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Emtricitabine - Gilead Sciences

Drug Profile

Emtricitabine - Gilead Sciences

Alternative Names: 524W91; BW-524W91; Coviracil; Emtriva; FTC

Latest Information Update: 14 Mar 2021

At a glance

  • Originator Emory University
  • Developer Gilead Sciences
  • Class Antiretrovirals; Deoxyribonucleosides; Pyrimidine nucleosides; Small molecules
  • Mechanism of Action DNA polymerase beta inhibitors; DNA polymerase gamma inhibitors; DNA polymerase I inhibitors; DNA polymerase II inhibitors; HIV 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-1 infections
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed HIV infections
  • No development reported Hepatitis B

Most Recent Events

  • 06 Jan 2020 No development reported - Phase-II for HIV infections (In adolescents, In children, In infants) in South Africa (PO)
  • 05 Dec 2018 Gilead offered Japan Tobacco to terminate the exclusive licenses for HIV drugs in Japan
  • 27 Aug 2018 Japan Tobacco and Gilead sign a letter of intent to initiate discussion to terminate license agreement for HIV drugs in Japan

Development Overview

Introduction

Emtricitabine, an oxathiolane nucleoside with a resistance profile similar to lamivudine, was discovered at Emory University in the US and is being developed by Gilead Sciences. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with demonstrated potent activity against HIV and hepatitis B virus (HBV). The drug is an inhibitor of DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ. Emtricitabine is launched for the treatment of HIV infections in the US, the EU, Mexico, Japan, South America and Australia. The compound was also in clinical trials for the treatment of hepatitis B. However, emtricitabine was never approved for hepatitis B and no recent activity for this indication has been reported. Phase III development for HIV infections in adults was underway in South Africa, however, the development has been discontinued.

Emtricitabine was first approved in July 2003 in the USA as a once-daily NRTI and is indicated for the treatment of HIV infection in adults in combination with other antiretroviral medications. Emtricitabine is also indicated for use in children and adolescents, aged 1 month to 17 years, with HIV-1 infections. Emtricitabine is also available as a 10 mg/mL solution.

Gilead has also developed fixed-dose combinations of emtricitabine and other products such as tenofovir disoproxil fumarate [see separate profiles].

In August 2012, Gilead entered a collaboration agreement with Mylan Laboratories, Ranbaxy Laboratories Limited and Strides Arcolab, to promote low-cost generic versions of emtricitabine in developing countries - including single tablet regimens, and fixed-dose combinations of emtricitabine co-formulated with other Gilead HIV medicines [1] .

As at January 2020, no recent reports of development had been identified for phase II HIV infections for oral capsule and liquid in adolescents, in children and in infants in South Africa.

Company Agreements

In September 2019, Japan Tobacco announced that the transfer date of the marketing approvals of six anti-HIV drugs (mentioned below) to Gilead Sciences is set for December 1, 2019. After the transfer of the marketing approvals has completed, Gilead will be responsible for the distribution of these six drugs, which Torii Pharmaceutical is currently responsible for, under the terms and conditions for a provisional measure. In December 2018, Gilead had offered Japan Tobacco Inc. (JT) to terminate the exclusive licenses for the six HIV drugs (current HIV drugs), emtricitabine, tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, elvitegravir/emtricitabine/tenofovir disoproxil fumarate/cobicistat, cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide, emtricitabine/tenofovir alafenamide, in Japan. The termination date for the agreement was set as January 1, 2019. JT and Torii Pharmaceutical (JT's business subsidiary) also had agreed to terminate the license agreements by which JT grants Torii the exclusive rights to market these six anti-HIV drugs in Japan. Gilead also notified that they have decided to manage the regulatory approval process and market a novel anti-HIV drug bictegravir/emtricitabine/tenofovir alafenamide, developed by Gilead in Japan, through Gilead Sciences K.K., Japanese subsidiary of Gilead. Upon completion of termination procedure, JT will pay ¥42.1 billion (ADIS conversion US$37 million) to Torii after Torii and JT terminate the license agreements. Torii will co-operate with JT for transfering the current HIV Drugs to Gilead K.K. to secure stable supply. Until Gilead K.K. completely succeeds JT’s marketing approval of the Current HIV Drugs in Japan, as a transitional measure, Torii is responsible for distribution and Gilead K.K. is responsible for providing information to medical institutions. Torii will receive ¥1.1 billion (ADIS conversion US$0.97 million) from JT for the above responsibility. In August 2018, Japan Tobacco signed a non-binding letter of intent for initiating a discussion with Gilead Sciences to terminate the license agreements. Earlier, in 2011, Gilead and JT signed an exclusive license agreements for the development and commercialization of six HIV drugs (mentioned earlier). While JT and Torii signed an exclusive license agreements, under which Torii has been marketing the current HIV drugs in Japan. In July 2003, Gilead Sciences, Inc. announced that the company had entered into a licensing agreement with Japan Tobacco Inc. (JT) under which JT will commercialise products in Gilead's HIV portfolio in Japan. The agreement includes Viread® (tenofovir disoproxil fumarate), Emtriva(emtricitabine) and a future co-formulation of the 2 products. Under the terms of the agreement, Gilead will receive an up-front fee and is entitled to receive additional cash payments upon achievement of certain milestones. JT also will make payments to Gilead based on product sales. JT will submit applications for Viread® and Emtriva to Japanese regulatory authorities in the near future. [2] [3] [4] [5] [6] [7]

In July 2005, Gilead Sciences and Royalty Pharma entered into an agreement with Emory University to purchase Emory's royalty interest for emtricitabine. Under the terms of the agreement Gilead and Royalty will make a payment of $US525 million to Emory in exchange for elimination of royalties due to the University on worldwide net sales of the drug. The payment will be split 65%/35% between Gilead and Royalty, respectively, following which Gilead will be obligated to pay Royalty a relative royalty on net sales [8] . The purchase was completed on 22 July 2005 [9] .

Emtricitabine was originally licensed to Glaxo Wellcome. The licence was subsequently taken over by Triangle Pharmaceuticals, a company formed by a group of researchers and executives from Glaxo Wellcome. Clinical evaluation of emtricitabine was re-initiated by Triangle.

In January 2003, Triangle Pharmaceuticals was acquired by, and merged into, Gilead Sciences. Gilead intends to develop and launch a tenofovir disoproxil fumarate/emtricitabine (Triangle) fixed-dose, combination treatment for HIV by 2005.

In June 1999, Triangle Pharmaceuticals (now Gilead Sciences) entered a marketing and development agreement with Abbott Laboratories covering 6 antiviral agents, including emtricitabine. Under this agreement, Abbott receives exclusive sales and marketing rights for emtricitabine outside the USA. Subsequently, in July 2002, following a mutual decision by both companies, Triangle announced the reacquisition from Abbott, worldwide product rights, including rights to all profits, for emtricitabine for the treatment of HIV and hepatitis B, amdoxovir for the treatment of HIV, and clevudine for the treatment of hepatitis B [see separate profiles for amdoxovir and clevudine]. Upon approval of emtricitabine for the treatment of HIV in the US and in Europe, Abbott will now make available to Gilead unsecured lines of credit of $US30 million and $US12.5 million, respectively. If Gilead secures certain types of non-dilutive financing from other parties, the lines of credit will be reduced.

