Application for Inclusion of Emtricitabine and Tenofovir Alafenamide Fixed Dose Combination Tablets (Descovy®) on the WHO Model List of Essential Medicines

Home , Didanosine, Lopinavir, Stavudine, Tenofovir alafenamide, Tipranavir

Submitted by

Gilead Sciences Inc.

December 2016

Gilead Sciences Inc. 333 Lakeside Drive Foster City California 94404 USA

Gilead Sciences Submission Reference number: GSI-DSY-161201

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Contents

1. Summary statement of the proposal for inclusion ...... 5

2. Name of the focal point in WHO submitting or supporting the application ...... 7

3. Name of the organization(s) consulted and/or supporting the application ...... 7

4. International Nonproprietary Name (INN, generic name) of the medicine ...... 7

5. Formulation proposed for inclusion ...... 8

6. International availability ...... 9

7. Listing type requested ...... 11

8. Information supporting the public health relevance ...... 12

8.1 Epidemiological information on disease burden 12

9. Treatment details ...... 15

9.1 Indications and usage 15

9.2 Dosage and administration 16

9.2.1 Special populations 16

9.3 Reference to existing WHO and other clinical guidelines 17

10. Summary of comparative effectiveness in a variety of clinical settings ...... 20

10.1 Identification of clinical evidence 20

10.2 Summary of available data on comparative effectiveness of Descovy® 26

10.2.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – design and results of the pre-specified pooled analysis 26

10.2.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – design and results of the cross-study comparison 30

10.2.3 Phase 3 study of switch to EVG/COBI/FTC/TAF – GS-US-292-0109 – design and results at 48 weeks 32

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

10.2.4 Phase 3 study of switch from FTC/TDF to FTC/TAF – GS-US-311-1089 – design and results at 48 weeks 35

10.2.5 Phase 3 study of switch from FTC/TDF to FTC/TAF in renal impairment – GS- US-292-0112 – design and results at 48 and 96 weeks 38

10.2.6 Phase 3 study of switch to FTC/TAF in multi-drug resistant HIV-infected adults – GS-US-292-0119 – design and results at 24 and 48 weeks 40

10.3 Summary of the efficacy of Descovy® 42

10.4 Summary of the resistance profile of Descovy® 43

10.5 Summary of available estimates of comparative effectiveness 43

11. Summary of comparative evidence on safety ...... 45

11.1 Estimate of total patient exposure to Descovy® 45

11.2 Description of adverse effects/reactions 45

11.3 Renal safety profile 46

11.3.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – renal safety 46

11.3.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – renal safety 48

11.3.3 Phase 3 switching study to EVG/COBI/FTC/TAF – GS-US-292-0109 – renal safety 49

11.3.4 Phase 3 switching study from FTC/TDF to FTC/TAF – GS-US-311-1089 – renal safety 49

11.3.5 Phase 3 switching study from FTC/TDF to FTC/TAF in renal impairment – GS- US-292-0112 – renal safety 50

11.3.6 Phase 3 switching study to FTC/TAF in multi-drug resistant HIV-infected adults – GS-US-292-0119 – renal safety 51

11.4 Bone safety profile 52

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

11.4.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – bone safety 52

11.4.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – bone safety 53

11.4.3 Phase 3 switching study to EVG/COBI/FTC/TAF – GS-US-292-0109 – bone safety 54

11.4.4 Phase 3 switching study from FTC/TDF to FTC/TAF – GS-US-311-1089 – bone safety 56

11.4.5 Phase 3 switching study from FTC/TDF to FTC/TAF in renal impairment – GS- US-292-0112 – bone safety 57

11.5 Lipid safety profile 57

11.6 Drug–drug interactions 58

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacologic class or therapeutic group ...... 62

12.1 Range of costs of the proposed medicine 62

12.1.1 Europe 62

12.1.2 Developing countries 63

13. Summary of regulatory status of the medicine Descovy® ...... 63

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) ...... 63

14.1 Specifications of Descovy® tablets 63

15. Proposed (new/adapted) text for the WHO Model Formulary ...... 64

15.1 Other antivirals 64

16. References ...... 66

Appendix 1. Descovy® Access PI 72

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

1. Summary statement of the proposal for inclusion

The fixed dose, once-daily combination of emtricitabine (FTC) and tenofovir alafenamide (TAF) – Descovy® – is proposed for inclusion in the WHO Model List of Essential Medicines as a treatment for HIV-1 infection in adults and children aged 12 years (≥35 kg) and older when used in combination with other antiretroviral agents [Descovy® 200 mg/10 mg film coated tablets Summary of Product Characteristics (SmPC), 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

The principal reasons for requesting this inclusion are as follows:  As one of the preferred backbones of HIV combination therapy, tenofovir (as tenofovir disoproxil fumarate [TDF]) in combination with FTC continues to underpin much of the treatment of HIV infection [DHHS, 2016; EACS, 2016; WHO, 2016]  FTC/TDF as the fixed dose combination tablet Truvada® is listed in the WHO EML as a treatment for HIV-1 infection in adults and children aged 12 years and older when used in combination with other antiretroviral agents. Truvada® (FTC/TDF) in combination with efavirenz (as the fixed combination Atripla®) is listed in the consolidated WHO treatment guidelines as preferred first-line treatment of HIV infection [WHO, 2016]  Current estimates of 13.3 million patient-years of experience with TDF-based regimens in 2016 is testament to its efficacy and safety in people living with HIV [Gupta et al, 2016]  While TDF-based therapy is generally well tolerated, chronic use is known to have adverse renal effects that in rare instances can include Fanconi’s syndrome [Herlitz et al, 2010; Rodriguez-Novoa et al, 2010; Poizot-Martin et al, 2013]. It is also associated with a decrease in bone mineral density and an increased risk of fragility fractures, which people with HIV are vulnerable to [Grant & Cotter, 2016]  Earlier initiation of antiretroviral therapy (ART) together with a long duration of therapy due to an ageing HIV population demands efficacious antiretroviral drugs

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

with improved safety and tolerability for life-long administration [Negin & Cumming, 2010]  Life-long adherence to ART is also critical to prevent the emergence of antiretroviral drug resistance  In older HIV patients, some antiretroviral drugs have side effects that overlap the complications associated with ageing [Deeks et al, 2013]  TAF is a novel prodrug of tenofovir that is converted intracellularly to tenofovir diphosphate, allowing for significantly higher drug concentrations in peripheral blood cells and lower plasma levels of the pharmacologically active metabolite than its predecessor TDF [Bonora et al, 2016; Ray et al, 2016]  Because of its unique metabolic pathway, TAF achieves a 91% reduction in plasma levels of tenofovir while maintaining similar intracellular concentrations [Zack et al, 2016]  Preferential accumulation of tenofovir diphosphate in immune cells following administration of TAF means that much smaller doses can be used in comparison with TDF (10–25 mg versus 300 mg per day, respectively). This translates into smaller pills and easier co-formulation with other antiretroviral drugs  Tenofovir diphosphate is eliminated via the kidneys. The reduced systemic exposure associated with TAF administration reduces the risk of renal and bone toxicity compared with TDF [Ray et al, 2016; Zack et al, 2016]  TAF, first formulated in a fixed dose combination with FTC, cobicistat and elvitegravir (Genvoya®), has been evaluated for efficacy and safety in four separate populations of people living with HIV as follows: o Treatment-naïve adults o Treatment-naïve adolescents o Treatment-experienced adults o Adults with renal impairment  Overall, results from clinical studies in these patient populations have shown that regimens containing TAF were as efficacious as those containing TDF and had an improved safety profile with respect to kidney function and bone health

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

 These findings suggest that FTC/TAF, as an alternative HIV backbone to FTC/TDF, may mitigate the off-target effects of TDF on the kidneys and bones of people living with HIV  Given the pivotal role that TDF plays in the treatment of HIV infection today, this new prodrug of tenofovir offers people living with HIV a well-tolerated treatment option that enables treatment with tenofovir for people living with HIV in whom TDF is contraindicated because of underlying renal or bone disease  Dosage adjustments are not necessary when using TAF; with TDF, dose interval adjustments are required in patients with creatinine clearance 30–49 mL/min  This benefit has already been recognized in treatment guidelines, with the latest updated guidelines of the US Department of Health and Human Services (DHHS), the International Antiviral Society USA (IAS USA), the British HIV Association (BHIVA) and the European AIDS Clinical Society (EACS) recommending TAF as part of an initial treatment regimen for ART-naïve adults and adolescents either as FTC/TAF in combination with a third agent or as EVG/COBI/FTC/TAF [DHHS, 2016; Günthard et al, 2016; BHIVA, 2016; EACS, 2016].

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

Gottfried Hirnschall, Director of the HIV/AIDS Department and the Global Hepatitis Programme (GHP) of the World Health Organization

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

WHO

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

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Descovy® is a single tablet regimen that contains a fixed dose combination of FTC and TAF.

Emtricitabine (FTC, Emtriva®) INN: Emtricitabine

Tenofovir alafenamide (TAF) Modified INN: Tenofovir alafenamide

5. Formulation proposed for inclusion

There are two doses of Descovy® available in the European Union. Both doses of tablet contain 200 mg of FTC and either 10 mg or 25 mg of TAF [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

The 200 mg/10 mg dose tablets are grey, rectangular-shaped, film-coated, of dimensions 12.5 mm x 6.4 mm, debossed with “GSI” on one side and with “210” on the other side. The 200 mg/25 mg dose tablets are blue rectangular-shaped, film coated, of dimensions 12.5 mm x 6.4 mm, debossed with “GSI” on one side and with “225” on the other side [Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

The qualitative composition of Descovy® tablets is as described in Tables 1a and 1b [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

Table 1a. Qualitative composition of Descovy® 200 mg/10 mg tablets

Tablet core Microcrystalline cellulose Croscarmellose sodium Magnesium stearate Film coating Polyvinyl alcohol Titanium dioxide Macrogol 3350

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Talc Iron oxide black (E172)

Table 1b. Qualitative composition of Descovy® 200 mg/25 mg tablets Tablet core Microcrystalline cellulose Croscarmellose sodium Magnesium stearate Film coating Polyvinyl alcohol Titanium dioxide Macrogol 3350 Talc Indigo carmine aluminum lake (E132)

6. International availability

Descovy® is a registered trademark of Gilead Sciences, Inc. or its related companies in the USA and other countries.

Descovy® tablets are currently manufactured, packaged, labeled and tested for Gilead Sciences, Inc. at the facilities listed in Table 2. All the sites are currently approved and listed in the USA New Drug Application (NDA). The manufacturing steps conducted at all facilities are in compliance with European Union (EU) and US Food and Drug Administration (US FDA) Good Manufacturing Practice (GMP) guidelines.

Gilead Sciences’ mission is to transform care for HIV and other life-threatening diseases. To achieve this, Gilead Sciences believes it is important to apply innovation not just to drug discovery but also to finding new ways to get affordable medicines to people in need as quickly as possible. Gilead Sciences’ model for HIV treatment provision in developing countries has evolved over time, in response to lessons learned, stakeholder feedback and evidence of program effectiveness. Gilead Sciences learned early on the importance of partnership and collaboration for increasing drug access. Today, Gilead is committed to ensuring access to Descovy® around the world and, to this end, works with a network of regional business partners, generic licensing partners and other

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 stakeholders to expand treatment globally. To distribute HIV medicines securely and efficiently worldwide, Gilead Sciences began working in 2005 with a network of regional business partners. These include manufacturing partners in the Bahamas and South Africa licensed by the US FDA and regional and local distribution partners covering Africa, Asia, the Caribbean, eastern Europe, Latin America, the Middle East, and the Pacific region. Gilead Sciences has rapidly recognized the importance of generic licensing and under the terms of licensing agreements (available at www.gilead.com), partners are able to produce generic TDF-based HIV therapy for sale in 112 resource-limited countries. Partners set their own process and may also create fixed dose combinations with other HIV medicines. Partners receive a full technology transfer of the Gilead Sciences’ manufacturing process, enabling them to quickly scale-up production.

Table 2. Manufacturing, packaging, labeling and testing facilities for Descovy® tablets

Manufacturing site Function(s) Patheon, Inc. Manufacturing, packaging, labeling, 2100 Syntex Court release and stability testing Mississauga, Ontario Canada L5N 7K9 Gilead Sciences, Inc. Packaging, labeling and drug product 650 Cliffside Drive release San Dimas, California 91773 USA Gilead Sciences, Inc. Packaging, labeling and drug product 333 Lakeside Drive release Foster City, California 94404 USA Eurofins Lancaster Laboratories, Inc. Release and stability testing 2425 New Holland Pike Lancaster PA 17601 USA AndersonBrecon, Inc. Packaging and labeling 4545 Assembly Drive Rockford, IL 61109 USA Gilead Sciences Ireland UC Drug product release IDA Business and Technology Park Carrigtohill County Cork Ireland 10

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Millmount Healthcare Ltd. Packaging and labeling (secondary only) Block-7 City North Business Campus County Meath Ireland

Currently, 16 Indian manufacturers and one South African company hold licenses to manufacture Gilead Sciences HIV medicines. Licensees have received more than 30 WHO pre-qualification and/or US FDA tentative approvals for their products. Gilead Sciences has developed generic Indian licenses that provide significant capacity for supply of product in the least developed countries, and which now have a proven track record in delivering high volume/low margin and quality HIV products, and in achieving the lowest possible prices. In July 2011, Gilead Sciences amended its licensing agreements with Indian manufacturers to grant them future rights to produce generic versions of pipeline HIV medicines contingent upon regulatory approval.

Also in July 2011, Gilead Sciences became the first innovator pharmaceutical company to sign an agreement with the Medicines Patent Pool (MPP), an international organization that expands access to medicines through the sharing of drug patents. Gilead Sciences has granted the MPP similar licensing terms to those of its Indian partners for Gilead Sciences HIV medicines, as well as future rights to generic single tablet regimens (see www.medicinespatentpool.org for details). MPP may sub-license Indian manufacturers to produce these medicines for low- and middle-income countries. In its 2011 annual report MPP said that the agreement with Gilead Sciences had set “new public health standards, beyond any previous voluntary licensing agreement with a pharmaceutical company” for transparency, scope, pipeline products and flexibility [MPP, 2011].

7. Listing type requested

Listing is requested on the Model List of Essential Medicines as an example of the therapeutic class of HIV nucleoside/nucleotide analog reverse transcriptase inhibitors.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

8. Information supporting the public health relevance

8.1 Epidemiological information on disease burden

Recent estimates suggest that worldwide at least 36.7 million people are living with HIV [UNAIDS, 2016a], the vast majority of whom live in low- and middle-income countries. HIV infection has had the greatest effect on the people of eastern and southern Africa, where most transmission occurs between heterosexuals and, vertically, from mother to child. Of the 2.1 million people who became infected with HIV globally in 2015, 960,000 incident cases occurred in eastern and southern Africa of which 56,000 were among children. There were 1.1 million lives lost to AIDS-related illnesses globally in 2015, of which 470,000 were in eastern and southern Africa [UNAIDS, 2016a; UNAIDS, 2016b].

