Application for Inclusion of Fixed Dose, Three-Drug Combination Odefsey

Application for inclusion of fixed dose, three-drug combination Odefsey® (emtricitabine/rilpivirine/tenofovir alafenamide) tablets on the WHO Model List of Essential Medicines

Submitted by

Gilead Sciences Inc.

December 2016

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

Gilead Submission Reference number: GSI-ODF-161201

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

Contents

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

2. Name of the focal point in WHO submitting or supporting the application ...... 6

3. Name of the organization(s) consulted and/or supporting the application ...... 6

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

5. Formulation proposed for inclusion ...... 7

6. International availability ...... 8

7. Listing type requested ...... 10

8. Information supporting the public health relevance ...... 10

8.1 Epidemiological information on disease burden ...... 10

9. Treatment details ...... 15

9.1 Indications and usage ...... 15

9.2 Dosage and administration ...... 15

9.2.1 Special populations ...... 16

9.3 Reference to existing WHO and other clinical guidelines ...... 16

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 Odefsey® ...... 21

10.2.1 Background studies on RPV-containing regimens ...... 22

10.2.2 Background studies on FTC/TAF-containing regimens ...... 29

10.2.3 Bioequivalence study GU-US-366-1159 ...... 35

10.2.5 Phase 3 switching study from FTC/TDF containing regimens to Odefsey® – GU-US-1216 and GU-US-1160 ...... 37

10.3 Summary of the efficacy of Odefsey® ...... 41 2

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

10.4 Summary of the resistance profile of Odefsey® ...... 42

10.5 Summary of available estimates of comparative effectiveness...... 44

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

11.1 Estimate of total patient exposure to Odefsey® ...... 45

11.3 Renal safety profile ...... 47

11.4 Bone safety profile ...... 55

11.4.1 Studies on FTC/TAF-containing regimens ...... 56

11.5 Lipid safety profile ...... 62

11.6 Drug–drug interactions ...... 62

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacologic class or therapeutic group ...... 65

12.1 Range of costs of the proposed medicine ...... 65

12.1.1 USA and Europe ...... 65

12.1.2 Developing countries ...... 66

13. Summary of regulatory status of the medicine ...... 66

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) ...... 66

14.1 Specifications of Odefsey® (FTC/RPV/TAF) tablets ...... 66

15.1 Other antivirals ...... 67

16. References ...... 69

Appendix 1. Access Prescribing Information for Odefsey ...... 78

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

1. Summary statement of the proposal for inclusion

The fixed dose, once-daily, single-tablet regimen Odefsey® (emtricitabine/rilpivirine/tenofovir alafenamide; FTC/RPV/TAF) is proposed for inclusion in the WHO Model List of Essential Medicines as a complete treatment for HIV-1 infected individuals aged 12 years and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA ≤100,000 copies/mL. It is also indicated as a replacement for a stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months and have no history of treatment failure and no known substitutions associated with resistance to the individual components of Odefsey®. 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 the treatment of HIV infection and is backed by more than 13 million patient-years of experience [Gupta et al, 2016] 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, 2015]. Despite excellent efficacy and global availability, efavirenz (EFV) is associated with neuropsychiatric side effects which can affect life-long compliance [Shubber et al, 2013], as well as a 2-fold increased hazard of suicidality compared with a regimen without EFV [Mollan et al, 2014]. Concerns have also been raised about its safety in early pregnancy, with some guidelines suggesting it should only be used after the first 8 weeks of gestation [Andany & Walmsley, 2016] Rilpivirine (RPV), included in the fixed dose, once-daily single-tablet regimen, Complera® (FTC/RPV/TDF), is considered is considered to have a well-established safety profile and is better tolerated non-nucleoside reverse transcriptase inhibitor (NNRTI) to efavirenz [Nelson et al, 2013; Behrens et al, 2014]. Studies have shown that in patients with low viral load (HIV-1 RNA ≤100,000 copies/mL), Complera® is better tolerated than Atripla®, which translates into greater effectiveness [Nelson et al, 2013]. With a use-in-pregnancy FDA category B2 rating [Complera US PI, December 2016], Complera® may be preferred over EFV-based regimens for use in treatment-naive pregnant women 4

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

 TDF-based therapy is generally well tolerated. However, 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] as well as adverse effects on bone mineral density (BMD) that increases the risk of fragility fractures and for which people with HIV are vulnerable [Grant & Cotter, 2016]  Earlier initiation of antiretroviral therapy (ART) together with longer duration of therapy and an ageing HIV population demands antiretroviral drugs with improved safety and tolerability profiles for life-long administration  Life-long adherence to ART is also critical to preventing the emergence of antiretroviral drug resistance  In older HIV patients, some antiretroviral drugs have side effects that overlap the complications associated with ageing  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, 2016a]  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 vs. 300 mg per day, respectively). This translates into smaller pills and easier co-formulation with other antiretroviral drugs including rilpivirine  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®), and now in combination with FTC and rilpivirine

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

(Odefsey®), 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 not only as efficacious as those containing TDF but also had an improved side-effect profile with respect to kidney function and bone health  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  Odefsey® (FTC/RPV/TAF) has the potential to offer the same tolerability benefits as Complera® (FTC/RPV/TDF) in its target population but with an enhanced renal and bone safety profile. This has the potential to extend treatment to people living with HIV in whom TDF (and by extension Complera®) is contraindicated because of underlying renal or bone disease. As the smallest commercially available single-tablet regimen, Odefsey® (FTC/RPV/TAF) has advantages over other regimens for HIV-infected individuals for whom pill size is a concern.

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

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

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

Odefsey® is a single-tablet regimen that contains a fixed dose combination of emtricitabine (FTC), rilpivirine (RPV) and tenofovir alafenamide (TAF).

Emtricitabine (FTC, Emtriva®) INN: Emtricitabine

Rilpivirine (RPV, Edurant®) INN: Rilpivirine hydrochloride

Tenofovir alfenamide (TAF) Modified INN: Tenofovir alafenamide

5. Formulation proposed for inclusion

Each tablet of Odefsey® contains 200 mg of emtricitabine, rilpivirine hydrochloride equivalent to 25 mg of rilpivirine and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide. The tablets are grey, capsule-shaped, film-coated, debossed with “GSI” on one side and with “225” on the other side [Odefsey® SmPC, 2016].

The qualitive composition of Odefsey® tablets is as described in Table 1 [Odefsey® SmPC, 2016].

Table 1: Qualitative composition of Odefsey® tablets [Odefsey® SmPC, 2016] Tablet core Croscarmellose sodium Lactose (as monohydrate) Magnesium stearate Microcrystalline cellulose Polysorbate 20 7

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

Povidone Film coating Macrogol Polyethylene glycol Titanium dioxide (E171) Talc Iron oxide black (E172)

6. International availability

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

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

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 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 8

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

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 Odefsey® tablets

Manufacturing Site Function(s) Patheon, Inc. Manufacturing, packaging,labeling,release 2100 Syntex Court 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 Millmount Healthcare Ltd. Packaging and labeling (secondary only) Block-7 City North Business Campus County Meath Ireland

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

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 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 Fixed Dose Combinations.

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,

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 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 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].

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

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, 2013]. 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, 2016a]. Eastern and southern Africa continues to bear the greatest burden with respect to mother-to-child transmission [UNAIDS, 2016a].

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, 2016a]. 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.

Published data from the ongoing PROMISE study, a randomized clinical of maternal ART to prevent in utero and intrapartum transmission of HIV in low- to medium-income countries, showed that triple maternal ART regimens as advocated by the WHO were more effective in preventing transmission than zidovudine alone albeit at higher risk of pre-term delivery and low birth weight [Fowler et al, 2016]. The findings reinforce the need for safe and effective regimens given the large number of pregnant women who need ART in sub-Saharan Africa [Barnhart & Shelton, 2015].

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

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 sub-Saharan Africa [UNODC, 2016]. 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 achieve 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

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 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 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 Department of Health and Human Services (DHHS) and the International Antiviral Society USA (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 modelling 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, there are two main target populations for Odefsey® in HIV-1 infected adults and pediatric patients aged 12 years and older as follows:

 Treatment-naïve individuals with HIV-1 RNA ≤100,000 copies/mL  Virologically suppressed HIV-1 infected individuals (HIV-1 RNA <50 copies/mL) on stable ART

Although published data on the percentage of ARV-naïve subjects with HIV <100,000 copies/mL in resource-limited countries are sparse, demographic data from the Phase 4 Prospective Evaluation of Antiretroviral in Resource Limited Settings (PEARLS) trial provides some measure of relative frequency. Of the 1571 HIV-infected persons enrolled in the trial, 47% of whom were female, 721 patients had a baseline viral load <100,000 14

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 copies/mL and 850 with ≥100, 000 copies/mL [Campbell et al, 2012]; thus, approaching half of the study population had low viral loads. The vast majority of patients in PEARLS lived in low- to middle-income countries that included Brazil, Haiti, India, Malawi, Peru, South Africa, Thailand and Zimbabwe. This suggests that Odefsey® may be suitable for a significant proportion of the HIV-positive population in resource-limited settings.

Other HIV-infected individuals with pre-treatment viral loads of ≤100,000 copies/mL who may also preferentially benefit from treatment with Odefsey® include:  People currently taking Complera® or Atripla® who would benefit from switching to TAF for improved safety and tolerability  Women in the very early stages of pregnancy for whom EFV may constitute a risk and peri- and postmenopausal women at increased risk of osteoporosis  People for whom a TDF-containing regimen is contraindicated

9. Treatment details

9.1 Indications and usage

Odefsey® is indicated for the treatment of adults and adolescents (aged 12 years and older with body weight at least at least 35 kg) infected with HIV-1 without known mutations associated with resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, tenofovir or emtricitabine and with a viral load ≤100,000 HIV-1 RNA copies/mL [Odefsey® SmPC, 2016; Odefsey® USPI, 2016].

Additionally, in the USA it is indicated to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA <50 copies/mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Odefsey® [Odefsey® USPI, 2016].

9.2 Dosage and administration

One tablet taken orally once daily with food in adults and pediatric patients 12 years of age and older with body weight at least 35 kg and creatinine clearance ≥30 mL/min [Odefsey® USPI, 2016; Odefsey® SmPC, 2016]. 15

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

9.2.1 Special populations

Geriatric use: Clinical studies on TAF included 97 subjects aged 65 years and older, of whom 80 received TAF-based regimens. No differences in safety or efficacy were observed between elderly subjects and those aged between 12 and <65 years [Odefsey® USPI, 2016]. No dose adjustment is therefore required in elderly patients [Odefsey® SmPC, 2016].

