Labs and Laurus lab, which will enable these companies to develop and manufacture generic versions of tenofovir alafenamide for 112 countries. Gilead Sciences entered into a licensing agreement with Medicines Patent Pool and subsequently, the latter entered into sub-licensing agreement with the Indian and Chinese companies to fast-track the production of generic versions of tenofovir alafenamide in developing countries [2] .. Earlier, in July 2014, Gilead entered into a licensing agreement with the Medicines Patent Pool to fast-track the production of generic versions of tenofovir alafenamide for low- and middle-income countries, after its approval in the US [3] [4] .

Key Development Milestones

According to Gilead Science's company pipeline, as at March 2014, single-agent tenofovir alafenamide is being developed as a treatment for hepatitis B virus (HBV) infections. The agent is only listed as a treatment for HIV infections as a component of fixed dose combination regimens.

Hepatitis B

In November 2016, Gilead announced that the US FDA approved tenofovir alafenamide for the treatment of adults with chronic hepatitis B infection. Gilead has submitted the NDA to the US FDA in January 2016, for which the FDA had assigned priority review status. The approval is based on 48-week data from two international Phase 3 studies (108 and 110) [see below] [5] [6] [7] [8] [9] .

Gilead Sciences, in December 2016, announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved 25mg tenofovir alafenamide, a once-daily treatment for suppression of viral replication in chronic hepatitis B patients with evidence of hepatitis B virus replication and abnormal liver function. The Japanese approval is supported by 48-week data from two international phase III studies (studies 108 and 110) among 1 298 treatment-naïve and treatment-experienced adult patients with HBeAg-negative and HBeAg-positive chronic HBV infection. In March 2016, Gilead Sciences had submitted an NDA to Japan’s Pharmaceutical and Medical Devices Agency (PMDA) for tenofovir alafenamide 25 mg, for treatment of adults with chronic hepatitis B virus infection [10] [11] .

In January 2017, Gilead announced that the European Commission granted marketing authorisation for tenofovir alafenamide for the treatment of chronic hepatitis B virus infection. Gilead announced in November 2016 that Committee for Medicinal Products for Human Use (CHMP) of the EMA has adopted a positive opinion on the company's MAA for tenofovir alafenamide for chronic hepatitis B infection in adults and adolescents (=12 years and =35 kg body weight) [12] [13] . In February 2016, Gilead announced that the European Medicines Agency (EMA) fully validated the MAA for tenofovir alafenamide for once daily treatment for adults with chronic hepatitis B virus. The MAA is now under assessment by the EMA. The submission was based on the results from the studies 108 and 110 [6] [14] [7] [8] [9] .

Tenofovir alafenamide (25mg od) was approved by the Taiwan Food and Drug Administration, Ministry of Health and Welfare, for the treatment of hepatitis B in treatment-experienced and treatment-naïve patients, in 2017. The approval was supported by data from the phase III 108 and 110 studies [see below], conducted among 1 632 treatment-naïve and treatment-experienced adult patients, with HBeAg-negative and HBeAg-positive HBV disease (which included 120 patients treated in Taiwan). The drug was subsequently launched in the geography [15] .

In June 2017, Health Canada approved tenofovir alafenamide, once-daily, 25mg tablets, for the treatment of adults with chronic hepatitis B virus (HBV) infection with compensated liver disease, by granting a Notice of Compliance (NOC). The approval was based on 48-week data from two phase III trials, study 108 and study 110 [see below], intergrated analysis of which showed improved renal and bone safety as well as higher rates of normalisation of blood serum alanine aminotransferase (ALT) levels as compared with tenofovir disoproxil fumarate [16] .

In November 2018, China National Medical Products Administration (NMPA) approved tenofovir alafenamide, once-daily, 25mg tablets (Vemlidy®) for the treatment of hepatitis B virus infection in treatment-naive and treatment-experienced adults and adolescents (aged ≥12 years with body weight at least 35 kg) in China. The approval was based on data from two phase III trials (Studies 108 and Study 110) [17] . Earlier in February 2018, Gilead announced the submission of a marketing application of tenofovir alafenamide for the treatment of hepatitis B virus in China [18] .

In November 2019, long term analysis of two phase III trials in Hepatitis B infections that evaluated impact of Hepatitis B infections treatment on hepatocellular carcinoma was released by Gilead Sciences [19] .

In January 2020, Gilead Sciences completed a phase III trial that evaluated the efficacy, safety, and tolerability of switching to tenofovir alafenamide versus continuing tenofovir disoproxil fumarate in virologically suppressed patients with chronic hepatitis B virus infection (GS-US-320-4018; EudraCT2016-003632-20; NCT02979613). The randomised, double-blind, parallel, placebo-controlled trial was initiated in December 2016, and enrolled 490 patients in the US, Canada, Hong Kong, Italy, South Korea, Taiwan, Spain and the UK, in September 2019 [20] . In April 2019, Gilead Sciences presented safety and efficacy data from the study at the International Liver Congress 2019 (ILC-2019) [21] . Later, in November 2019, updated data was presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2019). In August 2020, data at 96-week from 488 patients demonstrated that tenofovir alafenamide, sustained viral suppression while improving markers of renal and bone health, after switching from tenofovir disoproxil fumarate [22] [23] [24] . Additional results from the trial were presented at the The International Liver Congress 2020 (ILC-2020) [25] .

In September 2013, Gilead Sciences initiated a phase III trial (study 110) that is investigating the safety and efficacy of tenofovir alafenamide compared to that of tenofovir disoproxil fumarate in treatment-naive and -experienced adult subjects with HBeAg-positive chronic hepatitis B virus infection (GS-US320-0110; NCT01940471). The randomised, double-blind study enrolled 873 patients in the US, Australia, Bulgaria, Canada, China, France, Germany, Hong Kong, India, Italy, Japan, South Korea, New Zealand, Poland, Romania, Russia, Singapore, Spain, Taiwan, Turkey and the UK [2] . Due to the review timeline difference in China and other countries, enrolment was completed in the main study before China was able to participate. Therefore, details for the China cohorts were registered in separate trial record (NCT02836249). Top-line results demonstrating non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate, thereby meeting the primary endpoint were released by Gilead in January 2016. Updated efficacy and safety results were presented at the The International Liver Congress 2017 (ILC-2017), in April 2017. In June 2018, pharmacodynamics results from the trial were presented at the Digestive Disease Week 2018 (DDW-2018) [26] [27] [8] [28] .

Gilead Sciences initiated a phase III trial (study 108) in September 2013, to investigate the safety and efficacy of tenofovir alafenamide against tenofovir disoproxil fumarate in treatment-naive and -experienced adult subjects with HBeAg-negative chronic hepatitis B virus infection (GS-US-320-0108; NCT01940341). The randomised, double-blind trial enrolled 425 patients in the US, Australia, Canada, China, France, Germany, Hong Kong, India, Italy, Japan, South Korea, New Zealand, Poland, Romania, Russia, Singapore, Spain, Taiwan, Turkey and the UK. Due to the review timeline difference in China and other countries, enrolment was completed in the main study before China was able to participate. Therefore, details for the China cohorts were registered in separate trial record (NCT02836236). Top-line results demonstrating non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate, thereby achieving the primary endpoint were released by Gilead in January 2016. In April 2017, adverse events data were presented at the the International Liver Congress 2017 (ILC-2017). Later, in April 2019, updated efficacy data was presented at the International Liver Congress 2017 (ILC-2019) [29] [30] [8] [31] .

In April 2017, the company released pooled results from two phase III studies (108 and 110) [see above]. In November 2018, updated one-year data was presented at the 69th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD - 2018) [32] [33] . In November 2019, Gilead Sciences presented pooled results from two phase III studies (108 and 110) [see above] at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2019) [34] . In November 2020, updated pooled analysis from the trials were presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2020) [35] [36] .

Gilead Sciences has initiated phase III trials of the fixed combination cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide [see Adis Insight Drug profile 800029668]. The combination was found to be non-inferior to Gilead's Stribild® [2] [37] [38] [39] [40] .

