June 2016 Australian Public Assessment Report for Elvitegravir / Cobicistat / Emtricitabine / Tenofovir alafenamide (as fumarate) Proprietary Product Name: Genvoya Sponsor



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Common abbreviations


Abbreviation

Meaning

AE

adverse event

aGFR

actual glomerular filtration rate

AhR

aryl hydrocarbon receptors

AIDS

acquired immunodeficiency syndrome

APR

Antiretroviral Pregnancy Registry

ART

antiretroviral therapy

ARV

antiretroviral

ATV/co

cobicistat-boosted atazanavir

ATV/r

ritonavir-boosted atazanavir

AUCtau

Area under the concentration versus time curve to the end of the dosing period

BCRP

breast cancer resistance protein

BMD

bone mineral density

Cat A

cathepsin A

CC50

Half maximal cytotoxic concentration

CD4

cluster determinant 4

CES1

carboxylesterase 1

CHMP

Committee for Medicinal Products for Human Use

CKD-EPI

Chronic Kidney Disease epidemiology collaboration equation

CI

confidence interval

Cmax

Peak plasma concentration

COBI

cobicistat (Tybost)

CsA

ciclosporin

Ctau

Plasma concentration at the end of the dosing period

CYP

Cytochrome P450

DNA

deoxyribonucleic acid

dNTP

2' deoxynucleoside triphosphate

DRV

darunavir

DTG

dolutegravir

DXA

dual-energy x-ray absorptiometry

EASC

European AIDS Clinical Society

EC50

concentration of a compound inhibiting virus replication by 50%

EOP2

End of Phase 2

EVG, E

elvitegravir (Vitekta)

EVG/COBI/FTC/TAF

elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (co-formulated)

EFV

efavirenz

eGFR

estimated glomerular filtration rate

eGFRCG

estimated glomerular filtration rate calculated using the Cockcroft-Gault equation

ESRD

end-stage renal disease

EU

European Union

FAS

Full Analysis Set

FDA

Food and Drug Administration

FDC

fixed dose combination

FTC

emtricitabine (Emtriva)

FTC-DP

emtricitabine diphosphate

GD7

Gestation day 7

GCP

Good Clinical Practice

Gilead

Gilead Sciences

GLP

Good laboratory practice

GLSM

geometric least-squares mean

GS-7340

tenofovir alafenamide (TAF)

HBV

hepatitis B virus

HCV

hepatitis C virus

HD

High dose

HIV, HIV-1, HIV-2

human immunodeficiency virus, type 1, type 2

HSV-2

Herpes simplex virus -2

IC95

concentration that results in xx% inhibition

ICH

International Conference on Harmonization (of Technical Requirements for Registration of Pharmaceuticals for Human Use)

IN

integrase

IND

Investigational New Drug

INSTI

integrase strand-transfer inhibitor

ISS

Integrated Summary of Safety

kcal

Kilo calories

LD

Low dose

Ki

Kinetic inhibition (constant)

KM

Kaplan-Meier

LDL

low-density lipoprotein

LOCF

last observation carried forward

LSM

least-squares mean

M = F

missing = failure

mtDNA

mitochondrial DNA

N or n

number of subjects in a population (N) or subset (n)

NOAEL

no-observed-adverse-effect-level

NNRTI

non nucleoside reverse transcriptase inhibitor

NNRTI-R

NNRTI resistant

NRTI

nucleoside reverse transcriptase inhibitor

NRTI-R

NRTI resistant

NtRTI

nucleotide reverse transcriptase inhibitor

NtRTI-R

NtRTI resistant

NTx

collagen type 1 cross-linked N-telopeptide

OAT

organic anion transporters

OATP

organic anion transporting polypeptide

P1NP

procollagen type 1 N-terminal propeptide

PBMC

peripheral blood mononuclear cell

PD

pharmacodynamic(s)

P-gp

P-glycoprotein

PK

pharmacokinetic(s)