Renal impairment: Odefsey® is not recommended for use in patients with severe renal impairment (estimated creatinine clearance <30 mL/min) [Odefsey® USPI, 2016].

Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of Odefsey® in patients with severe hepatic impairment (Child-Pugh Class C) [Odefsey® USPI, 2016]. Therefore, Odefsey® is not recommended for use in patients with severe hepatic impairment.

Odefsey® is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of Odefsey®. Hepatic function should therefore be monitored closely in these patients [Odefsey® USPI, 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, Odefsey® provides an NRTI backbone of FTC and tenofovir (as

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

TAF) as preferred first-line therapy (Table 3) but includes the second-generation NNRTI, RPV, in place of first-generation EFV.

Table 3. Current recommendations of the WHO Consolidated Guidelines on use of ART for treating HIV infection [WHO, 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, the WHO recommend a fixed dose combination of EFV/FTC (or 3TC)/TDF in a single pill as preferred first-line regimen for pregnant and 17

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 breastfeeding women [WHO, 2016]. However, mindful that EFV carries a potential risk of teratogenicity in early pregnancy and has in the past been contraindicated in pregnancy, alternatives to EFV may be appropriate. With a use-in-pregnancy category B rating, RPV may be a suitable alternative to EFV in women of child-bearing potential [Sharma & Saravolatz, 2013].

Following regulatory approval of FTC/TAF-containing regimens in North America and Europe, they have been rapidly incorporated into treatment guidelines. The US DHHS has released updated versions of their antiretroviral treatment (ART) 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 (Table 4). These were the first guidelines to recommend a TAF-containing regimen and have been strongly endorsed by the International Antiviral Society-USA (IAS-USA) in its evidence-based review of ARVs [Günthard et al, 2016]. Because of its restricted use to HIV-infected individuals with a pre-treatment viral load of <100,000 copies/mL, Odefsey® is listed in the DHHS guidelines as an alternative rather than a preferred treatment option (Table 4).

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

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

a 3TC may be substituted for FTC, or vice versa, if a non-fixed dose NRTI combination is desired. b The evidence supporting this regimen is based on relative bioavailability data coupled with data from randomized, controlled switch trials demonstrating the safety and efficacy of TAF-containing regimens. 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

In its 2016 interim updated guidelines, the British HIV Association (BHIVA) 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 anyone of the following: atazanavir/r, darunavir/r, dolutegravir, elvitegravir/c, raltegravir or rilpivirine. The 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 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].

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 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] rilpivirine. In addition, review articles that included information on TAF were identified and the reference lists of these examined for any further articles of relevance. The search yielded a number of publications that were selected for a comparative assessment of the efficacy of Odefsey®. They included the pivotal bioequivalence (pharmacokinetic comparability) study between components of Odefsey® (FTC/RPV/TAF) and the reference products for each component, namely RPV (Edurant®) and FTC/TAF as Genvoya® (elvitegravir, cobicistat/FTC/TAF) [Zack et al, 2016a]. This study, together with a supportive food effect study, underpinned US FDA approval of Odefsey® [Tauber, 2016]. These studies are supported by data from two ongoing switch studies, in which virologically suppressed HIV-infected adults were switched from either Complera® (FTC/RPV/TDF) or Atripla® (EVF/FTC/TDF) to Odefsey® (FTC/RPV/TAF) [Orkin et al, 2016].

A large body of clinical data from studies of the antiviral components of the fixed dose, single-tablet regimen provide primary evidence in support of the safety, efficacy and tolerability of Odefsey® in HIV-infected adults and adolescents. Specifically, they include four trials, including the registration studies for Complera® (FTC/RPV/TDF), that

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 evaluated RPV-containing regimens and five on FTC/TAF-containing regimens as Genvoya® (elvitegravir, cobicistat/FTC/TAF) (Table 5).

Table 5. Summary of key studies on the individual antiviral components of Odefsey® in individuals with HIV-1 infection [Odefsey Formulary Monograph, 2016]

10.2 Summary of available data on comparative effectiveness of Odefsey®

Evidence for the effectiveness of Odefsey® in adults and adolescents with HIV infection is primarily supported by data from clinical studies on the individual antiviral components of the fixed dose, single-tablet regimen, as illustrated in Table 5, together with data from a formal bioequivalence study. This study established pharmacokinetic comparability between Odefsey® and its references, RPV (Edurant®) and FTC/TAF as Genvoya® (elvitegravir, cobicistat/FTC/TAF). Data from two ongoing switching studies are also presented, the purpose of which was to demonstrate that patients could be switched from a successful TDF-based regimen to one containing TAF without loss of efficacy [Orkin et al, 2016].

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10.2.1 Background studies on RPV-containing regimens

ECHO and THRIVE – a pooled analysis These were both Phase 3, double-blind, randomized, active-controlled trials in over 1,300 treatment-naïve, HIV-infected adults, of whom 550 were randomized to treatment with RPV + FTC/TDF and 546 to treatment with EFV + FTC/TDF for up to 96 weeks [Cohen et al, 2013; Molina et al, 2011; Nelson et al, 2013]. Overall, the two groups in the FTC/TDF treatment arms were well-balanced with respect to demographic and baseline disease characteristics (Table 6) [Nelson et al, 2013].

Table 6. Demographic and baseline characteristics of subjects in the TDF/FTC arms of ECHO and THRIVE (pooled data)

The primary objective in each Phase 3 trial was to establish noninferiority of RPV versus EFV for the primary efficacy parameter of HIV-1 RNA <50 copies/mL at Weeks 48 and 96, with a maximum allowable difference of 12% (non-inferiority margin). Results showed that in the overall study population, an RPV-based regimen met the primary endpoint at Weeks 48 and 96 (Figure 1). Virologic failure (HIV-1 RNA ≥50 copies/mL) with an RPV-based regimen was higher in adults with a baseline viral load >100,000 copies/mL and CD4+ cell count below 200 cells/µL [Complera USPI, 2016].

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Figure 1. Virologic response in the ECHO and THRIVE trials at Weeks 48 and 96 (pooled analysis)

Overall, the results of the pooled analysis show that a RPV-containing regimen (RPV + FTC/TDF) was non-inferior to EFV plus FTC/TDF in HIV-infected patients with viral loads up to and including HIV-RNA 100,000 copies/mL, although a greater number of virologic failures occurred in the RPV arm at higher viral loads.

PAINT – Pediatric Study in Adolescents Investigating a New NNRTI (RPV)

This open-label, single arm, Phase 2 trial was designed to investigate the efficacy and safety of a once-daily 25-mg dose of RPV in combination with two nucleoside reverse transcriptase inhibitors (zidovudine, abacavir or TDF with either lamivudine or FTC) in treatment-naïve HIV-infected adolescents aged 12 to <18 years who weighed ≥32 kg and had a baseline viral load ≤100,000 copies/mL (Figure 2) [Crauwels et al, 2014].

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

Figure 2. Design of the PAINT study in treatment-naïve HIV-infected adolescents [Crauwels et al, 2014]

In the initial dose-finding phase of the study, a single oral dose of RPV 25 mg gave similar exposures in adolescents to that seen in adults in the ECHO and THRIVE trials (Figure 3).

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Figure 3. Mean (SD) plasma concentration-time curves of RPV 25 QD in adolescents in the PAINT study and adults in the ECHO and THRIVE pharmacokinetic substudy [Crauwels et al, 2014]

This international study enrolled a total of 36 HIV-infected adolescents in India (n=3), Thailand (n=1), Uganda (n=11), South Africa (n=20) and the USA (n=1) (Table 7).

Table 7. Demographic and baseline characteristics of subjects in the PAINT study who were evaluated for efficacy [Lombard et al, 2015]

Characteristic Total number of patients

N=36

Female, n (%) 20 (56)

Median age, years (range) 14.5 (12–17)

≥12 to ≤15 years, n (%) 18 (50)

Median weight, kg (range) 45 (33–93)

Race, n (%)

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Asian 4 (11)

Black or African-American 32 (89)

Median log BL VL, copies/mL (range) 4.757 (3.31–5.83) 10

BL VL ≤100,000 copies/mL, n (%) 28 (78)

BL VL >100,000 copies/mL, n (%) 8 (22)*

Mode of HIV infection, n (%)

Mother-to-child transmission 30 (83)

Heterosexual contact 4 (11)

Other or unknown 2 (6)

Median duration of infection, years 1.30 (0.0–11.2) (range)

Results of the efficacy analysis showed that overall 75% of individuals responded to the RPV-containing regimen at Week 24, while the response was 86% in those with a baseline viral load of ≤100,000 copies/mL compared with 38% of those with a baseline viral load >100,000 copies/mL (Figure 4). Seven patients experienced virologic failure, of whom four had a baseline viral load >100,000 copies/mL [Lombard et al, 2015]. Virologic suppression was maintained to Week 48, with 72% of all patients responding and 79% (22/28) and 50% (4/8) of those with baseline viral loads of ≤100,000 copies/mL and >100,000 copies/mL, respectively [Lombard et al, 2016]. At the same time, median CD4+ cell count increased by 184 cells/mm3 (range -135 to 740 cells/mm3).

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Figure 4. Rates of virologic suppression (HIV-RNA <50 copies/mL) at Week 24 in treatment-naïve HIV-infected adolescents in the PAINT study [Lombard et al, 2015]

Overall, the results of this study demonstrate comparability of exposure for a once-daily oral dose of RPV 25mg between HIV-infected adolescents and adults, which translates into high response rates in treatment-naïve adolescents, especially in those with baseline viral loads of ≤100,000 copies/mL.

SPIRIT – Switching boosted PI to Rilpivirine in combination with Truvada as an STR

This was a randomized, open-label Phase 3b study of 48 weeks’ duration designed to demonstrate the non-inferiority of switching virologically suppressed patients (HIV-RNA <50 copies/mL) from a ritonavir-boosted protease inhibitor and two NRTIs (PI/r + 2 NRTI) to RPV + FTC/TDF in order to simplify treatment. Patients on PI/r + 2 NRTI as a first or second regimen (stable for more than 6 months) and with no prior NNRTI use were eligible for inclusion. Patients were randomized (2:1) to either switch immediately

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 to RPV + FTC/TDF (n=317) or remain on the PI regimen for 24 weeks (n=159), and then to switch to Complera® (Figure 5).

Figure 5. Design of the Phase 3b SPIRIT clinical study

The primary endpoint was non-inferiority (12% margin) of RPV + FTC/TDF to the PI- containing regimen in relation to maintenance of virologic suppression (HIV-RNA < 50 copies/mL) at 24 weeks, while secondary endpoints were maintenance of virologic suppression at 48 weeks as well as safety and tolerability [Palella et al, 2014].