In July 2021, Gilead Sciences and Vir Biotechnology initiated a phase IIa trial to assess the safety and efficacy of tenofovir alafenamide as a combination therapy with selgantolimod [see AdisInsight Drug profile 800048419], VIR 2218 [see AdisInsight Drug profile 800050552] and nivolumab [see AdisInsight Drug profile 800022442] for the treatment of chronic hepatitis B (GS-US-465-4439; EudraCT2021-000672-11; NCT04891770). The open label, randomised trial intends to enrol approximately 120 patients in New Zealand [41] .

In January 2021, Gilead Sciences in collaboration with Spring Bank Pharmaceuticals completed a phase II trial that evaluated the safety and efficacy of inarigivir soproxil in combination with tenofovir alafenamide (Vemlidy®) in chronic hepatitis B patients (GS-US-464-4437; NCT03434353). The trial was initiated in February 2018, and enrolled 70 patients in Hong Kong and South Korea [42] [43] .

In November 2019, Gilead Sciences announced that a phase II trial met its primary end point. In the open-label phase II trial 93 hepatitis B patients with moderate to severe renal impairment and those with end-stage renal disease (ESRD) on chronic hemodialysis (HD) who were virally suppressed taking TDF and/or other antivirals for at least 48 weeks, were switched to tenofovir alafenamide for 96 weeks. At week 24, all patients with ESRD and 97% of patients with moderate or severe renal impairment met the primary endpoint of maintaining viral load suppression. In renally-impaired HBV patients, who were switched to tenofovir alafenamide, there were increases in hip and spine bone mineral density and decreases in most bone turnover markers including in ESRD patients on HD, as well as decreases in renal tubular markers and increases in glomerular filtration rate (eGFRCG). Another phase II trial that enrolled 31 virally suppressed HBV patients with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C) who were switched to tenofovir alafenamide and treated for 24 weeks showed similar results [19] .

In September 2020, Gilead Sciences completed a phase II trial that evaluated the safety and efficacy of switching to tenofovir alafenamide from tenofovir disoproxil fumarate (TDF) and/or other oral antiviral treatment (OAV) in virologically suppressed chronic Hepatitis B patients with renal and/or hepatic impairment (NCT03180619; EudraCT2016-004625-16; GS-US320-4035). The open label trial was initiated in June 2017, and enrolled 124 patients in the US, Canada, Hong Kong, Italy, New Zealand, South Korea, Taiwan, France and the UK. The study consists of 2 parts, with 93 renally impaired patients enrolled in Part A and 31 hepatically impaired participants enrolled in Part B. In November 2019, pharmacodynamics and safety data was presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2019) [44] [45] . In August 2020, efficacy and safety results from the trial were presented at the International Liver Congress 2020 (ILC-2020) [46] [47] . Later in June 2021, the efficacy and safety results from 2 years of the trial were presented at the International Liver Congress 2021 (ILC-2021) [48] .

In September 2016, Gilead Sciences initiated a phase II trial to assess the pharmacokinetics, safety and antiviral efficacy of tenofovir alafenamide 25mg tablet od for the treatment of long term hepatitis B infection in adolescent patients (P221/2016; GS-US-320-1092; NCT02932150; EudraCT2016-000785-37). The randomised, double-blind, parallel, placebo-controlled trial is recruiting 75 patients in the US, Belgium, Russia, Hong Kong and South Korea [49] .

In May 2021, Gilead Sciences completed a phase II trial that evaluated the safety and efficacy of tenofovir alafenamide 25mg daily versus tenofovir disoproxil fumarate in adult chronic hepatitis B infection patients with stage 2 or greater chronic kidney disease and have received a liver transplant (370890; GS-US320-3912; ACTRN12616000898459p; NCT02862548). The randomised, open label trial was initiated in September 2016, and enrolled 51 patients in New Zealand. In November 2018, the company presented data from the trial at the 69th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2018) [50] [51] .

A phase I/II trial evaluating multiple doses of tenofovir alafenamide, compared with tenofovir disoproxil fumarate, was completed in the US, Australia, New Zealand, Canada and the UK (NCT01671787). The study enrolled a total of 51 treatment-naive patients with hepatitis B, and was completed in April 2013 [52] .

Gilead Sciences completed a phase I study to evaluate the pharmacokinetics and safety of tenofovir alafenamide, in subjects with normal hepatic function and patients with hepatic impairment, in April 2015 (NCT02296853; GS-US-320-1615). The primary endpoint of the study was the pharmacokinetic profiles of tenofovir alafenamide and its metabolite, tenofovir, assessed before dosing and day 1 following dosing. Incidence of adverse events were assessed up to 31 days. The open-label trial was initiated in December 2014 and enrolled 20 subjects in the US, Germany and New Zealand [53] .

HIV-1 infections

In November 2015, tenofovir alafenamide received orphan drug designation in Japan for the treatment of HIV infections by the Pharmaceuticals and Medical Devices Agency (PMDA), Japan (PMDA website, November 2015).

In March 2016, University of Gothenburg initiated a phase IV trial to determine the change in cerebrospinal fluid viral load (HIV-RNA levels) or intrathecal immune activation after switching from either abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) to tenofovir alafenamide (TAFCNS2015; EudraCT2015-004427-31). The trial is recruiting 20 patients in Sweden [54] .

In November 2015, Gilead reported that tenofovir alafenamide administered at a dose less than one-tenth that of tenofovir disoproxil fumarate demonstrated potent antiviral efficacy and improvements in renal and bone safety laboratory markers in several phase III trials for the treatment of HIV infection [9] .

In July 2017, Gilead Sciences completed a phase III trial that evaluated the efficacy of tenofovir alafenamide, in antiretroviral treatment-experienced HIV-1 positive patients (GS-US-292-0117; EudraCT2013-002830-19; NCT01967940). The randomised, open label trial was initiated in October 2013, and enrolled 55 patients in the US, Dominican Republic, Russia, Thailand, Uganda, Germany and the UK [55] .

Gilead has presented positive results from a phase II study of tenofovir alafenamide in patients with HIV-1 infections (Study 102), including at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC-2013) [56] [39] [40] .

In May 2017, Gilead initiated a phase II trial to evaluate the changes in renal glomerular and tubular function with after the switch from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV/HBV-coinfected patients with mild to moderate renal dysfunction and to assess the virological efficacy of tenofovir alafenamide on HBV infection (NCT03115736; INSEL-HINF2017-1). The trial is enrolling approximately 50 patients in Switzerland [57] .

In April 2019, University of California in collaboration with Gilead Sciences initiated phase I/II UCLACAREMITO trial to compare potential mitochondrial toxicities of tenofovir alafenamide and tenofovir disoproxil fumarate [see ADIS Insight drug profile800010140] in large HIV cohorts (NCT03251144; CO-US311-4393). The open, prospective trial intends to recruit 26 patients in USA [58] .

Phase I/II testing of tenofovir alafenamide for 30 treatment-naive patients with chronic HIV-1 infection was initiated by Gilead during the first quarter of 2002 and completed in 2003 (NCT00036634). Gilead reported positive results showing that a significant and rapid viral load decay was seen over 14 days with both doses of the prodrug and no safety issues were noted [59] .

Gilead had previously discontinued its development programme for tenofovir alafenamide in October 2004. Based on the safety, tolerability and efficacy of Gilead's HIV products established in clinical studies and commercial use, Gilead did not believe that tenofovir alafenamide had a profile that differentiated it to an extent that supported its continued development [60] .

Pharmacokinetic studies

In November 2016, the University of North Carolina in collaboration with Gilead Sciences completed a phase I trial that assessed the dose-proportional distribution of tenofovir alafenamide in plasma and mucosal tissues and tenofovir diphosphate in peripheral blood mononuclear cells and mucosal tissues of healthy volunteers (14-2797; NCT02357602). The open-label trial was initiated in May 2015, enrolled 24 female volunteers in the US [61] .

Labeling information

The US approved label for tenofovir alafenamide has a black box warning related to lactic acidosis/severe hepatomegaly with steatosis and post-treatment severe acute exacerbation of hepatitis B [5] . The drug is not alone recommended for the treatment of HIV-1 infection because it can develop HIV-1 resistance in HBV/HIV-1 coinfected patients. Tenofovir alafenamide can cause or worsen renal impairment [33] .