PP

Per Protocol

PRT

proximal renal tubulopathy

PTH

parathyroid hormone

PXR

pregnane X receptor

Q1, Q3

first quartile, third quartile

QTcF

Fridericia’s corrected QT interval for heart rate

QUAD

Stribild

-R

resistant

RNA

ribonucleic acid

rNTP

ribonucleoside triphosphate

RT

reverse transcriptase

RTV

ritonavir

SAE

serious adverse event

SAP

statistical analysis plan

SD

standard deviation

SI

selectivity index (ratio of CC50 to IC50 )

SIV

Simian immunodeficiency virus

SOC

system organ class

STB

elvitegravir/cobicistat/emtricitabine/ tenofovir disoproxil fumarate (co-formulated; Stribild)

STR

single-tablet regimen (also referred to as FDC for E/C/F/TAF)



half life

T3

Triiodothyronine

TAF

tenofovir alafenamide

TAM

thymidine analog mutation

TDF

tenofovir disoproxil fumarate (Viread)

TFV

tenofovir

TFV-DP

tenofovir diphosphate

TFV-MP

tenofovir monophosphate (previously referred to as PMPAp)

TVD

emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada)

UGT

uridine diphosphate glucuronosyltransferase

ULN

upper limit of normal

UPCR

urine protein to creatinine ratio

US

United States

I. Introduction to product submission

Submission details


Type of submission:

New chemical entity/ new fixed dose combination

Decision:

Approved

Date of decision:

12 January 2016

Date of entry onto ARTG

15 January 2016



Active ingredients:

Elvitegravir / Cobicistat / Emtricitabine / Tenofovir alafenamide (as fumarate)

Product name:

Genvoya

Sponsor’s name and address:

Gilead Sciences Pty Ltd

Level 6/ 417 St Kilda Rd

Melbourne


Dose form:

Fixed dose combination tablet

Strength:

150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine and 10 mg of tenofovir alafenamide(TAF)

Container:

HDPE bottle

Pack size:

30 tablets

Approved therapeutic use:

Genvoya is indicated as a single tablet regimen for the treatment of HIV-1 infection in adults and adolescents aged 12 years of age and older with body weight at least 35 kg who are either treatment, naive; or virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see clinical trials). Patients must not have a history of treatment failure or known mutations associated with resistance to the antiretroviral components of Genvoya.

Genvoya is a fixed dose combination of one integrase inhibitor, one pharmacokinetic enhancer and two nucleos(t)ide HIV‐1 reverse transcriptase inhibitors.

Route of administration:

Oral

Dosage:

One tablet taken daily with food

ARTG number:

233398

Product background


This AusPAR describes the application by Gilead Sciences Pty Ltd (the sponsor) to register Genvoya for the following indication:

Genvoya is indicated for the treatment of HIV-1 infection in adults and paediatric patients 12 years of age and older without any known mutations associated with resistance to the individual components of Genvoya

This application seeks to register a fixed dose combination tablet comprising of 150 mg of elvitegravir (EVG), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC) and 10 mg of tenofovir alafenamide (as fumarate) (TAF). The proposed indication is for the treatment of HIV-1 infection in adults and paediatric patients 12 years of age and older without any known mutations associated with resistance to the individual components of Genvoya.

The similar registered product, Stribild, was recently approved for the following indication:

Stribild is indicated as a single tablet regimen for the treatment of HIV infection in treatment naive adults. Stribild is also indicated in certain virologically suppressed (HIV-1 RNA < 50 copies/mL) adult patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen. Patients must not have a history of treatment failure or known mutations associated with resistance to the antiretroviral components of Stribild (tenofovir DF, emtricitabine or elvitegravir).’

Genvoya contains the same doses of EVG, COBI and FTC as the registered fixed dose combination Stribild; however Stribild contains 300 mg tenofovir disoproxil fumarate (TDF) the first approved oral pro drug of tenofovir (TFV) which is replaced in Genvoya by 10 mg of TAF. The components of Genvoya EVG, FTC and TAF are anti-HIV drugs. COBI is a CYP3A inhibitor that increases systemic levels of EVG, it has no anti-HIV activity.