Results showed that at Week 24, switching to RPV + FTC/TDF was non-inferior to remaining on a PI-based regimen in terms of maintaining virologic suppression (93.7% vs. 89.9%; 95% CI -2.0% to 8.9%), with virologic failure rates lower in patients immediately switching to RPV + FTC/TDF (1.0%) compared with those remaining on the PI-based regimen (5.0%) [Fisher et al, 2012]. Patients immediately switching to RPV + FTC/TDF continued to experience sustained virologic suppression through 48 weeks, with the rate of virologic failure remaining low at 3.0% [Palella et al, 2014].

Overall, these results showed that switching patients from a ritonavir-boosted regimen to RPV + FTC/TDF allowed maintenance of virologic suppression with an accompanying low risk of virologic failure.

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Figure 6. Maintenance of virologic suppression in HIV-1 infected adults switching to a RPV-containing regimen from a PI-based regimen

10.2.2 Background studies on FTC/TAF-containing regimens

Phase 3 registration studies of Genvoya® (elvitegravir/cobicistat/FTC/TAF) in treatment- naïve subjects – GS-US-292-0104 and GS-US-292-0111

These were identical, randomized, double-blind, multicenter, active-controlled Phase 3 trials (Figure 7), one of which was carried out at 134 sites in North America, Europe, Australia, Japan, and Thailand (GS-US-292-0104) and the other at 128 sites in North America, Europe, and Latin America (GS-US-292-0111). The demographic and disease characteristics at baseline were generally representative of an adult HIV-1 infected treatment-naïve population and similar between treatment arms (Table 8) [Sax et al, 2015].

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Figure 7. Design of studies GS-US-292-0104 and GS-US-292-0111 in which subjects were randomized to either Genvoya® (elvitegravir, cobicistat/FTC/TAF) or Stribild® (elvitegravir, cobicistat/FTC/TDF)

Table 8. Demographic and baseline characteristics of subjects in studies GS- US-292-0104 and GS-US-292-0111 (pooled analysis)

The proportion of subjects with a viral load <50 copies/mL (non-inferiority margin of 12%) at Week 48 was the primary efficacy endpoint in both trials. Results showed that treatment with Genvoya® (elvitegravir/cobicistat/FTC/TAF) was non-inferior to Stribild® (elvitegravir/cobicistat/FTC/TDF) at Week 48, with viral suppression (<50 copies/mL) achieved in 92% and 90% of patients, respectively (Figure 8). Using a viral load assay with a lower limit of quantification (<20 copies/mL), 84% of subjects in each regimen

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 had an undetectable viral load [Sax et al, 2015]. At Week 48, only 4% of patients experienced virologic failure in the two treatment arms.

Figure 8. Rates of virologic suppression (HIV-RNA <50 copies/mL) at Week 48 in treatment-naïve HIV-infected adults in studies GS-US-292-0104 and GS-US-292-0111 (pooled analysis)

Phase 3 studies of Genvoya® (elvitegravir/cobicistat/FTC/TAF) and Stribild® (elvitegravir, cobicistat/FTC/TDF) in treatment-naïve adolescents – GS-US-292-0106 and GS-US-236- 0112 These were both open-label, single-arm studies in which 100 treatment-naïve adolescents, aged ≥12 to <18 years and weighing at least 35 kg, received 48 weeks’ 31

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 treatment with either Genvoya® (elvitegravir/cobicistat/FTC/TAF) or Stribild® (elvitegravir/cobicistat/FTC/TDF) [Kizito et al, 2015]. To be eligible, subjects were also required to have a baseline viral load of >1000 copies/mL and CD4 count of >100 cells/mm3.

There were differences between the two study populations with respect to gender, geography and mode of HIV transmission (Table 9).

Table 9. Baseline demographics and disease characteristics in patients enrolled in studies GS-US-292-0106 and GS-US-236-0112

Treatment regimens

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

N=50 N=50

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

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

Country of Uganda 30 (60) 0 origin

South Africa 3 (6) 22 (44)

Thailand 6 (12) 14 (28)

USA 11 (22) 14 (28)

Viral load Mean (SD) 4.62 (0.59) 4.60 (0.55) 0.98 HIV-1 RNA log10 copies/mL

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

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

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<200 cells/µL, 4 (8) 2 (4) n (%)

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

Heterosexual 12 (24) 12 (24) sex

Homosexual 8 (16) 19 (38) sex

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 Week 24, 90% (45/50) of subjects treated with Genvoya® (elvitegravir/cobicistat/FTC/TAF) had responded to treatment compared with 88% (44/50) of those on Stribild® (elvitegravir/cobicistat/FTC/TDF). Most virologic failures were associated with decreased adherence to ART [Kizito et al, 2015].

Figure 9. Virologic response and post-treatment changes in CD4 cell count over 24 weeks in studies GS-US-292-0106 and GS-US-236-0112

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Overall the results of this cross-study comparison suggest that a TAF-containing regimen is as effective as a comparable TDF-containing regimen in treatment-naïve adolescents infected with HIV.

Phase 3 switching study from FTC/TDF to FTC/TAF in renal impairment – GS-US-292- 0112 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, in which renally-impaired HIV- infected individuals on stable combination ART were switched to once-daily Genvoya® (elvitegravir/cobicistat/FTC/TAF) (Figure 10) [Pozniak et al, 2016].

Figure 10. Design of study GS-US-292-0112

This study had an older HIV-infected population, many of whom had comorbidities known to affect renal function. Most subjects (65%) were on TDF-based regimens before switching to Genvoya® (elvitegravir/cobicistat/FTC/TAF).

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Table 10. Baseline demographics and disease characteristics in patients enrolled in study GS-US-292-0112

Virologic suppression (HIV-1 RNA <50 copies/mL) was the main efficacy endpoint. Results showed that at Week 48 following switching, 92% of patients maintained 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].

Overall the results of this study show that HIV-infected adults with mild-to-moderate renal impairment can be successfully switched to a TAF-containing regimen from a previous ART regimen without loss of efficacy.

10.2.3 Bioequivalence study GU-US-366-1159

This study, which formed the basis of the regulatory approval of Odefsey® in the US and Europe, was designed to evaluate the bioequivalence of fixed dose, single tablet 35

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Odefsey® (FTC/RPV/TAF) at dosages of 200mg/25mg/25mg to Genvoya (elvitegravir, cobicistat/FTC/TAF) at dosages of 150 mg/150 mg/200 mg and 10 mg for the FTC/TAF components and to Edurant® (RPV 25 mg) for the RPV 25mg component of the FDC taken concurrently under fed conditions [Zack et al, 2016]. The differences in TAF dosage of 10 mg in Genvoya® compared to 25 mg in FTC/RPV/TAF are explained by the presence of cobicistat in Genvoya®, a pharmacoenhancer that has been shown to achieve comparable TAF exposures when combined with TAF 10 mg to those observed when TAF 25 mg is given alone [Zack et al, 2016a].

The Phase 1 randomized, single-dose, open-label study, carried out in 96 healthy male and female subjects, used a 3-way, 6-sequence, crossover design in which subjects were randomized to 1 of 6 treatment sequences (ABC [1], ACB [2], BAC [3], BCA [4], CAB [5], and CBA [6]) as described in Table 11.

Table 11. Sequence of treatment in the Odefsey® bioequivalence study

Results showed that FTC and TAF administered as Odefsey® (RPV/FTC/TAF 25/200/25 mg) met the primary endpoints of the study and demonstrated bioequivalence to Genvoya® (elvitegravir, cobicistat/FTC/TAF 150/150/200/10 mg) under fed conditions (moderate fat). RPV administered as Odefsey® (RPV/FTC/TAF) also demonstrated bioequivalence to RPV 25 mg (Edurant®) tablet under fed conditions. The 90% CIs for the geometric least-squares mean (GLSM) ratios of the primary PK parameters AUClast,

AUCinf, and Cmax for test versus reference treatments were within the protocol-specified bioequivalence boundary of 80% to 125% for FTC, RPV, and TAF. FTC and TAF administered as Odefsey® (RPV/FTC/TAF) and Genvoya® (elvitegravir, cobicistat/FTC/TAF) had similar median Tmax and t1/2 values. Rilpivirine administered as

® ® Odefsey (RPV/FTC/TAF) and RPV (Edurant ) tablet also had similar median Tmax and 36

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

t1/2 values. Table 12 shows the statistical analyses of FTC, RPV, and TAF pharmacokinetic parameters between test (Odefsey®) and reference treatments.

Table 12. Statistical comparisons of FTC, RPV and TAK pharmacokinetic parameters for test versus reference treatments

Overall the results of this registration study show that the FTC, RPV and TAF exposures of Odefsey® (RPV/FTC/TAF) are bioequivalent to the FTC/TAF exposures of Genvoya® and Edurant® and support its clinical effectiveness in HIV-1 infected individuals.

10.2.5 Phase 3 switching study from FTC/TDF containing regimens to Odefsey® – GU-US-1216 and GU-US-1160

These are both ongoing Phase 3b randomized, double-blind, multicenter studies of 96- weeks duration, in which virologically suppressed adults (HIV-1 RNA levels <50 copies/mL) on a stable regimen of either Complera® (FTC/RPV/TDF) or Atripla® (EFV/FTC/TDF) either continue baseline treatment or are switched to treatment with Odefsey® (RPV/FTC/TAF) (Figure 11) [Orkin et al, 2016]. The primary objective of each study is to evaluate the efficacy of switching from Complera® or Atripla® to Odefsey® at Week 48 as defined by the FDA snapshot algorithm. Secondary objectives are to evaluate bone safety by the percent change from baseline in hip and spine BMD at Week 48 and Week 96, and overall safety and tolerability through to Week 96.

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Figure 11. Design of Odefsey® (RPV/FTC/TAF) switching studies GU-US-1216 and GU-US-1160

More than 1500 adults with HIV-1 infection participated in the two trials, the vast majority of whom were men and of Caucasian ethnicity (Table 13) [Orkin et al, 2016].

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

Table 13. Demographics and baseline characteristics of HIV-infected adults enrolled in switching studies GU-US-1216 and GU-US-1160

Both studies showed that Odefsey® (RPV/FTC/TAF) maintained similar rates of virologic suppression as the initial TDF-based regimens based on the proportion of patients with HIV-1 RNA below 50 copies/mL. At Week 48, virologic suppression was maintained in 94% of subjects taking Odefsey® compared with 94% of those who on remained on Complera® (FTC/RPV/TDF) in study 1216. The corresponding rates for Odefsey® in study 1160 were 90% versus 92% for the subjects who continued with Atripla® (EFV/FTC/TDF) (Figures 12 and 13) [Orkin et al, 2016].