Patent Information

As at December 2020, Gilead Sciences reported that tenofovir alafenamide, as a single agent treatment for hepatitis B virus infections, was protected by patent coverage in the US through 2025, and in the EU valid through 2026 [62]

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Tablet
  • Class Amines, Antivirals, Phosphorus compounds, Propionates, Purines, Small molecules
  • Target Nucleotide reverse transcriptase
  • Mechanism of Action Nucleotide reverse transcriptase inhibitors
  • WHO ATC code

    J05A (Direct acting antivirals)

  • EPhMRA code

    J5B (Antivirals, excluding anti-HIV products)

    J5C (HIV antivirals)

  • Chemical name propan-2-yl (2S)-2-[[[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate
  • Molecular formula C21 H29 N6 O5 P
  • SMILES N1=CN=C(N)C2=C1N(C=N2)CC(OCP(OC1C=CC=CC=1)(=O)NC(C(OC(C)C)=O)C)C
  • Chemical Structure
  • CAS Registry Number 379270-37-8

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

acquired immunodeficiency syndrome

Outcome Measure

CD4

1

hepatitis B

Inclusion

Creatinine

1

hepatitis B

Outcome Measure

RBP4

hemoglobin subunit epsilon 1

Creatinine

B2M

1

1

1

2

hepatitis C

Outcome Measure

SET nuclear proto-oncogene

RBP4

B2M

1

1

1

HIV infections

not specified

Neopterin

1

HIV infections

Inclusion

GM-CSF

1

HIV infections

Outcome Measure

SET nuclear proto-oncogene

RBP4

GM-CSF

B2M

1

1

1

2

HIV-1 infections

Inclusion

CD4

1

HIV-1 infections

Outcome Measure

CD4

2

Biomarker

Drug Name Biomarker Name Biomarker Function
Tenofovir alafenamide - Gilead Sciences 24,25-Dihydroxyvitamin D Outcome Measure
Alkaline phosphatase Outcome Measure
B2M Outcome Measure
beta-hCG Outcome Measure
CD4 Exclusion, Outcome Measure
CD8a Outcome Measure
CTx Outcome Measure
Cystatin C Outcome Measure
hemoglobin subunit epsilon 1 Outcome Measure
RBP4 Outcome Measure
SET nuclear proto-oncogene Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
HIV infections - Treatment-experienced Phase II Switzerland PO / Tablet University Hospital Inselspital 23 May 2017
HIV infections - Combination therapy, Treatment-experienced Phase I/II USA PO / Tablet Gilead Sciences, University of California 01 Apr 2019
HIV-1 infections - Treatment-experienced Phase III Dominican Republic, Germany, Russia, Thailand, USA, Uganda, United Kingdom PO / Tablet Gilead Sciences 25 Oct 2013
Hepatitis B HBeAg-negative and HBeAg-positive HBV disease Treatment-experienced, Treatment-naive Marketed Taiwan, USA PO / Tablet Gilead Sciences 29 Apr 2019
Hepatitis B ≥ 12 years and older with body weight at least 35 kg In adolescents, In adults, Treatment-experienced, Treatment-naive Registered China, European Union, Iceland, Liechtenstein, Norway PO / Tablet Gilead Sciences 18 Nov 2018
Hepatitis B - Treatment-experienced, Treatment-naive Registered Canada, Japan PO / Tablet Gilead Sciences 19 Jun 2017
Hepatitis B - Treatment-experienced, Treatment-naive Phase III Australia, Hong Kong, India, Italy, New Zealand, Russia, Singapore, South Korea, Turkey PO / Tablet Gilead Sciences 01 Sep 2013
Hepatitis B - Treatment-experienced Phase III Canada, Hong Kong, Italy, South Korea, Spain, Taiwan, United Kingdom PO / Tablet Gilead Sciences 29 Dec 2016
Hepatitis B - Treatment-experienced Phase II Switzerland PO / Tablet University Hospital Inselspital 23 May 2017
Hepatitis B - Combination therapy Phase II Hong Kong, New Zealand, South Korea PO / Tablet Gilead Sciences 01 Jul 2021
Hepatitis B - In adolescents, Treatment-experienced, Treatment-naive Phase II Belgium, Hong Kong, Russia, South Korea, USA PO / Tablet Gilead Sciences 01 Nov 2016
Hepatitis B - Treatment-naive Phase I/II Australia, New Zealand, United Kingdom PO / Tablet Gilead Sciences 31 Mar 2012

Orphan Status

Indication Patient Segment Country Organisation Event Date
HIV infections - Japan Japan Tobacco 19 Nov 2015

Commercial Information

Involved Organisations

Organisation Involvement Countries
Gilead Sciences Originator USA
Gilead Sciences Owner USA
Medicines Patent Pool Licensee World
Hetero Drugs Sub-licensee India
Cipla Sub-licensee India
Aurobindo Pharma Sub-licensee India
Laurus Labs Sub-licensee India
Desano Pharma Sub-licensee China
Emcure Pharmaceuticals Sub-licensee India
University of Gothenburg Collaborator Sweden
University of North Carolina Collaborator USA
University Hospital Inselspital Collaborator Switzerland
Vir Biotechnology Collaborator USA
University of California Collaborator USA
Erasmus MC Collaborator Netherlands

Brand Names

Brand Name Organisations Indications Countries
Vemlidy Gilead Sciences Hepatitis B Canada, European Union, Japan, USA

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
HIV/Hep B- TAF ex US Gilead Sciences Marketed 2016 100 2026 - 01 Feb 2021
HIV/Hep B- TAF US Gilead Sciences Marketed 2016 100 - - 01 Feb 2021

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
HIV/Hep B- TAF ex US 0 11 76 179 170 85 43 0 0 0 01 Feb 2021
HIV/Hep B- TAF US 0 111 245 309 294 147 73 0 0 0 01 Feb 2021
Total 0 122 321 488 464 232 116 0 0 0

Scientific Summary

Pharmacokinetics

Dogs and rhesus monkeys were dosed orally with tenofovir alafenamide; plasma and peripheral blood mononuclear cells (PBMCs) were collected over 24h and analysed for tenofovir and tenofovir alafenamide. The bioavailability of tenofovir in dogs and monkeys was approximately 20%. A single oral dose of GS 7340 in dogs and monkeys increased the concentration of tenofovir in PBMCs (AUC0-24) by >38-fold compared with an oral dose of tenofovir disoproxil fumarate (TDF). Efficient accumulation of tenofovir in lymphoid tissue was also observed at 24h [65] .

Adverse Events

Phase

III: In phase III trial, the rates of adverse events (AEs) of ≥ grade 2 and serious AEs were low and similar between tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) groups. No viral resistance was observed in the 1.2% (3/243) and 0.8% (2/245) TAF and TDF patients, respectively, who qualified for testing tenofovir alafenamide. The data was from 488 patients with virologically suppressed chronic hepatitis B who were switched to TAF [21] [20] .

Pooled analysis

Phase III:

Updated results from two phase III Study 108 and Study 110 indicated that tenofovir alafenamide (TAF) was safe and well tolerated with improved renal and bone safety in patients switching from tenofovir disoproxil fumarate (TDF). Rates of Grade 3/4 adverse events (AEs) and AEs leading to discontinuation were low and similar among groups. Previous results indicated that discontinuations due to adverse events were uncommon in both treatment arms (0.7% (n=2) for TAF vs. 0.7% (n=1) for tenofovir disoproxil fumarate in Study 108, and 1.0% (n=6) for tenofovir alafenamide vs. 1.0% (n=3) for tenofovir disoproxil fumarate in Study 110). The adverse events and serious adverse events were similar between older versus younger patients. There were no grade 3/4 AEs related to study drug in patients ≥ 65 reported. Most common adverse events reported in both studies included headache, upper respiratory tract infection, abdominal pain, fatigue, nausea, back pain, nasopharyngitis and cough, and occurred at similar rates in patients receiving either TAF or tenofovir disoproxil fumarate. TAF, compared with tenofovir disoproxil fumarate, demonstrated improvement in bone and renal laboratory safety parameters [35] [17] [6] [8] [31] [28] .