Manufacturing agreements

under a new manufacturing and supply agreement, initial launch quantities of emtricitabine will be manufactured by Abbott, and at Gilead's request, will supply additional material through to July 31, 2005. In exchange for the above rights, Gilead will relinquish rights to all remaining milestone payments and the right to co-promote Abbott's HIV product Kaletra® [lopinavir/ritonavir], in the US. Abbott will also receive 1% royalty on the first $US200 million of cumulative sales of emtricitabine for the treatment of HIV. Abbott's representative has resigned from Triangle's Board of Directors and Abbott's right to purchase additional Triangle shares has been terminated.

Key Development Milestones

Regulatory information

HIV infections

in September 2002, Triangle announced the submission of an NDA to the US FDA for marketing approval of emtricitabine [Coviracil®, Emtriva®] for the treatment of HIV disease. The submission included data from over 2 000 patients with two pivotal trials comparing emtricitabine to two widely prescribed drugs for HIV disease. The FDA accepted the filing in November 2002, indicating that the application was sufficiently complete for review. Subsequently, a Marketing Authorisation Application (MAA) was made to the European Agency for Evaluation of Medicinal Produtcts (EMEA) on January 6 2003, under the centralised procedure [10] .

The US FDA granted marketing approval for emtricitabine 200mg hard capsules on 2 July 2003. It is indicated for the treatment of HIV infection in adults in combination with other antiretroviral medications. Emtricitabine will be marketed in the US as Emtriva®, a 200mg one-capsule, once-daily, NRTI and was launched in July 2003 [11] . In September 2005, the US FDA approved Emtriva® oral solution for the treatment of HIV infection.

The scientific committee for the EMEA recommended granting marketing approval for emtricitabine in the 15 member states of the EU on 24 July 2003 [12] . The European Commision subsequently granted marketing authorisation for emtricitabine, 200mg hard capsule and 10 mg/mL oral solution, on October 28, 2003. The oral solution is for use in infants older than 4 months, children and patients unable to swallow hard capsules and patients with renal impairment who require dose reduction.
Emtricitabine will become available in individual European countries as local reimbursement approvals are obtained [13] .

Japan Tobacco and Torii Pharmaceutical have launched emtricitabine as Emtriva® 200mg capsules in Japan on 19 April 2005. The companies obtained import approval for the drug in March 2005 [14] .

In October 2004, emtricitabine was granted orphan drug designation for the treatment of HIV-1 infections in Japan by the Pharmaceuticals and Medical Devices Agency (PMDA), Japan (PMDA website, October 2004).

Clinical development

HIV infections

interim results of a phase III trial, Study 934, comparing a once-a-day regimen of tenofovir disoproxil fumarate, efavirenz [see separate profiles] and emtricitabine with a regimen of twice daily lamivudine/zidovudine [see separate profile] and once-daily efavirenz have been reported [15] [16] [17] .

In July 2003, results from the pivotal phase III/IV FTC-301 and FTC-302 trials presented at the 2nd IAS Conference on HIV Pathogenesis and Treatment (IAS-2003) show that emtricitabine is a potent, once-daily NRTI that can provide significant efficacy within a HAART regimen in treatment-naive HIV patients [18] .

In view of positive interim results, a Data Safety Monitoring Board recommended in July 2002 that a pivotal phase III trial of emtricitabine is unblinded early and that all patients are offered the regimen containing emtricitabine. The results reviewed by the DSMB had shown that the emtricitabine arm was statistically superior to the stavudine arm for primary and secondary endpoints for safety and efficacy [19] .

In February 2000 Triangle halted recruitment of patients in a pivotal phase III study (FTC-302), comparing emtricitabine and lamivudine, due to a higher than expected incidence of liver toxicity, resulting in two fatalities. The study was being conducted under a US IND in South Africa and had enrolled a total of 470 patients. In April 2000, the FDA issued a clinical hold on the study and subsequently, the study was terminated by the South African Medicines Control Council (MCC). The majority of patients who participated in the trial continued to receive treatment on compassionate grounds. Triangle had stated that it did not believe the liver toxicity was related to emtricitabine. Two additional studies with emtricitabine were initiated; one sponsored by Triangle and the other by the Agence Nationale de Receherche sur le SIDA located in France. Triangle met with the FDA in 2001 to discuss whether these studies are sufficient for an NDA application. In these discussions, the company presented new data suggesting nevirapine and not emtricitabine was the likely cause of earlier liver toxicities.

In February 2017, Gilead Sciences completed a phase II rollover protocol study to provide subjects completing the FTC-203 study in South Africa with continued access to emtricitabine (NCT00743340; GS-US162-0112). The open-label trial was initiated in November 2005 and enrolled 50 patients in South Africa [20] .

Hepatitis B virus infections

Triangle commenced phase III trials (FTCB-301) of emtricitabine for the treatment of hepatitis B in September 2000 using 200mg qd as the optimal dose. Emtricitabine has demonstrated efficacy in the treatment of chronic hepatitis B in 1-year results from a phase II study in patients co-infected with HIV. Forty-eight week results from study FTCB-102 were presented at the 53rd AASLD meeting held in Boston, USA, in November 2002.

Patent Information

Emtricitabine is subject to an ongoing patent dispute between Triangle (now Gilead Science) and Shire Pharmaceuticals (formerly BioChem Pharma). The US Patent and Trademark Office declared an interference between a 1990 BioChem Pharma patent covering emtricitabine as a therapy for HIV infections and a 1993 emtricitabine patent issued to Emory University and licensed to Triangle. In May 1999 Triangle settled similar patent litigation with Glaxo Wellcome over the use of emtricitabine to treat hepatitis B. Under this settlement, Triangle has access to 'development and clinical data and drug substance held by Glaxo relating to emtricitabine'. A final settlement was reached in June 2002 among Emory University, GlaxoSmithKline and Shire Pharmaceuticals on the patent issue. The terms of the settlement state that Emory will receive an exclusive license from Shire under Shire's patents relating to emtricitabine and Shire and GlaxoSmithKline will receive exclusive licenses under Emory's patents relating to lamivudine [21] .

The US and European patents for emtricitabine held by Gilead Sciences are due to expire in 2021 and 2016, repsectively.

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Capsule, Liquid, unspecified
  • Class Antiretrovirals, Deoxyribonucleosides, Pyrimidine nucleosides, Small molecules
  • Target DNA polymerase beta; DNA polymerase gamma; DNA polymerase I; DNA polymerase II; HIV reverse transcriptase
  • Mechanism of Action DNA polymerase beta inhibitors; DNA polymerase gamma inhibitors; DNA polymerase I inhibitors; DNA polymerase II inhibitors; HIV reverse transcriptase inhibitors
  • WHO ATC code

    J05A-F (Nucleoside and nucleotide reverse transcriptase inhibitors)

  • EPhMRA code

    J5B (Antivirals, excluding anti-HIV products)

    J5C (HIV antivirals)

  • Chemical name (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine
  • Molecular formula C8 H10 F N3 O3 S
  • SMILES NC1=NC(=O)N(C=C1F)C1OC(SC1)CO
  • Chemical Structure
  • CAS Registry Number 143491-57-0

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

hepatitis B

Exclusion

SRY

1

hepatitis B

Outcome Measure

CD8a

CD4

1

1

HIV infections

not specified

SRY

1

HIV infections

Exclusion

SRY

1

HIV infections

Inclusion

CD4

3

HIV infections

Outcome Measure

EH domain containing 3

CD8a

CD4

CD38

ATP binding cassette subfamily G member 2 (Junior blood group)

