Gilead Sciences 1

Application for inclusion of tenofovir disoproxil

fumarate (Viread®) tablets on the WHO Model List

of Essential Medicines

Submitted by

Gilead Sciences Inc.

March 13, 2015

Gilead Sciences Inc.

333 Lakeside Drive

Foster City

California 94404

USA

Gilead Submission Reference number:

Gilead Sciences 2

Contents

1.Summary statement of the proposal for inclusion ..................................................... 4

2. Name of the focal point in WHO submitting or supporting the application .................. 5

3. Name of the organization(s) consulted and/or supporting the application .................. 5

4. International Nonproprietary Name (INN, generic name) of the medicine .................. 5

5. Formulation proposed for inclusion ......................................................................... 5

6. International availability ......................................................................................... 6

7. Listing type requested ........................................................................................... 8

8. Information supporting the public health relevance .................................................. 8

8.1 Epidemiological information on disease burden ............................................. 8

8.2 Assessment of current use ........................................................................... 8

9. Treatment details .................................................................................................. 9

9.1 Indications and usage .................................................................................. 9

9.2 Dosage and administration ........................................................................... 9

9.2.1 Special populations ............................................................................... 9

9.3 Reference to existing WHO and other clinical guidelines ...............................10

10. Summary of comparative effectiveness in a variety of clinical settings ..............11

10.1 Identification of clinical evidence ..................................................................11

10.2 Summary of available data on comparative effectiveness of Viread® ..............11

10.3 Summary of the efficacy of Viread® in patients with CHB ...............................11

10.4 Summary of the resistance profile of Viread® in patients with CHB .................12

10.5 Impact of Viread® on patient health-related quality of life ...............................12

10.6 Effect of Viread® therapy on long-term patient outcomes ...............................12

10.7 Summary of available estimates of comparative effectiveness .......................12

11. Summary of comparative evidence on safety ...................................................13

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11.1 Estimate of total patient exposure to Viread® ...................................................13

11.2 Description of adverse effects/reactions .......................................................15

11.3 Renal safety profile .....................................................................................15

11.4 Viread® on bone parameters in CHB ...............................................................15

11.5 Drug interactions ........................................................................................16

11.6 Summary of comparative safety .....................................................................17

12. Summary of available data on comparative cost and cost-effectiveness within

the pharmacologic class or therapeutic group ...........................................................19

12.1 Range of costs of the proposed medicine .....................................................19

12.1.1 USA ....................................................................................................19

12.1.2 Developing countries ............................................................................19

12.2 Cost-effectiveness of medicines for HBV ........................................................19

13. Summary of regulatory status of the medicine ..................................................20

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International

Pharmacopoeia, United States Pharmacopoeia) .......................................................21

14.1 Specifications of Viread® tablets ..................................................................21

15. Proposed (new/adapted) text for the WHO Model Formulary .............................22

15.1 Other antivirals ...........................................................................................22

16. References ....................................................................................................23

Appendix 1. Access Prescribing Information for Viread® ..............................................27

Gilead Sciences 4

1. Summary statement of the proposal for inclusion

Viread® (tenofovir disoproxil fumarate, TDF) is a once-daily oral nucleotide analog

reverse transcriptase inhibitor that blocks reverse transcriptase, a crucial enzyme in

chronic hepatitis B virus infection and human immunodeficiency virus-1 (HIV) infection.

It is proposed for inclusion in the WHO Model List of Essential Medicines as a potent

treatment for chronic hepatitis B infection (CHB) in adult patients and in pediatric

patients over the age of 12 years. The use of Viread® is based primarily on efficacy and

safety data from two pivotal Phase 3 studies, Study 102 in hepatitis B e antigen -

negative patients and Study 103 in HBeAg-positive patients, in which Viread® was

shown to result in high rates of virological suppression with no detectable resistance

[Marcellin et al, 2008]. Data from the open-label follow-up phases of these studies

have since demonstrated that virological response is sustained through to 8 years of

therapy in adherent patients with no resistance reported and was associated with

regression of cirrhosis [Marcellin et al, AASLD 2014; Corsa et al, AASLD 2014; Marcellin

et al. 2013]. The efficacy and safety of Viread® observed in these clinical studies has

been confirmed in specific patient populations, including adolescents [Murray et al,

2012], patients with a high viral load [Gordon et al, 2013; Chan et al, 2014] and in

previously treated patients with lamivudine resistance [Fung et al, 2014]. Real-world

data are also available and demonstrate that the efficacy and safety of Viread®

observed in controlled trial situations are also apparent in more heterogenous patient

populations [Causse et al, EASL 2014; Petersen et al, EASL 2014; Lampertico et al,

AASLD 2013; Tabernero et al, EASL 2014].