A tenofovir alafenamide-based regimen was generally well-tolerated in a phase II study (Study 102), and no patient discontinued treatment due to renal adverse events. The frequency and nature of adverse events were generally similar between both arms. Grade 1 to 2 adverse events made up 90% of the adverse events. The most common adverse events occurring in at least 5% of tenofovir alafenamide recipients were nausea (18% vs. 12% for Stribild®), diarrhoea (12% in both study arms), fatigue (12% vs. 9% for Stribild®), headache (10% in both arms), upper respiratory tract infection (7% for vs. 12% for Stribild®) and flatulence (5% vs. 3% for Stribild®). There were no treatment-related serious adverse events in either treatment arm. Discontinuations due to adverse events were 3.6% vs. 0% for the tenofovir alafenamide and Stribild® arms, respectively. No statistically significant differences were seen in the frequency of laboratory abnormalities between patients receiving tenofovir alafenamide and those receiving Stribild®. Patients in this study received a once-daily single tablet regimen containing tenofovir alafenamide 10mg/elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg, or Stribild® [39] [40] .

Results from the phase III Study 110 revealed that the rates of treatment discontinuations for adverse events (<1.5%) and serious adverse events (≤6%) were low and similar across the two arms [27] [28] .

Phase II

Group A

The data is from 93 patients. At week 96 in virally suppressed CHB patients with moderate or severe renal impairment or ESRD on HD, TAF was well tolerated, with no grade 3/4 or serious adverse events related to treatment [63] . The data is from 93 patients. At week 48, in virally suppressed CHB patients with renal impairment, TAF was well tolerated, with no grade 3/4 or serious adverse events related to study drug (moderate-severe impairment 78; ESRD 15). Earlier at week 24 study, 7.5% grade 3 or 4 adverse events were reported. No serious adverse events related to study or discontinuations due to AEs were reported [44] [47] [45] .

Group B

The 96 weeks study data in virally suppressed CHB patients with hepatic impairment was well tolerated. Twenty- five (81%) patients completed 96 weeks of TAF treatment, out of which 6 discontinued early; 2-withdrew consent, 1-adverse event (grade 2 creatinine increase), 1-investigator decision, and 2-death (both not treatment- related). None of the patients showed any grade 3 or 4 adverse event (AE) or a serious AE related to treatment [48] [45] . The data is from 31 patients. At week 48, in CHB patients with hepatic impairment TAF was well tolerated with few having Grade 3 or 4 AEs (four patients); no serious AEs related to study drug, and one patient discontinued for worsening renal function unrelated to TAF [46]

In the Study 108, at week-96, rates of treatment discontinuations (< 2%) and occurrence of serious adverse events (≤ 11%) were similar in tenofovir alafenimide (TAF) and tenofovir disoproxil fumarate (TDF) arms. In the double-blind trial, 425 patients were randomised to receive TAF 25mg QD (n = 285) or TDF 300mg QD (n = 140) for 144 weeks [30] [31] .

Results from a phase II trial conducted in 51 adult chronic hepatitis B infection patients with stage 2 or greater chronic kidney disease demonstrated that serious adverse events were lower in the tenofovir alafenamide arm compared to the tenofovir DF arm (12% vs 24%); there were no treatment discontinuations [50] [51] .

Pharmacodynamics

Summary

Phase III:

Pharmacodynamics results form a phase III trial showed that out of total 873 patients, HBeAg loss and seroconversion occurred in 194 (22%) and 142 (16%) patients, respectively, at the end of 144 weeks. Patients with HBeAg loss had lower median HBsAg levels (3.8 versus 4.3 log10 IU/mL), higher median BL ALT (101 versus 83 U/L), higher prevalence of presumed cirrhosis (FibroTest ≥0.75: 13.2% versus 6.4%); lower median BL serum HBV DNA (7.7 versus 8.1 log10 IU/mL) and were infected with non-genotype D HBV (86% versus 75%) (All changes were statistically significant) [26] [28] .

Phase II:

In the phase II trial switching to tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) maintained HBV DNA <20 IU/mL and a high proportion had normal ALT levels, at week 24. Relative to baseline levels, switching to TAF from TDF resulted in increases in hip and spine BMD, decreases in bone turnover markers, as well as an increase in eGFR and improved markers of renal tubular function [44] [45] .

In Study 110, increases in serum creatinine were observed in patients receiving TAF (p = 0.02) [8] [28]

Antimicrobial Activity

Summary

Tenofovir alafenamide had 5- to 10-fold and 500- to 1000-fold greater anti-HIV activity than tenofovir disoproxil fumarate and tenofovir, respectively, in tissue culture. The prodrug had EC50 values of 5 nmol/L against HIV in MT-2 cells, mitogen-stimulated primary lymphocytes and primary macrophages. The EC50 value against hepatitis B virus in HepG2 cells was approximately 10 nmol/L [65] .

Therapeutic Trials

Phase III:

TAF met its primary endpoints in the phase III trial (Study 108) evaluating HBeAg-negative patients treated with tenofovir alafenamide or tenofovir disoproxil fumarate. At week 48, HBV DNA below 29 IU/mL was achieved by 94% (n=268/285) of patients receiving TAF and 92.9% percent (n=130/140; CI -3.6 to +7.2%; p=0.47) of patients receiving tenofovir disoproxil fumarate [8] .

The phase III study met its primary endpoint as at week 48, tenofovir alafenamide (TAF) demonstrated non-inferior efficacy to tenofovir disoproxil fumarate (TDF) with a similar rate (0.4%) having HBV DNA ≥ 20 IU/ml (difference in proportions: 0.0%, 95% CI − 1.9% to +2.0%), in patients with chronic hepatitis B (CHB). Increase in hip/spine bone mineral density was observed with less impact on bone turnover makers. In patients who were switched from TDF to TAF, increase in eGFR and decreases in markers of tubular Cockcroft- Gault (eGFR CG) function were observed. The data was from 488 patients with virologically suppressed CHB. At week 48, TDF patients switched to TAF showed improvements in renal (sCr, eGFRCG) parameters. Improvements in hip and spine BMD were seen at 48 weeks following switch. Antiviral efficacy was maintained in both groups (HBV DNA <20 IU/mL: TAF 96.7% vs TDF 96.6%, p=0.96) and TDF patients switching to TAF had similar rates of normal ALT, and similar serological responses at week 48. Out of 488 patients, 358 (73%) had at least 1 risk factor, while 192 (39%) patients had >2 risk factors present at baseline. Baseline demographics of patients with at least 1 risk factor were similar between both treatment groups. Comparable increases were reported in median eGFRCG (0.87 vs. 1.03 ml/min, p=0.95), median % decreases in tubular biomarkers (beta‐2 microglobulin/creatinine ratio, ‐36.0 vs ‐36.1 μg/g, p=0.75; retinol binding protein/creatinine ratio, ‐15.8 vs ‐17.8, p=0.67), increases in mean % change in hip (0.69 vs 0.64, p=0.84) and spine (1.84 vs 1.67, p=0.71) bone mineral density, and median % decreases in bone turnover markers (C‐type collagen sequence, ‐29.8 vs ‐28.8 ng/mL, p=0.57; procollagen type 1 N‐terminal propeptide, ‐20.4 vs ‐17.7, p=0.16) among patients previously treated with TDF for <4 and ≥4 years, respectively. Change in the fasting lipid parameters were not influenced by treatment duration. At 96 weeks, virologic suppression (HBV DNA <20 IU/ mL) was similarly maintained in patients switched to tenofovir alafenamide treatment at baseline versus, those switched to tenofovir alafenamide after 48 weeks of double blind tenofovir disoproxil fumarate treatment. There was increased rate of ALT normalisation in both groups at week 96. Similar increases in spine BMD were observed while increases in hip BMD were smaller in patients switched to tenofovir alafenamide at baseline versus, those switched at week 48. In the tenofovir disoproxil fumarate group, eGFR CG decreased at week 48 ( − 2.7 mL/ min); at week 96 an improvement was seen after switching to tenofovir alafenamide ( − 0.39 mL/min) [25] [23] [21] [20] .