1

2

5

1

1

HIV-1 infections

Inclusion

CD4

1

HIV-1 infections

Outcome Measure

CD4

1

HIV-2 infections

not specified

RAS like proto-oncogene A

1

HIV-2 infections

Inclusion

SRY

1

HIV-2 infections

Outcome Measure

CD4

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Emtricitabine - Gilead Sciences 8-Hydroxy-14,16-hentriacontanedione not specified
Adiponectin Outcome Measure
aldo-keto reductase family 1 member C1 Outcome Measure
Alkaline phosphatase not specified
Apo A-1 Outcome Measure
Apo B Outcome Measure
ATP binding cassette subfamily G member 2 (Junior blood group) Outcome Measure
B2M Outcome Measure, Safety
beta-hCG Outcome Measure
Bilirubin Outcome Measure
CCR5 Outcome Measure
CD14 Outcome Measure
CD163 Outcome Measure
CD28 molecule Outcome Measure
CD38 Outcome Measure
CD4 Exclusion, Inclusion, Outcome Measure, Safety
CD57 Outcome Measure
CD8a Outcome Measure, Safety
chromosome 8 open reading frame 17 Outcome Measure
CRP Outcome Measure
CXCL10 Outcome Measure
Cystatin C Outcome Measure, Safety
cytochrome P450 family 2 subfamily B member 6 Outcome Measure
cytochrome P450 family 4 subfamily F member 3 Outcome Measure
D-dimer Outcome Measure
dCTP Outcome Measure
Deoxyadenosine triphosphate Outcome Measure
EH domain containing 3 Outcome Measure
endogenous retrovirus group W member 1 Outcome Measure
ezrin Outcome Measure
Fumaric acid Outcome Measure
Gamma-Aminobutyric acid Outcome Measure
hemoglobin subunit epsilon 1 Inclusion, Outcome Measure
HLA-DR Outcome Measure
IGFBP7 Exclusion, Outcome Measure
IL10 Outcome Measure
IL6 Outcome Measure
immunoglobulin superfamily member 9 Inclusion, Outcome Measure
Insulin Outcome Measure
Neopterin Outcome Measure
PSA not specified
RANKL Outcome Measure
RAS like proto-oncogene A Outcome Measure
RBP4 Outcome Measure, Safety
SRY Exclusion, Inclusion, Outcome Measure
syndecan binding protein not specified
Tau protein Outcome Measure
tissue factor pathway inhibitor (lipoprotein-associated coagulation inhibitor) Outcome Measure
TNF-alpha Outcome Measure
Uric acid Outcome Measure
Y Chromosome not specified
YAP1 Exclusion, 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 - - Marketed Australia, Mexico, South America, USA PO / Capsule Gilead Sciences 30 Aug 2006
HIV infections - - Marketed European Union, France, Germany, Japan, United Kingdom PO / Capsule 19 Apr 2005
HIV infections - - Marketed European Union, USA PO / Liquid 03 Aug 2007
HIV infections - In adolescents, In children, In infants No development reported (II) South Africa PO / Liquid Gilead Sciences 06 Jan 2020
HIV infections - In adolescents, In children, In infants No development reported (II) South Africa PO / Capsule Gilead Sciences 06 Jan 2020
HIV infections - - Discontinued (III) South Africa PO / Capsule Gilead Sciences 13 Jun 2000
Hepatitis B - - No development reported (III) USA PO / unspecified Gilead Sciences 03 Apr 2010

Orphan Status

Indication Patient Segment Country Organisation Event Date
HIV-1 infections - Japan Japan Tobacco 13 Oct 2004

Commercial Information

Involved Organisations

Organisation Involvement Countries
Emory University Originator USA
Emory University Owner USA
Japan Tobacco Market Licensee Japan
Gilead Sciences Market Licensee Mexico, South Africa, South America, USA
Torii Pharmaceutical Sub-licensee Japan

Brand Names

Brand Name Organisations Indications Countries
Coviracil Panacos Pharmaceuticals Inc HIV infections USA
Emtriva Torii Pharmaceutical, Gilead Sciences HIV infections Europe, 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 ex US Gilead Sciences Marketed 2003 100 2016 01 Jun 2016 01 Feb 2021
HIV US Gilead Sciences Marketed 2003 100 2021 29 Sep 2021 01 Feb 2021

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
HIV ex US 4 2 2 2 2 2 2 2 2 2 01 Feb 2021
HIV US 21 20 17 8 4 2 2 2 2 2 01 Feb 2021
Total 25 22 19 10 6 4 4 4 4 4

Scientific Summary

  • Adverse Events Frequent: CNS disorders; Headache
    Occasional: Abdominal pain; Diarrhoea; Elevated creatine kinase levels; Hypertriglyceridaemia; Nausea; Skin eruptions
    Rare: Rhinitis

Pharmacokinetic Measures

Characterstic Measure
Linear Kinetics yes
Route of Elimination renal
bioavailability oral (%) 70 (Adult)
T½beta (h) 2.54 - 10 (Adult)
Tmax (h) 1.25 - 3 (Adult)

Pharmacokinetics

HIV infections

in 12 HIV-infected patients who received single oral doses of emtricitabine 100-1200mg with a 6-day washout period, emtricitabine was rapidly absorbed with a tmax of 3h. Excretion occurred mainly through the kidneys with a t½ < 4h. Food intake did not affect oral bioavailability [48] .

In a similar study in 18 HIV-infected volunteers, emtricitabine displayed linear kinetics following single oral doses of 100-1200mg. AUC ranged from 3.87-57.8 µg · h · ml-1, tmax was 1.25-1.61h and t½ was 2.54-2.83h. Oral bioavailability was 70% [56] .

In a phase I/II trial, 5 cohorts of 8 HIV-infected patients each received separate escalating doses of emtricitabine (25mg bid, 100mg qd, 200mg qd and 200mg bid) for 14 days. Cmax occurred within 2h and plasma concentration levels were maintained above the in vitro IC90 for all doses. Mean steady state trough concentration levels of emtricitabine following 100mg and 200mg qd dosing were -2 and 4-fold higher than the mean in vitro IC90, respectively. Mean t½ was 8h and emtricitabine demonstrated linear kinetics with little inter-subject variation [47] .

Paediatric patients with HIV

in a phase I trial, 23 children aged 2-17 years who were exposed to or infected with HIV were given single oral doses of emtricitabine 60 then 120 mg/m2. A nearly linear increase in plasma concentrations was observed between the 2 dose levels and plasma exposure was similar for capsule and solution formulations of the drug. At the higher dose level, the AUC of the capsule formulation was similar to that observed in adults given a 200mg dose (approximately 8.5 h · µg/ml) [43] .

The AUC0-24 of emtricitabine decreased with increasing age over the first 3 months of life when administered to neonates with HIV-1 infection. This was possibly due to an increased total body clearance rate as infant renal function matures during the first few months of life. Oral emtricitabine solution (3 mg/kg, od) was administered in two short four-day courses separate by an interval of > 2 weeks [22] .

Hepatitis B virus infections

cohorts of 8-11 patients with chronic hepatitis B received sequential escalating doses of emtricitabine 25mg, 50mg, 100mg, 200mg and 300mg for 8 weeks each. Emtricitabine was well absorbed after oral administration and plasma concentrations were greater than the IC50 for hepatitis B virus. The plasma elimination t½ ranged from 6-10h, Cmax ranged from 0.43-4.25 µg/mL, tmax ranged from 1.0-1.5h, CL/F ranged from 250-300 mL/min and AUC0-24 ranged from 1.76-17.39 µg·h·mL-1 [35] .

Adverse Events

In 12 HIV-infected patients receiving single oral doses of emtricitabine 100-1200mg, the drug appeared to be well tolerated [48] .

