SECTION 2.6 NONCLINICAL SUMMARY Section 2.6.1 Introduction EMTRICITABINE/RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION Gilead Sciences International Limited 07 August 2010 CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.1 Introduction Final TABLE OF CONTENTS SECTION 2.6 NONCLINICAL SUMMARY........................................................................................................1 TABLE OF CONTENTS .......................................................................................................................................2 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS...............................................................3 2.6. NONCLINICAL SUMMARY.......................................................................................................................4 2.6.1. Introduction.......................................................................................................................................4 2.6.1.1. Emtricitabine ...................................................................................................................5 2.6.1.2. Rilpivirine .......................................................................................................................6 2.6.1.3. Tenofovir Disoproxil Fumarate.......................................................................................6 2.6.1.4. Fixed Combination of Emtricitabine and Tenofovir Disoproxil Fumarate......................7 2.6.1.5. Fixed Combination of Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate..........................................................................................................................7 2.6.1.6. References.......................................................................................................................9 CONFIDENTIAL Page 2 07 August 2010 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.1 Introduction Final GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ARV antiretroviral bisPOC bis-isopropyloxycarbonylmethyl; disoproxil DAPY diarylpyrimidine dATP deoxyadenosine triphosphate DLV delaviridine, Rescriptor EC50 median effective concentration EFV efavirenz, Sustiva, Stocrin EFV/FTC/TDF efavirenz/emtricitabine/tenofovir DF, Atripla EMA European Medicines Evaluation Agency ETR etravirine, Intelence FDC fixed-dose combination FTC emtricitabine FTC/TDF emtricitabine, Truvada HIV-1 human immunodeficiency virus type 1 MAA marketing authorization application monoPOC PMPA tenofovir soproxil NNRTI nonnucleoside reverse transcriptase inhibitor NRTI nucleoside reverse transcriptase inhibitor NtRTI nucleotide reverse transcriptase inhibitor NVP nevirapine, Viramune PBMC peripheral blood mononuclear cell PMPApp tenofovir diphosphate RPV, TMC278 rilpivirine (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg RPV) TDF tenofovir DF, Viread TFV tenofovir, PMPA TMC Tibotec medicinal compound US United States WT wild type CONFIDENTIAL Page 3 07 August 2010 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.1 Introduction Final 2.6. NONCLINICAL SUMMARY 2.6.1. INTRODUCTION This dossier is being submitted in support of a marketing authorization application (MAA) for a fixed-dose combination (FDC) film-coated tablet that contains the active substances emtricitabine (FTC), rilpivirine (RPV, which is also referred to as TMC278 throughout this document), and tenofovir disoproxil fumarate (tenofovir DF, TDF). Emtricitabine and TDF are antiretroviral agents developed by Gilead Sciences that have been approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection as stand-alone agents Emtriva® (Commission Decision granted on 20 ) and Viread® (Commission Decision granted on 20 ), and in a FDC product Truvada (emtricitabine/tenofovir DF [FTC/TDF]; Commission Decision granted on 20 ). Emtricitabine, a nucleoside reverse transcriptase inhibitor (NRTI), and TDF, a nucleotide reverse transcriptase inhibitor (NtRTI), are listed as preferred agents in United States (US) and international treatment guidelines {15207}, {12716}, {14065}. Emtricitabine and TDF are also approved for the treatment of HIV-1 infection in combination with efavirenz (EFV), a nonnucleoside reverse transcriptase inhibitor (NNRTI). This FDC product is Atripla (efavirenz/emtricitabine/tenofovir DF [EFV/FTC/TDF]; Commission Decision granted on 20 ). These products are currently approved in the US, the European Community, and other countries worldwide for use in adults. In some regions, Emtriva and Viread are approved for use in adolescents; Emtriva, which is also available as an oral solution formulation, may be administered to children as young as 