In the period between 2001 and 2014, the number of people living with HIV increased worldwide from 29.7 to 36.9 million. While this increase reflects continuing disease transmission, it is also a measure of the success of ART, which has transformed HIV into a chronic infection for those with access to antiretroviral drugs and globally there has been a 35% reduction in incidence worldwide since 2000 [UNAIDS, 2015].

From 2013 to 2015, the number of people living with HIV on ART has increased by about a third, reaching 17.0 million people [UNAIDS, 2016b]. Gains were greatest in eastern and southern Africa. Coverage increased from 24% in 2010 to 54% in 2015, reaching a regional total of 10.3 million people. With widening access to ART, mortality rates have fallen and HIV-positive individuals are living longer. Since the first global treatment target was set in 2003, annual AIDS-related deaths have decreased by 43% [UNAIDS 2016b].

Adults aged 50 years and over now constitute an important cohort of the world’s HIV population. In high-income countries, such as the USA, older adults account for approximately 10% of the cumulative HIV infection caseload, while this figure is almost twice as high in parts of sub-Saharan Africa [Negin & Cumming, 2010]. Moreover, older adults often have more comorbidities, experience more adverse events and have a great

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 risk of drug–drug interactions, in part due to increased rates of polypharmacy, than younger HIV-infected patients [DHHS, 2016]. The accumulated toxic effects arising from decades of exposure to ART can cause significant metabolic disorders and end- organ damage [Deeks et al, 2013].

Among women of reproductive age (15–44 years), HIV/AIDS is the leading cause of death worldwide with unsafe sex the major risk factor for acquisition of HIV in low- income countries [WHO, 2013a]. Young women aged 15–24 years are particularly vulnerable to infection, accounting for 20% of new HIV infections in 2015 despite making up just 11% of the adult population [UNAIDS, 2016b].

Around 490,000 children became infected with AIDS in 2000 [UNAIDS, 2016c]. Since then, the adoption of universal screening of pregnant women, together with appropriate ART or prophylaxis (initially with single-dose nevirapine) and avoidance of breastfeeding by HIV-infected mothers, has seen the virtual elimination of perinatal transmission in high-income countries. While significant progress has been made towards eliminating perinatal transmission in medium- to low-income countries, 150,000 new cases of HIV occurred in children in 2015 [UNAIDS, 2016]. Eastern and southern Africa continues to bear the greatest burden with respect to mother-to-child transmission [UNAIDS, 2016].

ART-based prevention has the potential to reduce all modes of disease transmission including that from mother to child. Access to ART continues to improve, with coverage reaching 77% in 2015 [UNAIDS, 2016]. Nonetheless, ensuring adherence to ART remains a challenge in pregnant and breastfeeding mothers. The most important intervention for preventing mother-to-child transmission is to first identify and then treat all HIV-positive pregnant women who need ART for the sake of their own health. Regimens that are suitable for this population therefore have a key role to play in combating the HIV epidemic.

Globally, there are around 12 million people who inject drugs (PWID). About 1.65 million PWID are infected with HIV, accounting for almost one-third of HIV incidence outside of

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 sub-Saharan Africa [UNODC, 2015]. Epidemics of HIV in PWID have occurred in eastern and central Europe, southeast and central Asia, north Africa and the southern regions of South America [Vlahov et al, 2010; Jolley et al, 2012], while some of the highest prevalence rates of HIV among PWID (51%) have been recorded in eastern Europe and central Asia [UNAIDS, 2016b]. In many countries, access to services by PWID is limited because of stigma and discrimination, and the definition of drug dependence as a law enforcement rather than public health issue [Jolley et al, 2012; UNAIDS, 2016b].

A significant proportion of HIV-1 infected patients carry drug-resistant viruses, which can lead to decreased susceptibility to other antiviral drugs through cross resistance, limiting viable treatment options [Wittkop et al, 2011; WHO, 2012]. The incidence of transmitted drug resistance is rising or is underestimated in patients who have been chronically infected for longer periods of time, due to reversion. Pretreatment drug resistance has the potential to contribute to increasing rates of virologic failure at a population level, thus compromising long-term effectiveness of recommended first-line regimens. For example, a large European collaboration of HIV observational cohorts (EuroCoord-CHAIN joint project) reported increases in the chance of virologic failure of two to three times within 12 months of initiation of ART in populations in which resistance to components of standard first-line treatment was detected before the start of ART [Wittkop et al, 2011].

8.2 Assessment of current use ART is designed to result in maximal and durable suppression of viral load (to a level below which drug resistance mutations do not emerge), together with the restoration and/or preservation of immunologic function, improvement of quality of life, reduction of HIV-related morbidity and mortality, and prevention of HIV transmission.

Combination ART is the cornerstone of treatment for HIV, in which TDF acts as a backbone to which other antiretroviral drugs are added. The development of coformulated antiretroviral drugs into a single combination pill has simplified ART and is now considered standard of care [WHO, 2016]. Fixed dose combinations containing a

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

TDF backbone include Truvada® (FTC/TDF), Atripla® (efavirenz/FTC/TDF), Complera® (rilpivirine/FTC/TDF) and EVG/COBI/FTC/TDF. Since the approval of TDF (Viread®) in October 2001, cumulative post-marketing exposure to TDF-based regimens reached 10.9 million patients in 2015 and is forecast to rise to 13.3 million patients in 2016 [Gupta et al, 2016]. Fixed dose formulations of all these combinations – but containing TAF in place of TDF – have been developed as replacement therapy for TDF-based regimens, with EVG/COBI/FTC/TAF and Odefsey® (rilpivirine/FTC/TAF) already included in the US DHHS and the IAS USA treatment guidelines [DHHS, 2016; Günthard et al, 2016].

We anticipate that TAF-based regimens will have a similar place in therapy to TDF-based regimens but with benefit of an improved safety profile with respect to kidney and bone health thus expanding the use of tenofovir to more people living with HIV. Recent modeling data have predicted that TAF-containing regimens will be a major component of ART regimens by 2025, by which time conservative estimates suggest some 7.9 million patients will be receiving TAF-based therapy [Gupta et al, 2016].

8.3 Target population

In line with its licensed indication, the target population for Descovy is adults and adolescents (aged 12 years and older with a body weight ≥35 kg) with HIV-1 infection providing there are no contraindications for the fixed dose combination or any of its individual constituents. Within its approved indication, Descovy® may be particularly appropriate for the following HIV cohorts:

 People in whom TDF would be indicated as a component of ART  People currently taking a TDF-containing regimen and who would benefit from switching to TAF for greater tolerability  People for whom a TDF-containing regimen is contraindicated.

9. Treatment details

9.1 Indications and usage 15

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Descovy® is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and adolescents (aged 12 years and older with body weight ≥35 kg). It is not recommended for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

9.2 Dosage and administration

One tablet taken orally once daily, in combination with other antiretroviral agents, with or without food in adults and pediatric patients (12 years of age and older with body weight ≥35 kg) and creatinine clearance (CrCl) ≥30 mL/min. The filmcoated tablet should not be chewed, crushed or split [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

Choice of Descovy® formulation is governed according to the third agent used in the HIV treatment regimen. Tablets containing the TAF 10 mg dose are indicated for patients taking protease inhibitors (such as atazanavir, darunavir or lopinavir) as their third agent, boosted with either ritonavir or cobicistat.

Tablets containing the 25 mg dose of TAF are indicated for patients taking other classes of anti-HIV drugs that do not include a pharmacokinetic enhancer. These include NNRTIs, such as efavirenz, nevirapine and rilpivirine, integrase inhibitors, such as dolutegravir and raltegravir, and co-receptor blockers, such as maraviroc [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

9.2.1 Special populations

Elderly patients: No dose adjustment of Descovy® is required in elderly patients [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

Renal impairment: Descovy® is not recommended for use in patients with severe renal impairment (estimated CrCl <30 mL/min) [Descovy® 200 mg/10 mg film coated tablets

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

Hepatic impairment: No dose adjustment is required in patients with mild (Child– Turcotte–Pugh Class A) or moderate (Child–Turcotte–Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of Descovy® in patients with severe hepatic impairment (Child–Turcotte–Pugh Class C) [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016]. Therefore, Descovy® is not recommended for use in patients with severe hepatic impairment.

Descovy® is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of Descovy®. Hepatic function should therefore be monitored closely in these patients [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016].

9.3 Reference to existing WHO and other clinical guidelines

WHO consolidated treatment guidelines, which were published in mid 2016, recommend two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus one non- nucleoside reverse transcriptase inhibitors (NNRTI) for first-line therapy in HIV-1 infected patients, while avoiding stavudine (d4T) use. The guidelines promote treatment immediately following diagnosis, irrespective of CD4 cell count, and support adherence with the use of fixed dose combinations and simplifying therapies with the aim of maximal and durable suppression of viremia [WHO, 2016]. Consistent with current WHO treatment guidelines, Descovy® provides a dual NRTI backbone of FTC and tenofovir (as TAF) as part of preferred first-line therapy (Table 3).

Table 3. Current recommendations of the WHO Consolidated Guidelines on use of ART for treating HIV infection [WHO, 2016]

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Key to abbreviations: ART = antiretroviral therapy, TDF = tenofovir disoproxil fumarate, 3TC = lamivudine, FTC = emtricitabine, EFV = efavirenz, ABC = abacavir, LPV/r = lopinavir/ritonavir, AZT = zidovudine (azidothymidine), NVP = nevirapine, DTG = dolutegravir a For adults and adolescents, d4T should be discontinued as an option in first-line treatment. b ABC or boosted protease inhibitors (ATV/r, DRV/r, LPV/r) can be used in special circumstances. c Safety and efficacy data on the use of DTG and EFV400 in pregnant women, people with HIV/TB coinfection and adolescents younger than 12 years of age are not yet available. d Conditional recommendation, moderate-quality evidence. e EFV at lower dose (400 mg/day).

Pregnant women represent an important subgroup within the HIV-positive population, and for whom ART is vital in preventing perinatal transmission. In the current consolidated treatment guidelines, WHO recommends a fixed dose combination of TDF + lamivudine (3TC) (or FTC) + efavirenz (EFV) in a single pill as preferred first-line regimen for pregnant and breastfeeding women [WHO, 2016].

Following regulatory approval of Descovy® in North America and Europe, regimens containing FTC/TAF have been rapidly incorporated into treatment guidelines. The US DHHS has released updated versions of their HIV guidelines for adults and adolescents as well as for infants infected with HIV [DHHS, 2016]. The new adult guidelines include revised recommendations for first-line ART as well as management of treatment- experienced patients. Based on efficacy and safety data from Phase 3 randomized

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 controlled trials, EVG/COBI/FTC/TAF has been included as one of the recommended initial regimens for ART-naïve adults and adolescents with estimated CrCl ≥30 mL/min (Table 4). These were the first guidelines to recommend a TAF-containing regimen and have been strongly endorsed by the IAS USA in its evidence-based review of ARVs [Günthard et al, 2016]. The IAS USA advocates preferred use of an integrase inhibitor in combination with FTC/TAF in settings where this new agent is currently available [Günthard et al, 2016].

Table 4. Treatment of HIV-1 infection in treatment-naïve patients: summary of current US DHHS guidelines [DHHS, 2016]

Key to abbreviations: 3TC = lamivudine, ABC = abacavir, DTG = dolutegravir, TDF = tenofovir disoproxil fumarate , FTC = emtricitabine, EVG = elvitegravir, TAF = tenofovir alafenamide, c = COBI = cobicistat, RAL = raltegravir, DRV = darunavir, DRV/r = darunavir/ritonavir, EFV = efavirenz, ATV = atazanavir, ATV/r = atazanavir/ritonavir, RPV = rilpivirine

Since then, BHIVA, in its 2016 interim updated guidelines, recommends treatment-naïve subjects start combination ART with either FTC/TDF or FTC/TAF as the preferred NRTI backbone [BHIVA, 2016]. Third preferred agents can include any one of the following: atazanavir/r, darunavir/r, dolutegravir, elvitegravir/c, raltegravir or rilpivirine. The

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

European AIDS Clinical Society (EACS) has also updated its guidance to include FTC/TAF containing regimens as preferred first-line therapy and as an alternative to FTC/TDF [EACS, 2016]. FTC/TAF containing regimens are seen as especially beneficial in elderly HIV-infected individuals as well as those with or at increased risk of osteoporosis or renal impairment [EACS, 2016].

In addition to recommending treatment of all HIV-infected individuals, irrespective of CD4 count, the updated guidelines show a trend towards a reduced number of preferred regimens as the focus moves towards selecting regimens that combine efficacy with the best possible safety profile [Antela et al, 2016]. For example, in the new EACS treatment guidelines, preferred regimens have been reduced from 13 to 6 options, three of which are combinations of FTC/TAF with an integrase inhibitor [EACS, 2016].

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

10.1 Identification of clinical evidence

In compiling evidence for this submission, a search of the Medline® database was performed using the following search criteria: tenofovir alafenamide [and] HIV [and] randomized. In addition, review articles on TAF were identified and the reference lists of these examined for any further articles of relevance. The search yielded a number of publications from which Phase 3 studies are presented as the basis for the comparative assessment of efficacy.

Table 5 provides an overview of the design of the clinical studies supporting the use of Descovy® as NRTI backbone therapy in people with HIV. It includes two Phase 2 studies, one of which describes the use of FTC/TAF as part of the first protease inhibitor-based single tablet regimen (cobicistat-boosted darunavir plus FTC/TAF), to be developed for treatment of HIV-1 infection [Mills et al, 2015]. Table 5 also highlights the key registration studies in treatment-naïve adult patients that support its primary indication [Sax et al, 2015], as well as a study carried out in adolescents that was designed to 20

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 inform the use of FTC/TAF in patients between the ages of 12 and 18 years [Kizito et al, 2015]. Four switch studies in virologically suppressed patients are summarized, one of which focuses exclusively on patients with mild-to-moderate renal impairment [Pozniak et al, 2016], while another focuses on treatment-experienced patients with >2-class resistance [Huhn et al, 2016].