One patient in a phase I study developed a mild rash after an 800mg dose, and discontinued treatment prematurely [56] .

In an open-label pilot study conducted in France, the efficacy of emtricitabine was evaluated in 40 HIV-infected antiretroviral-naive patients. In this study participants received once daily emtricitabine in combination with didanosine and efavirenz. Most adverse events in this study were mild to moderate. Central nervous system complaints, occurring during the first days of therapy, were the most frequent adverse events. Others included headache, maculopapular rash, diarrhoea, biochemical abnormalities and abdominal pain. Six patients developed serious adverse events [45] .

In a phase I/II study in which 44 patients with hepatitis B virus infection received emtricitabine, 11% of patients experienced headache [51] .

In a phase II trial in 98 patients co-infected with HIV and hepatitis B, emtricitabine (25, 100 or 200 mg/day, od) was generally well tolerated. One patient in each dose group discontinued treatment as a result of adverse events [42] .

The safety of a triple-drug regimen containing once-daily emtricitabine in treatment-naïve Black African females was comparable to males treated with the same regimen. In this 48 week study, 234 HIV-infected patients (M=99, F=135) received, emtricitabine 200mg QD in combination with stavudine and either nevirapine (HIV RNA <100,00 copies/ml) or efavirenz (HIV RNA ≥100,000 copies/ml).The incidence of treament limiting adverse events in males was 12% compared with 11% in females [37] .

In a 48-week, open-label equivalence trial (FTC-303), 294 patients with HIV-1 RNA ≤400 copies/mL were randomised to either continue their lamivudine containing regimen or switch lamivudine 150mg bid to emtricitabine 200mg once daily. Adverse events were mild to moderate. Drug related severe or potentially life threatening adverse events were 5% and <1%, respectively [38] .

In a multicentre, open, sequential, dose-escalating, phase II study, 49 patients with hepatitis B infection were treated with emtricitabine 25, 50, 100, 200 and 300 mg/day, PO, for 2 months. One patient given emtricitabine 25 mg/day withdrew from the study due to mild vertigo and severe headache. Otherwise emtricitabine was well tolerated and there were no serious events [35] .

A randomised, double-blind, multicentre, phase III study compared the administration of emtricitabine once-daily with stavudine twice-daily. Antiretroviral naïve patients (n=571) with baseline viral loads >5000 copies/mL were randomised 1:1 to 200mg emtricitabine (n=286), once-daily or stavudine, twice-daily at standard doses (n=285). All patients also received open-label didanosine and efavirenz twice-daily. The once daily regimen containing emtricitabine was statistically superior in safety and tolerability. The Kaplan- Meier probability for tolerability failure was 13.9% for the stavudine arm and 6.7% for the emtricitabine arm. A higher incidence of diarrhoea, nausea and abnormal dreams was seen in the stavudine arm [33] [34] . Analyses at 60 weeks demonstrated that emtricitabine had a lower incidence of treatment-emergent side effects than stavudine. Based on Kaplan-Meier estimates, the researchers determined that rates of permanent discontinuation of study medication due to clinical adverse events were 7.4% for the emtricitabine arm and 16.6% for the stavudine arm (P=0.003). Patients taking emtricitabine were less likely than those taking stavudine to have diarrhea, nausea, abnormal dreams, paresthesia, neuropathy, and symptomatic hyperlactatemia/lactic acidosis. Only increased cough occurred significantly more frequently in the emtricitabine group [28] .

Stavudine (200mg twice daily), didanosine and efavirenz [27] .

Interim results from an open-label, phase III trial comparing a once-daily regimen of tenofovir disoproxil fumarate, emtricitabine and efavirenz with a regimen of twice daily lamivudine/zidovudine and once daily efavirenz demonstrated that fewer adverse event treatment discontinuations occurred in the emtricitabine treatment group (3%) compared with the lamivudine/zidovudine treatment group (9%). In the trial 509 treatment-naive HIV patients received either once-daily tenofovir disoproxil fumerate 300mg, emtricitabine 200mg, and efavirenz 600mg or twice-daily lamivudine 150mg/zidovudine 300mg and once-daily efavirenz 600mg for 24-weeks. The most common adverse events that led to treatment discontinuation were nausea, vomiting, anaemia and fatigue. The renal safety profile was similar in both treatment groups [16] .

Paediatric patients

in a phase I trial, single doses of emtricitabine 60 and 120 mg/m2 were generally well tolerated when administered to children infected with or exposed to HIV [43] .

In a phase II study, 82 patients aged between 4 months and 16 years received emtricitabine as part of HAART. Treatment-naive patients (n= 51) received 6 mg/kg (up to a maximum of 200 mg/day) plus twice-daily weight-adjusted doses of stavudine and lopinavir/ritonavir. Treatment-experienced patients (n=31) also received emtricitabine 6 mg/kg in place of lamivudine as part of their existing regimen. Three treatment-naive patients experienced moderate-to-severe adverse events (pancreatitis, vomiting, pleural effusion), as did two treatment-experienced patients (leucopenia, anaemia). Grade 3−4 laboratory abnormalities occurred in five patients; two patients experienced grade 3 neutropenia, but no other laboratory abnormality occurred in more than a single patient [31] .

This study (PACTG 1021) involved 30 treatment-naive patients; 17 of these patients were aged 12 years or younger and 13 were aged between 13 and 21 years. The study will eventually involve a total of 42 patients, including a cohort aged between 90 days and 3 years. The patients received once-daily emtricitabine 6 mg/kg, up to a maximum of 200 mg/day in addition to once-daily didanosine 240−400 mg/m2 and weight-adjusted doses of efavirenz (maximum dose of 600 mg/day for capsules or 720 mg/day for oral solution). The only grade 3 adverse event considered to be treatment-related was a rash attributed to efavirenz; the only notable laboratory abnormalities were a grade 3 elevation in creatine phosphokinase levels that was judged "possibly" treatment related, and a grade 4 elevation in γ-glutamyl transpeptidase levels that was not a protocol-specified laboratory value and was not reported until after the problem had resolved. One patient each was hospitalised for immune reconstitution syndrome, otitis media, and herpes zoster infection, none of which was considered to be treatment-related [32] .

Four-day courses of emtricitabine (3 mg/kg od) were safe and well tolerated by neonates < 3 months old exposed to HIV in utero [22] .

Pharmacodynamics

Summary

Preclinical studies

in the woodchuck hepatitis virus model of hepatitis B, emtricitabine administered IP for 25 days significantly reduced serum virus DNA levels. Levels returned to baseline 1 week after discontinuation of treatment [55] .

Oral administration of emtricitabine 0.9-88.8 mg/kg/day to mice with subcutaneous tumours of HBV-producing 2.2.15 cells resulted in reductions in intracellular and serum levels of HBV. No effect on tumour size or α-fetoprotein levels were observed [58] .

Clinical studies

retrospective analysis of data from data from 233 HIV-infected patients receiving triple combination antiretroviral therapy showed that regimens containing emtricitabine were associated with a lower incidence of the M184V mutation than those containing lamivudine. 14-42% of emtricitabine recipients with virological failure while undergoing treatment for HIV infections had the M184V mutation, compared with 42-78% of those receiving lamivudine [41] .

Antimicrobial Activity

Summary

Preclinical studies

in peripheral blood mononuclear cells, emtricitabine had similar activity to zidovudine against HIV-1 and was nontoxic to cells. The triphosphate metabolite of emtricitabine inhibited HIV-1 reverse transcriptase with a Ki of 0.2 µmol/L. Emtricitabine also had activity against HIV-2, simian immunodeficiency virus and hepatitis B virus. The mean IC50 value for emtricitabine from a series of 7 HIV-1 and HIV-2 isolates was found to be 0.002 mmol/L, which is 95-fold lower than that of zidovudine [48] .