The principal reasons for requesting this inclusion are as follows:

Chronic HBV infection imposes a significant burden on adults living in resource

limited settings [Lemoine et al, 2013]

At present, no oral antiviral agent is listed on the WHO Model List of Essential

Medicines for treatment of patients with chronic HBV.

Treatment with the nucleotide reverse transcriptase inhibitor, Viread®, is well

tolerated, results in potent antiviral activity in almost all adherent CHB patients

without the observed risk of resistance and is associated with long-term

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benefits including reversal of cirrhosis. As a result, Viread® has the potential to

meet the treatment needs of CHB patients with respect to:

o Sustained virological suppression in almost all adherent patients

[Marcellin et al, 2008; Marcellin et al, AASLD 2014] including those with

a high viral load before treatment and in those with resistance to other

oral agents [Fung et al, 2014]

o No risk of observed resistance even with long-term treatment [Marcellin

et al AASLD 2014; Corsa et al, AASLD 2014]

o Regression of liver fibrosis and reversal of cirrhosis [Marcellin et al,

2013]

2. Name of the focal point in WHO submitting or supporting the

application

Philippa Easterbook, 20 Avenue Appia, 1211 Geneva, 27-Switzerland.

3. Name of the organization(s) consulted and/or supporting the

application

World Health Alliance.

4. International Nonproprietary Name (INN, generic name) of the

medicine

Tenofovir disoproxil fumarate

5. Formulation proposed for inclusion

Viread® is a once-daily oral medication indicated for the treatment of CHB in adults or

in paediatric patients aged over 12 years at a dose of 300 mg. Each tablet includes 245

mg of tenofovir disoproxil (as fumarate). The tablets, of dimensions 16.8 mm x 10.3

mm, are almond-shaped, light blue, film coated and debossed with ‘GILEAD’ and

‘4331’ on one side and with ‘300’ on the other side.

The qualitative composition of Viread® tablets is as described in Table 1.

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Table 1: Qualitative composition of Viread® 300 mg tablets

Tablet core Film coating

Croscarmellose sodium Glycerol triacetate (E1518) Lactose monohydrate Hypromellose (E464) Magnesium stearate (E572) Indigo carmine aluminium lake (E132) Microcrystalline cellulose (E460) Lactose monohydrate) Starch pregelatinised Titanium dioxide (E171)

6. International availability

Viread® is a registered trademark of Gilead Sciences, Inc, or its related companies in

the USA and other countries.

Viread® tablets are currently manufactured, packaged, labeled and tested for Gilead

Sciences, Inc. at the facilities listed in Table 2. All of the sites are currently approved

and listed in the US New Drug Application (NDA). The manufacturing steps conducted

at all facilities are in compliance with European Union (EU) and US Food and Drug

Administration (FDA) Good Manufacturing Practice (GMP) guidelines.

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Table 2. Manufacturing, packaging, labeling and testing facilities for

Viread® tablets

Manufacturing site Function(s)

Patheon Inc.

Toronto Region Operations

2100 Syntex Court

Mississauga, Ontario L5N 7K9

Canada

Drug product manufacturing, packaging

and labeling, release testing, stability

testing

Patheon Inc.

Burlington Century Operations

977 Century Drive

Burlington, Ontario L7L 5J8

Canada

Release testing, stability testing

Patheon Inc.

111 Consumers Drive

Whitby, Ontario L1N 5Z5

Canada

Drug product manufacturing

Takeda GmbH1

Lehnitzstrasse 70-98

Oranienburg, Brandenburg

16515

Germany

Drug product manufacturing and

packaging, release testing

Gilead Sciences Ireland UC

IDA Business & Technology Park

Carrigtohill, County Cork

Ireland

Drug product manufacturing, packaging

and labeling, release testing, drug product

release

Aspen Port Elizabeth (Pty) Ltd.

Corner of Fairclough and Gibaud Roads

Korsten, Port Elizabeth 6020 ZAF

Drug product manufacturing and

packaging, release testing, stability testing

Catalent Germany

Schorndorf GmbH

Drug product packaging and labeling

Gilead Sciences 8

Steinbeisstrasse 2

Schorndorf, -D-73614

Germany

Gilead Sciences, Inc.

650 Cliffside Dr.

San Dimas, CA 91773

USA

Drug product packaging and labeling,

release testing, stability testing

Gilead Sciences, Inc.

333 Lakeside Dr.

Foster City, CA 94404

USA

Release and stability testing

7. Listing type requested

Listing is requested on the Model List of Essential Medicines as an example of an

individual medicine to be included in section 6 – Anti-infective medicines for chronic

hepatitis B.

8. Information supporting the public health relevance

8.1 Epidemiological information on disease burden

The health and economic burden of CHB is summarized in the ‘VIREAD for the

treatment of chronic hepatitis B AMCP dossier’ (pages 22–25) which has been

provided as part of this submission.