Table 5. Clinical studies supporting the comparative efficacy and safety of FTC/TAF

Study Design Population Treatment No. of Duration Demographics HIV-1 Efficacy endpoints regimens subjects characteristics at study entry (median) 1. Efficacy and Phase 2, HIV-1 E/C/FTC/TAF QD 171 48 weeks Male: 98% Viral load: Proportion of subjects safety of TAF randomized, infected, (n=112) versus White: 68% E/C/FTC/TAF: 4.55 with plasma viral load as part of a double-blind, treatment- E/C/FTC/TDF Median age: log10 copies/mL <50 copies/mL at Week single tablet double- naïve QD (n=58) 36 years E/C/FTC/TDF: 4.58 24 (FDA snapshot regimen (STR) dummy, multi- subjects log10 copies/mL analysis) center, active- CD4 count: and NCT01497899 controlled E/C/FTC/TAF: 385 Proportion of subjects GS-US-292-0102 study cells/mm3 with HIV-1 RNA <50 E/C/FTC/TDF: 397 copies/mL at Week 48 cells/mm3 (FDA snapshot analysis)

2. Efficacy and Phase 2, HIV-1 DRV/C/FTC/TAF 153 48 weeks Male: 93% Viral load: Proportion of subjects safety of TAF randomized, infected, QD (n=103) White: 60% DRV/C/FTC/TAF: with HIV-1 RNA <50 as part of a double-blind, treatment- versus DRV + C Median: age 4.7 log10 copies/mL copies/mL at Week 48 STR with the placebo- naïve + FTC/TDF QD 33 years DRV/C/FTC/TDF: (FDA snapshot analysis) protease controlled subjects (n=50) 4.6 log10 copies/mL inhibitor, DRV study CD4 count: DRV/C/FTC/TAF: NCT01565850 368 cells/mm3 GS-US-299- DRV/C/FTC/TDF: 0102 433 cells/mm3

3. Pre- Phase 3, HIV-1 E/C/FTC/TAF QD 1744 144 weeks E/C/FTC/TAF: Viral load: Non-inferiority (12% specified randomized, infected, (n=866) versus Male: 85% At least 1000 margin) of E/C/FTC/TAF pooled multicenter, treatment- E/C/FTC/TDF White: 56% copies/mL at versus E/C/FTC/TDF at efficacy and international, naïve QD (n=867) Median age: baseline Week 48 by FDA snapshot safety analysis double-blind, subjects 33 years Creatinine analysis of active- clearance: E/C/FTC/TAF

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versus controlled E/C/FTC/TDF: ≥50 mL/min at E/C/FTC/TDF study Male: 85% baseline White: 57% NCT01854775/ Median age: GS-US-292-0106 35 years and

NCT01818596/ GS-US-292-0112

4. Efficacy and Phase 3, open HIV-1 E/C/FTC/TAF QD 100 48 weeks FTC/TAF: Viral load: Proportion of subjects safety analysis label, infected, or E/C/FTC/TDF Male: 44% E/C/FTC/TAF: 4.62 with HIV-1 RNA <50 of multicenter, treatment- QD White: 22% log10 copies/mL copies/mL at Week 48 E/C/FTC/TAF cross-study naïve Median age: E/C/FTC/TDF: 4.60 versus comparison of subjects aged 15 years log10 copies/mL E/C/FTC/TDF E/C/FTC/TAF 12–<18 years CD4 count: in adolescent and FTC/TDF: E/C/FTC/TAF: 456 HIV patients E/C/FTC/TDF Male: 70% cells/mm3 White: 28% E/C/FTC/TDF: 402 NCT01854775/ Median: age cells/mm3 GS-US-292-0106 16 years

NCT01721109/ GS-US-236-0112

5. Switch from Phase 3, Virologically Switch to 1443 96 weeks FTC/TAF: CD4 count: Proportion of subjects FTC/TDF- randomized, suppressed E/C/FTC/TAF QD Male: 89% E/C/FTC/TAF: 675 who received at least one containing open label, HIV-infected (n=959) versus White: 68% cells/mm3 dose of study drug and regimen* to multicenter, patients (HIV- continuing with Median age: E/C/FTC/TDF: 662 had undetectable viral E/C/FTC/TAF active control RNA <50 TDF-based 41 years cells/mm3 load (HIV-1 RNA <50 study copies/mL) on therapy (n=477) copies/mL) at Week 48 NCT01815736/ regimens FTC/TDF: (non-inferiority margin of GS-US-292-0109 containing Male: 90% 12%) fixed dose White: 66% FTC/TDF for Median: age 40 years

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

at least 96 weeks 6. Switch from Phase 3, Virologically Switch to 668 48 weeks FTC/TAF: CD4 count: Proportion of subjects FTC/TDF to randomized, suppressed FTC/TAF QD Male 86% FTC/TAF: 663 with HIV-1 RNA <50 FTC/TAF double-blind, HIV-infected (n=333) or White 73% cells/mm3 copies/mL at Week 48 multicenter, patients (HIV- continue Median age FTC/TDF: 624 (non-inferiority margin of NCT02121795/ active control RNA <50 FTC/TDF 48 years cells/mm3 10%) GS-US-311-1089 study copies/mL) on (n=330) without FTC/TDF: regimens changing third Male 84% containing antiviral agent White 77% fixed dose Median age FTC/TDF 49 years

7. Switch to Phase 3, Virologically Switch to 242 48 weeks Male 79% CD4 count: Proportion of subjects E/C/FTC/TAF single-arm, suppressed E/C/FTC/TAF QD White 82% 632 cells/mm3 with HIV-1 RNA <50 open-label HIV-infected Median age copies/mL at Week 48 by NCT01818596/ study in stable patients (HIV- 58 years FDA Snapshot analysis GS-US-292-0112 renal RNA <50 impairment copies/mL) for at least 6 months and CrCL 30–69 mL/min 8. Switch to Phase 3, open- Virologically Switch to 135 48 weeks Male: 75% HIV-RNA<50 Proportion of subjects E/C/FTC/TAF label, suppressed E/C/FTC/TAF Black: 45% copies/mL with HIV-1 RNA <50 plus DRV randomized, HIV-infected plus DRV QD Hispanic: 14% copies/mL at Weeks 24 multicenter patients on a Median age: and 48 by FDA Snapshot NCT01968551/ study DRV- 49 years analysis GS-US-292-0119 containing regimen for ≥4 months, with two prior failed regimens, and no history of Q151M, T69ins, or DRV RAMs

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

*Either E/C/F/TDF, EFV/FTC/TDF, RTV + ATV + FTC/TDF, or ATV + C + FTC/TDF. Key to abbreviations: C = cobicistat; DRV = darunavir; EFV = efavirenz; E = elvitegravir; FTC = emtricitabine; QD = once daily; RAM = resistance-associated mutation; STR = single tablet regimen; TAF = tenofovir alafenamide fumarate; TDF = tenofoir disoproxil fumarate.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

10.2 Summary of available data on comparative effectiveness of Descovy®

Evidence for the effectiveness of Descovy® in adults and adolescents with HIV infection is primarily supported by data from two identical randomized, double-blind clinical trials, studies 104 and 111, the pooled results of which provided the basis for approval of EVG/COBI/FTC/TAF and are summarized below [Sax et al, 2015]. Together with an earlier Phase 2 trial of similar design [Sax et al, 2014], the data showed that TAF was non-inferior to TDF over 48 weeks in its ability to control viral load in treatment-naïve HIV-infected adults. The efficacy of FTC/TAF was also demonstrated in a separate study of the efficacy and safety of EVG/COBI/FTC/TAF in children aged 12 years or older and with a body weight of at least 35 kg [Gaur et al, 2016; Kizito et al, 2015]. Bioequivalence (PK comparability) studies had previously demonstrated that FTC 200/10 mg administered simultaneously with elvitegravir and cobicistat, and FTC/TAF 200/25 mg administered without a PK enhancer, was bioequivalent to a single tablet regimen of EVG/COBI/FTC/TAF. This allows for extrapolation of the efficacy data generated in the registration trials for EVG/COBI/FTC/TAF [Zack et al, 2016].

Data on four switch studies are presented, the purpose of which was to demonstrate that virologically suppressed patients could be switched from a TDF-based regimen to one containing TAF without loss of efficacy. They included a study in patients with mild-to-moderate renal impairment (CrCL 30–69 mL/min), for whom treatment with TDF-based regimens may confer risks [Cooper et al, 2010], and one designed to explore the role of a TAF-based regimen in HIV-1 infected adults with two-class or greater resistance on a multi-pill regimen [Huhn et al, 2016].

10.2.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – design and results of the pre-specified pooled analysis

Design Both studies were identical, randomized, double-blind, multicenter, active-controlled, Phase 3 trials carried out at 134 sites in North America, Europe, Australia, Japan and Thailand (GS-US- 292-0104) and 128 sites in North America, Europe and Latin America (GS-US-292-0111).

Treatment-naïve adults infected with HIV-1 were eligible if aged ≥18 years with viral load 26

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>1000 copies/mL, viral sensitivity to the N(t)RTI background regimen, and a CrCl rate of at least 50 mL/min. Patients were randomized (1:1) to 48 weeks’ treatment with once-daily EVG/COBI/FTC/TAF or EVG/COBI/FTC/TDF taken with food. Patients also received placebo tablets matching the alternative treatment; thus investigators, patients and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group.

The proportion of subjects with a viral load <50 copies/mL (with a maximum allowable difference of 12%) at Week 48, as defined by the FDA snapshot algorithm [FDA, 2013], was the primary efficacy parameter in both trials. Virologic failure was defined as a plasma HIV-1 RNA

≥50 copies/mL and less than 1 log10 reduction from baseline at Week 8, or 50 copies/mL or more HIV-1 RNA after previous suppression to <50 copies/mL or >1 log10 increase in HIV-1 RNA from nadir [Sax et al, 2015].

Subjects A total of 1744 patients were randomized to treatment, of whom 866 received EVG/COBI/FTC/TAF and 867 received EVG/COBI/FTC/TDF. The demographic and disease characteristics at baseline were generally representative of an adult HIV-1 infected treatment- naïve population that included subjects from high-, mid- and low-income countries and were balanced between treatment groups (Table 6).

Table 6. Baseline demographics and disease characteristics in patients enrolled in studies GS-US-292-0104 and GS-US-292-0111 (pooled data) 27

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Virologic response rate Treatment with EVG/COBI/FTC/TAF was non-inferior to EVG/COBI/FTC/TDF at Week 48, with viral suppression (<50 copies/mL) achieved in 92% and 90% of patients, respectively. Using a viral load assay with a lower limit of quantification (<20 copies/mL), 84% of subjects in each regimen had an undetectable viral load. While virologic success rates were similar for most subgroups in the two treatment arms, response rates were significantly higher with the TAF-based regimen in women and in those who had baseline viral loads <100,000 copies/mL, while CD4 28

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 cell count increases at Week 48 were also significantly greater in patients receiving the TAF- based regimen (Figure 1) [Sax et al, 2015].

Figure 1. Pooled results from studies GS-US-292-0104 and GS-US-292-0111 where A is the primary endpoint, B is efficacy with respect to baseline HIV-RNA and CD4 cell count, and C is efficacy in selected sub-groups

-0.7%

Virologic failure occurred in seven and five subjects on the TAF- and TDF-based regimen, respectively, all of whom had developed resistance to FTC while five and three subjects,

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 respectively, had developed resistance to the integrase inhibitor elvitegravir. All eight cases were, however, susceptible to the integrase inhibitor, dolutegravir [Sax et al, 2015].

Almost 90% of subjects continued to receive treatment with either EVG/COBI/FTC/TAF or EVG/COBI/FTC/TDF in long-term extensions to the two trials. At Week 96, 86.6% of subjects in the TAF arm and 85.2% in the TDF arm had maintained viral suppression with HIV-1 RNA of <50 copies/mL (difference 1.5%; 95%CI [-1.8%, 4.8%]) [Wohl et al, 2016a].

10.2.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – design and results of the cross-study comparison

Design These were both open-label, single-arm studies in which treatment-naïve adolescents, aged ≥12 to <18 years and weighing at least 35 kg, received 48 weeks’ treatment with either EVG/COBI/FTC/TAF or EVG/COBI/FTC/TDF [Gaur et al, 2016; Kizito et al, 2015].

In addition to meeting age and weight criteria, eligible subjects were required to have a baseline viral load of >1000 copies/mL and CD4 count of >100 cells/mm3.

Subjects A total of 50 adolescent males and 50 adolescent females were assigned to treatment in each study. There were differences between the two study populations with respect to sex, geography and mode of transmission (Table 7).

Table 7. Baseline demographics and disease characteristics in patients enrolled in studies GS-US-292-0106 and GS-US-236-0112 30

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Treatment regimens

E/C/FTC/TAF E/C/FTC/TDF P value

N=50 N=50

Age Median (range), 15 (12–17) 16 (12–17) 0.040 years

Gender Male, n (%) 22 (44) 35 (70) 0.009

Country of origin Uganda, n (%) 30 (60) 0

South Africa, n (%) 3 (6) 22 (44)

Thailand, n (%) 6 (12) 14 (28)

USA, n (%) 11 (22) 14 (28)

Viral load HIV-1 RNA log10 4.65 (0.59) 4.60 (0.55) 0.98 copies/mL, Mean (SD)

>100,000 11 (22) 10 (20) 0.81 copies/mL, n (%)

CD4 count Cells/µL (Q1, Q3) 456 (332, 574) 402 (298, 486) 0.060

<200 cells/µL, 4 (8) 2 (4) n (%)

Mode of Vertical 32 (64) 17 (34) infection transmission, n (%)

Heterosexual sex, 12 (24) 12 (24) n (%)

Homosexual sex, 8 (16) 19 (38) n (%)

Intravenous drug 1 (2%) 0 use, n (%)

Virologic response rate Despite demographic differences, subjects in both treatment groups exhibited a rapid virologic response following treatment. Virologic suppression was achieved in all subjects by Week 12. At

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Week 24, 90% (45/50) of subjects treated with EVG/COBI/FTC/TAF had achieved HIV-1 RNA <50 copies/mL compared with 88% (44/50) of those on EVG/COBI/FTC/TDF. Most failures were associated with decreased adherence to ART [Gaur et al, 2016; Kizito et al, 2015].

Figure 2. Virologic response and post-treatment changes in CD4 cell count over 24 weeks in studies GS-US-292-0106 and GS-US-236-0112

BL = base line

10.2.3 Phase 3 study of switch to EVG/COBI/FTC/TAF – GS-US-292-0109 – design and results at 48 weeks

This was a 96-week randomized, open-label, active-controlled, multicenter, Phase 3 trial carried out at 168 sites in 19 countries in North America, Europe, Latin America, Asia, and Australia [Mills et al, 2016].

Adults (aged ≥18 years) with HIV-1 infection were eligible to participate if they were virologically suppressed (HIV-1 RNA <50 copies/mL) for at least 96 weeks, had an estimated glomerular filtration rate (eGFR) of >50 mL/min, and were on a regimen containing FTC/TDF as follows: coformulated EVG/COBI/FTC/TDF; efavirenz plus FTC/TDF; cobicistat-boosted atazanavir plus FTC/TDF; or ritonavir-boosted atazanavir plus FTC/TDF.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Following enrollment, subjects were randomly assigned (2:1) to switch to EVG/COBI/FTC/TAF (TAF group) or to stay on their previous TDF-containing regimen (TDF group).

The proportion of subjects with a viral load <50 copies/mL at Week 48, as defined by the FDA snapshot algorithm, was the primary efficacy parameter. Virologic failure was defined as HIV-1 RNA >50 copies/mL in this study. Failure was defined as missing HIV-1 RNA data in the Week 48 window, discontinuation of the study drug, or a change in treatment before Week 48.

Subjects Of the 1436 subjects randomized, 959 were switched to fixed dose EVG/COBI/FTC/TAF, while 459 continued with their pre-existing TDF-based regimen. Baseline disease characteristics and demographics were balanced between the two treatment groups with the exception of ethnic origin, where more patients in the TAF group were of Hispanic or Latino origin (p=0.0006; Table 8).