Clinical studies

in a phase I pharmacokinetic and safety study, plasma levels of emtricitabine (100-1200mg doses) were well above the in vitro IC50 value of ≈ 0.5 ng/ml in all 18 HIV-infected volunteers [56] .

Therapeutic Trials

HIV infections

Once-daily emtricitabine reduced viral load in patients with HIV infection in a phase I/II study. 80 patients were randomised to receive emtricitabine 25, 100 or 200mg once daily or lamivudine 150mg twice daily for 10 days. Emtricitabine 200mg/day was the most effective treatment. 58% of emtricitabine 200 mg/day recipients had a 2 log10 decrease in viral load or a reduction below detectable levels; 21% of emtricitabine 200 mg/day recipients had both. Two days after completion of therapy, emtricitabine 200 mg/day recipients had an absolute decrease in viral load of 1.63 log10 [46] .

There is a lower incidence of the amino acid mutation M184V in antiretroviral therapy naive patients receiving emtricitabine as part of a triple drug regimen compared with patients who received lamivudine. A randomised double-blind study compared emtricitabine with lamivudine in a background of stavudine and either nevirapine or efavirenz. 47/468 (10%) patients were classified as virological failures and 32/47 had at least one mutation associated with the study mechanism. The incidence of the study associated mutation(s) was higher in the lamivudine arm (88.2%) than in the emtricitabine arm (56.7%). Similarly, the frequency of the M184V mutation was significantly higher in the lamivudine treated patients (58.8% vs 16.7%) [40] .

The efficacy of a triple-drug regimen containing once-daily emtricitabine in treatment-naïve Black African females was comparable to males treated with the same regimen. In this 48 week study, 234 HIV-infected patients (M=99, F=135) received, emtricitabine 200mg QD in combination with stavudine and either nevirapine (HIV RNA <100,00 copies/mL) or efavirenz (HIV RNA ≥100,000 copies/mL). HIV RNA levels were monitored every 12 weeks and adverse events very 4 weeks. No significant differences were seen in the efficacy of the treatment in males versus females. The rate of virological failure was 14%(M) vs 10%(F); CD4 cell count 203 cells/mL (M) vs 182 cell/mL (F) [37] .

Emtricitabine treatment resulted in superior and durable increases in absolute CD4+ count from baseline compared to stavudine (163 cells/mm3 (8.6%) vs 137 cells/mm3 (5.1%)) by week 60. Patients were randomised to receive either emtricitabine (200mg once daily) or stavudine (200mg twice daily), didanosine and efavirenz [27] .

Patients administered the combination therapy tenofovir disproxil fumarate/emtricitabine/efavirenz (tdf/e/e) had a greater response rate than those administered lamivudine/zidovudine/efavirenz (l/z/e) in a phase III trial, Study 934. Initially, 517 patients with HIV infection were randomised to receive tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg and efavirenz 600 mg, all dosed once daily, or lamivudine/zidovudine twice daily and efavirenz 600mg once daily. At 24, 48 and 96 weeks, 88%, 84% and 75% of patients in the tdf/e/e arm had an HIV RNA level <400 copies/mL. Of the patients in the l/z/e arm, 80%, 73% and 62% of patients had an HIV RNA level of <400 copies/mL at 24, 48 and 96 weeks, respectively. In addition, patients receiving tdf/e/e combination therapy consistently had a greater improvement in CD4 count from baseline compared with l/z/e recipients. At 24 weeks, patients had an increase from baseline of 129 and 111 CD4 cells/mm3, at 48 weeks the increase was 190 and 158 cells/mm3, and at 96 weeks it was 270 and 237 cells/mm3, in the tdf/e/e and l/z/e arms, respectively [15] [50] [53] [57] [49] .

After 144 weeks of treatment in Study 934, 71% of patients who received tdf/e/e achieved and maintained viral load <400 copies/mL compared with 58% of l/z/e patients. Viral load <50 copies/mL was achieved and maintained in 64% of tdf/e/e patients and in 56% of l/z/e patients. Results also showed a mean increase from baseline in CD4 cell counts of 312 cells/mm2 for patients who received tdf/e/e and an increase of 271 cells/mm2 in patients who received l/z/e [17] .

Oral emtricitabine 3 mg/kg administered to neonates < 3 months old with HIV-1 infection produced plasma levels similar to those found to be safe and efficacious in adults and children ≥ 3 months old [22] .

In highly active antiretroviral therapy (HAART)

once daily emtricitabine had greater antiviral efficacy than twice daily abacavir when used with stavudine and efavirenz. Treatment-naïve HIV-1-infected patients (n=37) with plasma HIV-1 RNA (VL) ≥5000 copies/mL were randomised to receive FTC 200mg o.d or abacavir 300mg b.i.d in addition to stavudine and efavirenz. At week 24, 83.3% of patients receiving emtricitabine had a VL≤50 copies/mL compared with 62% of patients receiving abacavir [30] .

Once daily regimen containing emtricitabine in a background of didanosine/efavirenz was statistically superior in efficacy, safety and tolerability to a twice-daily regimen of stavudine in a background of didanosine/efavirenz, once daily. This randomised, double-blind, multicentre, phase III study (FTC-301) compared the administration of emtricitabine once-daily with stavudine twice-daily. Antiretroviral naïve patients (n=571) with baseline viral loads >5000 copies/mL were randomised 1:1 to 200mg emtricitabine (n=286), once-daily or stavudine, twice-daily at standard doses (n=285). All patients also received open-label didanosine and efavirenz twice-daily. Patients were evaluated at baseline, every 4 weeks up to week 48 and then every 12 weeks. The Kaplan-Meier probabilities at week 52 were, for virological failure, 14.1% for stavudine and 4.7% for emtricitabine (p<0.001); for efficacy failure, 35.1% for stavudine and 19.1% for emtricitabine (p<0.001). A significantly greater mean increase in CD4+ cell counts was seen in the emtricitabine arm (152 cells/mm3) compared with the stavudine arm (117 cells/mm3) [33] [34] . At 60 weeks, Kaplan-Meier analyses demonstrated that 79.4% of 286 patients receiving emtricitabine had persistent suppression of HIV RNA (<400 copies/mL) compared with 62.8% of 285 patients given stavudine (P<0.0001). When the analysis used a viral suppression level of <50 copies/mL at 60 weeks, the results were 75.6% and 53.7%, respectively (P<0.0001) [28] .

Results from study FTC-302 show that emtricitabine is more effective than standard therapy in reducing viral load (VL). The study compared emtricitabine 200mg o.d with lamivudine 150mg b.i.d in a background of stavudine b.i.d and efavirenz o.d. The Kaplan-Meier probability of virologic failure (not achieving <50 copies/mL or >50 copies/mL on two consecutive visits) at week 48 was 6.5% (emtricitabine) and 11.0% (lamivudine). Overall, emtricitabine was significantly superior to the combined control arms (P=0.01) [18] .