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Figure 12. Rates of virologic suppression at Week 48 following the switch from Complera® to Odefsey® in study 1216 [Orkin et al, 2016]

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

Figure 13. Rates of virologic suppression at Week 48 following the switch from Atripla® to Odefsey® in study 1160 [Orkin et al, 2016]

Overall Week-48 data from these trials show that virologically suppressed HIV-infected individuals can be switched from a TDF-containing regimen to Odefsey® (RPV/FTC/TAF) without loss of efficacy.

10.3 Summary of the efficacy of Odefsey® After Atripla®, Complera® was only the second single tablet regimen to be approved for treatment of HIV infection. In Odefsey®, the TDF component of Complera® has been replaced by TAF with potential for even greater safety and tolerability but without impacting efficacy. The efficacy of Odefsey® has been directly demonstrated in two switching studies that followed an earlier bioequivalence study, in which pharmacokinetic comparability was demonstrated between Odefsey® and its references, RPV and FTC/TAF as Genvoya® (elvitegravir, cobicistat/FTC/TAF). In addition to these specific studies, the efficacy of the individual components of Odefsey® have been extensively studied in clinical trials 41

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 and from their use in real-world settings. There is therefore a substantial body of clinical data to support the efficacy of Odefsey® in both treatment-naïve adults and adolescents with HIV-1 infection as well as those virologically suppressed on TDF-containing regimens and who wish to switch to a TAF-based regimen.

10.4 Summary of the resistance profile of Odefsey® 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 resistance profile of Odefsey® (RPV/FTC/TAF) is based largely on studies of its individual components. From the available in vitro data and the data generated in treatment-naïve patients, the following resistance-associated mutations in HIV-1 RT, when present at baseline, may affect the activity of Odefsey®: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L and the combination of L100I and K103N. A negative impact by NNRTI mutations other than those listed above, such as mutations K103N or L100I as single mutations, cannot be excluded as this was not studied in vivo in a sufficient number of patients [Odefsey® USPI, 2016].

In treatment-naïve adults

With respect to the FTC/TAF component of Odefsey® (RPV/FTC/TAF), the resistance profile of Odefsey® is based on studies of Genvoya® (elvitegravir, cobicistat/FTC/TAF) in the treatment of HIV-1 infection [Odefsey® SmPC, 2016]. In the Week 96 pooled analysis of patients receiving Genvoya® (elvitegravir, cobicistat/FTC/TAF) in the Phase 3 studies (GS-US-292-0104 and GS-US-292-0111), the development of one or more primary resistance-associated mutations was observed in HIV-1 isolates from 10 of 866 (1.2%) patients treated with Genvoya®. Among these 10 HIV-1 isolates, the mutations that emerged were M184V/I (n=9) and K65R/N (n=2) in RT and T66T/A/I/V (n=2), E92Q (n=4), Q148Q/R (n=1), and N155H (n=2) in integrase [Odefsey® SmPC, 2016].

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

With respect to the RPV component of Odefsey® (RPV/FTC/TAF), the resistance profile of Odefsey® was based on a pooled analysis at Week 96 of adults receiving RPV or EFV in combination with FTC/TDF in the pivotal ECHO and THRIVE trials Odefsey® SmPC, 2016]. HIV-1 isolates from 43 patients had an amino acid substitution associated with NNRTI (n=39) or NRTI (n=41) resistance. The NNRTI resistance-associated mutations that developed most commonly were: V90I, K101E, E138K/Q, V179I, Y181C, V189I, H221Y and F227C. The presence of V90I and V189I at baseline did not affect the response. Fifty-two percent of HIV-1 isolates with emergent resistance in the RPV arm developed concomitant NNRTI and NRTI mutations, most frequently E138K and M184V. The mutations associated with NRTI resistance that developed in three or more patient isolates were: K65R, K70E, M184V/I and K219E. Through Week 96, fewer patients in the RPV arm with baseline viral load ≤100,000 copies/mL had emerging resistance- associated substitutions and/or phenotypic resistance to RPV (7/288) than patients with baseline viral load >100,000 copies/mL (30/262) [Odefsey® SmPC, 2016].

In virologically suppressed patients

One patient with emergent resistance (M184M/I) was identified in a clinical study of virologically suppressed patients who switched from a regimen containing FTC/TDF to Genvoya® (elvitegravir, cobicistat/FTC/TAF) in a fixed dose combination tablet (GS-US- 292-0109, n=959) [Odefsey® SmPC, 2016].

In switching study, GS-US-264-0106, of the 469 patients treated with Complera® (FTC/RPV/TDF) (317 patients who switched at baseline and 152 patients who switched at Week 24), HIV-1 isolates from 4 of these patients had developed resistance by Week 48 (total of 4 of 469 patients, 0.9%). Of the 24-treated patients that had the NNRTI- associated K103N substitution pre-existing at baseline, 22 maintained virologic suppression after switching to Complera® (FTC/RPV/TDF). One patient with pre-existing K103N at baseline had virologic failure with additional emergent resistance by Week 48 [Odefsey® SmPC, 2016].

In switching study, GS-US-264-0111, no emergent resistance developed among patients that switched to Complera® (FTC/RPV/TDF) from Atripla® (EFV/FTC/TDF) (0 of 49 43

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 patients) at Week 48 [Odefsey® SmPC, 2016].

Cross-resistance

In patients receiving RPV in combination with FTC/TDF in Phase 3 studies, most HIV-1 isolates with emergent phenotypic resistance to RPV had cross-resistance to at least one other NNRTI (28/31). Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of RPV resistance [Odefsey Formulary Monograph, 2016; Odefsey® SmPC, 2016].

Tenofovir resistance substitutions K65R and also the K70E substitution result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine [Odefsey Formulary Monograph, 2016; Odefsey® SmPC, 2016].

10.5 Summary of available estimates of comparative effectiveness

Both TDF and TAF are prodrugs of tenofovir, possibly the most widely used antiretroviral drug in use today, especially when combined with FTC. With an improved pharmacokinetic profile, TAF has potential to provide equivalent efficacy to TDF- containing regimens 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 Genvoya® (elvitegravir, cobicistat/FTC/TAF) and Stribild® (elvitegravir, cobicistat/FTC/TDF) in treatment-naïve subjects. These large, identical, Phase 3 trials and powered to demonstrate non-inferiority have shown that a regimen containing FTC/TAF provides equivalent antiviral efficacy to one containing FTC/TDF. Together with data from the pivotal Phase 3 trials on Complera® (FTC/RPV/TDF), these studies collectively provide supportive evidence of the clinical efficacy of Odefsey® (RPV/FTC/TAF) in treatment-naïve subjects with HIV infection. RPV-based regimens are indicated for treatment-naïve HIV-1 patients with HIV-1 RNA ≤100,000 copies/mL and consistent with the data on Complera® (FTC/RPV/TDF) the same holds true for Odefsey® (RPV/FTC/TAF) [Odefsey® SmPC, 2016].

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

While no head-to-head comparisons have been conducted between Odefsey® (RPV/FTC/TAF) and Complera® (FTC/RPV/TDF) in treatment-naïve HIV-infected subjects, early data from the two switching studies suggest that virologically suppressed HIV-infected individuals can be switched from a TDF-containing regimen, including, Complera®, to Odefsey® (RPV/FTC/TAF) without any loss of efficacy [Orkin et al, 2016]. Thus, Odefsey® (RPV/FTC/TAF) can be expected to provide comparable efficacy to Complera® (FTC/RPV/TDF) in HIV-1 infected adults and adolescents.

11. Summary of comparative evidence on safety

11.1 Estimate of total patient exposure to Odefsey®

To date, relatively few adults with HIV infection (~1500) have been treated with Odefsey® (FTC/RPV/TAF) in either clinical trials or in real-life clinical settings but this is anticipated to change as TAF-containing fixed dose combinations gradually supersede TDF-based therapy in the coming years [Gupta et al, 2016]. It is worth noting that TDF- based therapy is supported by more than 13 million patient years of use [Gupta et al, 2016] and RPV by approximately 5 years of clinical experience [Zack et al, 2016].

11.2 Description of adverse effects/reactions

In addition to the Odefsey® (FTC/RPV/TAF) Phase 3 switching studies in virologically suppressed subjects, the safety and tolerability of Odefsey® has been derived largely from the same studies that were used to support efficacy determinations.

Among 866 treatment-naïve adult patients who received Genvoya® (elvitegravir, cobicistat/FTC/TAF) in the pivotal Phase 3 trials, diarrhea (17%), nausea (15%) and headache (14%) were the most frequently reported treatment-emergent adverse events (TEAEs) and occurred with similar frequency in the TDF-treatment arm [Sax et al, 2015]. TEAEs leading to treatment discontinuation were infrequent: 7 (0.8%) of subjects in the TAF-treatment arm stopped taking Genvoya® (elvitegravir, cobicistat/FTC/TAF) and 11 (1.3%) stopped taking Stribild® (elvitegravir, cobicistat/FTC/TDF) for TEAEs 45

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 attributed to study medication [Sax et al, 2015]. The nature and frequency of TEAEs seen in the trials enrolling treatment-naïve subjects were largely mirrored in those in virologically suppressed subjects switched to a TAF-containing regimen.

Likewise, RPV + FTC/TDF was well tolerated by adult subjects enrolled in the pivotal ECHO and THRIVE trials. Here the frequency of treatment-related grade 2–4 AEs was significantly higher in the EFV + FTC/TDF arm (33%) compared with the RPV + FTC/TDF arm (17%) (Table 14). These findings reflect in particular the differences between EFV and RPV with respect to adverse neuropsychiatric side effects and adverse skin reactions [Nelson et al, 2013; Behrens et al, 2014].

Table 14. Treatment-emergent adverse events occurring in ≥2% of subjects at Week 96 (pooled FTC/TDF subgroup of ECHO and THRIVE) [Nelson et al, 2013]

Studies in HIV-infected adolescents suggest that Odefsey® (FTC/RPV/TAF) will be equally well tolerated by younger patients with HIV infection as older subjects. In the PAINT study, somnolence, rash and nausea were the most common AEs considered

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 possibly related to RPV. Only one patient discontinued RPV-based therapy and this was for pulmonary tuberculosis [Lombard et al, 2015].

