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:

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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 Gilead Sciences 2

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

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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. Drug product manufacturing, packaging Toronto Region Operations and labeling, release testing, stability 2100 Syntex Court testing Mississauga, Ontario L5N 7K9 Canada Patheon Inc. Release testing, stability testing Burlington Century Operations 977 Century Drive Burlington, Ontario L7L 5J8 Canada Patheon Inc. Drug product manufacturing 111 Consumers Drive Whitby, Ontario L1N 5Z5 Canada Takeda GmbH1 Drug product manufacturing and Lehnitzstrasse 70-98 packaging, release testing Oranienburg, Brandenburg 16515 Germany Gilead Sciences Ireland UC Drug product manufacturing, packaging IDA Business & Technology Park and labeling, release testing, drug product Carrigtohill, County Cork release Ireland Aspen Port Elizabeth (Pty) Ltd. Drug product manufacturing and Corner of Fairclough and Gibaud Roads packaging, release testing, stability testing Korsten, Port Elizabeth 6020 ZAF

Catalent Germany Drug product packaging and labeling Schorndorf GmbH

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Steinbeisstrasse 2 Schorndorf, -D-73614 Germany Gilead Sciences, Inc. Drug product packaging and labeling, 650 Cliffside Dr. release testing, stability testing San Dimas, CA 91773 USA Gilead Sciences, Inc. Release and stability testing 333 Lakeside Dr. Foster City, CA 94404 USA

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 Gilead Sciences 8

 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 Gilead Sciences 9

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

Gilead Sciences 10 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 Cmax AUC Cmin drug Change in Viread® pharmacokinetic parameters (%) Atazanavir 14 24 22 Atazanavir/ 34 37 29 ritonavir Darunavir/ritonavir 24 22 37 Indinavir 14 No change No change Lopinavir/ritonavir No change 32 51 Saquinavir/ No change No change 23 ritonavir 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 21 25 40 With ritonavir 28 25 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 No change No change 23 saquinavir 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 Package size Wholesale acquisition strength cost (US$) Tablet containing: 30 tablets $17 for low income markets 245 mg tenofovir disoproxil fumarate

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 Jun 2011 Grenadines 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.

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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.

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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.

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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.

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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.

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Appendix 1. Access Prescribing Information for Viread®®

Access PI.pdf

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