Pooled analysis

Phase III

Pooled results from two phase III studies (108 study and 110 study) in HBeAg-positive (n = 425) and HBeAg-negative (n = 873) patients with chronic hepatitis B, treated with tenofovir alafenamide (TAF) 25 mg or tenofovir disoproxil fumarate (TDF) 300 mg once daily demonstrated that antiviral efficacy of TAF was non-inferior to that of TDF with superior renal and bone safety. After 5 years of treatment virologic suppression rates remained high with improved renal and bone safety in patients switching from TDF. High rates of virologic control were achieved and maintained in patients receiving TAF throughout and for TDF patients who rolled over to TAF at Weeks 96 or 144. Rates of ALT normalization and serologic responses were also comparable among groups. After experiencing declines in eGFRCG and in hip/spine BMD over 2 or 3 years of TDF treatment, renal and bone outcomes were improved following the switch to open-label (OL) TAF [35] .Previous results showed similar viral suppression rates over two years. At week 48 and 96, there were similar rates of viral suppression for TAF versus TDF (77% versus, 79% and 87% versus, 88%, respectively). Relative to the highest viral load level (≥8 log10 IU/mL), rates of ALT normalisation did not differ by baseline HBV DNA categories in the overall population by MV analysis. TAF treatment was noted to be a significant predictor. Baseline HBV DNA levels did not impact rates of ALT normalisation with TAF, whereas a parabolic pattern was observed (higher rates at HBV DNA ≥7 to <8 and <5 log10 IU/mL) with TDF. Other factors significantly associated (p<0.05) with a reduced rate of ALT normalization were history of fatty liver (both treatments), increased prothrombin time (TDF), and HBeAg-positive status and diabetes (TAF). Earlier results showed reduction in the incidence of hepatocellular carcinoma (HCC) through four years. Through four years of follow‐up, HCC occurred in 16/1632 patients (0.98%; TAF 7/1 093 [0.64%]; TDF 9/539 [1.67%]). Out of 16 cases of HCC, five and 11 were in cirrhotic and non cirrhotic patients respectively. Median (Q1, Q3) time to HCC onset was 566 (318, 855) days (TAF 747 [392, 1370], TDF 460 [180, 729] days). At baseline, relative to those without HCC, patients with HCC were older (median age 53 versus 40 years; p < 0.001), had lower HBV DNA (6.3 versus 7.3 log10 IU/mL; p = 0.041), and were more likely to be cirrhotic (FibroTest score ≥0.75; 31% versus 10%; p = 0.004). With treatment (TAF or TDF), HCC incidence was significantly reduced (16 observed versus 35.3 predicted; SIR [95% CI] 0.45 [0.278 ‐0.740]) [Table]. For TAF‐treated patients, a significant risk reduction was seen (seven observed versus 22.4 predicted, SIR [95% CI] 0.31 [0.149‐0.655]), whereas with TDF there was a reduction in incidence but it did not achieve significance (nine observed versus 12.9 predicted, SIR [95% CI] 0.7 [0.364, 1.344]) [36] [34] . Combined results from two phase III trials (Study 108 and Study 110) demonstrated statistically significant increase in ALT normalisation levels in patients treated with tenofovir alafenamide (TAF) as compared with those treated with tenofovir disoproxil fumarate (TDF). Significant increases in eGFR from open-label baseline were observed within each group at week 192. Significant CG increases in hip and spine BMD from open-label baseline occurred within each group, the magnitude was greater after 2 years of open-label tenofovir alafenamide only for hip BMD. Within each group, virologic suppression (HBV DNA < 29 IU/ml) was maintained from open-label baseline to week 192 in patients who remained on TAF treatment (open-label tenofovir alafenamide 96 week group: 88% and 88%; open-label tenofovir alafenamide 48 week group: 94% and 93%, respectively), while at week 192, within each group the rate of ALT normalisation increased from open-label baseline after switching to TAF (55% open-label tenofovir alafenamide 96 week and 37% open-label tenofovir alafenamide 48 week). At week 48 patients receiving TAF experienced significantly smaller mean percentage decrease from baseline in hip and spine bone mineral density (p<0.001). Additionally, the median change in estimated glomerular filtration rate (eGFR) from baseline to week 48 favored TAF in both studies (p < 0.01). A post-hoc analysis evaluated a subset of 541 patients from Studies 108 and 110 who completed 96 weeks of treatment with double-blind TAF or TDF and were then switched to open-label treatment TAF. Among patients switched from TDF to TAF at week 96 (n=180), virologic suppression was maintained and the rates of ALT normalization by central laboratory criteria and AASLD criteria significantly increased during the subsequent 24 weeks of TAF therapy. One-year data showed that high rates of virologic suppression (HBV DNA <29 IU/mL) were maintained in both groups (TDF to TAF 84% and DB TDF 88%; p=0.31 [M=F]), while a greater rate of ALT normalization was seen in TDF to TAF patients at 1 year following switch (45% vs 29% by 2018 AASLD criteria; p=0.043 [M=F]). Virologic response rates at Week 96 were 90% (n=257/285) and 91% (n=127/140) in HBeAg-negative patients (Study 108) receiving TAF and over TDF, respectively. In HBeAg-positive patients (Study 110), virologic response rates at Week 96 were 73 percent (n=423/581) and 75 percent (n=218/292) in the TAF and TDF groups, respectively. Patients receiving TAF also demonstrated ongoing benefits at Week 96 in bone and renal safety parameters, including smaller declines from baseline in hip and spine bone mineral density (BMD) and smaller declines from baseline in estimated creatinine clearance compared with patients taking TDF in both studies. Viral resistance analyses showed no resistance to TAF or TDF at Week 96. The randomised, double-blinded phase III studies evaluated the use of TAF given once-daily versus TDF given once-daily in treatment-naïve and treatment-experienced adults with HBeAg-negative and HBeAg-positive chronic HBV infection. Further, over one year, significant improvements in hip and spine BMD were seen in patients switching from TDF to TAF while those remaining on TDF either had continued decline (hip BMD) or a smaller increase (spine BMD) [29] [8] [33] [32] [31] [28] .

Phase II:

Patients receiving a tenofovir alafenamide-based regimen showed a similar virological response to those receiving Stribild® (87% versus 90%, respectively; primary endpoint), according to 24-week results of a phase II trial (Study 102) in treatment-naive patients with HIV-1 infection. Significantly smaller reductions from baseline were also seen in bone mineral density at the lumbar spine and hip (p < 0.005) among patients receiving the tenofovir alafenamide-based regimen, and small differences were seen in serum creatinine and calculated creatinine clearance in favour of the tenofovir alafenamide-based regimen (p < 0.02). Patients in this study received a once-daily single tablet regimen containing tenofovir alafenamide 10mg/elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg, or Stribild® (containing tenofovir disoproxil 300mg/elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg) [2] [39] [40] .

At 14 days, tenofovir alafenamide (50 mg/day) or tenofovir alafenamide (150 mg/day) were associated with significantly greater time-weighted decreases from baseline in plasma HIV-1 RNA levels, compared with tenofovir disoproxil fumarate (-0.95 and -1.07, respectively, vs -0.54 log10 copies/mL; p < 0.05 and p < 0.001, respectively; primary endpoint), in 30 patients with HIV-1 infections in a phase II trial [64] .

Group A

In phase II trial evaluating the switching to TAF in virally suppressed CHB patients with moderate or severe renal impairment or ESRD on HD, the 96 weeks study results demonstrated that the renally-impaired CHB patients, including ESRD patients on HD, those were switched to TAF from TDF and/or other OAVs maintained high rates of viral suppression, and bone and renal parameters remained stable or slightly improved after 2 years of treatment. The data is from 93 patients (moderate-severe impairment 78; ESRD 15) out of 93 patients enrolled, twelve (13%; 11 mod-severe RI and 1 ESRD) patients discontinued the study early (5-withdrew consent, 3-deaths [none treatment-related], 2-AE, and 2-investigator decision).Relative to baseline levels, switching to TAF resulted in small median % increases in hip/spine BMD in those with moderate to severe RI, and small median decreases in ESRD patients. 2 patients with mod-severe RI had a bone fracture (ankle, rib). Median eGFR CG increased while urinary markers of proximal tubular function progressively decreased in moderate to severe RI patients [63] . HBV DNA<20 IU/mL was maintained in nearly all patients and a high proportion had normal ALT levels. Five patients discontinued study drug early (withdrew consent) with last available HBV DNA <20 U/mL; one patient had HBV DNA ≥20 IU/mLand one patient died. Relative to baseline levels, switching to TAF resulted in stable hip/spine bone mineral density (BMD) in moderate to severe renal impairment patients, with a slight decrease in hip BMD in end stage renal disease (ESRD) patients. Slight improvements were observed in renal parameters including estimated Glomerular Filtration Rate by the Cockcroft-Gault formula (eGFR CG) and markers of renal tubular function in moderate to severely impaired patients. Switching to TAF showed maintenance of viral suppression with stable or improved bone and renal safety at week 24 in CHB patients with moderate to severe renal impairment (eGFR by Cockcroft-Gault [eGFRCG] <60 mL/ min) and ESRD patients on HD [47] [45] .