In the two Phase 3 switching studies in which virologically suppressed adults received Odefsey® (FTC/RPV/TAF), there was no difference between Odefsey® in the frequency of AEs following switching (Table 15). Rates of premature discontinuation were also comparable between treatment arms and didn’t exceed 2.5% in any treatment arm [Orkin et al, 2016].

Table 15. Frequency of AEs in Odefsey® (FTC/RPV/TAF) switching studies GU- US-1216 and GU-US-1160

Given that there is little overlap in the toxicities of FTC, RPV and TAF, no additional or exacerbated toxicities would be expected with the use of Odefsey® (FTC/RPV/TAF) as a fixed dose combination tablet. This has been borne out in the two switching studies.

11.3 Renal safety profile Because tenofovir and emtricitabine are principally excreted via the kidney, the renal 47

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 safety profile of TAF-containing regimens has been studied in detail and was a pre- specified safety outcome measure in many of the clinical trials in which TAF-containing regimens were evaluated.

Across the 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 Studies on FTC/TAF-containing regimens

Across the clinical trials that compared FTC/TAF-containing regimens with FTC/TDF- containing regimens, FTC/TAF backbones had appreciably less impact on renal laboratory parameters in treatment-naïve adults and adolescents as well as in virologically suppressed adults with impaired renal function who switched to a TAF- based regimen.

In Phase 3 registration studies GS-US-292-0104 and GS-US-292-0111, treatment with Genvoya® (elvitegravir, cobicistat/FTC/TAF) had significantly less impact on estimated glomerular filtration rate (eGFR) at Week 48 (Figure 14). Subjects receiving the TAF- containing regimen also 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 -3 versus 20; p<0.0001), retinol binding protein (median % change 9 versus 51, respectively; p,0.0001) and β-2 microglobulin (median % change -32 versus 24, respectively; p<0.0001) at Week 48 [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 al, 2016].

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

Figure 14. Changes in eGFR at Week 48 in studies GS-US-292-0104 and GS- US-292-0111 (pooled data)

In studies GS-US-292-0104 and GS-US-292-0111, the beneficial effects on kidney function with the TAF-containing regimen were sustained at Week 96, where again there were more favorable changes in proteinuria, albuminuria and tubular proteinuria than that seen with the TDF-containing regimen [Wohl et al, 2016]. 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 6 in the TDF-containing arm (p=0.03) [Wohl et al, 2016].

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, 2015]. 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 on TDF with increasing CKD risk, consistent with the emergence of a proximal renal tubulopathy, such as Fanconi Syndrome. Treatment discontinuations for adverse renal events as well

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

as changes in eGFRCG and quantitative proteinuria all favored TAF across CKD risk group [Wohl et al, 2015].

In the Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS-US- 236-0112 – 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 15) [Kizito et al, 2015]. No subjects developed proximal renal tubulopathy or Fanconi syndrome.

Figure 15. Changes in quantitative proteinuria at Week 24 in treatment-naïve adolescents (studies GS-US-292-0106 and GS-US-236-0112)

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

In contrast to the other trials, in which subjects had normal renal function, switching study GU-US-292-0112 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 a TAF-containing regimen. Over 48 weeks, eGFR remained stable in the patients switched to Genvoya® (elvitegravir, cobicistat/FTC/TAF) (Figure 16), while median urine protein-to-creatinine ratio (UPCR) decreased in those who switched to the FTC/TAF regimen (Figure 17).

Figure 16. Changes in eGFR from baseline to Week 48 in switching study GS- US-292-0112

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

Figure 17. Median UPCR at baseline and Week 48 in virologically suppressed adults with renal impairment (study GS-US-292-0112)

Over 96 weeks of this 144-week trial, treatment with Genvoya® (elvitegravir, cobicistat/FTC/TAF) was associated with stable eGFR, reductions in proteinuria and improvements in proximal renal tubular function. Of the 12 subjects (5%) who discontinued treatment with Genvoya® (elvitegravir, cobicistat/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 Genvoya® (elvitegravir, cobicistat/FTC/TAF) achieving stable GFR and significant reductions in total and tubular proteinuria [Post et al, 2016].

In the first two clinical trials on Odefsey® (FTC/RPV/TAF), and consistent with the findings from the other studies in which FTC/TAF was compared with FTC/TDF,

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 treatment with Odefsey® led to improvements in renal health in HIV infected subjects. Over the first 48 weeks following switching from either Complera® or Atripla®, patients in the Odefsey® (FTC/RPV/TAF) treatment arm experienced improvements in renal function that included significant improvements in total and tubular proteinuria (Figures 18–20).

Figure 18. Change in eGFR at Week 48 in Odefsey® (FTC/RPV/TAF) studies 1216 and 1160

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

Figure 19. Change in proteinuria at Week 48 in Odefsey® (FTC/RPV/TAF) studies 1216 and 1160

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

Figure 20. Change in tubular proteinuria at Week 48 in Odefsey® (FTC/RPV/TAF) studies 1216 and 1160

Overall the results of these studies provide robust evidence to show that the pharmacological properties of TAF translate into an improved renal side-effect profile when compared with TDF. As RPV does not require any dose adjustment in patients with mild or moderate renal dysfunction and as Complera ® (FTC/RPV/TDF) had no greater frequency of adverse renal events than Atripla® (EVF/RPV/TDF) [Behrens et al, 2014], Odefsey® (FTC/RPV/TAF) can be expected to have a particularly benign side-effect profile with respect to its effects on the kidneys of HIV-infected subjects.

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

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 adolescents was therefore a pre-specified safety outcome measure in the TAF-related clinical trials.

In the 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 Studies on FTC/TAF-containing regimens

In what is believed to be the largest dataset on BMD in people with HIV, treatment- naïve adults receiving the TAF-containing regimen in studies GS-US-292-0104 and GS- US-292-0111 had significantly smaller reductions in both lumbar spine and hip BMD at week 48 compared with those on the TDF-containing regimen (Figure 21) [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. 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, 2016].

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

Figure 21. Percentage change in spine and hip BMD at Week 48 in studies GS- US-292-0104 and GS-US-292-0111 (pooled data)

Fractures were uncommon in both treatment groups and none was attributed to study medications [Sax et al, 2015].

Among treatment-naïve adolescents with HIV-1 infection, those receiving a regimen containing TAF in study GU-US-292-0106 saw an increase in median spine BMD at Week 24 (+1.3%) compared with a mean decrease (-0.9%) in those on a TDF-containing regimen in study GU-US-236-0112 (Figure 22) [Kizito et al, 2015].

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

Figure 22. Percentage change in spine BMD in studies GS-US-292-0106 and GS-US-236-0112

These findings are supported by data from several Phase 3 switching studies that included GS-US-292-0109, a study in which virologically suppressed subjects stable on a TDF-containing regimen for at least 96 weeks were switched to a TAF-containing regimen [Mills et al, 2016]. Following the switch to a TAF-containing regimen, subjects saw significant improvements in both spine and hip BMD (Figure 23), together with greater recovery from osteopenia and osteoporosis. 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.

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

Figure 21. Percentage change in spine and hip BMD at Week 48 in study GS- US-292-0109

Similar results were reported in study GS-US-311-1089. Here, 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 [Gallant et al, 2016]. Fractures were again uncommon in both treatment groups and none was attributed to study medications [Gallant et al, 2016].

Among virologically suppressed HIV-infected older adults with mild-to-moderate renal impairment, improvements occurred in hip and spine BMD when patients were 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 (Figure 23) [Pozniak et al, 2016]. These improvements were sustained through 96-weeks treatment [Post et al, 2016].

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

Figure 23. Percentage change in spine and hip BMD at Weeks 24 and 48 in study GS-US-292-0112

In the first two clinical trials on Odefsey® (FTC/RPV/TAF), and consistent with the findings from the other studies in which FTC/TAF was compared with FTC/TDF, treatment with Odefsey® led to improvements in bone health in HIV infected subjects. Over the first 48 weeks following switching from either Complera® or Atripla®, patients in the Odefsey® (FTC/RPV/TAF) treatment arm experienced improvements in both hip and spine BMD (Figures 24 and 25).

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

Figure 24. Percentage change hip BMD at Week 48 in studies 1216 and 1160

Figure 25. Percentage change spine BMD at Week 48 in studies 1216 and 1160

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

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 results showed a significant reduction in levels of total, LDL, and non-HDL cholesterol. In comparative studies, some of which have been 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 Odefsey® are described in the current Odefsey® US Prescribing Information, the Summary of Product Characteristics (SmPC) and Formulary Monograph and listed in Table 16.

RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.

TAF is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3 and so drugs that strongly affect P-gp activity may lead to changes in TAF absorption. 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 Odefsey® and development of resistance. Co-administration of Odefsey® with other drugs that inhibit P-gp may increase the absorption and plasma concentration of TAF. 62

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

Table 16. Established and other potentially significant drug interactions with Odefsey [Odefsey USPI, 2016]

Based on drug interaction studies conducted with the fixed dose combination or components of Odefsey®, no clinically significant drug interactions have been either observed or expected when Odefsey® is combined with the following drugs: acetaminophen, atorvastatin, buprenorphine, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, lorazepam, metformin, midazolam, naloxone, norbuprenorphine, norethindrone, norgestimate/ethinyl estradiol, sildenafil, simeprevir and sofosbuvir [Odefsey Formulary Monograph, 2016].

11.7 Summary of comparative safety

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

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, including in combination with RPV as Complera®. 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 are prone to kidney disease (HIV-associated nephropathy) [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. Stribild® (elvitegravir, cobicistat/FTC/TDF) is not recommended for HIV infected individuals with creatinine clearance of <70 mL/min, while Complera® (FTC/RPV/TDF) is not recommended in patients with levels below 50mL/min [Complera USPI, 2016].

Switching studies in virologically suppressed subjects suggest that Odefsey® (FTC/RPV/TDF) is at least as well tolerated as Complera® (FTC/RPV/TDF) and Atripla® (EFV/FTC/TDF) 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 eGFR, less proteinuria and albuminuria across many studies [Ray et al, 2016].

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.

Switching studies in virologically suppressed subjects suggest that treatment with Odefsey® (FTC/RPV/TDF) has a significantly reduced impact on lumbar spine and hip BMD, with potential to confer long-term benefit.

After pill load and dosing frequency, adverse events are the third most important factor influencing adherence to ART [Stone et al, 2014]. 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. Switching studies with TAF- containing regimens that include the two studies with Odefsey® (FTC/RPV/TAF), suggest that Odefsey® will be just as well tolerated by people living with HIV, including younger 64

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 individuals, with the added benefit of an improved safety profile with respect to kidney and bone health. Potentially, it extends the use of 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].