8.2 Assessment of current use

In the USA, Viread® is indicated for the treatment of CHB in adults and pediatric

patients 12 years of age or older, who are nucleoside treatment naïve and treatment-

experienced with documented resistance to lamivudine. Viread® is not presently

recommended for patients with CHB aged <12 years or in those weighing less than 35

kg as efficacy and safety have not been established [Viread® US PI].

In Europe, Viread® is indicated for the treatment of CHB in adults [Viread® SmPC] with:

Compensated liver disease, with evidence of active viral replication, persistently

elevated serum alanine aminotransferase (ALT) levels and histological

evidence of active inflammation and/or fibrosis

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Evidence of lamivudine-resistant hepatitis B virus

Decompensated liver disease.

Viread® is also indicated for the treatment of CHB in adolescents aged 12 to <18 years

with:

Compensated liver disease and evidence of immune active disease, i.e. active

viral replication, persistently elevated serum ALT levels and histological

evidence of active inflammation and/or fibrosis.

Viread® was approved for use in CHB by the US Food and Drug Administration (FDA)

and the European Medicines Agency (EMA) in 2008 and is recommended by the

American Association for the Study of Liver Diseases (AASLD) [Lok and McMahon,

Hepatol 2009], the European Association for the Study of Liver Diseases (EASL)

[EASL 2012] and the Asia-Pacific Association for the Study of the Liver (APASL) [Liaw

et al. Hepatol Int 2012] as a first-line therapy for chronic hepatitis B,.

9. Treatment details

9.1 Indications and usage

Viread® is indicated for the treatment of CHB in adults and pediatric patients aged 12

years and older.

9.2 Dosage and administration

The recommended dose of Viread® in adult and pediatric patients aged over 12 years

is 300 mg once daily taken orally without regard to food.

Limited clinical experience at doses higher than the therapeutic dose of Viread® 300

mg is available and therefore the effects of higher doses are not known. If overdose

occurs the patient must be monitored for evidence of toxicity, and standard supportive

treatment applied as necessary. Tenofovir is efficiently removed by hemodialysis with

an extraction coefficient of approximately 54%. Following a single 300 mg dose of

Viread®, a 4-hour hemodialysis session removed approximately 10% of the

administered tenofovir dose [Viread® US PI].

9.2.1 Special populations

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Pregnancy Category B: Viread® should be used during pregnancy only if clearly

needed [Viread® US PI]. There are no well-controlled studies in pregnant women.

Nursing mothers: Tenofovir has been shown to be excreted in human milk. There is

insufficient information on the effects of tenofovir in newborns/infants. Therefore

Viread® should not be used during breast-feeding. As a general rule, it is recommended

that HBV-infected women do not breastfeed their infants in order to avoid transmission

of the virus to the infant [Viread® US PI].

Pediatric use: Viread® can be used in children with CHB aged over the age of 12 years.

The safety and efficacy of Viread® have not been established in children under the age

of 12 years [Viread® US PI].

Geriatric use: Clinical trials of Viread® did not include sufficient numbers of subjects

aged 65 years and over. In general, dose selection for elderly patients should be

cautious, keeping in mind the greater frequency of impaired hepatic, renal or cardiac

function and of concomitant disease.

Renal impairment: It is recommended that the dosing interval for Viread® be modified in

patients with estimated creatinine clearance <50 mL/min or in patients with end-stage

renal disease who require dialysis [Viread® US PI].

Hepatic impairment: No dose adjustment of Viread® is required for patients with hepatic

impairment [Viread® US PI].

9.3 Reference to existing WHO and other clinical guidelines

Evidence-based guidelines on the management of CHB have been issued by a number

of internationally recognized bodies, including AASLD, EASL and APASL. The potent

antiviral efficacy of Viread® combined with its high barrier to resistance and well-

tolerated safety profile has resulted in it being recommended as a first-line therapy for

patients with CHB by all three international associations [AASLD 2009; EASL 2012;

Liaw et al, 2012; Lok and McMahon, 2009]. In March 2015, the WHO published the first

set of management guidelines for patients with CHB, they recommend Viread® as both

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a first-line therapy and as the preferred therapy for patients with documented

resistance to other antiviral agents [WHO Guidelines, 2015].

10. Summary of comparative effectiveness in a variety

of clinical settings

10.1 Identification of clinical evidence

The benefit of Viread® for the treatment of CHB infection in compensated and

decompensated disease is based on virological, biochemical, and serological

responses in patients with HBeAg-positive and HBeAg-negative CHB. Treated patients

included those who were treatment-naïve, lamivudine (LAM)-experienced, adefovir

dipivoxil (ADV)-experienced and patients with LAM and/or ADV resistance mutations at

baseline. Benefit has also been demonstrated based on histological responses in

compensated patients. The evidence of the benefit of Viread® on efficacy and histology

parameters is based on data up to Week 384 (8 years) from two ongoing Phase 3

clinical trials (Studies 102 and 103) of TDF in adults, primarily nucleos(t)ide-naïve

subjects with CHB [Marcellin et al. 2013; Marcellin et al. AASLD 2014]. In addition,

efficacy has been demonstrated in a prospective study in Chinese subjects[Hou et al.