Table 8. Baseline demographics and disease characteristics in patients enrolled in switching study GS-US-292-0109

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Virologic response rate At Week 48, 97% of subjects who switched to the FTC/TAF regimen and 93% of those continuing with a FTC/TDF-based regimen had maintained a viral load of <50 copies/mL [Mills et al, 2016]. The difference in percentage of 4.1 (95% CI: 1.6, 6.7) was statistically significant (p=0.0002) when adjusted for previous treatment regimen. Switching to the open-label TAF regimen was therefore superior to continuing with a TDF-containing regimen.

Patients previously on a regimen of efavirenz plus FTC/TDF or of boosted atazanavir plus FTC/TDF had significant efficacy advantages when switched to TAF (96 versus 90% pre- randomization, respectively and 97 versus 92% pre-randomization, respectively). By contrast, patients who switched from EVG/COBI/FTC/TDF to EVG/COBI/FTC/TAF had similar rates of virologic success at Week 48 (98% versus 97%, respectively).

Virologic failures were similar between groups with 10 (1%) occurring in the TAF group and six (1%) in the TDF group [Mills et al, 2016].

10.2.4 Phase 3 study of switch from FTC/TDF to FTC/TAF – GS-US-311-1089 – design and results at 48 weeks

Design This was a 96-week randomized, double-blind, multicenter Phase 3 trial carried out at 78 sites in Europe and North America [Gallant et al, 2016].

Adults (aged ≥18 years) with HIV-1 infection were eligible to participate if they were virologically suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months on a fixed dose regimen containing FTC/TDF and had an estimated glomerular filtration rate (eGFR) of >50 mL/min. Following enrollment, subjects were randomly assigned (1:1) to switch to fixed dose FTC 200 mg plus 10 mg or 25 mg TAF or to continue with FTC/TDF, while remaining on the third agent that had been part of the subject’s pre-existing treatment regimen.

The proportion of subjects with a viral load <50 copies/mL (with a maximum allowable difference of 10%) at Week 48 as defined by the FDA snapshot algorithm was the primary efficacy parameter. Virologic failure was defined as HIV-1 RNA >50 copies/mL, missing HIV-1 RNA data in the Week 48 window, and discontinuation of study drug or a change in treatment 35

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 before Week 48.

Subjects Of the 663 subjects randomized, 334 switched to an FTC/TAF regimen while 334 continued with FTC/TDF based therapy [Gallant et al, 2016]. The demographics, disease characteristics at baseline, and choice of third antiretroviral agent were similar between subjects who switched to TAF and those who remained on FTC/TDF (Table 9).

Table 9. Baseline demographics and disease characteristics in patients enrolled in switching study GS-US-311-1089

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Virologic response rate At Week 48, 94% of subjects who switched to an FTC/TAF regimen and 93% of those continuing with a FTC/TDF-based regimen had maintained a viral load of <50 copies/mL. Thus, switching to FTC/TAF was non-inferior to continuing FTC/TDF for the primary efficacy endpoint.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Results were similar for subjects who achieved HIV-1 RNA <20 copies/mL, with response rates at Week 48 of 92% and 91% for FTC/TAF and FTC/TDF treated patients, respectively. Virologic success was similar between treatment groups with respect to age, sex, race, and study drug adherence (Figure 3) [Gallant et al, 2016]. Of the 663 patients who received treatment, two in the TAF group and one in the TDF group met the protocol-defined virologic failure criteria and were tested for resistance.

Figure 3. Differences in virologic response between treatment arms at Week 48 in patient subgroups

10.2.5 Phase 3 study of switch from FTC/TDF to FTC/TAF in renal impairment – GS- US-292-0112 – design and results at 48 and 96 weeks

Design This was a 144-week single-arm, open-label, Phase 3 study performed at 70 outpatient centers in the United States, Thailand, United Kingdom, Australia, Spain, France, Dominican Republic, Mexico, and the Netherlands [ClinicalTrials.gov, 2013a; Pozniak et al, 2016].

Adults (aged ≥18 years) with HIV-1 infection were eligible to participate if they had no known history of resistance to elvitegravir or FTC/TDF, CD4 cell count of ≥50 cells/μL, plasma HIV-1 38

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

RNA concentrations at undetectable levels for at least 6 months preceding the screening visit and HIV-1 RNA <50 copies/mL at screening. The were also required to have eGFRCG 30–69 mL/min, stable renal function, and the cause of underlying chronic kidney disease was required to be stable without change in medical management for 3 months prior to baseline. Eligible patients, all of whom were stable on combination ART, were switched to once-daily EVG/COBI/FTC/TAF.

The primary endpoint was the change from baseline at Week 24 in eGFRCG, eGFRCKD-Epi-CysC based on Cystatin C, and eGFRCKD-Epi-creat based on serum creatinine. Secondary endpoints included the proportion of subjects with a viral load <50 copies/mL at Week 48, as defined by the FDA snapshot algorithm, was the main efficacy parameter. Virologic failure was defined as HIV-1 RNA ≥50 copies/mL, confirmed by a second sample drawn within 3–6 weeks [Pozniak et al, 2016].

Subjects A total of 242 HIV-infected adults, with an average age of 58 years, met inclusion criteria and were switched to EVG/COBI/FTC/TAF. This study had an HIV-infected population that was older than the other studies, with many with comorbidities known to affect renal function. A majority of subjects (65%) were on TDF-based regimens before switching to EVG/COBI/FTC/TAF (Figure 4).

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Figure 4. Baseline demographics, disease characteristics and initial ART in patients enrolled in switching study GS-US-292-0112

Virologic response rate At Week 48 following switching, 92% of patients maintained an HIV-1 RNA <50 copies/mL, while 17 (7%) did not have virologic data available and three (1%) experienced virologic failure [Pozniak et al, 2016]. By follow-up at Week 96, 88% of patients (214/242) had maintained viral suppression, while only 2% (5/242) experienced virologic failure [Post et al, 2016].

10.2.6 Phase 3 study of switch to FTC/TAF in multi-drug resistant HIV-infected adults – GS-US-292-0119 – design and results at 24 and 48 weeks

Design This was a Phase 3 open-label study carried out at 83 centers in North America to determine the efficacy and safety of switching treatment-experienced adults infected with multi-drug resistant HIV-1 from a multi-pill darunavir/ritonavir regimen to fixed dose EVG/COBI/FTC/TAF plus darunavir (DRV) [Huhn et al, 2016; ClinicalTrials.gov, 2013b].

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Adults (aged ≥18 years) with HIV-1 infection and a history of two antiretroviral regimen failures and ≥2-class resistance, including TDF resistance mutations (K65R, ≤3 thymidine analogue mutations) were eligible to participate if virologically suppressed (

Subjects meeting eligibility criteria were randomized (2:1) to once-daily EVG/COBI/FTC/TAF plus 800 mg of DRV or to continue their DRV-containing baseline regimen.

The proportion of subjects with a viral load <50 copies/mL at Week 24, as defined by the FDA snapshot algorithm, was the primary efficacy parameter.

Subjects Of the 135 subjects enrolled in this study, 89 received once-daily EVG/COBI/FTC/TAF plus 800 mg DRV while 46 continued their DRV-containing regimen. Median age at baseline was 49 years in the TAF-based treatment arm and 47 years in the control arm. The study population was predominantly male (82% and 61% in the two arms, respectively) with more than half (59%) of all subjects of Black and Hispanic origin. Before switching all study participants were taking a median of five pills/day, with two thirds taking a twice-daily or more frequent regimen. About half the subjects in each treatment arm were taking the integrase inhibitor raltegravir and more than half in each arm were taking TDF. Baseline resistance was similar in the two treatment arms [Huhn et al, 2016].

Virologic response rate At Week 24, 97% (86/89) of subjects switched to EVG/COBI/FTC/TAF plus DRV had maintained a viral load below 50 copies/mL compared with 91% (42/46) of those who continued their baseline regimen (difference 5.3%, 95% CI: -3.4% to 17.4%). Simplification to EVG/COBI/FTC/TAF plus DRV was noninferior to continuation of baseline regimens at week 24 and also met prespecified criteria for noninferiority and superiority at week 48 for the same outcome [Huhn et al, 2016]. After 48 Weeks’ treatment, a significantly higher proportion of subjects switched to EVG/COBI/FTC/TAF plus DRV had a viral load below 20 copies/mL (90

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 versus 72%, respectively, P=0.012). In the EVG/COBI/FTC/TAF plus DRV arm, two patients had viremia at Week 24 but were suppressed at Week 36 and Week 48 [Huhn et al, 2016].

10.3 Summary of the efficacy of Descovy® As results of the two Phase 3 pivotal clinical trials in HIV-infected, treatment-naïve subjects have shown, a regimen containing FTC/TAF was non-inferior to a similar regimen containing FTC/TDF. These results are important because they demonstrate for the first time that treatments containing tenofovir in either EVG/COBI/FTC/TAF or EVG/COBI/FTC/TDF in a fully powered, head-to-head comparison can exceed the 90% threshold for virologic suppression (plasma HIV-1 RNA <50 copies/ mL) [Sax et al, 2015]. Moreover, continued treatment to 96 weeks in these trials showed that the high rates of virologic suppression seen at 48 weeks were sustained [Wohl et al, 2016a].

Overall, results from the clinical trials described above as well as the earlier Phase 2 studies show that TAF-based regimens are as effective as TDF-based regimens for first-line treatment of HIV-1 infection in adults and adolescents. The robust efficacy seen in treatment-naïve subjects also extends to virologically suppressed adults without history of virologic failure who switch regimens, including those with mild-to-moderate renal impairment. In treatment- experienced HIV-infected adults who have developed resistance to several standard regimens, switching to EVG/COBI/FTC/TAF plus DRV was associated with durable maintenance of virologic suppression and improvements in specific markers of renal safety when compared to multiple daily dosing regimens with the added convenience of a simple, once-daily, two-pill option [Huhn et al, 2016]. Compared with baseline regimens, the switch to EVG/COBI/FTC/TAF plus darunavir resulted in higher mean treatment satisfaction scores and fewer days with missed doses suggesting that this strategy may lead to greater adherence and improved quality of life [Huhn et al, 2016].

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

10.4 Summary of the resistance profile of Descovy® The potential for the development of viral mutations that are resistant to treatment with nucleos(t)ide analogs is an important consideration in people receiving oral antiviral agents for HIV infection.

The integrated resistance analysis of the Phase 2 and two pivotal Phase 3 trials in treatment- naïve adults, that included HIV-1 genotypic analysis at screening and genotypic/phenotypic analysis for patients with HIV-1 RNA>400 copies/mL at virologic failure, showed that resistance development to FTC/TAF was extremely rare. Seven patients (0.7%, 7/978) developed NRTI resistance-associated mutations (RAMs), five of whom (0.5%, 5/978) also developed primary INSTI-RAMs. Similar results were seen in subjects treated with a TDF-containing regimen; seven patients (0.8%, 7/925) developed NRTI RAMs, four of whom (0.4%, 4/925) also developed primary INSTI-RAMs [Margot et al, 2016].

In the Phase 3 switch study, the FTC RAM M184V/1 (a mutation selected by FTC) was detected in one patient prior to re-suppression. In all other Phase 3 trials, FTC, tenofovir and elvitegravir RAMs were not detected in any subjects who met the criteria for resistance testing, which included highly treatment-experienced patients switching to EVG/COBI/FTC/TAF plus darunavir [Abram et al, 2016].

These data suggest that FTC/TAF has a very low propensity to select mutations associated with drug resistance (<1%) and, similar to FTC/TDF, its efficacy appears unaffected by the presence of pre-treatment RAMs [Abram et al, 2016].

10.5 Summary of available estimates of comparative effectiveness

With an improved pharmacokinetic profile, TAF has potential to provide equivalent efficacy to TDF but with reduced tenofovir-related toxicity, especially in relation to kidney and bone health.

Clinical studies comparing TAF with TDF have focused predominantly on head-to-head comparisons between EVG/COBI/FTC/TAF and EVG/COBI/FTC/TDF in treatment-naïve subjects. These large, identical, Phase 3 trials, which were powered to demonstrate non-inferiority, have 43

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 shown that a regimen containing FTC/TAF provides equivalent antiviral efficacy to one containing FTC/TDF. Virologic suppression was accompanied by improvements in CD4 counts, with immunologic recovery similar to that observed in the comparator arms. As mentioned earlier, these trials were notable for their exceptionally high rates of viral suppression, which probably reflects the inclusion of the integrase inhibitor, elvitegravir, in the fixed dose combinations. Integrase inhibitors are among the most potent antiretroviral drugs currently available [Jilek et al, 2012].

A regimen containing FTC/TAF also proved as effective as a TDF-based regimen in maintaining virologic suppression in adult subjects whose viral load was suppressed to below 50 copies/mL. In one of the largest switching trials ever conducted (GS-US-311-109), switching subjects from a TDF-containing regimen to one containing TAF was as at least as effective, if not better, than maintaining subjects on a TDF-containing regimen and efficacy was maintained for up to 96 weeks. FTC/TAF also demonstrated similar efficacy to FTC/TDF in maintaining virologic suppression when used as a fixed dose component with a range of third antiretroviral agents that included EVG/COBI, efavirenz, atazanavir/COBI or atazanavir/ritonavir. The same held true when switching stable renally impaired subjects from a TDF-containing regimen to one containing FTC/TAF, indicating that FTC/TAF is effective in this special patient population. Overall, comparative findings demonstrate that efficacy is maintained when switching patients to TAF from a successful ART regimen that included TDF.

Patients who become resistant to components of ART constitute a difficult-to-treat population. In treatment-experienced adult subjects, a single tablet regimen containing FTC/TAF, to which DRV 800 mg was added, proved more effective in maintaining viral suppression than the DRV- containing baseline therapy with the added benefit of a simple dosing regimen.

The pivotal Phase 3 studies provide the comparative efficacy data with respect to age, sex, race, baseline CD4+ count, baseline HIV-1 viral load, region, and study drug adherence for FTC/TAF versus FTC/TDF. Response rates were similar in each treatment arm for these subgroups, although women and people of Black origin taking EVG/COBI/FTC/TDF had somewhat lower response rates compared with those on EVG/COBI/FTC/TAF. Although the

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 number of women in both treatment arms were balanced, women comprised 15% of the population in these studies, which may have influenced these results. In addition, people of Asian origin averaged ~10% of the study population. Nonetheless, FTC/TAF appears to have similar efficacy to FTC/TDF across a wide age range of treatment-naïve HIV-infected people that includes adolescents (12–17 years) and older subjects (>65 years) drawn from regions across the world.

11. Summary of comparative evidence on safety

11.1 Estimate of total patient exposure to Descovy®

Cumulative post-marketing patient exposure for Descovy® now amounts to 14,498 patient- years up till 30 September 2016. This figure includes adults, adolescents and both treatment- naïve, virologically suppressed and treatment-experienced subjects.