Group B

The results from the 96 weeks study in virologically suppressed chronic Hepatitis B patients with hepatic impairment demonstrated that out of 31 patients enrolled, six patients discontinued the study, with two patients withdrawing the consent; one as per the investigator's decision; one with creatinine increase and two patients died. The study with the remaining 25 patients, who completed the 96 weeks of TAF treatment demonstrated that 96% of patients had HBV DNA <20 IU/ml with a high proportion having normal alanine aminotransferase (ALT) levels. The median (Q1, Q3) Child-Turcotte-Pugh (CTP) and MELD scores were 6 (5, 8) and 10 (7.5, 14.2), respectively. A normal eGFRCG was reported to be 98.5 ml/min. 19% patients had osteoporosis on spine DXA. The bone and renal parameters also remained stable [48] . Results at week 48 demonstrated that all 31 patients showed HBV DNA <20 IU/mL, 81% had normal ALT and CTP/MELD scores were stable. After switching to tenofovir alafenamide in the evaluated patients, CTP, MELD, and FT scores were unchanged while bone and renal parameters were stable [46] .

Updated results from the phase III, Study 110, evaluating HBeAg-positive patients showed virological response rates of 73% and 75% in the TAF and TDF groups, respectively (adjusted difference in proportions: −2.2%, 95% CI, −8.3% to +3.9%). A greater percentage of TAF patients achieved normalisation of serum ALT values with similar proportions of TAF and TDF patients experiencing HBeAg loss and HBsAg loss was uncommon. Patients on TAF experienced lesser changes in hip and spine BMD than TDF patients through 96 weeks of treatment. There were smaller declines in eGFRCG and smaller changes in renal tubular markers observed with TAF at week 48, which remained through week 96. Earlier results from the study demonstrated that 63.9% (n=371/581) of tenofovir alafenamide patients and 66.8 percent (n=195/292; CI -9.8% to +2.6%; p = 0.25) of tenofovir disoproxil fumarate patients achieved HBV DNA below 29 IU/mL at week 48. Smaller increases in serum creatinine were observed in patients receiving TAF in Study 110 (p=0.02) [27] [8] [28] .

Results from a phase II trial conducted in 51 adult chronic hepatitis B infection patients with stage 2 or greater chronic kidney disease demonstrated that following 48 weeks of tenofovir alafenamide (TAF) treatment, all patients had HBV DNA <20 IU/mL. Median increases in eGFR CKD-EPI were greater in patients who received TAF compared to those who continued tenofovir DF (TDF) therapy (median change: +3.9 vs. +0.2 mL/min/1.73m 2 , respectively). In the TAF group, increases in hip and spine BMD changes were seen compared with decreases in TDF treated patients at Week 48 (mean [SD] percent change for TAF vs TDF: spine: +0.689 [4.24] vs. -0.762 [3.20] p=0.20; hip: +1.007 [1.44] vs. -0.334[2.57] p=0.03). The differences in changes in eGFR CKD-EPI and BMD between TDF and TAF treatment were greater in patients with baseline risk factors for severe renal dysfunction such (age>60y, eGFR CKD-EPI <50mL/ min/1.73m 2 and calcineurin inhibitors use [50] [51] .

In a long term pooled analysis from two phase III trials that evaluated impact of hepatitis B treatment on hepatocellular carcinoma (HCC) incidence, 1 632 hepatitis B infection patients were randomized to receive either tenofovir alafenamide or tenofovir disoproxil fumarate once daily in two cohorts. One percent patients from tenofovir alafenamide cohort developed hepatocellular carcinoma and 1.9% patients from tenofovir disoproxil fumarate cohort hepatocellular carcinoma, with median onset time of 104 weeks. HCC incidences observed were significantly lower than the predicted incidence using the REACH-B model [19] .

Future Events

Expected Date Event Type Description Updated
15 Jul 2021 Trial Update Gilead Sciences in collaboration with Vir Biotechnology plans a phase IIa trial for chronic Hepatitis B (Combination therapy) in July 2021 (NCT04891770) (700337265) (PO, tablet) 13 Jul 2021
30 Jun 2017 Trial Update Gilead Sciences plans a phase II trial for Hepatitis B (NCT03180619) 26 Jul 2017
31 May 2017 Trial Update University Hospital Inselspital plans a phase II trial for HIV infection and Hepatitis B (NCT03115736) 26 Jul 2017