APASL 2014] and four prospective real-life cohort studies of TDF in adults [Causse et

al. EASL 2014; Petersen et al. EASL 2014; Lampertico et al. AASLD 2013; Tabenero

et al. EASL 2014]. Efficacy and safety data at 72 weeks from a separate study on the

treatment of adolescents aged 12 years and older (Study 115) and the safety and

efficacy results from a prospective study in patients with decompensated liver function

are also summarised in the supporting documents provided [Murray et al. 2012].

10.2 Summary of available data on comparative effectiveness of Viread®

The clinical program for Viread® in chronic hepatitis B includes pivotal Phase 3 studies

that were described in the initial submission dossier (provided as part of this

submission) as well as subsequent long-term analyses and studies in different patient

populations. This section of the submission highlights where supporting data for the

comparative effectiveness of Viread® can be found.

10.3 Summary of the efficacy of Viread® in patients with CHB

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Two pivotal Phase 3 clinical trials demonstrated the efficacy of Viread® in the treatment

of HBeAg-negative (Study 102) and HBeAg-positive (Study 103) patients. The results

of the 48-week analysis are detailed in ‘VIREAD for the treatment of chronic hepatitis B

AMCP dossier’ (pages 70–75 and 78–83) which is provided as part of this submission.

Data from the initial follow-up period (up to Week 72) are also provided in this section.

Since the US FDA and EMA regulatory submissions, substantial data have been

published from long-term follow-up analyses of Studies 102 and 103, with 8-year data

now being available. In addition, support for the efficacy of Viread® in a wide range of

patient populations has been provided by many other studies. The results of these

studies are summarized in the supporting document ‘Efficacy and safety in chronic

hepatitis B infection’ which is provided as part of this submission.

10.4 Summary of the resistance profile of Viread® in patients with CHB

The potential for the development of viral mutations that are resistant to treatment with

nucleos(t)ide analogs is an important consideration in patients receiving oral antiviral

agents for chronic HBV infection. A summary of the resistance analyses demonstrating

that Viread® has a high barrier to resistance is provided in the supporting document

‘Virological profile in CHB’ which is provided as part of the submission.

10.5 Impact of Viread® on patient health-related quality of life

Treatment with Viread® is well tolerated and is associated with long-term benefits

including reversal of cirrhosis.

10.6 Effect of Viread® therapy on long-term patient outcomes

The protocols for the pivotal Phase 3 studies have resulted in paired biopsies to be

available for a substantial proportion of patients. As a result, the effect of Viread®

therapy on fibrosis regression and reversal of cirrhosis has been demonstrated. The

results of these subanalyses are described in detail in the supporting document

‘Efficacy and safety in chronic hepatitis B infection’, which is provided as part of this

submission.

10.7 Summary of available estimates of comparative effectiveness

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The long-term efficacy results from the pivotal Phase 3 studies (102 and 103) have

demonstrated that subjects treated with Viread® had sustained virological suppression

with no detectable resistance through to Year 8 [Marcellin et al, AASLD 2014; Corsa et

al, AASLD 2014]. A Chinese registration study with a similar design to studies 102 and

103 demonstrated the high potency of TDF and reported comparable results to the

previous studies [Hou et al, APASL 2014]. No resistance to Viread® has been detected

in any of the clinical studies up to Year 8.

A 5-year subanalysis of data from Studies 102 and 103 demonstrated the efficacy of

Viread® in patients with a high viral load at baseline; these patients achieved similar

levels of virological suppression as patients with lower levels of baseline HBV DNA

[Gordon et al, 2013]. This was confirmed in a separate study of patients with a high

viral load and normal transaminase levels [Chan et al, 2014].

The efficacy of Viread® demonstrated in clinical trials has been confirmed in real-world

studies. Results from four real-world cohorts (GEMINIS, VIREAL, Lampertico et al, and

CIBERHEP) have demonstrated that in subjects treated with Viread® for at least 3

years, virologic response rates were high and similar to those observed in Studies 102

and 103 [Causse et al, EASL 2014; Petersen et al, EASL 2014; Lampertico et al,

AASLD 2013; Tabernero et al, EASL 2014]. Elderly subjects with comorbidities also

exhibited high rates of virologic suppression [Petersen et al, EASL 2014, Hezode et al,

2013].