11.2 Description of adverse effects/reactions

Assessment of the frequency of treatment-emergent adverse events (TEAEs) following treatment with FTC/TAF in clinical trials showed that it was generally well tolerated by adults and adolescents, of whom 2396 subjects received it as part of the fixed dose combination EVG/COBI/FTC/TAF [Genvoya SmPC, 2016]. Among 866 treatment-naïve adult patients receiving EVG/COBI/FTC/TAF in the pivotal Phase 3 trials, diarrhea (17%), nausea (15%) and headache (14%) were the most frequently reported adverse events and occurred with similar frequency in the TDF-treatment arm [Sax et al, 2015]. Adverse events leading to treatment discontinuation were infrequent: seven (0.8%) subjects in the TAF-treatment arm stopped taking EVG/COBI/FTC/TAF and 11 (1.3%) stopped taking EVG/COBI/FTC/TDF for adverse events attributed to study medication [Sax et al, 2015].

The nature and frequency of adverse events seen in the trials enrolling treatment-naïve subjects were largely mirrored in virologically suppressed subjects switched to a TAF-containing regimen. Again, rates of discontinuation for adverse events were low, ranging from 1–2% [Mills et al, 2016; Gallant et al, 2016].

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

11.3 Renal safety profile Because tenofovir and FTC are principally excreted via the kidney, the renal safety profile of FTC/TAF has been studied in detail and was a pre-specified safety outcome measure in the clinical trials.

Across the Phase 2 and 3 clinical trials, the effect of TAF compared with TDF on proximal renal function was assessed using standard clinical measures of proteinuria and albuminuria as well as markers of proximal renal tubular cell dysfunction that included retinol binding protein and β- 2 microglobulin. These low molecular weight proteins are freely filtered at the glomerulus, and hence are almost entirely removed from the ultrafiltrate and catabolized in the proximal renal tubules [Hall et al, 2009; Post et al, 2010].

11.3.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – renal safety

Compared with subjects on the TDF-containing regimen, subjects receiving the TAF-containing regimen had significantly smaller mean serum creatinine increases (0.08 versus 0.12 mg/dL, respectively; p<0.0001) as well as significantly less proteinuria (median % change urine [protein]:creatinine ratio -3 versus 20; p<0.0001), retinol binding protein (median % change urine [protein]:creatinine ratio 9 versus 51, respectively; p<0.0001) and β-2 microglobulin (median % change urine [protein]:creatinine ratio -32 versus 24, respectively; p<0.0001) at Week 48 (Figure 5) [Sax et al, 2015]. Taken together, the urinary protein data show a substantially lower level of markers of renal tubular dysfunction among treatment-naïve adult subjects receiving TAF-based therapy [Antela et a, 2016].

Figure 5. Changes in quantitative proteinuria at Week 48 in studies GS-US-292-0104 and GS-US-292-0111 (pooled data)

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The beneficial effects of TAF-containing regimen on kidney function were sustained at Week 96, where again there were more favorable changes in proteinuria, albuminuria and tubular proteinuria than seen with the TDF-containing regimen [Wohl et al, 2016a]. While there were no cases of proximal renal tubulopathy, including Fanconi syndrome, in either treatment arm following 48 weeks’ treatment, two subjects on the TDF-containing regimen developed proximal tubulopathy at Week 96. At Week 96 there were no discontinuations associated with renal adverse events in subjects on the TAF-containing regimen but there were six in the TDF- containing arm (p=0.03) [Wohl et al, 2016a].

In a post-hoc analysis of renal outcomes by baseline risk for chronic kidney disease (CKD), incident CKD through 2 years was 0.1% for TAF-based therapy compared with 1.6% for the TDF-containing regimen [Wohl et al, 2016b]. Although incident CKD was observed in all CKD risk groups (low and high), a graded increase in incident CKD was observed with increasing CKD risk (from 1–5%). Tubular proteinuria increased in patients on TDF with increasing CKD risk, consistent with the emergence of a proximal renal tubulopathy, such as Fanconi syndrome.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Treatment discontinuations for adverse renal events as well as changes in eGFRCG and quantitative proteinuria all favored TAF across CKD risk group [Wohl et al, 2016b].

11.3.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – renal safety

No differences were observed after 24 weeks’ treatment with either a TAF- or TDF-containing regimen in respect of median change in creatinine clearance (+0.08 mg/dL in both groups), eGFR (-15.0 and -14.0 mL/1.73 m2 for TAF and TDF, respectively) or median serum cystatin C. However, similar to the results seen in treatment-naïve adult subjects, adolescents experienced more favorable changes in renal tubular biomarkers on a TAF-containing regimen than on a TDF-containing regimen (Figure 6) [Gaur et al, 2016; Kizito et al, 2015]. No subjects developed proximal renal tubulopathy or Fanconi syndrome.

Figure 6. Changes in quantitative proteinuria at Week 24 in studies GS-US-292-0106 and GS-US-236-0112

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

11.3.3 Phase 3 switching study to EVG/COBI/FTC/TAF – GS-US-292-0109 – renal safety

Virologically suppressed subjects stable on a TDF-containing regimen for at least 96 weeks saw significant improvements in renal tubular biomarkers following a switch to a TAF-containing regimen (EVG/COBI/FTC/TAF), with improvement evident within the first 2 weeks of switching [Mills et al, 2016]. Total proteinuria and proximal tubular proteinuria decreased in patients receiving TAF, irrespective of prior treatment regimen, while they increased among patients receiving TDF. This lead to a significant difference between treatment groups throughout the study and at the Week 48 endpoint (p<0.001). Two patients on the TAF-containing regimen discontinued because of adverse renal effects compared with five continuing with a TDF- containing regimen. One patient taking cobicistat-boosted atazanavir plus FTC/TDF developed Fanconi’s syndrome and discontinued TDF-based treatment.

11.3.4 Phase 3 switching study from FTC/TDF to FTC/TAF – GS-US-311-1089 – renal safety

Virologically suppressed subjects stable on a TDF-containing regimen for at least 6 months saw significant improvements in renal tubular biomarkers following a switch to a TAF-containing regimen that included the same third agent as in the baseline regimen (Table 10). Mean change from baseline in serum creatinine concentration in the TAF group was –0.08 mg/dL (SD 0.238) compared with –0.04 mg/dL (SD 0.126) in the TDF group (p=0.005), while eGFR increased from baseline in the TAF group compared with minimal changes in the TDF group at weeks 2 through to 48 (median change of 8.4 mL/min (IQR 0.2–15.6) versus 2.8 mL/min (–5.1 to 10.9), respectively, p<0.0001) [Gallant et al, 2016].

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Table 10. Changes in quantitative proteinuria at Week 24 in study GS-US-311-1089

11.3.5 Phase 3 switching study from FTC/TDF to FTC/TAF in renal impairment – GS-US-292-0112 – renal safety

In contrast to the other trials, in which subjects had normal renal function, this open-label study focused on HIV subjects with stable but mild-to-moderate renal dysfunction (eGFR 30– 69mL/min) and with renal safety as the primary outcome measure (change from baseline at Week 24 in eGFR, eGFR based on Cystatin C and eGFR based on serum creatinine) [Pozniak et al, 2016; Post et al, 2016]. Consistent with results from the trials in HIV-infected subjects with normal renal function, virologically suppressed subjects had significant improvements in renal tubular biomarkers when switched from a TDF- or non-TDF regimen to EVG/COBI/FTC/TAF. Over 96 weeks of this 144-week trial, treatment with EVG/COBI/FTC/TAF was associated with stable eGFR, reductions in proteinuria and improvements in proximal renal tubular function (Figure 7).

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Figure 7. Changes in quantitative proteinuria at Week 96 in study GS-US-292-0112

Of the 12 subjects (5%) who discontinued treatment with EVG/COBI/FTC/TAF at Week 96, five (2%) did so because of decreased eGFR. Three subjects experienced renal disease progression, two of whom had poorly controlled hypertension. Two subjects with a medical history of TDF- associated Fanconi syndrome continued treatment with EVG/COBI/FTC/TAF achieving stable eGFR and significant reductions in total and tubular proteinuria [Post et al, 2016]. 11.3.6 Phase 3 switching study to FTC/TAF in multi-drug resistant HIV-infected adults – GS-US-292-0119 – renal safety

Among treatment-experienced virologically suppressed subjects, those switched to EVG/COBI/FTC/TAF plus DRV saw significant improvements in markers of renal tubular function (a 17% decline in retinol binding protein and a 35% decline in β-2 microglobulin), whereas they increased by 11% and 13%, respectively, in those continuing with the baseline regimen. No differences were observed in median change in eGFR (2.5 in the EVG/COBI/FTC/TAF plus DRV versus -0.1mL/min in the baseline regimen arm; p=0.62) or urine protein/creatinine (Cr) ratio (- 14% in the EVG/COBI/FTC/TAF plus DRV arm versus -4% in baseline regimen arm; p=0.21). There were no drug-related serious adverse events and no treatment discontinuations due to adverse events in either treatment arm [Huhn et al, 2016].

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

11.4 Bone safety profile

Studies in HIV-infected people have shown TDF to be associated with small but significant decreases in BMD that in rare instances can lead to fragility fractures, especially among younger HIV-infected adults (25–54 years) [Battalora et al, 2014]. The comparative effect of TAF on bone metabolism versus TDF in HIV-infected adults and adolescents was therefore a pre- specified safety outcome measure in the TAF-related clinical trials.

Across the Phase 2 and 3 clinical trials, the effect of TAF compared with TDF on bone metabolism was assessed with respect to changes in BMD, as assessed by dual-energy X-ray absorptiometry (DEXA), and frequency of fractures.

11.4.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – bone safety

In the largest data set on BMD in people with HIV, treatment-naïve adults receiving the TAF- containing regimen had significantly smaller reductions in both lumbar spine and hip BMD at Week 48 compared with those on the TDF-containing regimen [Sax et al, 2015]. Mean percentage change in spine BMD was -1.30% versus -2.86% for TAF and TDF, respectively, (P<0.0001). Corresponding changes for hip BMD were -0.66% and -2.95%, respectively, (P<0.0001). While 76% of patients treated with the TAF-containing regimen had no change in hip BMD and 17% had bone loss (defined as >3%), only 46% of those in the TDF treatment arm had no change in BMD, while 50% had bone loss. Similarly, spine BMD changes were less (68% were stable; 26% lost bone mass) in the TAF treatment arm while 51% remained stable and 45% had BMD loss at Week 48 in the TDF treatment arm. The benefit of a TAF-containing regimen on bone metabolism was even more pronounced after 96 weeks’ treatment (Figure 8). Spine BMD in patients receiving the TAF-containing regimen increased towards baseline (mean % change at Week 48: -1.291% and at Week 96: -0.960), while remaining lower in subjects on the TDF-containing regimen (mean % change at Week 48: -2.830% and at Week 96: -2.792%) [Wohl et al, 2016a].

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Figure 8. Percentage change in spine and hip BMD at Week 96 in studies GS-US- 292-0104 and GS-US-292-0111 (pooled data)

Fractures were uncommon in both treatment groups and no fractures were attributed to study medications [Sax et al, 2015].

11.4.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – bone safety Among treatment-naïve adolescents with HIV-1 infection, those receiving a regimen containing TAF saw an increase in median spine BMD at Week 24 (+1.25%) compared with a mean decrease (-0.99%) in those on a TDF-containing regimen (Figure 9) [Gaur et al, 2016; Kizito et al, 2015].

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Figure 9. Percentage change in spine BMD in studies GS-US-292-0106 and GS-US- 236-0112

11.4.3 Phase 3 switching study to EVG/COBI/FTC/TAF – GS-US-292-0109 – bone safety Virologically suppressed subjects stable on a TDF-containing regimen for at least 96 weeks saw significant improvements in both spine and hip BMD following the switch to a TAF-containing regimen (Table 11), together with greater recovery from osteopenia and osteoporosis [Mills et al, 2016].

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Table 11. Percentage change in spine and hip BMD at Week 48 in study GS-US-292- 0109

In a subset of patients who received 144 weeks of ritonavir-boosted atazanavir plus FTC/TDF (study GS-US-236-0103), the mean percentage reduction from baseline in hip BMD was 4.58% (SD 4.17) [Mills et al, 2015]. Subjects in this subset randomly assigned to the TAF group in the present study (n=41), saw a 1.35% (SD 3.07) improvement in hip BMD, while those continuing baseline treatment saw a further 0.77% reduction (SD 2.45). There was a corresponding improvement in spine BMD of 2.83% (SD 4.76) in those switched to TAF (n=42), whereas those continuing baseline treatment experienced further reductions of 0.74% (SD 3.55%) [Mills et al, 2016].

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Fractures were uncommon in both treatment groups and none was attributed to study medications [Mills et al, 2016]. No fragility fractures occurred in either treatment arm.

11.4.4 Phase 3 switching study from FTC/TDF to FTC/TAF – GS-US-311-1089 – bone safety Virologically suppressed subjects stable on a TDF-containing regimen for at least 6 months saw significant improvements in both spine and hip BMD when switched to 48-weeks treatment with a TAF-containing regimen, while there was either no change or a decrease in BMD in those who continued baseline ART (Figure 10) [Gallant et al, 2016].

Figure 10. Percentage change in spine and hip BMD at Weeks 24 and 48 in study GS- US-311-1089

Distribution of BMD status (i.e. normal, osteopenia, or osteoporosis) adjusted for baseline status differed significantly between treatment arms at Week 48 at both the hip (P=0.012) and spine (P=0.037) [Gallant et al, 2016]. This difference was driven by a higher percentage of subjects in the TAF arm experiencing an improvement in BMD status (i.e. osteopenia to normal, osteoporosis to normal or osteopenia) and a correspondingly lower percentage of subjects in the group with worsening BMD status (i.e. normal to osteopenia or osteoporosis, or osteopenia to osteoporosis).

Fractures were uncommon in both treatment groups and no fractures attributed to study 56

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 medications [Gallant et al, 2016].

11.4.5 Phase 3 switching study from FTC/TDF to FTC/TAF in renal impairment – GS-US-292-0112 – bone safety Virologically suppressed HIV-infected subjects with mild-to-moderate renal impairment saw improvements in hip and spine BMD when switched to a TAF-containing regimen for up to 96 weeks. At Week 48, the increase in hip and spine BMD was +1.47 and +2.29, respectively, (p<0.05) for those switched from a TDF-containing regimen while remaining stable for those on a non-TDF containing regimen pre-switch. These improvements were sustained through 96 weeks’ treatment (Figure 11) [Pozniak et al, 2016; Post et al, 2016]. Figure 11. Percentage change in spine and hip BMD at Weeks 48 and 96 in study GS- US-292-0112

11.5 Lipid safety profile

Treatment with TDF has consistently been associated with a reduction in plasma lipid levels compared with other ART regimens in treatment-naive patients. The independent effect of tenofovir on lipids was most clearly demonstrated in a study in which TDF was added to stable background treatment in virologically suppressed patients [Tungsiripat et al, 2010], where

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 results showed a significant reduction in levels of total, LDL, and non-HDL cholesterol. In both the Phase 2 and larger Phase 3 comparative studies presented here, increases in total, LDL, and HDL cholesterol, and triglycerides, were greater in the TAF-containing treatment arms than in those containing TDF. However, the difference in total cholesterol to HDL ratio at Week 48 was not significantly different between treatment groups. The modest increase in lipid levels with TAF appears similar to that seen with other (non-TDF) NRTI backbones [Antela et al, 2016].