Tenofovir alafenamide is a prodrug for tenofovir (TFV), which is metabolised intracellularly to the active metabolite, tenofovir diphosphate (TFV-DP). Intracellularly, TFV-DP competes with deoxyadenosine triphosphate for incorporation into nascent DNA, and acts as a DNA chain terminator during HIV reverse transcription.

Tenofovir alafenamide is more stable in plasma than TDF and is activated intracellularly to TFV by cathepsin A (Cat A), which is highly expressed in lymphoid tissues.1 Given the intracellular mechanism of action of TAF, there is greater potential for intracellular accumulation in HIV-1 target cells and lower extracellular exposures to TFV, with the potential for less toxicity (nephrotoxicity and reduced bone mineral density). The clinical dose of TAF is therefore much lower than the clinical dose of TDF with replacement of TDF 300 mg with TAF 10 mg in Genvoya and is intended to reduce the renal and bone toxicities associated with TDF.

Table 1. Comparison of composition of Stribild and Genvoya

Genvoya

Stribild

Comments

Elvitegravir 150mg

Elvitegravir 150mg

HIV-1 integrase strand transfer inhibitor.

Cobicistat 150mg

Cobicistat 150mg

Pharmacokinetic enhancer through CYP3A inhibition, no direct antiviral activity. Enhances exposure of Elvitegravir (CYP3A substrate) and TAF (via P-glycoprotein inhibition).

Emtricitabine 200mg

Emtricitabine 200mg

Nucleoside reverse transcriptase inhibitor (NRTI)

Tenofovir alafenamide 10 mg*

Tenofovir disoproxil fumarate 300 mg

Nucleotide reverse transcriptase inhibitor (NRTI). Tenofovir alafenamide is a prodrug of tenofovir.

*New chemical entity

Given the duration for which a newly diagnosed person with HIV may take an antiretroviral therapy (ART) regimen, the Genvoya fixed dose combination tablet may provide a single treatment that optimises tolerability, long term safety, and efficacy. There are specific and complex challenges for the treatment of adolescents, who represent the population that will require antiretroviral therapy (ART) for the longest time.

Other TAF based antiretroviral therapy that are currently under development include fixed dose combinations for;


  • emtricitabine/tenofovir alafenamide (FTC/TAF)

  • emtricitabine/tenofovir alafenamide/rilpivirine (FTC/TAF/ rilpivirine)

  • emtricitabine/tenofovir alafenamide/cobicistat/darunavir (FTC/TAF/COBI/darunavir).2

Regulatory status


The product received initial registration on the Australian Register of Therapeutic Goods (ARTG) on 15 January 2016.

At the time the TGA considered this application, similar applications had been approved in, or were under consideration in the countries/jurisdictions show in Table 2 below.



Table 2. Overseas regulatory status

Country

Submission date and approval status

Approved indication (if available)

European Union (EU)

27 November 2014 Approval pending after CHMP positive opinion3

Genvoya is indicated for the treatment of adults and adolescents (aged 12 years and older with body weight at least 35 kg) infected with human immunodeficiency virus-1 (HIV-1) without any known mutations associated with resistance to the integrase inhibitor class, emtricitabine or tenofovir.

USA

5 Nov 2014 Approved 5 Nov 2015

Genvoya is indicated as a complete regimen for the treatment of HIV-1 infection in adults and paediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Genvoya.

Canada

6 January 2015 Approval pending4

Genvoya (150 mg elvitegravir/150 mg cobicistat/200 mg emtricitabine/10 mg tenofovir alafenamide) is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 12 years of age and older (and weighing ≥ 35 kg) and with no known mutations associated with resistance to the individual components of Genvoya.

Product Information


The approved Product Information (PI) current at the time this AusPAR was prepared can be found as Attachment 1. For the most recent PI, please refer to the TGA website at .
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