Liver biopsies from baseline and Week 240 were available for 348 subjects enrolled in

Studies 102 and 103 which allowed the effect of 5 years of Viread® treatment on

histological parameters to be assessed [Marcellin et al, 2013]. Overall, 87% patients

showed histological improvement with Viread® therapy. Of the patients with paired

biopsies available, 96 patients had cirrhosis at baseline (Ishak score ≥5) and of these

74% showed reversal of cirrhosis (defined as Ishak score ≤4).

11. Summary of comparative evidence on safety

11.1 Estimate of total patient exposure to Viread®

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Table 3. Estimated cumulative post-marketing exposure to Viread®

in Europe and North America

Product Period Cumulative post-marketing

exposure (patient-years)

Viread® Up to 31 October 2014 2,928,235

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11.2 Description of adverse effects/reactions

Two pivotal Phase 3 clinical trials demonstrated the tolerability of Viread® in the

treatment of HBeAg-negative (Study 102) and HBeAg-positive (Study 103) patients.

The safety results of the 48-week analysis are detailed in ‘VIREAD for the treatment of

chronic hepatitis B AMCP dossier’ (pages 76–77 and 83–84) which is provided as part

of this submission. Data from the initial follow-up period (up to Week 72) are also

provided in this section.

Since the US FDA and EMA regulatory submission, substantial data have been

published from long-term follow-up analyses of Studies 102 and 103, with 8-year data

now being available. In addition, support for the safety efficacy of Viread® in a wide

range of patient populations has been provided by many other studies. The results of

these studies is summarized in the supporting document ‘Efficacy and safety in chronic

hepatitis B infection’ which is provided as part of this submission.

11.3 Renal safety profile

Tenofovir is principally excreted via the kidney and therefore the renal safety profile of

Viread® has been studied in detail. These data are detailed in the supporting document

‘Renal safety profile in CHB monoinfection’ which is provided as part of this

submission.

11.4 Viread® on bone parameters in CHB

Chronic liver disease is associated with low bone mineral density and increased risk of

fracture [Collier et al, 2007; Arteh et al, 2010] and therefore the effect of Viread® on

bone parameters has been studied in detail. These data are detailed in the supporting

document ‘Bone parameters in chronic hepatitis B infected adults and adolescents’

which is provided as part of this submission.

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11.5 Drug interactions

Drug-drug interactions with Viread® as described in the Viread® US PI are summarized

in Table 4. The only clinically relevant drug interactions are with didanosine (where

coadministration should be undertaken with caution), HIV-1 protease inhibitors, and

adefovir dipivoxil.

Table 4. Changes in pharmacokinetic parameters when Viread® is co-

administered with other agents

Co-administered

drug

Cmax AUC Cmin

Change in Viread® pharmacokinetic parameters (%)

Atazanavir 14 24 22

Atazanavir/

ritonavir

34 37 29

Darunavir/ritonavir 24 22 37

Indinavir 14 No change No change

Lopinavir/ritonavir No change 32 51

Saquinavir/

ritonavir

No change No change 23

Tacrolimus 13 No change No change

Tipranavir/ritonavir 23–38 2 7–14

Change in coadministered drug pharmacokinetic parameters (%)

Abacavir 12 No change No change

Atazanavir

No ritonavir

With ritonavir

21

28

25

25

40

23

Darunavir

With ritonavir

16

21

24

Didanosine 20 No change Not applicable

Emtricitabine No change No change 20

Entecavir No change 13 No change

Indinavir 11 No change No change

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Lamivudine 24 No change No change

Ritonavir

With

saquinavir

No change

No change

23

Saquinavir

With ritonavir

22

29

47

Tipranavir

With ritonavir

11–17

9–18

12–21

11.6 Summary of comparative safety

All safety analyses conducted in both clinical and real-world clinical studies of Viread®

have demonstrated that it is well tolerated. Overall, approximately one-quarter of

patients experienced adverse events while receiving Viread®, most of which were mild

in severity. The most frequently occurring adverse event in clinical trials was nausea

which affected 5.4% of patients in the pivotal Phase 3 studies [Viread® SmPC]. Th

adverse reactions in adolescents were consistent with those in the adult population

[Murray et al, 2012].

Tenofovir is primarily excreted via the kidney and renal failure, renal impairment,

elevated creatinine, hypophosphatemia and proximal tubulopathy have been reported

with the use of Viread® in clinical practice. As a result, creatinine clearance should be

calculated prior to initiating therapy with Viread® and regular renal monitoring is

recommended. Interruption of Viread® treatment should be considered in patients

where creatinine clearance is <50 L/min or serum phosphate is <1.0 mg/dL. There are

limited data of use of Viread® in patients with impaired renal dysfunction and therefore it

should only be used if the potential benefits of treatment are considered to outweigh

the potential risks. Cumulative open-label data up to Year 8 of Studies 102 and 103

demonstrated a low occurrence of renal events in patients receiving Viread® and the

incidence of predefined renal events was low [Marcellin et al, AASLD 2014]. Other

clinical studies have confirmed that renal parameters remained stable during Viread®

treatment [Berg et al, 2014; Fung et al, EASL 2013; Teperman et al, 2013; Murray et al,

2012]. Similarly, four real-world cohort studies (VIREAL, GEMINIS, Lampertico et al,

and CIBERHEP) demonstrated that renal function remained relatively stable

throughout at least 3 years of treatment [Causse et al, EASL 2014; Petersen et al,

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EASL 2014; Lampertico et al, AASLD 2013; Taberno et al, EASL 2014]. Mean

glomerular filtration rate was also stable in elderly patients with comorbidities [Causse

et al, EASL 2014].