11.6 Drug–drug interactions Drug–drug interactions with Descovy® are described in the Descovy® SmPC [Descovy® 200 mg/10 mg film coated tablets SmPC, 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016, ]. TAF is a substrate of p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3 and so drugs that strongly affect P-gp activity may lead to changes in TAF absorption (Table 12). Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of Descovy® and development of resistance. Co-administration of Descovy® with other drugs that inhibit P-gp may increase the absorption and plasma concentration of TAF. TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1, nor an inhibitor or inducer of CYP3A in vivo. TAF is a weak inhibitor of CYP3A in vitro.

Table 12. Established and other potentially significant drug interactions with TAF [Descovy® 200 mg/25 mg film coated tablets SmPC, 2016]

Medicinal product by Effects on medicinal Recommendation therapeutic areas product levels concerning Co- administration with Mean percent change in AUC, Descovy® Cmax, Cmin1 Antiretrovirals: protease inhibitors

Tipranavir/ritonavir Interaction not studied with Co-administration with either of the components of Descovy® is not Descovy®. recommended.

Tipranavir/ritonavir results in P-gp induction. TAF exposure is expected to decrease when tipranavir/ritonavir is used

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with Descovy®.

Anticonvulsants

Oxcarbazepine Interaction not studied with Co-administration of either of the components of Descovy® and Phenobarbital Descovy®. oxcarbazepine, phenobarbital or Phenytoin Co-administration of phenytoin is not oxcarbazepine, phenobarbital, recommended. or phenytoin, all of which are P-gp inducers, may decrease TAF plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Carbamazepine* (titrated Co-administration Co-administration of from 100 mg to 300 mg of carbamazepine, a P-gp Descovy® and twice a day) inducer, decreases TAF carbamazepine is not plasma concentrations, recommended. *A study to assess the which may result in loss of pharmacokinetics of therapeutic effect and carbamazepine combined development of resistance. with a FTC/TAF-containing

ART regimen has been conducted but data have not yet been presented.

Antimycobacterials

Rifabutin† Interaction not studied with Co-administration Rifampicin either of the components of of Descovy® and Rifapentine Descovy®. Co-administration rifabutin, rifampicin or of rifampicin, rifabutin and rifapentine is not †A study to assess the rifapentine, all of which are P- recommended. pharmacokinetics of rifabutin combined with a FTC/TAF- gp inducers, may decrease containing ART regimen in TAF plasma concentrations, patients with TB/HIV co- which may result in loss of infection is planned. therapeutic effect and development of resistance. Anti-hepatitis C virus medicinal products

Boceprevir Boceprevir Co-administration Telaprevir Telaprevir with boceprevir or telaprevir has the potential to adversely

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

affect the intracellular activation and clinical antiviral efficacy of TAF, therefore coadministration of Descovy® and boceprevir or telaprevir is not recommended. Antidepresssants

Setraline (50 mg once Co-administration with TAF No dose adjustment of daily) has no effect on TAF, while sertraline is required. plasma levels of sertraline Dose Descovy® may increase according to concomitant antiretroviral Herbal products

St. John's wort (Hypericum Interaction not studied with Co-administration perforatum) either of of Descovy® with St the components of Descovy®. John's wort is not Co-administration recommended. of St. John's wort, a P-gp inducer, may decrease TAF plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

11.7 Summary of comparative safety

FTC/TDF (Truvada®) has a well-established safety profile from more than a decade of use as the backbone to first-line treatment for HIV-1 infection. However, many experts advise against using TDF in people with impaired kidney function unless the benefits are considered to outweigh the risks. People with HIV have increased rates of kidney disease (HIV-associated nephropathy) compared to those without HIV [Wyatt et al, 2009; Phair & Palella, 2011], which can be exacerbated by ART [Atta et al, 2008]. Therefore, current prescribing information for TDF-containing fixed dose combinations advises dose reductions for HIV-infected people with pre-existing kidney impairment. EVG/COBI/FTC/TDF, the comparator in the pivotal Phase 3

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 trials in treatment-naïve adults, is not recommended for HIV-infected individuals with creatinine clearance of <70 mL/min.

Head-to-head comparative studies, together with switching studies in virologically suppressed subjects, including those with existing renal impairment, suggest that Descovy® is well tolerated as TDF by people with HIV but with the benefit of a more favorable renal side-effect profile. Treatment with a TAF-containing regimen is associated with markedly less renal toxicity than TDF as demonstrated by statistically significantly smaller increases in serum creatinine and corresponding decreases in estimated glomerular filtration rate, and less proteinuria and albuminuria [Ray et al, 2016]. Switching studies suggest that the benefits occur early in the course of therapy and continue for up to 144 weeks.

Adverse effects on bone, manifest as decreases in BMD, is the companion issue to TDF-related renal toxicity and can contribute to increasing bone fragility in people with HIV, which is increasingly important as the HIV population ages.

Head-to-head comparative studies together with switching studies in virologically suppressed subjects indicate better BMD preservation with administration of a TAF-containing regimen compared to one containing TDF. In treatment-naïve subjects, treatment with EVG/COBI/FTC/TAF caused less bone turnover as indicated by bone biomarkers and smaller declines in hip and spine BMD over 48 weeks than the TDF-containing regimen. In subjects virologically suppressed on other regimens, switching to EVG/COBI/FTC/TAF appeared to have favorable effects including BMD increases in hip and bone DEXA values. This was especially true when the previous regimen contained TDF. Clinical trial data that extend beyond 48 weeks suggest that the bone loss advantage of a TAF-containing regimen is sustained. Longer-term data from observational cohort studies will help to establish whether long-term use of TAF translates into a reduction in risk of fragility fractures, something that was not observed in the trials conducted to date.

Low rates of discontinuations for tenofovir-related toxicity and resistance development has been central to the success of TDF as the backbone to life-long treatment of HIV. Results from head- to-head comparisons and switching studies with TAF suggest that FTC/TAF is just as well tolerated by people living with HIV, including younger individuals, with the added benefit of an improved safety profile with respect to kidney and bone health. Potentially, it extends the use of 61

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 tenofovir to people with HIV who have mild-to-moderate kidney dysfunction and to adolescents who have not reached peak bone mass [Ray et al, 2016] as well as to older subjects (especially women) who are among those most at risk of osteoporosis [Aguiar et al, 2015].

There are no adequate and well-controlled studies of Descovy® or its components in pregnant women. For tenofovir alafenamide, there are no or limited data (less than 300 pregnancy outcomes). However, studies of tenofovir alafenamide in animals have shown no evidence of harmful effects on fertility parameters, pregnancy or foetal development (see section 5.3).

A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine. In addition, animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to fertility parameters, pregnancy, foetal development, parturition or postnatal development.

Descovy® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether tenofovir alafenamide is excreted in human milk. However, animal studies have shown that tenofovir is excreted in breast milk. In addition, there is evidence to show that emtricitabine is excreted in human milk.

As there is insufficient information on the effects of emtricitabine and tenofovir in newborns/ infants, Descovy® should not be used during breast-feeding.

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 Europe

The European Medicines Agency (EMA) approved FTC/TAF on 21 April 2016 as a fixed dose combination treatment for HIV-1 infection in adult and pediatric patients (12 years of age and 62

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 older with body weight ≥35 kg) and creatinine clearance ≥30 mL/min. As the first new HIV treatment backbone approved by the EMA in more than a decade, FTC/TAF is indicated for use in combination with other antiretroviral agents. FTC/TAF is also available in the USA following its approval by the US FDA on 4 April 2016 at the wholesale acquisition cost of $1,466 per 30 day supply.

12.1.2 Developing countries

Gilead’s mission is to transform care for HIV and other life-threatening diseases throughout the world, to which end our HIV treatment access effort has been based on the principle of tiered pricing of branded medicines based on a country’s ability to pay. Developing countries that are classified as low-income or lower-middle-income by World Bank, as well as those with significant unmet HIV/AIDS disease burden, are designated as Access countries. Prices in the Access countries account only for production and other related costs. Gilead’s no-profit price for a 30-day supply of Descovy® to in-country Access Program distribution partners is US $17.00. Descovy® will be made available to Governments at this no-profit transfer price, regardless of dose of TAF component, in addition to distribution and other related costs (these may vary from country to country).

13. Summary of regulatory status of the medicine Descovy® At present, Descovy® is licensed for treatment of HIV infection in Europe, the US and Canada.

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia)

14.1 Specifications of Descovy® tablets

British Pharmacopoeia: No standards available International Pharmacopoeia: No standards available US Pharmacopoeia: No standards available

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

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

15.1 Other antivirals

Antiretrovirals Fixed dose combinations Tablet: 200 mg of emtricitabine and 10 mg of tenofovir alafenamide 200 mg of emtricitabine and 25 mg of tenofovir alafenamide

Also known as Descovy®.

Uses: Descovy® is licensed in Europe, the USA and Canada for use in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and adolescents (aged 12 years and older with body weight at least 35 kg).

Contraindications: None Precautions: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs in combination with other antiretrovirals. Descovy® is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Descovy® have not been established in patients co-infected with human immunodeficiency virus-1 (HIV-1) and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of Descovy®. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are co-infected with HIV-1 and HBV and discontinue Descovy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Dose: One tablet taken once daily with or without food in patients 12 years old and older with body weight at least 35 kg and a creatinine clearance greater than or equal to 30 mL per minute. 64

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Adverse effects: Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea.

Please refer to the Summary of Product Characteristics for further details on Descovy®.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

16. References

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Antela A, Aguiar C, Compston, et al. The role of tenofovir alafenamide (TAF) in future HIV management. HIV Med 2016;17(suppl 2):4–16

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Bonora S, Calcagno A, Trentalange A, Di Perri G. Elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide for the treatment of HIV in adults. Exerpt Opin Pharmacother 2016;17(3):409–19

ClinicalTrials.gov. Open-label Safety Study of E/C/F/TAF (Genvoya®) in HIV-1 Positive Patients With Mild to Moderate Renal Impairment (NCT01818596), 2013a. Available at: https://clinicaltrials.gov/ct2/show/NCT01818596 (accessed November 2016)

ClinicalTrials.gov. Phase 3 Open-Label Study to Evaluate Switching From Optimized Stable Antiretroviral Regimens Containing Darunavir to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Single Tablet Regimen (STR) Plus Darunavir (DRV) in Treatment Experienced HIV-1 Positive Adults (NCT01818596), 2013b. Available at: https://clinicaltrials.gov/ct2/show/NCT01968551 (accessed November 2016)

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Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). Updated 14 July 2016. Available at: http://aidsinfo.nih.gov/guidelines (accessed November 2016)

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Gaur AH, Kizito H, Prasitsueubsai W, et al. Safety, efficacy, and pharmacokinetics of a single- tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial. Lancet HIV 2016; 3(12):e561–8

Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV 2016;3(4):e158-65

Grant PM, Cotter AG. Tenofovir and bone health. Curr Opin HIV AIDS 2016;11(3):326–32

Gupta A, Juneja S, Vitoria M, et al. Projected uptake of new antiretroviral (ARV) medicines in adults in low- and middle-income countries: A forecast analysis 2015–2025. PLoS ONE 2016; DOI:10.1371/journal.pone.0164619

Günthard H, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults 2016 Recommendations of the International Antiviral Society–USA Panel. JAMA 2016;316(2):191–210

Hall AM, Edwards SG, Lapsley M, et al. Subclinical tubular injury in HIV-infected individuals on antiretroviral therapy: a cross-sectional analysis. Am J Kidney Dis 2009;54:1034–42

Herlitz LC, Mohan S, Stokes MB, et al. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int 2010;78(11):1171– 7

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Jilek BL, Zarr M, Sampah ME, et al. A quantitative basis for antiretroviral therapy for HIV-1 infection. Nature Med 2012;18: 446–451

Jolley E, et al. HIV among people who inject drugs in Central and Eastern Europe and Central Asia: a systematic review with implications for policy. BMJ Open 2012;2:e001465 Kizito H, Gaur A, Prasithsirikul W, et al. Safety, efficacy, and pharmacokinetics of integrase inhibitor-based E/C/F/TAF single-tablet regimen in treatment-naive HIV-infected adolescents through 24 weeks of treatment. Abstract 953. Presented at: 22nd Conference on Retroviruses and Opportunistic Infections. 2015. Seattle, WA

Margot NA, Kitrinos KM, Fordyce M, et al. Rare emergence of drug resistance in HIV-1 treatment-naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. HIV Clin Trials 2016;17(2):78–87

Medicines Patent Pool (MPP) 2011. Stimulating Innovation Expanding Access Improving Health - Annual Report. 2010- 2011. Available at: http://www.medicinespatentpool.org/wp- content/uploads/Medicines-Patent-Pool-Annual-Report-2010-2011-RevFinal.pdf (accessed November 2016)

Mills A, Arribas JR, Andrade-Villanueva J, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis 2016;16(1):43–52

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Post FA, Wyatt CM, Mocroft A. Biomarkers of impaired renal function. Curr Opin HIV AIDS 2010;5:524–530

Post FA, Tebas P, Clarke A, et al. Longer-term safety of tenofovir alafenamide in renal impairment. Poster 680 presented at the Conference on Retroviruses and Opportunistic Infections. 2016, Boston, MA, USA

Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48- week results from a single-arm, multicenter, open-label phase 3 study. J Acquir Immune Defic Syndr 2016;71(5):530–7

Ray AS, Fordyce MW, Hitchcock MJM. Tenofovir alafenamide: a novel prodrug of tenofovir for the treatment of human immunodeficiency virus. Antiviral Res 2016;125:63–70

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Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Appendix 1. Descovy® Access PI

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

DESCOVY is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of DESCOVY have not been established in patients coinfected with human immunodeficiency virus-1 (HIV-1) and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of DESCOVY.

Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue DESCOVY. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

DESCOVY is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

Limitations of Use:

DESCOVY is not indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation of DESCOVY

Prior to initiation of DESCOVY, patients should be tested for hepatitis B virus infection [see Warnings and Precautions (5.2)].

Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating DESCOVY therapy and should be monitored during therapy in all patients [see Warnings and Precautions (5.5)].

2.2 Recommended Dosage 73

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DESCOVY is a two-drug fixed dose combination product containing 200 mg of emtricitabine (FTC) and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of DESCOVY is one tablet taken orally once daily with or without food in adults and pediatric patients 12 years of age and older with body weight at least 35 kg and creatinine clearance greater than or equal to 30 mL per minute [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

For specific dosing recommendations for coadministered third agents, refer to their respective prescribing information [see Drug Interactions (7)].

2.3 Not Recommended in Patients with Severe Renal Impairment

DESCOVY is not recommended in patients with estimated creatinine clearance below 30 mL per minute [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].