In an open-label pilot study conducted in France (ANRS 091), the efficacy of emtricitabine was evaluated in 40 HIV-infected antiretroviral-naive patients. In this study participants received once daily emtricitabine 200mg, didanosine 250mg if <60kg or 400mg if >60kg and efavirenz 600mg. At 24 weeks, 39/40 patients (98%) had a viral load of <400 copies/ml and 39/39 evaluable patients (100%) had undetectable viral loads. Intent-to-treat analysis showed that 37/40 patients (93%) had a viral load of <50 copies/ml at 24 weeks. Researchers involved in the study pointed out this is one of the first studies to suggest that potent antiviral activity can be achieved with a once daily HAART regimen. At the 96-week follow-up, 85% of the patients had maintained a plasma HIV RNA level <400 copies/mL and 80% had plasma HIV RNA <50 copies/mL. CD4 cell counts had increased by a median of 259 cells/µL [45] [36] .

Continued suppression of HIV-1 RNA was seen in HIV-infected adults who switched from a stable HAART regimen containing lamivudine to one containing emtricitabine. In a 48-week, open-label equivalence trial (FTC-303), 294 patients with HIV-1 RNA ≤400 copies/mL were randomised to either continue their lamivudine containing regimen or switch lamivudine 150mg bid to emtricitabine 200mg once daily. At 48 weeks, patients with HIV RNA ≤400 copies/ml were offered emtricitabine as part of the HAART regimen in study FTC-350. 77% of the patients receiving emtricitabine had HIV RNA ≤400 copies/mL at week 48. 214 of these patients elected to continue with emtricitabine in study FTC-350 for 72 weeks. 61% of the patients maintained HIV RNA levels at ≤400 copies/mL and 53% had ≤50 copies/ml at 72 weeks [38] .

Paediatric trials

treatment of children with emtricitabine achieved a level of systemic exposure comparable to that observed in adults with good virological activity. In this study, 82 patients aged between 4 months and 16 years received emtricitabine as part of HAART. Treatment-naive patients (n= 51) received 6 mg/kg (up to a maximum of 200 mg/day) plus twice-daily weight-adjusted doses of stavudine and lopinavir/ritonavir. Treatment-experienced patients (n=31) also received emtricitabine 6 mg/kg in place of lamivudine as part of their existing regimen. Interim analysis of data at 24 weeks showed high virological response rates among both groups. In the treatment-naive and treatment-experienced groups, the proprtion patients with HIV RNA levels <400 copies/mL were 92.2 an 83.9%, respectively; the proportion of patients with HIV RNA levels <50 copies/mL were 62.7 and 71 %, respectively. Treatment-experienced patients had no overall change in viral load during emtricitabine-based therapy, whereas the median reduction among treatment-naive patients was 3.08 log10 copies/mL [31] .

An easily administered once-a-day combination of emtricitabine/didanosine/efavirenz is virologically active for at least 16 weeks. This study (PACTG 1021) involved 30 treatment-naive patients; 17 of these patients were aged 12 years or younger and 13 were aged between 13 and 21 years. The study will eventually involve a total of 42 patients, including a cohort aged between 90 days and 3 years. The patients received once-daily emtricitabine 6 mg/kg, up to a maximum of 200 mg/day in addition to once-daily didanosine 240−400 mg/m2 and weight-adjusted doses of efavirenz (maximum dose of 600 mg/day for capsules or 720 mg/day for oral solution). A 16-week intention-to-treat analysis showed that high proportions of patients, including those aged ≤ 12 years, experienced virological responses. Among the overall patient population, viral loads of < 400 copies/mL and < 50 copies/mL were achieved in 87% and 74% of patients, respectively. Viral loads of < 400 copies/mL were achieved in 92% of the 13 patients aged < 12 years. Furthermore, all patients experienced an improvement in immune function, indicated by increases in CD4+ cell counts from baseline; the median increase was 200 cells/mm3 [32] .

Co-infection with hepatitis B virus and HIV

in a 15-day phase I/II evaluation of emtricitabine for HIV, 2 patients had detectable levels of hepatitis B virus (HBV) DNA. Over the 15-day exposure to emtricitabine these patients demonstrated a mean decrease in HBV DNA of betweeen 0.78 and 1.42 log10 with a maximum reduction in HBV DNA of between 1.55 and 1.99 log10 [52] .

Oral emtricitabine (25-200 mg/day, od) demonstrated efficacy in a phase II trial in 98 patients with chronic hepatitis B/HIV co-infection. At 1 year, 38, 42 and 54%, respectively, of emtricitabine 25, 100 and 200mg recipients had HBV levels < 3700 copies/ml. The incidence of YMDD mutation at 1 year was 4% in the 200mg group [42] .

Patients treated with emtricitabine as part of HAART demonstrated potent suppression of HBV DNA in co-infected patients with HIV RNA suppression. Median baseline HBV DNA was 8.75 log10 copies/mL and median HBV DNA change from baseline was -2.26, -2.44, 3.13 and 2.75 log10 copies/mL at 12, 24, 36 and 48 weeks. For the inactive d4T control group, the median change in HBV DNA was -0.05, -0.21, -0.60 and 0.02 log10 copies/mL. Among emtricitabine treated patients, 7/19, 8/19, 11/18 and 9/16 had HBV DNA <limit of detection, respectively [29] .

Chronic hepatitis B virus infections

In a phase I/II dose-selection trial, 98 patients with chronic hepatitis B infection were randomised to receive emtricitabine 25, 100 or 200mg, once daily for 24 weeks. At 24 weeks, median reductions from baseline in viral load of 2.3, 2.9 and 3 log10 were observed in emtricitabine 25mg, 100mg and 200mg recipients, respectively. In addition, HBV DNA levels were suppressed to < 4700 copies/ml (the limit of detection) in 22, 24 and 61% of emtricitabine 25mg, 100mg and 200mg recipients, respectively. At 48 weeks, the median decrease in viral load from baseline was 2.59, 3.12 and 2.92 log10 copies/ml and HBeAg loss occurred in 32, 38 and 50% of HBe antigen positive patients in the 25, 50 and 200mg cohorts respectively [44] [39] .

At week 48, all patients (n = 94) were switched to open-label emtricitabine, 200mg, once daily (QD), through to week 96, and then followed for an additional six months off therapy. At 96 weeks, 76% of patients had normal ALT levels; 41% had undetectable viremia; 51% had lost HBeAg and 29% had seroconverted to HBeAb. Compared to week 48, ten new patients had lost HbeAg, seven developed HBeAb, two regained HBeAg and two lost HBeAb. The incidence of L526M+/-M550V/I associated resistance was 19% for patients receiving emtricitabine 200mg for the full two years. Preliminary data from the treatment free follow-up period showed that 8 patients experienced viral rebound [54] .

Emtricitabine at daily doses ≥ 100mg is effective for treating patients with hepatitis B. In this multicentre, open, sequential, dose-escalating, phase II study, 49 patients with hepatitis B infection were treated with emtricitabine 25, 50, 100, 200 and 300 mg/day, PO, for 2 months. 43, 88, 73, 89, and 90% of the patients had decreases in HBV DNA level of ≥ 2 log10 copies/mL, respectively, with median decreases of 1.68, 3.15, 2.65, 3.04 and 3.33 log10 copies/mL at each dose level. Overall, HBV DNA level decreases were maintained for 48h after the final emtricitabine dose. Four weeks after completion, HBV DNA levels approached baseline levels. Viral loads decreased by 1, ≥2, ≥3 log10 copies/mL in 96, 78 and 53% of patients, respectively [35] .