Chronic liver disease is associated with low bone mineral density and increased risk of

fracture [Collier et al, 2007; Arteh et al, 2010]. The effect of Viread® on bone

parameters has been investigated in several studies including in the open-label phase

of Studies 102 and 103 (from Week 192). During this period, 31 subjects had

treatment-emergent fractures all of which were trauma related and not considered to be

related to Viread®; dose modification, treatment interruption or discontinuation of

therapy was not required by any patient. There were few clinically significant shifts in T-

score or Z-scores between Weeks 192 and 384. In Study 121, 280 CHB patients,

including patients with osteoporosis or osteopenia in the spine (7% and 34%,

respectively) or hip (1% or 22%, respectively) at baseline, received Viread® for up to

240 weeks. At Week 96 there was no evidence of accelerated bone loss. There was an

initial decline in bone mineral density followed by a plateau which was consistent with

the pattern seen in HIV patients, but the initial decline was less pronounced than that

seen in HIV. This pattern on bone mineral density decline was also observed in a

cohort of 170 Viread®-treated patients [Gill et al, 2015]. A similar cohort of 124 CHB

patients received Viread® for 15 months. During this period, 26% progressed to

osteopenia, but there were no cases of osteoporosis and lumbar spine and femoral

neck T-scores remained stable [Vigano et al, AASLD 2011]. In patients with osteopenia

at the time of the first scan, 77% had stable bone mineral density after 15 months of

Viread®. Study 115 in adolescents demonstrated that no patient treated with Viread® for

72 weeks experienced a ≥6% decrease in lumbar spine bone mass density [Murray et

al, 2012]. There were no bone fractures or bone-related adverse events. This was a

placebo-controlled study, and as expected in an adolescent population, both Viread®

and placebo groups experienced an overall increase in mean lumbar spine bone

mineral density; however this was greater in the placebo group than in the Viread®

group (P=0.046 and P=0.053 at Weeks 48 and 72, respectively).

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12. Summary of available data on comparative cost and

cost-effectiveness within the pharmacologic class or

therapeutic group

12.1 Range of costs of the proposed medicine

12.1.1 USA

The US FDA approved Viread® in 2008 for the treatment of CHB infection in adults and

in pediatrics aged over 12 years [Viread® US PI].

The wholesale cost of Viread® in access markets is shown in Table 5.

Table 5. Wholesale access costs of Viread®

Dosage form and product

strength

Package size Wholesale acquisition

cost (US$)

Tablet containing:

245 mg tenofovir disoproxil

fumarate

30 tablets

$17 for low income markets

12.1.2 Developing countries

Gilead works with its network of regional business partners to provide Viread at

reduced prices in 125 low- and middle-income countries. The company has also

established licensing agreements with 19 generic drug manufacturers in India, South

Africa and China, granting them rights to produce and sell high-quality, low-cost

generic versions of Gilead HBV medicines in 112 developing countries.

12.2 Cost-effectiveness of medicines for HBV

The cost of effectiveness of medicines for chronic HBV infection and the cost

effectiveness of Viread® is described in the ‘VIREAD for the treatment of chronic

hepatitis B AMCP dossier’ (pages 140–161) which has been provided as part of this

submission.

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13. Summary of regulatory status of the medicine

Table 6. Countries with Marketing Authorization status for Viread® tablets

The developing countries where Viread® is approved for use in patient with CHB are

shown in Table 6.