Development History

Event Date Update Type Comment
01 Jul 2021 Phase Change - II Phase-II clinical trials in Hepatitis B (Combination therapy) in New Zealand (PO) (NCT04891770) Updated 13 Jul 2021
03 Jun 2021 Scientific Update Updated safety and efficacy data from a phase II trial in Hepatitis B presented at the the International Liver Congress 2021 (ILC-2021) [48] [63] Updated 18 Aug 2021
21 May 2021 Trial Update Gilead Sciences in collaboration with Vir Biotechnology plans a phase IIa trial for chronic Hepatitis B (Combination therapy) in July 2021 (NCT04891770) (PO, tablet) Updated 13 Jul 2021
05 May 2021 Trial Update Gilead Sciences completes a phase II trial for Hepatitis B (Treatment-experienced) in New Zealand (PO) (NCT02862548; ACTRN12616000898459p) Updated 15 Jun 2021
01 Feb 2021 Financial Update Credit Suisse financial data update Updated 14 Mar 2021
26 Jan 2021 Trial Update Gilead Sciences completes a phase II trial in Hepatitis B (Combination therapy) in Hong Kong, South Korea (PO) (NCT03434353) Updated 17 Feb 2021
31 Dec 2020 Patent Information Gilead Sciences has patent protection for tenofovir alafenamide in USA and European Union [62] Updated 28 Apr 2021
13 Nov 2020 Scientific Update Pooled efficacy and safety data from two phase III trials (108 study and 110 study) for Hepatitis B presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2020) [36] Updated 22 Jan 2021
20 Oct 2020 Trial Update Gilead Sciences completes a phase II trial for Hepatitis B (Treatment-experienced) in Canada, Hong Kong, Italy, New Zealand, South Korea, Taiwan, France and United Kingdom (PO, Tablet) (NCT03180619) Updated 20 Oct 2020
27 Aug 2020 Scientific Update Efficacy and adverse events data from a phase II trial in Hepatitis B presented at the the International Liver Congress 2020 (ILC-2020) [46] [47] Updated 16 Oct 2020
27 Aug 2020 Scientific Update Efficacy data from a phase III in Hepatitis B presented at the The International Liver Congress 2020 (ILC-2020) [25] Updated 16 Oct 2020
30 Jan 2020 Trial Update Gilead Sciences completes a phase III trial for Hepatitis B in USA, Canada, Hong Kong, Italy, South Korea, Spain, Taiwan and United Kingdom (NCT02979613) Updated 12 Mar 2020
10 Nov 2019 Scientific Update Pooled efficacy data from two phase III trials in Hepatitis B infections released by Gilead Sciences [19] Updated 21 Nov 2019
08 Nov 2019 Scientific Update Efficacy data from a phase III trial for Hepatitis B presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2019) [23] [22] Updated 29 Feb 2020
08 Nov 2019 Scientific Update Pharmacodynamic and adverse events data from a phase II trial in Hepatitis B presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2019) [44] Updated 29 Feb 2020
08 Nov 2019 Scientific Update Pooled efficacy data from two phase III trial for Hepatitis B presented at the 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2019) [34] Updated 29 Feb 2020
25 Sep 2019 Trial Update Gilead Sciences completes enrolment in its phase III trial for Hepatitis B in USA, Canada, Hong Kong, Italy, South Korea, Spain, Taiwan and United Kingdom (NCT02979613) Updated 29 Feb 2020
30 Aug 2019 Trial Update Gilead Sciences plans a phase I trial for Hepatitis B (In healthy adults) in USA (PO) (EudraCT2019-003269-16) Updated 06 Sep 2019
29 Apr 2019 Phase Change - Marketed Launched for Hepatitis B (Treatment-naive, Treatment-experienced) in Taiwan (PO) before April 2019 [15] Updated 03 May 2019
10 Apr 2019 Scientific Update Efficacy and adverse events data from a phase-III trial for Hepatitis B presented at the International Liver Congress (ILC-2019) [21] Updated 17 Sep 2019
10 Apr 2019 Scientific Update Updated efficacy data from two phase III trials in Hepatitis B presented at the International Liver Congress 2017 (ILC-2019) [29] Updated 17 Sep 2019
01 Apr 2019 Phase Change - I/II Phase-I/II clinical trials in HIV infections (Treatment-experienced, Combination therapy) in USA (PO) (NCT03251144) Updated 06 May 2021
18 Nov 2018 Phase Change - Registered Registered for Hepatitis B (Treatment-naive, Treatment-experienced, In adults, In adolescents) in China (PO) [17] Updated 21 Nov 2018
09 Nov 2018 Scientific Update Updated efficacy data from two phase III trials in Hepatitis B presented at the 69th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2018) [32] Updated 10 Dec 2018
09 Nov 2018 Scientific Update Adverse events and efficacy data from a phase II trial in Hepatitis B presented at the 69th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2018) [50] (NCT02862548) Updated 07 Dec 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
02 Jun 2018 Scientific Update Pharmacodynamics data from a phase III trial in Hepatitis B presented at the Digestive Disease Week 2018 (DDW-2018) [26] Updated 11 Jul 2018
28 Feb 2018 Phase Change - II Phase-II clinical trials in Hepatitis B (Combination therapy) in Hong Kong (PO) (NCT03434353) Updated 17 Feb 2021
27 Feb 2018 Phase Change - Preregistration Preregistration for Hepatitis B (Treatment-naive, Treatment-experienced) in China (PO) [18] Updated 28 Feb 2018
01 Feb 2018 Phase Change - II Phase-II clinical trials in Hepatitis B (Combination therapy) in South Korea (PO) (NCT03434353) Updated 04 Mar 2018
09 Aug 2017 Phase Change - Marketed Launched for Hepatitis B (Treatment-naive, Treatment-experienced) in USA before August 2017 (PO) Updated 09 Aug 2017
31 Jul 2017 Trial Update Gilead Sciences completes a phase III trial in HIV-1 infections (Treatment experienced) in Uganda, Thailand, Dominican Republic, Russia, United Kingdom, Germany, USA (PO) (EudraCT2013-002830-19) (NCT01967940) Updated 18 Sep 2017
29 Jun 2017 Trial Update Gilead Sciences initiates enrolment in a phase II trial for Hepatitis B (Treatment-experienced) in Canada, Hong Kong, Italy, New Zealand, South Korea, Taiwan, France and United Kingdom (PO, Tablet) (NCT03180619) Updated 20 Oct 2020
29 Jun 2017 Trial Update Gilead Sciences initiates enrolment in a phase II trial for Hepatitis B (Treatment-experienced) in USA (PO, Tablet) (NCT03180619) Updated 26 Jul 2017
19 Jun 2017 Phase Change - Registered Registered for Hepatitis B (Treatment-naive, Treatment-experienced) in Canada (PO) [16] Updated 24 Jun 2017
12 Jun 2017 Trial Update Gilead Sciences plans a phase II trial for Hepatitis B (NCT03180619) Updated 26 Jul 2017
23 May 2017 Phase Change - II Phase-II clinical trials in HIV infections and Hepatitis B(Treatment-experienced) in Switzerland (PO) (NCT03115736) Updated 26 Jul 2017
20 Apr 2017 Scientific Update Efficacy data from two phase III trials in Hepatitis B released by Gilead [33] Updated 26 Apr 2017
19 Apr 2017 Scientific Update Adverse events data from a phase III trial in Hepatitis B at the International Liver Congress 2017 (ILC-2017) [30] Updated 27 Jul 2017
19 Apr 2017 Scientific Update Efficacy and adverse events data from a phase III trial in Hepatitis B presented at the The International Liver Congress 2017 (ILC-2017) [27] Updated 25 Jul 2017
18 Apr 2017 Trial Update University Hospital Inselspital plans a phase II trial for HIV infection and Hepatitis B (NCT03115736) Updated 26 Jul 2017
05 Apr 2017 Trial Update Kindai University plans a clinical trial for Hepatitis B in Japan (UMIN000026465) Updated 05 Apr 2017
11 Jan 2017 Phase Change - Registered Registered for Hepatitis B (Treatment-naive, Treatment-experienced, In adolescents, In adults) in Liechtenstein, Iceland, Norway, European Union (PO) [12] Updated 13 Jan 2017
01 Jan 2017 Phase Change - Preregistration Preregistration for Hepatitis B (Treatment-naive, Treatment-experienced) in Taiwan (PO) before January 2017 [15] Updated 03 May 2019
01 Jan 2017 Phase Change - Registered Registered for Hepatitis B (Treatment-naive, Treatment-experienced) in Taiwan (PO) [15] Updated 03 May 2019
29 Dec 2016 Phase Change - III Phase-III clinical trials in Hepatitis B (Treatment-experienced) in United Kingdom, Taiwan, Spain, South Korea, Italy, Hong Kong, Canada (PO) (NCT02979613) Updated 29 Feb 2020
19 Dec 2016 Phase Change - Registered Registered for Hepatitis B (Treatment-naive, Treatment-experienced) in Japan (PO) [10] Updated 22 Dec 2016
01 Dec 2016 Trial Update Gilead Sciences initiates enrolment in a phase III trial for Hepatitis B (Treatment-experienced) in USA (PO, Tablet) (NCT02979613) Updated 14 Feb 2017
29 Nov 2016 Trial Update Gilead Sciences plans a phase III trial for Hepatitis B (Treatment-experienced) in USA, Canada, Hong Kong, Italy, South Korea, Taiwan, Spain and United Kingdom (PO, Tablet) (NCT02979613) Updated 07 Dec 2016