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

12.1 Range of costs of the proposed medicine

12.1.1 USA and Europe

The US FDA approved Odefsey® (FTC/RPV/TAF) on 1st March 2016 as a fixed dose combination treatment for HIV-1 infection in adult and pediatric patients 12 years and older who have no antiretroviral treatment history and HIV-1 RNA levels less than or equal to 100,000 copies per mL. Odefsey® is also indicated as replacement for a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Odefsey®. Odefsey® (FTC/RPV/TAF) is also available in Europe following its approval by the EMA on 23rd June 2016, where it is indicated for treatment of HIV-1 infection in adult and pediatric patients 12 years and older who have no antiretroviral treatment history and HIV-1 RNA levels less than or equal to 100,000 copies per mL.

Table 12 details wholesale acquisition cost in the USA.

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

Table 12. Wholesale acquisition costs of Odefsey® tablets in the USA and Europe [Odefsey Formulary Monograph, 2016]

Dosage form and product Package size Wholesale acquisition strength cost Tablet containing: 30 tablets $2345.87 25 mg of rilpivirine 200 mg of emtricitabine 300 mg of tenofovir alafenamide

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. Gilead’s no-profit price for a 30-day supply of Odefsey® to in-country Access Program distribution partners is US$32. Odefsey® will be made available to Governments at this no-profit transfer price in addition to distribution and other related costs (these may vary from country to country).

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

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

14.1 Specifications of Odefsey® (FTC/RPV/TAF) tablets

None available.

Application for inclusion of Odefsey 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, 25 mg rilpivirine and 25 mg of tenofovir alafenamide Also known as Odefsey®

Uses: Odefsey® is licensed in the USA and Europe as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA ≤100,000 copies per mL. It is also licensed in the USA to replace a stable antiretroviral regimen in those who are virologically- suppressed (HIV-1 RNA <50 copies/mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Odefsey®.

Contraindications: Odefsey® is contraindicated when coadministered with drugs where significant decreases in RPV plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance.

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. Odefsey® is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Odefsey® 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 FTC and/or TDF, and may occur with discontinuation of Odefsey®. 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 Odefsey®. If appropriate,

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 initiation of anti-hepatitis B therapy may be warranted.

Dose: One tablet taken once daily with a meal in patients 12 years old and older with body weight at least 35 kg and a creatinine clearance ≤30 mL per minute.

Adverse effects: The most common adverse reactions to RPV (incidence ≥2%, Grades 2–4) are depressive disorders, insomnia, and headache) and the most common adverse reaction to FTC/TAF (incidence ≥10%, all grades) is nausea.

Please refer to the Prescribing Information appropriate to the Gilead Access Program contained in Appendix 1 for further details on Odefsey®.

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

16. References

Aguiar C, Antela A, Compston J, et al. Going beyond undetectable: a review of the unmet long-term health needs of people living with HIV. Key Opinions in Medicine 2015; 1:1-12.

Andany N, Walmsley S. What’s new for antiretroviral treatment in women with HIV. Journal of Virus Eradication 2016;2:67–77.

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.

Atta MG, Deray G, Lucas GM. Antiretroviral nephrotoxicities. Semin Nephrol 2008 Nov. 28(6):563-75.

Barnhart M, Shelton JD. ARVs: The next generation. Going boldly together to new frontiers of HIV treatment. Global Health: Science and Practice 2015;3:1–11.

Battalora LA, Young B, Overton ET. Bones, fractures, antiretroviral therapy and HIV. Curr Infect Dis Rep 2014;16(2):393.

Behrens G, Rijnders B, Nelson M, et al. Rilpivirine versus efavirenz with emtricitabine/tenofovir disproxil fumarate in treatment-naïve HIV-1-infected patients with HIV-1 RNA ≤100,000 copies/mL: Week 96 pooled ECHO/THRIVE subananalysis. AIDS Patient Care 2014;28:168–175.

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.

British HIV Association. British HIV Association guidelines for the treatment of HIV-1

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 positive adults with antiretroviral therapy (2016 interim update). BHIVA, August 2016.

Campbell TB, Smeaton LM, Kumarasamy N, et al. Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings. PLoS Med 2012;9(8):e1001290.doi:10.1371/journalpmed.1001290.

Cohen CJ, Molina JM, Cassetti I, et al; ECHO, THRIVE study groups. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS 2013;27(6):939-950.

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

Appendix 1. Access Prescribing Information for Odefsey

Application for inclusion of Odefsey 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

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs in combination with other antiretrovirals [see Warnings and Precautions (5.1)].

ODEFSEY is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of ODEFSEY 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 ODEFSEY.

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 ODEFSEY. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE ODEFSEY is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY [see Microbiology (12.4) and Clinical Studies (14)].

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

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation of ODEFSEY

Prior to initiation of ODEFSEY, 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 ODEFSEY therapy and should be monitored during therapy in all patients [see Warnings and Precautions (5.10)].

2.2 Recommended Dosage

ODEFSEY is a 3-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of ODEFSEY is one tablet taken orally once daily with a meal in the following patient population: adults and in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg and a creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3)].

2.3 Testing After Initiation of ODEFSEY In virologically-suppressed patients, additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound [see Clinical Studies (14)].

2.4 Not Recommended in Patients with Severe Renal Impairment

ODEFSEY is not recommended in patients with estimated creatinine clearance below 30 mL per minute [see Warnings and Precautions (5.10) and Use in Specific Populations (8.6)].

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

3 DOSAGE FORMS AND STRENGTHS Each ODEFSEY tablet contains 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV) (equivalent to 27.5 mg of rilpivirine hydrochloride), and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate).

The tablets are gray, capsule-shaped, film-coated and debossed with “GSI” on one side and “255” on the other side.

4 CONTRAINDICATIONS

ODEFSEY is contraindicated when coadministered with the following drugs, as significant decreases in RPV plasma concentrations may occur due to cytochrome P450 (CYP) 3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to ODEFSEY or to the class of NNRTIs [see Warnings and Precautions (5.4), Drug Interactions (7) and Clinical Pharmacology (12.3)]:

 the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin  the antimycobacterials rifampin and rifapentine  proton pump inhibitors, such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole  the glucocorticoid systemic dexamethasone (more than a single dose)  St. John’s wort (Hypericum perforatum)

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 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. Given that ODEFSEY contains two nucleos(t)ide analogs (i.e., FTC and TAF), ODEFSEY should be discontinued 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).

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 hepatitis B virus (HBV) before initiating antiretroviral therapy [see Dosage and Administration (2.1)]. ODEFSEY is not approved for the treatment of chronic HBV infection, and the safety and efficacy of ODEFSEY 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 TDF, and may occur with discontinuation of ODEFSEY. Patients coinfected with HIV-1 and HBV who discontinue ODEFSEY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of antihepatitis 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 Skin and Hypersensitivity Reactions

Severe skin and hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunction, including elevations in hepatic serum biochemistries. During Phase 3 clinical trials of RPV, treatment- related rashes with at least Grade 2 severity were reported in 1% of subjects. Overall, most

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.2)].

Discontinue ODEFSEY immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.

5.4 Loss of Virologic Response Due to Drug Interactions

The concomitant use of ODEFSEY and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of ODEFSEY and possible development of resistance due to reduced exposure of RPV.

See Table 1 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Contraindications (4) and Drug Interactions (7)]. Consider the potential for drug interactions prior to and during ODEFSEY therapy; review concomitant medications during ODEFSEY therapy; and monitor for the adverse reactions associated with the concomitant drugs.

5.5 Prolongation of QTc Interval with Higher Than Recommended Dosages

In healthy subjects, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily – 3 and 12 times the recommended dosages, respectively) have been shown to prolong the QTc interval of the electrocardiogram [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)]. Consider alternatives to ODEFSEY when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsades de Pointes.

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

5.6 Depressive Disorders

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with RPV. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to ODEFSEY, and to determine whether the risks of continued therapy outweigh the benefits.

In Phase 3 trials of RPV in adult subjects (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated subjects (n=686) was 9%. Most events were mild or moderate in severity. In RPV- treated subjects, the incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1%, the incidence of discontinuation due to depressive disorders was 1%, and suicidal ideation and suicide attempt was reported in 4 and 2 subjects, respectively.

During the Phase 2 trial in RPV-treated pediatric subjects 12 to less than 18 years of age (N=36), the incidence of depressive disorders (regardless of causality, severity) was 19% (7/36) through 48 weeks. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.

5.7 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C, or marked elevations in liver- associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of ODEFSEY. A few cases of hepatic toxicity have been reported in adult patients receiving a RPV-containing regimen who had no preexisting hepatic disease or other identifiable risk factors.

Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with ODEFSEY is recommended in patients with underlying hepatic disease such 84

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 as hepatitis B or C, or in patients with marked elevations in liver- associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without preexisting hepatic dysfunction or other risk factors.

5.8 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.

5.9 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC and RPV, both components of ODEFSEY. 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.

5.10 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 with EVG+COBI, 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,

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 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)]. ODEFSEY 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 nonsteroidal 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 ODEFSEY 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 ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.11 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 ODEFSEY who have a history of pathologic bone fracture or other risk factors for osteoporosis

Application for inclusion of Odefsey tablets in the WHO Model List of Essential Medicines, December 2016 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 (PRT), 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 who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [see Warnings and Precautions (5.10)]. While not observed in clinical studies of FTC+TAF with EVG+COBI, the risk of osteomalacia with ODEFSEY 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)]  Skin and Hypersensitivity Reactions [See Warnings and Precautions (5.3)]  Depressive Disorders [See Warnings and Precautions (5.6)]  Hepatotoxicity [See Warnings and Precautions (5.7)]  Immune Reconstitution Syndrome [See Warnings and Precautions (5.9)]  New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.10)]  Bone Loss and Mineralization Defects [see Warnings and Precautions (5.11)]

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.

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

Adverse Reactions in Clinical Trials of RPV-Containing Regimens in Adult Subjects with HIV-1 Infection

In pooled 96-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reactions in subjects treated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 2−4) were headache, depressive disorders, and insomnia. The proportion of subjects who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317).

Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Adult Subjects 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 event [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. Median urine protein- to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48. In a 48-week trial

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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 by −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 an open-label 48-week trial of 36 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 32 kg) treated with 25 mg per day of RPV and other antiretrovirals, the most common adverse reactions were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%),

abdominal pain (8%), vomiting (6%) and rash (6%). 89

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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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing experience in patients receiving RPV-containing regimens. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Metabolism and Nutrition Disorders Weight increased

Skin and Subcutaneous Tissue Disorders

Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

Renal and Urinary Disorders Nephrotic syndrome

7 DRUG INTERACTIONS

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

Drugs that Induce or Inhibit CYP3A Enzymes

RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV [see Contraindications (4) and Clinical Pharmacology (12.3)]. 90

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Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.