Preliminary results from a phase III study (FTCB-301) showed that treatment with emtricitabine is associated with improvements in liver histology. In this 48-week, double-blind, placebo-controlled trial, 248 patients with chronic hepatitis B who had not previously received therapy with a nucleoside analogue were randomised (2:1) to receive emtricitabine 200mg once daily or placebo for 48 weeks. At study entry, patients had elevated levels of ALT and detectable serum levels of HBV DNA. After 48 weeks, 62% of patients treated with emtricitabine exhibited improvement in liver histology, compared with 25% of patients receiving placebo (p<0.001). Additionally, emtricitabine resulted in a median reduction in HBV DNA from baseline of 3 log10 copies/mL, compared with 0.44 log10 copies/mL in the placebo group (p<0.001). After 48 weeks, 56% of emtricitabine patients had HBV DNA below the assay lower limit of detection (4700 copies/mL), compared to 7% in the placebo arm (p<0.001). Additionally, patients treated with emtricitabine achieved a median ALT reduction of 52 IU/L, compared to a median ALT reduction of 25 IU/L for patients receiving placebo (p<0.001) [26] .

In a randomised, double-blind trial, emtricitabine plus adefovir dipivoxil combination therapy showed faster and more effective suppression of hepatitis B than adefovir dipivoxil alone. Thirty patients positive for HBeAg received either emtricitabine 200mg plus adefovir dipivoxil 10mg or adefovir dipivoxil 10mg plus placebo every day for 48 weeks. Median log10 reduction of viraemia was 5.04 versus 3.2 at week 28 and 5.3 versus −3.4 at week 48 for the combination therapy and adefovir dipivoxil alone, respectively; the differences were significant. There was a two-phase decay in hepatitis B virus kinetics; mean t1/2 was 1.4 days for the first phase and 24.4 days for the second phase. The infected cell loss rate was significantly greater with combination therapy than with monotherapy. Patients were either fast responders (< 300 copies/mL of virus at week 12) or slow responders (≥ 300 copies/mL of virus at week 12); significantly more patients receiving combination therapy were fast responders than those receiving monotherapy. HBeAg seroconversion occurred in two combination therapy recipients and one monotherapy recipient; all three cases were fast responders. The fast response was associated with enhanced T-cell reactivity [25] .

Emtricitabine 200mg alone or in combination with clevudine 10mg for 24 weeks elicited a fabourable antiviral response in 78 hepatitis B e antigen negative (HBeAg-) patients. After 24 weeks, median reductions in viral load from baseline among 52 experienced and 26 naïve patients were similar for emtricitabine + clevudine and emtricitabine alone groups. Among naïve patients, 69% and 67% of patients in the combination and monotherapy groups, respectively, had viral load <250 mg/dL at week 24, while among experienced patients, this proprotion was 86% and 63%, respectively. The overall incidence of emtricitabine-associated resistance mutations was 0% among treatment-naïve patients, compared with 7% in treatment-experienced patients [23] .

Similarly, emtricitabine, alone or in combination with clevudine10mg for 24 weeks elicited fabourable antiviral response in 85 hepatitis B e antigen positive (HBeAg+) patients. After 24 weeks, median reductions in viral load from baseline among 55 experienced and 30 naïve patients were similar for emtricitabine + clevudine and emtricitabine alone groups. Among experienced patients, the proportion of patients with viral load <250 mg/dL at week 24 was similar between treatment groups, while among naïve patients, this proportion was 50% and 19% in the combination and monotherapy groups, respectively. The overall incidence of emtricitabine-associated resistance mutations was 3% among treatment-naïve patients, compared with 22% in treatment-experienced patients [24] .