11 Nov 2016 Regulatory Status Gilead receives CHMP positive opinion for tenofovir alafenamide in Hepatitis B (Treatment naive, Treatment experienced, In adults, In adolescents) [13] Updated 14 Nov 2016
10 Nov 2016 Phase Change - Registered Registered for Hepatitis B (Treatment-naive, Treatment-experienced) in USA (PO) [5] Updated 14 Nov 2016
10 Nov 2016 Regulatory Status The US approved label of tenofovir alafenamide carries a black box warning [5] Updated 14 Nov 2016
01 Nov 2016 Phase Change - II Phase-II clinical trials in Hepatitis B (In adolescents, Treatment-naive, Treatment-experienced) in South Korea, Hong Kong, Russia and Belgium (PO) (NCT02932150) Updated 24 Jun 2017
01 Nov 2016 Trial Update Gilead Sciences and University of North Carolina completes a phase-I pharmacokinetic study in healthy female volunteers in USA (NCT02357602) Updated 09 Dec 2016
01 Sep 2016 Phase Change - II Phase-II clinical trials in Hepatitis B (In adolescents, Treatment-experienced, Treatment-naive) in USA (PO) (NCT02932150) Updated 08 Dec 2016
01 Sep 2016 Trial Update Gilead Sciences initiates a phase II trial for Hepatitis B (Treatment-experienced) in New Zealand (PO) (NCT02862548; ACTRN12616000898459p) Updated 20 Oct 2016
26 Aug 2016 Trial Update Gilead Sciences plans a phase II/III trial for Hepatitis B (In adolescents, Treatment-experienced, Treatment-naive) in USA, Russia, Hong Kong, South Korea and Taiwan (PO) (EudraCT2016-000785-37) Updated 02 Sep 2016
07 Jul 2016 Trial Update Gilead Sciences plans a phase II trial for Hepatitis B (Treatment-experienced) in New Zealand (PO) (ACTRN12616000898459p) Updated 11 Jul 2016
15 Apr 2016 Regulatory Status FDA assigns PDUFA action date of 11/11/2016 for tenofovir alafenamide for Hepatitis B (Treatment-naïve, Treatment-resistant) Updated 25 Apr 2016
31 Mar 2016 Phase Change - Preregistration Preregistration for Hepatitis B (Treatment-naive, Treatment-experienced) in Japan (PO) [11] Updated 05 Apr 2016
07 Mar 2016 Trial Update University of Gothenburg initiates a phase IV trial for HIV-1 infections in Sweden (PO) (EudraCT2015-004427-31) Updated 15 Apr 2016
25 Feb 2016 Phase Change - Preregistration Preregistration for Hepatitis B (Treatment-naive, Treatment-experienced) in European Union (PO) prior to February 2016 [14] Updated 29 Feb 2016
25 Feb 2016 Regulatory Status The EMA validates the MAA for tenofovir alafenamide for Hepatitis B (Treatment-naive, Treatment-experienced) [14] Updated 29 Feb 2016
12 Jan 2016 Phase Change - Preregistration Preregistration for Hepatitis B (Treatment-naive, Treatment-experienced) in USA (PO) [7] Updated 14 Jan 2016
12 Jan 2016 Regulatory Status Gilead announces its intention to file MAA to the European Medicines Agency in the first quarter of 2016 [7] Updated 14 Jan 2016
07 Jan 2016 Scientific Update Top-line efficacy, pharmacodynamics and adverse events data from a phase III trial (Study 110) in Hepatitis B released by Gilead Sciences [8] Updated 07 Jan 2016
05 Jan 2016 Scientific Update Top-line efficacy and adverse events data from a phase III trial (Study 108) in Hepatitis B released by Gilead Sciences [8] Updated 07 Jan 2016
19 Nov 2015 Regulatory Status Tenofovir alafenamide - Gilead Sciences receives Orphan Drug status for HIV infections in Japan (PMDA website, December 2015) Updated 16 Mar 2020
01 May 2015 Trial Update Gilead Sciences and University of North Carolina initiates enrolment in a phase I pharmacokinetic study in healthy female volunteers in USA (NCT02357602) Updated 02 Jun 2015
01 Apr 2015 Trial Update Gilead Sciences completes a phase I pharmacokinetics study for Hepatitis B in USA, Germany and New Zealand (NCT02296853) Updated 02 Jun 2015
11 Feb 2015 Trial Update Gilead Sciences and University of North Carolina plan a phase I pharmacokinetic study in healthy female volunteers in USA (NCT02357602) Updated 11 Feb 2015
01 Dec 2014 Trial Update Gilead Sciences initiates enrolment in a phase I pharmacokinetics study for Hepatitis B in USA (NCT02296853) Updated 10 Jan 2015
01 Dec 2014 Licensing Status Gilead Sciences enters into a manufacturing and distribution agreement with Mylan Laboratories Limited [1] Updated 06 Dec 2014
25 Nov 2014 Trial Update Gilead Sciences plans a phase I pharmacokinetics study for Hepatitis B in USA, Germany and New Zealand (NCT02296853) Updated 25 Nov 2014
25 Sep 2014 Licensing Status Medicines Patent Pool sub-licenses Tenofovir alafenamide to Aurobindo, Cipla, Desano, Emcure, Hetero Labs and Laurus Labs in developing countries Updated 02 Oct 2014
24 Jul 2014 Licensing Status Tenofovir alafenamide licensed to Medicines Patent Pool worldwide in developing countries [4] Updated 28 Jul 2014
25 Oct 2013 Phase Change - III Phase-III clinical trials in HIV-1 infections (Treatment experienced) in Uganda, Thailand, Dominican Republic, Russia, United Kingdom, Germany (PO) (EudraCT2013-002830-19) (NCT01967940) Updated 18 Sep 2017
30 Sep 2013 Phase Change - III Phase-III clinical trials in HIV-1 infections (Treatment experienced) in USA (PO) (NCT01967940) Updated 05 Nov 2013
01 Sep 2013 Trial Update Gilead Sciences initiates enrolment in a phase III trial for Hepatitis B (Treatment naive, Treatment experienced) in USA, Australia, Canada, China, France, Germany, Hong Kong, India, Italy, Japan, South Korea, New Zealand, Poland, Romania, Russia, Singapore, Spain, Taiwan, Turkey and United Kingdom (NCT01940341) after September 2013 Updated 28 Aug 2015
01 Sep 2013 Phase Change - III Phase-III clinical trials in Hepatitis B (treatment-experienced, treatment-naive) in Bulgaria, China, Germany, Japan, Poland, Singapore and Turker after September 2013 (PO) Updated 28 Jul 2014
01 Sep 2013 Phase Change - III Phase-III clinical trials in Hepatitis B (treatment-experienced, treatment-naive) in Australia, France, Hong Kong, India, Italy, South Korea, New Zealand, Romania, Russia, Spain, Taiwan and United Kingdom (PO) after September 2013 (NCT01940471) Updated 24 Mar 2014
01 Sep 2013 Phase Change - III Phase-III clinical trials in Hepatitis B in Canada (PO) Updated 18 Sep 2013
01 Sep 2013 Phase Change - III Phase-III clinical trials in Hepatitis B in USA (PO) Updated 18 Sep 2013
30 Apr 2013 Trial Update Gilead completes a phase I/II trial in Hepatitis B (treatment-naive) in USA, Canada, Australia, New Zealand and United Kingdom (NCT01671787) Updated 12 Jul 2013
11 Mar 2013 Scientific Update Final efficacy and adverse events data from a phase II trial (Study 102) in HIV-1 infections presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI-2013) [40] Updated 11 Mar 2013
31 Oct 2012 Scientific Update Topline efficacy and adverse events data from a phase II trial (Study 102) in HIV-1 infections released by Gilead Sciences [39] Updated 02 Nov 2012
31 Mar 2012 Phase Change - I/II Phase-I/II clinical trials in Hepatitis B (treatment-naive) in Australia (PO) Updated 12 Jul 2013
31 Mar 2012 Phase Change - I/II Phase-I/II clinical trials in Hepatitis B (treatment-naive) in Canada (PO) Updated 12 Jul 2013
31 Mar 2012 Phase Change - I/II Phase-I/II clinical trials in Hepatitis B (treatment-naive) in New Zealand (PO) Updated 12 Jul 2013
31 Mar 2012 Phase Change - I/II Phase-I/II clinical trials in Hepatitis B (treatment-naive) in United Kingdom (PO) Updated 12 Jul 2013
31 Mar 2012 Phase Change - I/II Phase-I/II clinical trials in Hepatitis B (treatment-naive) in USA (PO) Updated 12 Jul 2013
15 Feb 2012 Phase Change - I Phase-I clinical trials in Hepatitis B in USA (PO) Updated 15 Feb 2012
24 Jan 2012 Phase Change - II Phase-II clinical trials in HIV-1 infections in USA (PO) Updated 15 Feb 2012
18 Mar 2011 Scientific Update Efficacy data from a Phase-II trial in HIV-1 infections released by Gilead Sciences [64] Updated 13 Jun 2011
31 Dec 2010 Phase Change - I Phase-I clinical trials in HIV infections in USA (PO) Updated 14 Jun 2011
22 Oct 2004 Phase Change - Discontinued(I/II) Discontinued - Phase-I/II for HIV-1 infections treatment in USA (PO) Updated 01 Nov 2004
22 Oct 2004 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Hepatitis B in USA (PO) Updated 01 Nov 2004
12 Feb 2004 Trial Update Phase I/II trials have been completed in HIV-1 infections treatment Updated 12 Feb 2004
03 Jul 2002 Phase Change - I/II Phase-I/II clinical trials in HIV-1 infections treatment in USA (PO) Updated 03 Jul 2002
04 Apr 2002 Phase Change - Preclinical Preclinical trials in Hepatitis B in USA (PO) Updated 04 Apr 2002
04 Apr 2002 Phase Change - Preclinical Preclinical trials in HIV infections treatment in USA (PO) Updated 04 Apr 2002

References

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