Drugs that Induce or Inhibit P-glycoprotein

TAF, a component of ODEFSEY, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity (e.g., cyclosporine) 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 ODEFSEY and development of resistance. Coadministration of ODEFSEY with other drugs that inhibit P-gp may result in increased absorption and plasma concentrations of TAF and possible adverse events.

Drugs that Increase Gastric pH

Coadministration of RPV with drugs that increase gastric pH (e.g., famotidine) may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs (see Table 1).

7.2 QT Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval. In a study of healthy subjects, higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in ODEFSEY) prolonged the QTc interval [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.2)]. Consider alternative medications to ODEFSEY in patients taking a drug with a known risk of Torsade de Pointes.

7.3 Drugs that Affect Renal Function

Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of ODEFSEY with drugs

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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 (5.10)].

7.4 Established and Other Potentially Significant Drug 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 ODEFSEY, the components of ODEFSEY (FTC, RPV and TAF) as individual agents, or are predicted drug interactions that may occur with ODEFSEY. For pharmacokinetic data, see Tables 5−8 [see Clinical Pharmacology (12.3)].

Table 1 Established and Other Potentially Significanta Drug Interactions

Concomitant Drug Class: Drug Effect on Concentrationb Clinical Comment Name Antacids:  RPV Administer antacids at least 2 hours (antacids taken at least 2 hours antacids before or at least 4 hours after before or at least 4 hours after RPV) (e.g., aluminum, ODEFSEY. magnesium  RPV (concomitant intake) hydroxide, or calcium carbonate) c Antimycobacteria  RPV Coadministration of ODEFSEY with ls:  TAF rifabutin is not recommended. rifabutin

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Azole Antifungal  RPVc,d No dosage adjustment is required when Agents:  TAF ODEFSEY is coadministered with azole c,d antifungal agents. Clinically monitor for fluconazole  ketoconazole itraconazole breakthrough fungal infections when ketoconazole azole antifungals are coadministered with posaconazole ODEFSEY. voriconazole c,d H2-Receptor  RPV Administer H2-receptor antagonists at Antagonists (famotidine taken 12 hours before least 12 hours before or at least 4 hours : RPV or 4 hours after RPV) after ODEFSEY. cimetidine  RPVc,d famotidine (famotidine taken 2 hours before nizatidine RPV) itidi

Concomitant Drug Class: Drug Effect on Concentrationb Clinical Comment Name Macrolide or  RPV Where possible, alternatives such as Ketolide  clarithromycin azithromycin should be considered. Antibiotics:  erythromycin clarithromycin erythromycin  telithromycin telithromycin Narcotic  R() methadonec No dosage adjustments are required Analgesics:  S(+) methadonec when initiating coadministration of methadone  RPVc methadone with ODEFSEY. However, clinical monitoring is recommended, as  methadonec (when used with methadone maintenance therapy may tenofovir) need to be adjusted in some patients. a This table is not all inclusive. b Increase=; Decrease=; No Effect= c The interaction was evaluated in a clinical study. All other drug interactions shown are predicted. d This interaction study has been performed with a dose higher than the recommended dose for RPV. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily.

7.5 Drugs Without Clinically Significant Interactions with ODEFSEY

Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been either observed or expected when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin,

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buprenorphine, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, lorazepam, metformin, midazolam, naloxone, norbuprenorphine, norethindrone, norgestimate/ethinyl estradiol, sildenafil, simeprevir and sofosbuvir.

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 ODEFSEY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258- 4263.

Risk Summary

There are insufficient human data on the use of ODEFSEY during pregnancy to inform a drug- associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) and rilpivirine (RPV) use in women during pregnancy have not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the Antiretroviral Pregnancy Registry. 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 US 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 ODEFSEY were administered separately during the period of organogenesis at exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and 70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dose of these components in ODEFSEY [see Data (8.1)]. Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in ODEFSEY. No adverse effects were observed in the offspring when TDF

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was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of ODEFSEY.

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 (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 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.

Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with RPV in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher 95

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than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with RPV, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.

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 similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of ODEFSEY. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. 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 ODEFSEY.

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 unknown if RPV and TAF are present in human breast milk. RPV is present in rat milk and 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 unknown if TAF is present in animal milk.

It is not known if ODEFSEY affects milk production or has effects on the breastfed infant. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral 96

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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 ODEFSEY.

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 ted 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

Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).

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 ODEFSEY as a complete regimen for the treatment of HIV-1 infection was established in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)]. Use of ODEFSEY in this age group is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults

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with HIV-1 infection, adequate and well-controlled studies of FTC+TAF with EVG+COBI in adults with HIV-1 infection, and by the following pediatric studies [see Clinical Studies (14)]:

• 48-week open-label trial of 36 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old weighing at least 32 kg treated with 25 mg per day of RPV and other antiretrovirals. The safety and efficacy of RPV and other antiretrovirals was similar to that of antiretroviral treatment-naïve HIV-1 infected adults on this regimen.

• 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.

Because it is a fixed-dose combination tablet, the dose of ODEFSEY cannot be adjusted for patients of lower age and weight. The safety and efficacy of ODEFSEY have not been established in pediatric patients less than 12 years of age or weighing less than 35 kg [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

In clinical trials, 80 of the 97 subjects enrolled aged 65 years and over received FTC+TAF with 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. Clinical trials of RPV did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

ODEFSEY is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute). No dosage adjustment of ODEFSEY is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14) ].

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8.7 Hepatic Impairment

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

10 OVERDOSAGE No data are available on overdose of ODEFSEY in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with ODEFSEY consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.

Emtricitabine (FTC): Limited clinical experience is available at doses higher than the recommended dosage of FTC in ODEFSEY. In one clinical pharmacology study, single doses of FTC 1200 mg (6 times the dose in ODEFSEY) 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.

Rilpivirine (RPV): Human experience of overdose with RPV is limited. There is no specific antidote for overdose with RPV. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV.

Administration of activated charcoal may be used to aid in removal of unabsorbed active substance.

Tenofovir Alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dosage of TAF in ODEFSEY. A single dose of 125 mg TAF (5 times the dose of

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TAF in ODEFSEY) 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

ODEFSEY (emtricitabine, rilpivirine, and tenofovir alafenamide) is a fixed-dose combination tablet containing emtricitabine (FTC), rilpivirine (RPV), and tenofovir alafenamide (TAF) for oral administration.

 FTC, a synthetic nucleoside analog of cytidine, is an HIV-1 nucleoside analog reverse transcriptase inhibitor (HIV-1 NRTI).  RPV is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI).  TAF, an HIV-1 NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

Each tablet contains 200 mg of FTC, 25 mg of RPV (equivalent to 27.5 of rilpivirine hydrochloride) and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, and povidone. The tablets are film-coated with a coating material containing iron oxide black, 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:

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

Rilpivirine: The chemical name of rilpivirine hydrochloride drug substance is 4-[[4-[[4- [(E)-2- cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6  HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

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:

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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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ODEFSEY is a fixed dose combination of antiretroviral drugs emtricitabine, rilpivirine, and tenofovir alafenamide [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

When higher than recommended RPV doses of 75 mg (3 times the recommended dosage in ODEFSEY) once daily and 300 mg (12 times the recommended dosage in ODEFSEY) once daily were studied in healthy adults, the maximum mean time- matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady- state administration of RPV 75 mg once

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daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6 times and 6.7 times, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.5)].

The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2 (5) milliseconds (i.e., below the threshold of clinical concern).

In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose and 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 FTC on the QT interval is not known.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of the components of ODEFSEY are provided in Table

2. The multiple dose pharmacokinetic parameters of FTC, RPV and TAF and its metabolite tenofovir are provided in Table 3.

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Table 2 Pharmacokinetic Properties of the Components of ODEFSEY

Tenofovir Rilpivirine Emtricitabine Alafenamide Absorption

Tmax (h) 4 3 1 Effect of moderate fat meal (relative AUC Ratio = 1.13 AUC Ratio = AUC Ratio = 1.45 to fasting)a (1.03, 1.23) 0.91 (0.89, 0.93) (1.33, 1.58) Effect of high fat meal (relative to AUC Ratio = 1.72 AUC Ratio = AUC Ratio = 1.53 fasting)a (1.49, 1.99) 0.88 (0.85, 0.90) (1.39, 1.69) Distribution % Bound to human plasma proteins ~99 <4 ~80 Source of protein binding data In vitro In vitro Ex vivo Blood-to-plasma ratio 0.7 0.6 1.0 Metabolism Cathepsin Ab (PBMCs) Not significantly Metabolism CYP3A CES1 (hepatocytes) metabolized CYP3A (minimal) Elimination Glomerular filtration and Metabolism (>80% of Major route of elimination Metabolism active oral dose) tubular c t1/2 (h) 50 10 0.51 % Of dose excreted in urined 6 70 <1 % Of dose excreted in fecesd 85 13.7 31.7 PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1. a Values refer to geometric mean ratio [fed/ fasted] in PK parameters and (90% confidence interval). High- calorie/high-fat meal = ~800 kcal, 50% fat. Moderate-fat meal = ~600 kcal, 27% fat. 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 o 14 fter multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14C] amide).

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Table 3 Multiple Dose Pharmacokinetic Parameters of Emtricitabine, Rilpivirine, Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration with a Meal in HIV- Infected Adults

Parameter a b Tenofovir d Mean (CV%) Emtricitabine Rilpivirine c Tenofovir Alafenamide

Cmax 2.1 (20.2) NA 0.16 (51.1) 0.02 (26.1) (microgram per mL)

AUCtau (microgram•hour per 11.7 (16.6) 2.2 (38.1) 0.21 (71.8) 0.29 (27.4) mL) C trough 0.10 (46.7) 0.08 (44.3) 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 with EVG+COBI (n=19). b From Population PK analysis in a trial of treatment-naïve adults with HIV-1 infection treated with RPV (n=679). c From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated within EVG+COBI+FTC+TAF (n=539). d From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with EVG+COBI+FTC+TAF (n=841).

Specific Populations

Patients with Renal Impairment

Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1 infected subjects with eGFR 60 to 89 mL per minute by Cockcroft-Gault method relative to HIV-1 infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end- stage renal disease [see Use in Specific Populations (8.6)].

Tenofovir Alafenamide: The pharmacokinetics of FTC+TAF with EVG+COBI in HIV-1 infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-

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Gault method) were evaluated within a subset of virologically-suppressed subjects in an open-label trial (Table 4).