3 DOSAGE FORMS AND STRENGTHS

Each DESCOVY tablet contains 200 mg of emtricitabine (FTC) and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate). The tablets are blue, rectangular-shaped, film-coated, debossed with “GSI” on one side and “225” on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Since TAF and FTC are nucleos(t)ide analogs, treatment with DESCOVY should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

5.2 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy [see Dosage and Administration (2.1)]. DESCOVY is not approved for the treatment of chronic HBV infection, and the safety and efficacy of DESCOVY have not been established in patients coinfected with HIV-1 and HBV.

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of DESCOVY. Patients coinfected with HIV-1 and HBV who discontinue DESCOVY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.3 Fat Redistribution

Redistribution or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.4 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC, a component of DESCOVY. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.5 New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC+TAF 75

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 with cobicistat (COBI) plus elvitegravir (EVG), there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of FTC+TAF with EVG+COBI in treatment-naïve subjects and in virally suppressed subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute [see Adverse Reactions (6.1)]. DESCOVY is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating DESCOVY therapy and should be monitored during therapy in all patients. Serum phosphorus should be monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs. Discontinue DESCOVY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.6 Bone Loss and Mineralization Defects

Decrease in Bone Mineral Density (BMD):

In animal toxicology studies and human clinical trials, TAF and tenofovir have been associated with decreases in BMD and increases in biochemical markers of bone metabolism suggestive of increased bone turnover. In clinical trials in HIV-1 infected treatment-naïve adults, a significant decline in BMD was observed in 15% of subjects treated with FTC+TAF with EVG+COBI [see Adverse Reactions (6.1)]. The long-term clinical significance of these changes has not been established.

Assessment of BMD should be considered for adults and pediatric patients treated with DESCOVY who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Calcium and vitamin D supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

Mineralization Defects:

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF-containing products. Hypophosphatemia and osteomalacia secondary to PRT have occurred in patients at risk of renal dysfunction 76

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [see Warnings and Precautions (5.5)]. While not observed in clinical studies of DESCOVY, the risk of osteomalacia with DESCOVY is not known.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

 Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning, and Warnings and Precautions (5.1)]    Severe Acute Exacerbations of Hepatitis B [see Boxed Warning and Warnings and Precautions (5.2)].    Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)].    New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.5)].    Bone Loss and Mineralization Defects [see Warnings and Precautions (5.6)]. 

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice.

Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment- Naïve Adults with HIV-1 Infection

In pooled 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI due to adverse events during the 48-week treatment period [see Clinical Studies (14)]. The safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to FTC+TAF with EVG+COBI (N=799). Antiretroviral treatment-naïve adult subjects treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.

Renal Laboratory Tests

In two 48-week trials in antiretroviral treatment-naïve HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. 77

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48. In a 48-week trial in virologically-suppressed TDF-treated adults who switched to FTC+TAF with EVG+COBI (N=959) with a mean baseline eGFR of 112 mL per minute, mean serum creatinine was similar to baseline and median UPCR was 61 mg per gram at baseline and 46 mg per gram at Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at Week 24.

Bone Mineral Density Effects

In the pooled analysis of two 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 −1.30% with FTC+TAF with EVG+COBI at the lumbar spine and −0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI subjects. The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 7 (0.8%) subjects in the FTC+TAF with EVG+COBI group.

In 799 virologically-suppressed TDF-treated adult subjects that switched to FTC+TAF with EVG+COBI, at Week 48 mean BMD increased (1.86% lumbar spine, 1.95% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1% of FTC+TAF with EVG+COBI subjects.

Adverse Reactions in Clinical Trials in Pediatric Subjects with HIV-1 Infection

In a 24 week, open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects aged 12 to less than 18 years old (weighing at least 35 kg) who received FTC+TAF with EVG+COBI, the safety of this combination was similar to that of adults. Among these pediatric subjects, mean BMD increased from baseline to Week 24, +1.7% at the lumbar spine and +0.8% for the total body less head. Mean changes from baseline BMD Z-scores were −0.10 for lumbar spine and −0.11 for total body less head at Week 24. Two subjects had significant (greater than 4%) lumbar spine BMD loss at Week 24.

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7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect One or More Components of DESCOVY

TAF, a component of DESCOVY, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption (see Table 1). Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of DESCOVY and development of resistance. Coadministration of DESCOVY with other drugs that inhibit P-gp may increase the absorption and plasma concentration of TAF. TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.

7.2 Drugs Affecting Renal Function

Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of DESCOVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high- dose or multiple NSAIDs [see Warnings and Precautions (5.5)].

7.3 Established and Other Potentially Significant Interactions

Table 1 provides a listing of established or potentially clinically significant drug interactions with recommended steps to prevent or manage the drug interaction (the table is not all inclusive). The drug interactions described are based on studies conducted with either DESCOVY, the components of DESCOVY (emtricitabine and tenofovir alafenamide) as individual agents, or are predicted drug interactions that may occur with DESCOVY. For magnitude of interaction, see Clinical Pharmacology (12.3).

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Table 1 Established and Other Potentially Significanta Drug Interactions Concomitant Drug Effect on

Class: Drug Name Concentrationb Clinical Comment

Antiretroviral Agents: Protease Inhibitors (PI)

tipranavir/ritonavir  TAF Coadministration with DESCOVY is not recommended.

Other Agents

TAF Anticonvulsants:  Consider alternative anticonvulsant. carbamazepine

oxcarbazepine

phenobarbital

phenytoin

 TAF Coadministration of DESCOVY with rifabutin, rifampin, or Antimycobacterials:

rifabutin rifapentine is not recommended. rifampin

rifapentine

TAF Herbal Products:  Coadministration of DESCOVY with St. John’s wort is not

St. John’s wort recommended. (Hypericum perforatum) a. This table is not all inclusive. b. =Decrease

7.4 Drugs without Clinically Significant Interactions with DESCOVY

Based on drug interaction studies conducted with the components of DESCOVY, no clinically significant drug interactions have been either observed or are expected when DESCOVY is combined with the following antiretroviral agents: atazanavir with ritonavir or cobicistat, darunavir with ritonavir or cobicistat, dolutegravir, efavirenz, ledipasvir, lopinavir/ritonavir, maraviroc, nevirapine, raltegravir, rilpivirine, and sofosbuvir. No clinically significant drug interactions have been either observed or are expected when DESCOVY is combined with the following drugs: buprenorphine, itraconazole, ketoconazole, lorazepam, methadone, midazolam, naloxone, norbuprenorphine, norgestimate/ethinyl estradiol, and sertraline.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DESCOVY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

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Risk Summary

There are insufficient human data on the use of DESCOVY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) use in women during pregnancy has not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the risk of overall major birth defects for FTC (2.4%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15−20%. In animal studies, no adverse developmental effects were observed when the components of DESCOVY were administered separately during the period of organogenesis at exposures 60 and 108 times (mice and rabbits, respectively) the FTC exposure and at exposure equal to or 53 times (rats and rabbits, respectively) the TAF exposure at the recommended daily dose of DESCOVY [see Data (8.1)]. Likewise, no adverse developmental effects were seen when FTC was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily dose of DESCOVY. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of DESCOVY.

Data

Human Data

Emtricitabine: Based on prospective reports to the APR through July 2015 of 2933 exposures to FTC-containing regimens during pregnancy (including 1984 exposed in the first trimester and 949 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.7% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.3% to 3.2%) with the second/third trimester exposure to FTC-containing regimens.

Animal Data

Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (area under the curve [AUC]) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended daily dose.

Tenofovir Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of DESCOVY. TAF is rapidly converted to tenofovir; the observed tenofovir exposures in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposures in humans at the recommended daily dose of DESCOVY.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.

FTC has been shown to be present in human breast milk; it is not known if TAF is present in human breast milk [see Data (8.2)]. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF [see Data (8.2)] . It is not known if TAF can be present in animal milk. While it is not known whether TAF is present in human breast milk, FTC has been shown to be present in human breast milk [see Data (8.2)].

It is not known if DESCOVY affects milk production or has effects on the breastfed child. Because of the potential for: 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving DESCOVY [see Data (8.2)].

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Data

Human Data

Emtricitabine: Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is present in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.

Animal Data

Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11 [see Data (8.1)]. Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure.

8.4 Pediatric Use

The efficacy and safety of DESCOVY, in combination with other antiretroviral agents, for the treatment of HIV-1 infection was established in pediatric patents aged 12 years old and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)]. Use of DESCOVY in this age group is supported by adequate and well controlled studies of FTC+TAF with EVG+COBI in adults and by a 24-week open- label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 35 kg) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI was similar to that of antiretroviral treatment-naïve HIV-1 infected adults on this regimen [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Safety and effectiveness of DESCOVY in pediatric patients less than 12 years of age or less than 35 kg have not been established.

8.5 Geriatric Use

In clinical trials, 80 of the 97 subjects enrolled aged 65 years and over received FTC+TAF and EVG+COBI. No differences in safety or efficacy have been observed between elderly subjects and those between 12 and less than 65 years of age.

8.6 Renal Impairment

DESCOVY is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute). No dosage adjustment of DESCOVY is 83

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute [see Dosage and Administration (2.3) and Clinical Studies (14)].

8.7 Hepatic Impairment

No dosage adjustment of DESCOVY is recommended in patients with mild (Child- Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. DESCOVY has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

No data are available on overdose of DESCOVY in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with DESCOVY consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Emtricitabine (FTC): Limited clinical experience is available at doses higher than the recommended dose of FTC in DESCOVY. In one clinical pharmacology study, single doses of FTC 1200 mg (6 times the FTC dose in DESCOVY) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.

Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.

Tenofovir alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dose of TAF. A single dose of 125 mg TAF (5 times the TAF dose in 200/25 mg DESCOVY) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

11 DESCRIPTION

DESCOVY (emtricitabine and tenofovir alafenamide) is a fixed dose combination tablet containing emtricitabine (FTC) and tenofovir alafenamide (TAF) for oral administration.

 FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse  transcriptase inhibitor (HIV NRTI).   TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. 

Each 200/25 mg tablet contains 200 mg of FTC and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets 84

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 are film-coated with a coating material containing indigo carmine aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl- 1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. FTC is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.

FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24 and has the following structural formula:

FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1- methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2- butenedioate (2:1).

Tenofovir alafenamide fumarate has an empirical formula of C21H29O5N6P•½(C4H4O4) and a formula weight of 534.50 and has the following structural formula:

Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

DESCOVY is a fixed dose combination of antiretroviral drugs emtricitabine (FTC) and tenofovir alafenamide (TAF) [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose or at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval. The effect of the other component of DESCOVY, FTC, or the combination of FTC and TAF on the QT interval is not known.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic (PK) properties of the components of DESCOVY are provided in Table 2. The multiple dose PK parameters of FTC and TAF and its metabolite tenofovir are provided in Table 3.

Table 2 Pharmacokinetic Properties of the Components of DESCOVY

Emtricitabine Tenofovir Alafenamide

Absorption T (h) 3 1 max

Effect of high fat meal (relative AUC Ratio = 0.91 (0.89, 0.93) AUC Ratio = 1.75 (1.64, 1.88) to fasting)a C Ratio = 0.74 (0.69, 0.78) C Ratio= 0.85 (0.75, 0.95) max max

Distribution

% Bound to human plasma <4 ~80

proteins

Source of protein binding data In vitro Ex vivo Blood-to-plasma ratio 0.6 1.0

Metabolism Metabolism Cathepsin Ab (PBMCs)

Not significantly metabolized CES1 (hepatocytes) CYP3A (minimal)

Elimination Major route of elimination Glomerular filtration and active

Metabolism (>80% of oral dose)

tubular secretion

t (h)c 1/2 10 0.51 d

% Of dose excreted in urine 70 <1 d % Of dose excreted in feces 13.7 31.7 PBMCs=peripheral blood mononuclear cells; CES1=carboxylesterase 1 a. Values refer to geometric mean ratio [High-fat meal/ fasting] in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~800 kcal, 50% fat. 86

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b.In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected. c. t1/2 values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150-180 hours within PBMCs. d. Dosing in mass balance studies: FTC (single dose administration of [14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14C] tenofovir alafenamide).

Table 3 Multiple Dose PK Parameters of Emtricitabine, Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration with Food in HIV-Infected Adults Parameter

Mean (CV%) Emtricitabinea Tenofovir Alafenamideb Tenofovirc

Cmax

2.1 (20.2) 0.16 (51.1) 0.02 (26.1)

(microgram per mL)

AUC tau (microgram•hour 11.7 (16.6) 0.21 (71.8) 0.29 (27.4)

per mL)

Ctrough

0.10 (46.7) NA 0.01 (28.5)

(microgram per mL)

CV=Coefficient of Variation; NA=Not Applicable a. From Intensive PK analysis in a phase 2 trial in HIV infected adults treated with FTC+TAF and EVG+COBI. b. From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with FTC+TAF with EVG+COBI (N=539). c. From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with FTC+TAF with EVG+COBI (N=841).

Specific Populations

Patients with Renal Impairment

The pharmacokinetics of FTC+TAF combined with EVG+COBI in HIV infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft- Gault method) were evaluated in a subset of virologically-suppressed subjects in an open-label trial (Table 4).

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Table 4 Pharmacokinetics of the Components of DESCOVY and a Metabolite

of TAF (Tenofovir) in HIV-Infected Adults with Renal Impairment

Compared to Subjects with Normal Renal Functiona

AUC (microgram·hour per mL) tau Mean (CV%)

≥90 mL per minute 60–89 mL per 30–59 mL per

(N=18)b minute (N=11)c Creatinine Clearance minute (N=18)

Emtricitabine 11.4 (11.9) 17.6 (18.2) 23.0 (23.6)

Tenofovir Alafenamide* 0.23 (47.2) 0.24 (45.6) 0.26 (58.8)

Tenofovir 0.32 (14.9) 0.46 (31.5) 0.61 (28.4)

*AUClast a. Trial in HIV infected adults with renal impairment treated with FTC+TAF with EVG+COBI. b. From a phase 2 trial in HIV-infected adults with normal renal function treated with FTC+TAF with EVG+COBI. c. These subjects had an eGFR ranging from 60 to 69 mL per minute.

Patients with Hepatic Impairment

Emtricitabine: The pharmacokinetics of FTC has not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.

Tenofovir Alafenamide: Clinically relevant changes in tenofovir pharmacokinetics in subjects with hepatic impairment were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment [see Use in Specific Populations (8.7)].

Hepatitis B and/or Hepatitis C Virus Coinfection

The pharmacokinetics of FTC and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.

Pediatric Patients

Exposures of FTC and TAF in 24 pediatric subjects aged 12 to less than 18 years who received FTC+TAF and EVG+COBI were decreased (23% for AUC) compared to exposures achieved in treatment-naïve adults following administration of this dosage regimen [see Use in Specific Populations (8.4)]. These exposure differences are not thought to be clinically significant based on exposure-response relationships.

Geriatric Patients

Pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of FTC+TAF and 88

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EVG+COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age [see Use in Specific Populations (8.5)]. Race

Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on race.

Gender

Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on gender.