Table 6. Developing Countries with Marketing Authorization status for Viread®

tablets

Territory Approved Territory Approved

Albania Jul 2011 Kazakhstan May 2012

Anguilla Jun 2011 Kenya Sep 2014

Antigua and Barbuda Jun 2011 Kiribati Jun 2011

Argentina May 2011 Kosovo Jun 2011

Armenia Sep 2011 Kyrgyzstan Jul 2012

Aruba Sep 2011 Lao Jan 2013

Azerbaijan May 2011 Mali Nov 2014

Bahamas Jun 2011 Mexico Nov 2012

Bangladesh Jun 2011 Moldova Jan 2013

Barbados Jun 2011 Mongolia Sep 2014

Belarus Dec 2013 Montserrat Jun 2011

Belize Jun 2011 Myanmar Dec 2012

Bhutan Nov 2012 Nauru Jun 2011

Bolivia Sep 2011 Nepal Sep 2014

Bosnia and Herzegovina Jun 2012 Niger Mar 2014

Brazil Dec 2010 Pakistan Jan 2013

British Virgin Islands Jun 2011 Palau Jun 2011

Burkina Faso Sep 2014 Panama Feb 2012

Cambodia Apr 2011 Paraguay Sep 2011

Chile Nov 2011 Peru Jun 2011

Colombia Mar 2013 Philippines Mar 2014

Costa Rica Mar 2013 Saint Kitts and Nevis Jun 2011

Cuba Jun 2011 Saint Lucia Jun 2011

Curacao Oct 2011 Saint Vincent and the Grenadines

Jun 2011

Dominica Jun 2011 Samoa Jun 2011

Ecuador Aug 2012 Solomon Islands Jun 2011

Egypt Mar 2012 Syria Apr 2013

Fiji Jun 2011 Thailand May 2013

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Gabon Nov 2014 Timor-Leste Jun 2011

Georgia Jun 2011 Tonga Jun 2011

Grenada Jun 2011 Turkmenistan Apr 2014

Guatemala Jun 2011 Turks and Caicos Jun 2011

Guinea Feb 2014 Tuvalu Jun 2011

Haiti Sep 2012 Ukraine Sep 2012

Honduras Jul 2012 Uruguay Apr 2011

India Dec 2011 Uzbekistan May 2011

Iran Apr 2012 Vanuatu Jun 2011

14. Availability of pharmacopoeial standards

(British Pharmacopoeia, International Pharmacopoeia,

United States Pharmacopoeia)

14.1 Specifications of Viread® tablets

Details for the European Pharmacopeia, US Pharmacopeia and in-house standards are

provided in the application for inclusion of Viread® in the WHO Model List of Essential

Medicines for use in patients infected with HIV.

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15. Proposed (new/adapted) text for the WHO Model

Formulary

15.1 Other antivirals

Tenfovir disoproxil fumarate

Tablet: 245 mg tenofovir disoproxil fumarate.

Also known as Viread®.

Uses: Viread® is licensed in the USA for the treatment of chronic hepatitis B in adults

and in pediatrics aged over 12 years.

Precautions: New onset or worsening renal impairment (can include acute renal

failure and Fanconi syndrome). Assess estimated creatinine clearance before initiating

treatment with Viread®. In patients at risk for renal dysfunction, assess estimated

creatinine clearance, serum phosphorus, urine glucose and urine protein before

initiating treatment with Viread® and periodically during treatment. Avoid administering

Viread®. with concurrent or recent use of nephrotoxic drugs. Do not use with other

tenofovir-containing products. Consider assessment of bone mineral density in patients

with a history of pathologic fracture or other risk factors for osteoporosis or bone loss.

Dose: One tablet taken orally once daily, with or without food.

Adverse effects: The most common adverse reactions in patients with compensated

liver disease was nausea (<10%). In patients with decompensated liver disease

(incidence greater than or equal to 10%, all grades) adverse reactions observed with

treatment with Viread® were abdominal pain, nausea, insomnia, pruritus, vomiting,

dizziness and pyrexia.

Please refer to the Prescribing Information appropriate to the Gilead Access Program

contained in Appendix 1 for further details on Viread®.

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16. References

Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease.

Dig Dis Sci. 2010;55:2624–2628.

Berg T, Zoulim F, Moeller B, et al. Long-term efficacy and safety of emtricitabine plus

tenofovir DF vs tenofovir DF monotheray in adefovir-experienced chronic hepatitis B

patients. J Hepatol 2014;60:715–722.

Causse X, Pageaux GP, Zoulim F, et al. 3-year treatment with tenofovir in real-life is

effective and well tolerated in CHB patients, including the elderly and patients with

comorbidities [Poster 1062]. Paper presented at: 49th Annual Meeting of The European

Association for the Study of the Liver (EASL); April 9–13, 2014; London, United

Kingdom.

Chan HL, Chan CK, Hui AJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B

e antigen-positive patients with normal levels of alanine aminotransferase and high

levels of hepatitis B virus DNA. Gastroenterology 2014;146:1240–1248.

Collier J. Bone disorders in chronic liver disease. Hepatology 2007;46:1271–1278.

Corsa A, Liu Y, Flaherty JF, et al. No detectable resistance to tenofovir disoproxil

fumarate (TDF) in HBeAg+ and HBeAg- patients with chronic hepatitis B (CHB) after

eight years of treatment [Poster 1707]. Paper presented at: The 65th Annual Meeting

of the American Association for the Study of Liver Diseases: The Liver Meeting

(AASLD); November 7–11, 2014; Boston MA United States.

European Association for the Study of the Liver (EASL) Clinical Practice Guidelines:

management of chronic hepatitis B virus infection. J Hepatol 2012;57:167–185.