4 months of age. Rilpivirine, an NNRTI, is an investigational agent that is being submitted for approval by Tibotec BVBA. Gilead Sciences has coformulated FTC and TDF, the standard of care NRTI backbone, with RPV into a FDC tablet. This FDC tablet is referred to as emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF; dose strength 200/25/300 mg, respectively) throughout this document. Each FTC/RPV/TDF FDC tablet contains FTC, RPV, and TDF at the same dosages as recommended for the individual components, i.e., 200 mg of FTC, 25 mg RPV (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg RPV), and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg tenofovir disoproxil or 136 mg of tenofovir [TFV]). The FTC/RPV/TDF FDC tablet has demonstrated bioequivalence to each of the individual dosage forms (FTC, TDF, and RPV). It is proposed that the FTC/RPV/TDF FDC tablet be indicated for the treatment of HIV-1 infection in adults and taken orally once daily with a meal. In accordance with the advice received from the European Medicines Evaluation Agency (EMA) at the EMA Strategy meeting held on 20 (see meeting minutes provided in Module 1.2, Annex 5.14), the MAAs for RPV as a single agent and for the FTC/RPV/TDF FDC tablet are being submitted in parallel by Tibotec BVBA and Gilead Sciences, respectively. CONFIDENTIAL Page 4 07 August 2010 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.1 Introduction Final Emtricitabine, RPV, and TDF have been assessed individually in comprehensive nonclinical studies. As the RPV component is a new chemical entity, this FDC MAA dossier contains full data on this new component while providing the key data on the Truvada (i.e. FTC, TDF, and FTC/TDF) components. All Truvada studies considered to support the FDC are included to ensure that this is a ‘stand-alone dossier.’ This is in agreement with the feedback received at the presubmission meeting with the EMA on 20 and with the meeting with the Rapporteur/Co-Rapporteur on 20 (see Module 1.2.5.14, final minutes). To assist the reviewer, a listing of all the FTC, TDF, FTC/TDF, and EFV/FTC/TDF nonclinical reports is provided in Module 2.4, Section 2.4.7. Information from all nonclinical studies with FTC, RPV, and TDF should be considered in the context of the substantial clinical experience with FTC and TDF within antiretroviral combination therapy for the treatment of HIV-1 infection, the Phase 2 and Phase 3 clinical experience with RPV, and with RPV administered in combination with Truvada (FTC/TDF). 2.6.1.1. Emtricitabine Emtricitabine is a NRTI. It is the active ingredient in Emtriva 200 mg capsules and 10mg/mL oral solution that have been approved in the US, the European Community, and other countries worldwide in combination with other antiretroviral agents for the treatment of HIV-1 infection. The international birthdate for FTC is 20 . Emtricitabine is a synthetic analogue of the naturally occurring 2ƍ-deoxycytidine, a pyrimidine nucleoside. The chemical name of FTC is 5-fluoro-1-[(2R,5S-2-hydroxymethyl)- 1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of the compound and has also been referred to as (-)-2’,3’-dideoxy-5-fluoro-3’-thiacytidine. It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. The chemical structure of FTC is as follows: N O H2N N O F OH S Following absorption, FTC is phosphorylated by cellular enzymes to emtricitabine 5'-triphosphate (FTC-TP), the active metabolite. Emtricitabine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase through high affinity binding, competing with the natural substrate deoxycytidine 5'-triphosphate. Emtricitabine 5'-triphosphate is efficiently incorporated into the nascent (viral) DNA chain by HIV-1 RT resulting in termination of DNA synthesis due to the lack of a hydroxyl group in the 3’- position of the sugar moiety of FTC, which in turn inhibits viral replication. In a clinical study, the intracellular half-life of FTC-TP in peripheral blood mononuclear cells was 39 hours. Intracellular triphosphate levels increased with dose, but reached a plateau at doses of 200 mg or greater. Emtricitabine has activity against retroviruses and hepadnaviruses. CONFIDENTIAL Page 5 07 August 2010 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.6.1 Introduction Final 2.6.1.2. Rilpivirine Tibotec Medicinal Compound 278 (TMC278, rilpivirine, RPV), a substituted diarylpyrimidine (DAPY) derivative, is a potent NNRTI with in vitro activity against wild type (WT) HIV-1 and HIV-1 NNRTI-resistant mutants, which has been developed for long term treatment of HIV-infected treatment-naive adults in combination with commercialized antiretroviral (ARV) agents. TMC278 has not yet been