Drug Interaction Studies

The effects of coadministered drugs on the exposure of TAF are shown in Table 5 and the effects of DESCOVY or its components on the exposure of coadministered drugs are shown in Table 6 [these studies were conducted with DESCOVY or the components of DESCOVY (FTC or TAF) administered alone]. For information regarding clinical recommendations, see Drug Interactions (7).

Table 5 Drug Interactions: Changes in TAF Pharmacokinetic Parameters a in the Presence of Coadministered Drug(s) Tenofovir Mean Ratio of TAF PK Parameters Coadministered

(90% CI); Coadministered Drug(s) Dosage Alafenamide

Dosage N Drug (once daily) No effect = 1.00 (once daily)

(mg)

(mg) Cmax AUC Cmin

1.77 1.91

Atazanavir 300 (+100 ritonavir) 10 10 (1.28, 2.44) (1.55, 2.35) NC

2.83 2.65

Cobicistat 150 8 12 (2.20, 3.65) (2.29, 3.07) NC

800 (+150 b 0.93 0.98

cobicistat) (0.72, 1.21) (0.80, 1.19) Darunavir 25 11 NC

1.42 1.06

Darunavir 800 (+100 ritonavir) 10 10 (0.96, 2.09) (0.84, 1.35) NC

1.24 1.19

Dolutegravir 50 10 10 NC (0.88, 1.74) (0.96, 1.48)

0.78 0.86

Efavirenz 600 40b 11 (0.58, 1.05) (0.72, 1.02) NC

2.19 1.47

Lopinavir 800 (+200 ritonavir) 10 10 (1.72, 2.79) (1.17, 1.85) NC

1.01 1.01

Rilpivirine 25 25 17 (0.84, 1.22) (0.94, 1.09) NC

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50 (dosed as a 1.00 0.96 c

Sertraline single dose) 10 19 (0.86, 1.16) (0.89, 1.03) NC

NC=Not Calculated a. All interaction studies conducted in healthy volunteers. b. Study conducted with DESCOVY (FTC/TAF). c. Study conducted with FTC+TAF with EVG+COBI.

Table 6 Drug Interactions: Changes in PK Parameters for Coadministered Drug in the Presence of DESCOVY or the Individual a Components Tenofovir Mean Ratio of Coadministered Coadministered

Drug PK Parameters (90% CI); Coadministered Drug Dosage Alafenamide

Dosage N Drug (once daily) No effect = 1.00 (once daily)

(mg)

(mg) Cmax AUC Cmin

0.98 0.99 1.00

Atazanavir 300 +100 ritonavir 10 10 (0.89, 1.07) (0.96, 1.01) (0.96, 1.04)

1.06 1.09 1.11

Cobicistat 150 8 14 (1.00, 1.12) (1.03, 1.15) (0.98, 1.25)

1.02 0.99 0.97

Darunavir 800 +150 cobicistat 25b 11 (0.96, 1.09) (0.92, 1.07) (0.82, 1.15)

0.99 1.01 1.13

Darunavir 800 +100 ritonavir 10 10 (0.91, 1.08) (0.96, 1.06) (0.95, 1.34)

1.15 1.02 1.05

Dolutegravir 50 mg 10 10 (1.04, 1.27) (0.97, 1.08) (0.97, 1.13)

1.00 1.00 0.98

Lopinavir 800 +200 ritonavir 10 10 (0.95, 1.06) (0.92, 1.09) (0.85, 1.12)

1.02 1.12

2.5 (orally) NC

25 18 (0.92, 1.13) (1.03, 1.22)

c Midazolam

0.99 1.08

1 (intravenous) NC

(0.89, 1.11) (1.04, 1.14)

0.93 1.01 1.13

Rilpivirine 25 25 16 (0.87, 0.99) (0.96, 1.06) (1.04, 1.23)

50 (dosed as a d 1.14 0.93

single dose) (0.94, 1.38) (0.77, 1.13) Sertraline 10 19 NC

NC=Not Calculated a. All interaction studies conducted in healthy volunteers. b. Study conducted with DESCOVY (FTC/TAF). c. A sensitive CYP3A4 substrate. d. Study conducted with FTC+TAF with EVG+COBI.

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12.4 12.5 Microbiology

Mechanism of Action

Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'- triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.

Tenofovir Alafenamide: TAF is a phosphonoamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.

Tenofovir has activity against HIV-1. Cell culture studies have shown that both tenofovir and FTC can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

Antiviral Activity in Cell Culture

Emtricitabine: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI- CCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for FTC were in the range of 0.0013–0.64 micromolar. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 micromolar).

In a study of FTC with a broad panel of representatives from the major classes of approved anti-HIV agents (NRTIs, non-nucleoside reverse

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transcriptase inhibitors [NNRTIs], integrase strand transfer inhibitors [INSTIs], and PIs) no antagonism was observed for these combinations.

Tenofovir Alafenamide: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4-T lymphocytes. The EC50 values for TAF ranged from 2.0 to 14.7 nM.

TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).

In a study of TAF with a broad panel of representatives from the major classes of approved anti-HIV agents (NRTIs, NNRTIs, INSTIs, and PIs) no antagonism was observed for these combinations.

Resistance

In Cell Culture

Emtricitabine: HIV-1 isolates with reduced susceptibility to FTC were selected in cell culture and in subjects treated with FTC. Reduced susceptibility to FTC was associated with M184V or I substitutions in HIV-1 RT.

Tenofovir Alafenamide: HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was observed.

In Clinical Trials

The resistance profile of DESCOVY in combination with other antiretroviral agents for the treatment of HIV-1 infection is based on studies of FTC+TAF with EVG+COBI in the treatment of HIV-1 infection. In a pooled analysis of antiretroviral-naïve subjects, genotyping was performed on plasma HIV-1 isolates from all subjects with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure, at Week 48, or at time of early study drug discontinuation. Genotypic resistance developed in 7 of 14 evaluable subjects. The resistance-associated substitutions that emerged were M184V/I (N=7) and K65R (N=1). Three subjects had virus with emergent R, H, or E at the polymorphic Q207 residue in reverse transcriptase.

One subject was identified with emergent resistance to FTC or TAF (M184M/I) out of 4 virologic failure subjects in a clinical study of virologically-suppressed subjects who switched from a regimen containing FTC+TDF to FTC+TAF with EVG+COBI (N=799).

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Cross-Resistance

Emtricitabine: FTC-resistant viruses with the M184V or I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine-thymidine analog substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N substitution or other substitutions associated with resistance to NNRTIs was susceptible to FTC.

Tenofovir Alafenamide: Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir.

HIV-1 with multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R, showed reduced susceptibility to TAF in cell culture.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Emtricitabine

In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the recommended dose of 200 mg per day in DESCOVY) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose in DESCOVY).

FTC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dosage in DESCOVY. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dosage in DESCOVY.

Tenofovir Alafenamide

Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of the daily recommended dose of DESCOVY. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (DESCOVY) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.

TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.

There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 62 times (25 mg TAF) the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.

13.2 Animal Toxicology and/or Pharmacology

Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three and nine month administration of TAF; reversibility was seen after a three month recovery period. No eye toxicity was observed in the dog at systemic exposures of 5 (TAF) and 15 (tenofovir) times the exposure seen in humans with the recommended daily TAF dose in DESCOVY.

14 CLINICAL STUDIES

In trials of FTC+TAF with EVG+COBI in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (N=866) and to replace a stable antiretroviral regimen in those who were virologically-suppressed for at least 6 months with no known resistance substitutions (N=799), 92% and 96% of patients in the two populations, respectively, had HIV-1 RNA less than 50 copies per mL at Week 48.

In a trial of FTC+TAF with EVG+COBI in 23 treatment-naïve HIV-1 infected pediatric patients aged 12 to less than 18 years old and weighing greater than 35 kg, the virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 91% at 24 weeks.

In a trial in 248 HIV-1 infected adult patients with estimated creatinine clearance greater than 30 mL per minute but less than 70 mL per minute, 95% (235/248) of

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 the combined population of treatment-naïve subjects (N=6) began on FTC+TAF with EVG+COBI and those previously virologically-suppressed on other regimens (N=242) and switched to FTC+TAF with EVG+COBI had HIV-1 RNA less than 50 copies per mL at Week 24.

16 HOW SUPPLIED/STORAGE AND HANDLING

DESCOVY 200 mg/25 mg tablets are blue, rectangular-shaped, and film-coated with “GSI” debossed on one side and “225” on the other side. Each bottle contains 30 tablets (NDC 61958-2002-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.

Store below 30 °C (86 °F).

 Keep container tightly closed.   Dispense only in original container. 

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Lactic Acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to DESCOVY. Advise patients that they should stop DESCOVY if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.1)].

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of DESCOVY [see

Warnings and Precautions (5.2)]. Advise the patient to not discontinue DESCOVY without first informing their healthcare provider.

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and 95

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Precautions (5.3)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.4)].

New Onset or Worsening Renal Impairment

Advise patients to avoid taking DESCOVY with concurrent or recent use of nephrotoxic agents. Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs [see Warnings and Precautions (5.5)].

Decrease in Bone Mineral Density

Advise patients that decreases in bone mineral density have been observed with the use of DESCOVY. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.6)].

Missed Dosage

Inform patients that it is important to take DESCOVY on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance [see Dosage and Administration (2.2)].

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to DESCOVY [see Use in Specific Populations (8.1)].

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

DESCOVY is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Patient Information ® DESCOVY (emtricitabine and tenofovir alafenamide) tablets Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with DESCOVY. For more information, see the section “What should I tell my healthcare provider before taking DESCOVY?”

Read this Patient Information before you start taking DESCOVY and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about DESCOVY? DESCOVY can cause serious side effects, including:

1. Build-up of lactic acid in your blood (lactic acidosis). Lactic acidosis may happen in some people who take DESCOVY or similar medicines (nucleoside analogs). Lactic acidosis is a serious medical emergency that can lead to death.

Lactic acidosis can be hard to identify early, because the symptoms could seem like symptoms of other health problems. Call your healthcare provider right away if you get any of the following symptoms which could be signs of lactic acidosis:

 feel very weak or tired  feel cold, especially in your arms and legs  have unusual (not normal) muscle pain  feel dizzy or lightheaded  have trouble breathing  have a fast or irregular heartbeat

 have stomach pain with nausea or vomiting   2. Severe liver problems. Severe liver problems may happen in people who take DESCOVY. In some cases, these liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis).

Call your healthcare provider right away if you get any of the following symptoms of liver problems:  nausea   your skin or the white part of your eyes   turns yellow (jaundice)   pain, aching, or tenderness on the right  dark “tea-colored” urine  side of your stomach area   light-colored bowel movements (stools)   loss of appetite 

You may be more likely to get lactic acidosis or severe liver problems if you are female, very overweight (obese), or have been taking DESCOVY or a similar medicine containing a nucleoside analog for a long time. 3. Worsening of Hepatitis B virus infection. DESCOVY is not for use to treat chronic hepatitis B virus (HBV) infection. If you have hepatitis B virus (HBV) infection and take DESCOVY, your HBV may get worse (flare-up) if you stop taking DESCOVY. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.

 Do not run out of DESCOVY. Refill your prescription or talk to your healthcare provider  before your DESCOVY is all gone.   Do not stop taking DESCOVY without first talking to your healthcare provider.    If you stop taking DESCOVY, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking it. 97

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016



Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

For more information about side effects, see the section “What are the possible side effects of DESCOVY?” What is DESCOVY? DESCOVY is a prescription medicine that is used together with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in people 12 years of age and older. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

DESCOVY is not for use to help reduce the risk of getting HIV-1 infection by sexual contact in adults at high risk. DESCOVY contains the prescription medicines emtricitabine (EMTRIVA®) and tenofovir alafenamide. It is not known if DESCOVY is safe and effective in children under 12 years of age or who weigh less than 77 lb. DESCOVY when used together with other HIV-1 medicines to treat HIV-1 infection may help:  Reduce the amount of HIV-1 in your blood. This is called “viral load”.    Increase the number of CD4+ (T) cells in your blood that help fight off other infections. 

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

DESCOVY does not cure HIV-1 infections or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses. Avoid doing things that can spread HIV-1 infection to others.  Do not share or re-use needles or other injection equipment.    Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.    Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. 

Ask your healthcare provider any questions about how to prevent passing HIV-1 to other people. What should I tell my healthcare provider before taking DESCOVY? Before taking DESCOVY, tell your healthcare provider if you:  have liver problems, including hepatitis B virus infection   have kidney problems   have bone problems   have any other medical conditions    are pregnant or plan to become pregnant. It is not known if DESCOVY can harm your unborn baby. Tell your healthcare provider if you become pregnant while taking DESCOVY.   Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and  your baby. Talk with your healthcare provider about how you can take part in this registry.   are breastfeeding or plan to breastfeed. Do not breastfeed if you take DESCOVY.    You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.    At least one of the medicines in DESCOVY can pass to your baby in your breast milk. It is not known if the other medicine in DESCOVY can pass into your breast milk.  Talk with your healthcare provider about the best way to feed your baby.

Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

Tell your healthcare provider about all the medicines you take, including prescription and over- the-counter medicines, vitamins, and herbal supplements. Some medicines may interact with DESCOVY. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

 You can ask your healthcare provider or pharmacist for a list of medicines that interact with DESCOVY.    Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take DESCOVY with other medicines.  How should I take DESCOVY?

 Take DESCOVY exactly as your healthcare provider tells you to take it. DESCOVY must be  taken together with other HIV-1 medicines to treat HIV-1 infection.   Take DESCOVY 1 time each day with or without food.    Do not change your dose or stop taking DESCOVY without first talking with your healthcare  provider. Stay under a healthcare provider’s care when taking DESCOVY.   Do not miss a dose of DESCOVY.    If you take too much DESCOVY, call your healthcare provider or go to the nearest hospital emergency room right away.    When your DESCOVY supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to DESCOVY and become harder to treat.  What are the possible side effects of DESCOVY? DESCOVY may cause serious side effects, including:  See “What is the most important information I should know about DESCOVY?”    Changes in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known.    Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.    New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and while you are taking DESCOVY. Your healthcare provider may tell you to stop taking DESCOVY if you develop new or worse kidney problems.    Bone problems can happen in some people who take DESCOVY. Bone problems may include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones.  The most common side effect of DESCOVY is nausea. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of DESCOVY. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088. 100

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Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016

How should I store DESCOVY?  Store DESCOVY below 86 °F (30 °C).   Keep DESCOVY in its original container.   Keep the container tightly closed. 

Keep DESCOVY and all medicines out of reach of children. General information about the safe and effective use of DESCOVY. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DESCOVY for a condition for which it was not prescribed. Do not give DESCOVY to other people, even if they have the same symptoms you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DESCOVY that is written for health professionals. For more information, call 1-800-445-3235 or go to www.DESCOVY.com. What are the ingredients in DESCOVY? Active ingredients: emtricitabine and tenofovir alafenamide. Inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing indigo carmine aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 DESCOVY is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2016 Gilead Sciences, Inc. All rights reserved. 208215-GS-000

This Patient Information has been approved by the U.S. Food and Drug Administration Issued 04/2016

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