Fung S, Kwan P, Fabri M, et al. Randomized comparison of tenofovir disoproxil

fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with

lamivudine-resistant chronic hepatitis B. Gastroenterology 2014;146:980–988,e981.

Gilead Sciences 24

Fung S, Kwan P, Horban A, et al. Tenofovir disoproxil fumarate (TDF) is safe and well

tolerated in chronic hepatitis B (CHB) patients with pre-existing mild renal impairment

[Poster 744]. Paper presented at: 48th European Association for the Study of the Liver

(EASL); April 24–28, 2013; Amsterdam.

Gill US, Zissimopoulos A, Al-Shamma S, et al. Assessment of bone mineral density in

tenofovir treated chronic hepatitis B patients: can the fracture risk assessment tool

identify those at greatest risk? J Infect Dis 2015;211:374–382.

Gordon SC, Krastev Z, Horban A, et al. Efficacy of tenofovir disoproxil fumarate at 240

weeks in patients with chronic hepatitis B with high baseline viral load. Hepatology

2013;58:505–513.

Hézode C, Causse X, Larrey D, et al. Virological response and tolerance of tenofovir DF

(TDF) in the elderly are similar to younger patients in real life practice [Poster 748].

Paper presented at: 48th Annual Meeting of The European Association for the Study of

the Liver (EASL); April 24–28, 2013, Amsterdam, The Netherlands.

Hou J, Gao Z, Xie Q, et al. Tenofovir disoproxil fumarate vs adefovir divipoxil in Chinese

patients with chronic hepatitis B after 48 weeks: a randomized controlled trial. J Viral

Hepat 2015;22:85–93.

Lampertico P, Soffredini R, Yurdaydin C, et al. Four years of tenofovir monotherapy for

NUC naïve field practice European patients suppresses HBV replication in most patients

with a favorable renal safety profile but does not prevent HCC in patients with or

without cirrhosis [Poster 933]. Paper presented at: The Liver Meeting The 64th Annual

Meeting of the American Association for the Study of Liver Diseases (AASLD);

November 1–5, 2013; Washington, D.C.

Gilead Sciences 25

Lemoine M, Nayagam S, Thursz M. Viral hepatitis in resource-limited countries and

access to antiviral therapies: current and future challenges. Future Virol 2013; 8: 371–

380.

Liaw YF, Kao J-H, Piratvisuth T, et al. Asian-Pacific consensus statement on the

management of chronic hepatitis B: a 2012 update. Hepatol Int 2012; 6:531–561.

Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50:661–2.

Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with

tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up

study. Lancet 2013;381:468–475.

Marcellin P, Gane E, Flisiak R, et al. Long-term treatment with tenofovir disoproxil

fumarate for chronic hepatitis B infection is safe and well tolerated and associated with

durable virologic response with no detectable resistance: 8 year results from two phase

3 trials. Paper presented at: The 65th Annual Meeting of the American Association for

the Study of Liver Diseases: The Liver Meeting (AASLD); November 7–11, 2014;

Boston MA United States.

Marcellin P, Heathcote E, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir

dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442–2455.

Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebo-controlled trial of

tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology

2012;56:2018–2026.

Petersen J, Heyne R, Mauss S, et al. Effectiveness of tenofovir for chronic hepatitis B in

field practice (Presentation O122). Paper presented at: 49th Annual Meeting of The

European Association for the Study of the Liver (EASL); April 9–13, 2014; London,

United Kingdom.

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Tabernero D, Sánchez-Tapias JM, Calleja JL, et al. Long-term efficacy of tenofovir in

previously treated and naive patients. Results from the Spanish Chronic Hepatitis B

Registry (CIBERHEP) [Poster 1058]. Paper presented at: 49th Annual Meeting of The

European Association for the Study of the Liver (EASL); April 9–13, 2014; London, UK.

Teperman LW, Poordad F, Bzowej N, et al. Randomized trial of emtricitabine/tenofovir

disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver

transplantation. Liver Transpl 2013;19:594–601.

Vigano M, Lampertico P, Soffredini R, et al. The course of bone mineral density in

patients with chronic hepatitis B long-term treated with nucleos(t)ide analogs: a

longitudinal cohort study [Poster]. Poster presented at: 62nd Annual Meeting of the

American Association for the Study of Liver Diseases, November 4–8, 2011, San

Francisco, California, USA.

Viread® Prescribing Information, October 2013.

Viread® Summary of Product Characteristics, December 2014.

World Health Organization. Guidelines for the prevention, care and treatment of

persons with chronic hepatitis B infection. www.who.int/hiv/pub/hepatitis/hepatitis-b-

guidelines/en/. Accessed March 2015.

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Appendix 1. Access Prescribing Information for Viread®®

Access PI.pdf