Development History

Event Date Update Type Comment
01 Feb 2021 Financial Update Credit Suisse financial data update Updated 14 Mar 2021
06 Jan 2020 Phase Change - No development reported(II) No development reported - Phase-II for HIV infections (In adolescents, In children, In infants) in South Africa (PO) Updated 06 Jan 2020
05 Dec 2018 Licensing Status Gilead offered Japan Tobacco to terminate the exclusive licenses for HIV drugs in Japan [6] Updated 06 Dec 2018
27 Aug 2018 Licensing Status Japan Tobacco and Gilead sign a letter of intent to initiate discussion to terminate license agreement for HIV drugs in Japan [5] Updated 06 Dec 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
13 Feb 2017 Trial Update Gilead Sciences completes a phase-II trial in HIV infections (In adolescents, In children, In infants) in South Africa (PO, Liquid) (PO, Capsule) (NCT00743340) Updated 10 Mar 2017
03 Apr 2010 Phase Change - No development reported(III) No development reported - Phase-III for Hepatitis B in USA (PO) Updated 03 Aug 2010
24 Jul 2007 Scientific Update 144-Week results from a phase III clinical trial (Study 934) added to the Viral Infections therapeutic trials section [17] Updated 26 Oct 2007
18 Dec 2006 Scientific Update 96 week results from a phase III clinical trial (Study 934) in patients with HIV infection added to the adverse events and Viral Infections therapeutic trials sections [15] Updated 20 Dec 2006
30 Aug 2006 Phase Change - Marketed Launched for HIV infections in South America (PO) Updated 03 Aug 2010
03 Aug 2006 Phase Change - Marketed Launched for HIV infections in Mexico (PO) Updated 03 Aug 2010
07 Mar 2006 Scientific Update Data presented at the 13th Conference on Retroviruses and Opportunistic Infections (CROI-2006) have been added to the adverse events, pharmacokinetics and Viral infections therapeutic trials sections [22] Updated 07 Mar 2006
09 Dec 2005 Scientific Update Data presented at the 56th Annual Meeting and Postgraduate Course of the American Association for the Study of Liver Diseases (AASLD-2005) have been added to the Viral Infections therapeutic trials section [23] , [24] Updated 09 Dec 2005
22 Nov 2005 Phase Change - II Phase-II clinical trials in HIV infections (In adolescents, In children, In infants) in South Africa (PO, Capsule) (NCT00743340) Updated 10 Mar 2017
22 Nov 2005 Phase Change - II Phase-II clinical trials in HIV infections (In adolescents, In children, In infants) in South Africa (PO, Liquid) (NCT00743340) Updated 10 Mar 2017
30 Sep 2005 Phase Change - Registered Registered for HIV infections treatment in USA (PO, Liquid) Updated 04 Oct 2005
25 Jul 2005 Licensing Status Gilead Sciences and Royalty Pharma have purchased Emory University's royalty interest in emtricitabine Updated 25 Jul 2005
30 Apr 2005 Phase Change - Marketed Launched for HIV infections in Australia (PO) Updated 04 Aug 2010
19 Apr 2005 Phase Change - Marketed Launched for HIV infections treatment in Japan (PO) Updated 15 Mar 2006
23 Mar 2005 Phase Change - Registered Registered for HIV infections treatment in Japan (PO) Updated 12 Apr 2005
01 Feb 2005 Phase Change - Marketed Launched for HIV infections in European Union (PO) Updated 03 Aug 2010
25 Jan 2005 Phase Change - Preregistration Preregistration for HIV infections treatment in Japan (PO) Updated 12 Apr 2005
05 Nov 2004 Scientific Update Data from a media release have been added to the adverse events and Viral Infections therapeutic trials sections [16] Updated 05 Nov 2004
04 Nov 2004 Scientific Update Data presented at the 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2004) have been added to the Viral Infections therapeutic trials section [25] Updated 04 Nov 2004
13 Oct 2004 Regulatory Status Emtricitabine - Gilead Sciences receives Orphan Drug status for HIV-1 infections in Japan (PMDA website, October 2004) Updated 18 Mar 2020
31 Dec 2003 Phase Change - Marketed Launched for HIV infections treatment in France (PO) Updated 12 Feb 2004
31 Dec 2003 Phase Change - Marketed Launched for HIV infections treatment in Germany (PO) Updated 12 Feb 2004
31 Dec 2003 Phase Change - Marketed Launched for HIV infections treatment in United Kingdom (PO) Updated 13 Jan 2004
01 Dec 2003 Scientific Update Data from a media release have been added to the Viral Infections therapeutic trials section [26] Updated 01 Dec 2003
31 Oct 2003 Phase Change - Registered Registered for HIV infections treatment in Europe Union (PO) Updated 31 Oct 2003
07 Aug 2003 Licensing Status Emtricitabine has been licensed to Japan Tobacco in Japan Updated 07 Aug 2003
06 Aug 2003 Regulatory Status The EMEA's Committee for Proprietary Medicinal Products has recommended approval of emtricitabine for HIV infections treatment in the EU Updated 06 Aug 2003
30 Jul 2003 Scientific Update Data presented at the 2nd IAS Conference on HIV Pathogenesis and Treatment (IAS-2003) have been added to the adverse events and Viral infections therapeutic trials section [27] , [28] Updated 30 Jul 2003
28 Jul 2003 Scientific Update Data presented at the 2nd IAS Conference on HIV Pathogenesis and Treatment (IAS-2003) have been added to the Viral infections therapeutic trials section [29] , [18] , [30] Updated 28 Jul 2003
11 Jul 2003 Phase Change First global launch of emtricitabine in USA Updated 11 Jul 2003
11 Jul 2003 Phase Change - Marketed Launched for HIV infections treatment in USA (PO) Updated 11 Jul 2003
03 Jul 2003 Phase Change - Registered Registered for HIV infections treatment in USA (PO) Updated 03 Jul 2003
02 Apr 2003 Scientific Update Two studies have been added to the adverse events and Viral Infections therapeutic trials sections [31] , [32] Updated 02 Apr 2003
03 Mar 2003 Company Involvement Triangle Pharmaceuticals has been acquired by and merged into Gilead Sciences Updated 03 Mar 2003
09 Jan 2003 Phase Change - Preregistration Preregistration for HIV infections treatment in Europe (PO) Updated 09 Jan 2003
04 Dec 2002 Company Involvement Gilead and Triangle have signed a definitive agreement for the acquisition of Triangle by Gilead Updated 14 Jan 2003
12 Nov 2002 Regulatory Status The NDA for marketing approval of emtricitabine has been accepted by the FDA Updated 12 Nov 2002
10 Oct 2002 Scientific Update A study has been added to the adverse events and Viral Infections therapeutic trials sections [33] , [34] Updated 10 Oct 2002
05 Sep 2002 Phase Change - Preregistration Preregistration for HIV infections treatment in USA (PO) Updated 05 Sep 2002
15 Aug 2002 Licensing Status Triangle has reacquired product rights from Abbott Laboratories Updated 15 Aug 2002
09 Aug 2002 Trial Update In view of positive interim results, a Data Safety Monitoring Board has recommended that a pivotal phase III trial of emtricitabine is unblinded early [19] Updated 09 Aug 2002
22 Jul 2002 Scientific Update A phase II study has been added to the pharmacokinetics, adverse events and Viral Infections therapeutic trials section [35] Updated 22 Jul 2002
14 Jun 2002 Licensing Status Patent disputes involving emtricitabine have been settled Updated 14 Jun 2002
11 Apr 2002 Scientific Update Final results from study ANRS 091 have been added to the Viral Infections therapeutic trials field [36] Updated 11 Apr 2002
24 Jan 2002 Scientific Update Two studies have been added to the Viral Infections therapeutic trials and adverse events section [37] , [38] Updated 24 Jan 2002
05 Dec 2001 Scientific Update A study has been added to the Viral Infections therapeutic trials section [39] Updated 05 Dec 2001
28 Sep 2001 Scientific Update A study has been added to the Viral Infections therapeutic trials section [40] Updated 28 Sep 2001
14 Aug 2001 Scientific Update A clinical study has been added to the Viral Infections pharmacodynamics section [41] Updated 14 Aug 2001
13 Aug 2001 Scientific Update A study has been added to the adverse events and Viral Infections therapeutic trials sections [42] Updated 13 Aug 2001
08 Jan 2001 Scientific Update A paediatric study has been added to the adverse events and pharmacokinetics sections [43] Updated 08 Jan 2001
03 Nov 2000 Scientific Update A dose escalation study in hepatitis B-infected patients has been added to the Viral infections therapeutic trials section [44] Updated 03 Nov 2000
06 Oct 2000 Scientific Update A pilot study of a once-daily emtricitabine regimen has been added to the adverse events and Viral infections therapeutic trials section [45] Updated 06 Oct 2000
30 Sep 2000 Phase Change - III Phase-III clinical trials for Hepatitis B in USA (PO) Updated 30 Sep 2000
13 Jun 2000 Phase Change - Discontinued(III) Discontinued - Phase-III for HIV infections treatment in South Africa (PO) Updated 09 Aug 2002
29 May 2000 Phase Change - III Phase-III clinical trials for HIV infections treatment in Europe (PO) Updated 29 May 2000
29 May 2000 Phase Change - III Phase-III clinical trials for HIV infections treatment in Mexico (PO) Updated 29 May 2000
29 May 2000 Phase Change - III Phase-III clinical trials for HIV infections treatment in South America (PO) Updated 29 May 2000
29 May 2000 Phase Change - III Phase-III clinical trials for HIV infections treatment in USA (PO) Updated 29 May 2000
13 Apr 2000 Regulatory Status The FDA has issued a clinical hold on a study being conducted in South Africa in HIV patients Updated 13 Apr 2000
08 Jun 1999 Licensing Status Triangle Pharmaceuticals and Abbott Laboratories have entered a development and marketing agreement for 6 antiviral drugs, including emtricitabine Updated 08 Jun 1999
17 May 1999 Licensing Status Glaxo Wellcome has signed a licensing agreement with Emory University and Triangle Pharmaceuticals Updated 17 May 1999
05 Feb 1999 Scientific Update A phase I/II study has been added to the Viral Infections therapeutic trials section [46] Updated 05 Feb 1999
19 Jan 1999 Phase Change - I Phase-I clinical trials for Hepatitis B in USA (PO) Updated 19 Jan 1999
19 Jan 1999 Phase Change - II Phase-II clinical trials for Hepatitis B in USA (PO) Updated 19 Jan 1999
19 Jan 1999 Phase Change - III Phase-III clinical trials for HIV infections treatment in South Africa (PO) Updated 19 Jan 1999
19 Jan 1999 Scientific Update A phase I/II study has been added to the pharmacokinetics section [47] Updated 19 Jan 1999
16 May 1996 Phase Change - II Phase-II clinical trials for Hepatitis B in European Union (PO) Updated 16 May 1996
16 May 1996 Phase Change - II Phase-II clinical trials for Hepatitis B in North America (PO) Updated 16 May 1996
16 May 1996 Phase Change - II Phase-II clinical trials for HIV infections treatment in European Union (PO) Updated 16 May 1996
16 May 1996 Phase Change - II Phase-II clinical trials for HIV infections treatment in North America (PO) Updated 16 May 1996
17 Oct 1995 Scientific Update A study has been added to the pharmacokinetics, antimicrobial activity and adverse events sections [48] Updated 17 Oct 1995
15 Aug 1995 Phase Change - I Phase-I clinical trials for Hepatitis B in Spain (Unknown route) Updated 15 Aug 1995
15 Aug 1995 Phase Change - I Phase-I clinical trials for HIV infections treatment in Spain (Unknown route) Updated 15 Aug 1995

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