Table 4 Pharmacokinetics of the FTC, TAF, and a Metabolite of TAF (Tenofovir) in HIV-Infected Adults with Renal Impairment as Compared to Subjects with Normal Renal Function

AUCtau (microgram-hour per mL) Mean (CV%) ≥90 mL per 60–89 mL per 30–59 mL per Creatinine Clearance minute minute (N=11)b minute (N=18) (N=18)a 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 From a phase 2 trial in HIV-infected adults with normal renal function treated with FTC+TAF with EVG+COBI. b These subjects had an eGFR ranging from 60 to 69 mL per minute.

Patients with Hepatic Impairment

Emtricitabine: The pharmacokinetics of FTC have 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.

Rilpivirine: In a study comparing 8 subjects with mild hepatic impairment (Child- Pugh score A) to 8 matched controls and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple-dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment [see Use in Specific Populations (8.7)].

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)].

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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. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure of RPV.

Pediatric Patients

Exposures of TAF in 24 pediatric subjects with HIV-1 infection aged 12 to less than 18 years who received FTC+TAF with EVG+COBI were decreased (23% for TAF AUC) compared to exposures achieved in treatment-naïve adults following administration of FTC+TAF with EVG+COBI. These exposure differences are not thought to be clinically significant based on exposure-response relationships.

FTC exposures were similar in adolescents compared to treatment-naïve adults. The PK of RPV in antiretroviral HIV-1-infected pediatric subjects 12 to less than 18 years of age who received RPV 25 mg once daily were comparable to those in HIV-1 infected adults. As in adults, there was no impact of body weight on RPV PK in pediatric subjects [see Use In Specific Populations (8.4)].

Geriatric Patients

The 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 with EVG+COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.

The pharmacokinetics of RPV have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5)].

Race

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

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Gender

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

Drug Interaction Studies

Rilpivirine: RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV.

RPV at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

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.

The drug interaction studies described in Tables 5-8 were conducted with ODEFSEY (FTC/RPV/TAF) or the components of ODEFSEY (FTC, RPV, or TAF) administered individually.

The effects of coadministered drugs on the exposures of RPV and TAF are shown in Tables 5 and 6, respectively. The effects of RPV and TAF on the exposure of coadministered drugs are shown in Tables 7 and 8, respectively. For information regarding clinical recommendations, see Drug Interactions (7).

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Table 5 Changes in Pharmacokinetic Parameters for RPV in the Presence of oadministered Drugs in Healthy Subjects

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12.4 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 (RT) 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.

Rilpivirine: RPV is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does not inhibit the human cellular DNA polymerases , , and mitochondrial DNA polymerase .

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 human immunodeficiency virus (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 cell culture.

Antiviral Activity in Cell Culture

Emtricitabine, Rilpivirine, and Tenofovir Alafenamide: The combinations of FTC, RPV, and TAF were not antagonistic with each other in cell culture combination antiviral activity assays. In addition, FTC, RPV, and TAF were not antagonistic with a panel of representatives from the major classes of approved anti-HIV agents (NNRTIs, NRTIs, INSTIs, and PIs).

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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 (PBMCs). The EC50 values for FTC were in the range of 0.0013–0.64 microM. 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 microM) and showed strain-specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 microM).

Rilpivirine: RPV exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM. RPV demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510– 10,830 nM). RPV demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07–1.01 nM and was less active against group O primary isolates with EC50 values ranging from 2.88–8.45 nM.

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– 14.7 nM.

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

Resistance

In Cell Culture

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

Rilpivirine: RPV-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to RPV included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C, and M230I and L.

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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

In HIV-1-Infected Subjects With No Antiretroviral Treatment History

Emtricitabine and Tenofovir Alafenamide: The resistance profile of ODEFSEY 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.

Rilpivirine: In the Week 96 pooled resistance analysis for adult subjects receiving RPV or efavirenz in combination with FTC/TDF, the emergence of resistance was greater among subjects’ viruses in the RPV+FTC/TDF arm compared to the efavirenz + FTC/TDF arm and was dependent on baseline viral load. In the Week 96 resistance analysis, 14% (77/550) of the subjects in the RPV+FTC/TDF arm and 8% (43/546) of the subjects in the efavirenz + FTC/TDF arm qualified for resistance analysis; 61% (47/77) of the subjects who qualified for resistance analysis (resistance-analysis subjects) in the RPV+FTC/TDF arm had virus with genotypic and/or phenotypic resistance to RPV compared to 42% (18/43) of the resistance-analysis subjects in the efavirenz + FTC/TDF arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to emtricitabine or tenofovir emerged in viruses from 57% (44/77) of the resistance-analysis subjects in the RPV arm compared to 26% (11/43) in the efavirenz arm.

Emerging NNRTI substitutions in the RPV resistance analysis of subjects’ viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y,

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F227C/L, and M230L, which were associated with an RPV phenotypic fold change range of 2.6– 621. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance-analysis subjects than in efavirenz resistance-analysis subjects.

NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of less than or equal to 100,000 copies/mL compared to viruses from subjects with baseline viral loads of greater than 100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts greater than or equal to 200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts less than 200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.

In Virologically-Suppressed Subjects Emtricitabine and Tenofovir Alafenamide: 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).

Rilpivirine: Through Week 48, 4 subjects who switched their protease inhibitor- based regimen to FTC/RPV/TDF (4 of 469 subjects, 0.9%) and 1 subject who maintained their regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to a study drug. All 4 of the subjects who had resistance emergence on FTC/RPV/TDF had evidence of FTC resistance and 3 of the subjects had evidence of RPV resistance.

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Cross-Resistance

Emtricitabine: FTC-resistant viruses with the M184V/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.

Rilpivirine: Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of RPV: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.

Cross-resistance in site-directed mutant virus has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12 times decreased susceptibility to RPV, respectively. The combination of E138K and M184I showed 6.7 times reduced susceptibility to RPV compared to 2.8 times for E138K alone. The K103N substitution did not show reduced susceptibility to RPV by itself. However, the combination of K103N and L100I resulted in a 7 times reduced susceptibility to RPV. In another study, the Y188L substitution resulted in a reduced susceptibility to RPV of 9 times for clinical isolates and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to RPV (fold change range of 3.7–554) in 38% and 66% of mutants, respectively.

Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of RPV resistance.

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

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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 ODEFSEY) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose in ODEFSEY).

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 dose in ODEFSEY. 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 dose in ODEFSEY.

Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21 times (mice) and 3 times (rats) relative to those observed in humans at the recommended dose (25 mg once daily) in ODEFSEY.

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RPV has tested negative in the absence and presence of a metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.

In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily in ODEFSEY.

Tenofovir Alafenamide: Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats 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 ODEFSEY. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (ODEFSEY) 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 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

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(TAF) and 15 (tenofovir) times the exposure seen in humans at the recommended daily TAF dose in ODEFSEY.

14 CLINICAL STUDIES

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in adults as initial therapy in those with no antiretroviral treatment history and to replace a stable antiretroviral regimen in those who are virologically-suppressed [see Indications and Usage (1)] was established in trials of:

 RPV+FTC/TDF in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (n=550) and to replace a first or second stable antiretroviral regimen containing a protease inhibitor and ritonavir in those who were virologically-suppressed with no history of virologic failure or for at least 6 months with no known resistance substitutions (n=317). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) in these two populations was 77% at Week 96 and 89% at Week 48, respectively. Among treatment-naïve subjects, the virologic response rate at 96 weeks was 83% in subjects with baseline HIV-1 RNA less than or equal to 100,000 copies per mL and 71% in subjects with baseline HIV-1 RNA greater than 100,000 copies per mL. Further, the virologic response rate at 96 weeks among subjects with baseline CD4+ cell counts less than 200 and greater than or equal to 200 cells/mm3 were 68% and 82%, respectively.

 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). At Week 48, 92% and 96% of patients in the two populations, respectively, had HIV-1 RNA less than 50 copies per mL.

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in pediatric patients aged 12 to less than 18 years old and greater than 32-35 kg as initial therapy in those with no 120

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 RPV in combination with other antiretroviral agents in 36 treatment-naïve HIV-1 infected adolescents weighing at least 32 kg. The majority of subjects (24/36) received RPV in combination with FTC and TDF. Of these 24 subjects, 20 had a baseline HIV-1 RNA less than or equal to 100,000 copies per mL. The virologic response rate in these 20 subjects (i.e., HIV-1 RNA less than 50 copies per mL) was 80% (16/20) at 48 weeks.

 FTC+TAF with EVG+COBI in 23 adolescents weighing at least 35 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 91% at 24 weeks.

In the clinical trial of 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 the combined populations of treatment-naïve (N=6) begun 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-RNA levels less than 50 copies per mL at Week 24.

16 HOW SUPPLIED/STORAGE AND HANDLING

ODEFSEY tablets are gray, capsule-shaped, and film coated with “GSI” debossed on one side and “255” on the other side. Each bottle contains 30 tablets (NDC 61958-2101- 1), a silica gel desiccant, and a 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). 121

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Lactic Acidosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to ODEFSEY. Advise patients to stop taking ODEFSEY 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 ODEFSEY [see Warnings and Precautions (5.2)]. Advise the patient to not discontinue ODEFSEY without first informing their healthcare provider.

Severe Skin Reactions and Hypersensitivity Inform patients that skin reactions ranging from mild to severe, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with RPV-containing products. Instruct patients to immediately stop taking ODEFSEY and seek medical attention if they develop a rash associated with any of the following symptoms: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing swelling of the face, eyes, lips, mouth, tongue or throat which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems, as they may be a sign of a more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.3)].

Drug Interactions ODEFSEY may interact with many drugs and is not recommended to be coadministered with numerous drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort [see Contraindications (4), Warnings and Precautions (5.4) and Drug Interactions (7)].

Depressive Disorders

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Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with RPV. Inform patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.6)].

Hepatotoxicity Inform patients that hepatotoxicity has been reported with RPV, therefore, it is important to inform the healthcare professional if patients have underlying hepatitis B or C or elevations in liver-associated tests prior to treatment [see Dosage and Administration (2.1) and Warnings and Precautions (5.7)].

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 Precautions (5.8)].

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 (5.9)].

New Onset or Worsening Renal Impairment

Advise patients to avoid taking ODEFSEY 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 (5.10)].

Decrease in Bone Mineral Density

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who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.11)].

Missed Dosage

Inform patients that it is important to take ODEFSEY on a regular dosing schedule with a meal 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 ODEFSEY [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)].

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

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