Application for Inclusion of Emtricitabine and Tenofovir Alafenamide Fixed Dose Combination Tablets (Descovy®) 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 Sciences Submission Reference number: GSI-DSY-161201 1 Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 Contents 1. Summary statement of the proposal for inclusion ................................................... 5 2. Name of the focal point in WHO submitting or supporting the application ................. 7 3. Name of the organization(s) consulted and/or supporting the application ................. 7 4. International Nonproprietary Name (INN, generic name) of the medicine ................. 7 5. Formulation proposed for inclusion ........................................................................ 8 6. International availability ....................................................................................... 9 7. Listing type requested ........................................................................................ 11 8. Information supporting the public health relevance ............................................... 12 8.1 Epidemiological information on disease burden 12 9. Treatment details ............................................................................................... 15 9.1 Indications and usage 15 9.2 Dosage and administration 16 9.2.1 Special populations 16 9.3 Reference to existing WHO and other clinical guidelines 17 10. Summary of comparative effectiveness in a variety of clinical settings ............. 20 10.1 Identification of clinical evidence 20 10.2 Summary of available data on comparative effectiveness of Descovy® 26 10.2.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – design and results of the pre-specified pooled analysis 26 10.2.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – design and results of the cross-study comparison 30 10.2.3 Phase 3 study of switch to EVG/COBI/FTC/TAF – GS-US-292-0109 – design and results at 48 weeks 32 2 Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 10.2.4 Phase 3 study of switch from FTC/TDF to FTC/TAF – GS-US-311-1089 – design and results at 48 weeks 35 10.2.5 Phase 3 study of switch from FTC/TDF to FTC/TAF in renal impairment – GS- US-292-0112 – design and results at 48 and 96 weeks 38 10.2.6 Phase 3 study of switch to FTC/TAF in multi-drug resistant HIV-infected adults – GS-US-292-0119 – design and results at 24 and 48 weeks 40 10.3 Summary of the efficacy of Descovy® 42 10.4 Summary of the resistance profile of Descovy® 43 10.5 Summary of available estimates of comparative effectiveness 43 11. Summary of comparative evidence on safety .................................................. 45 11.1 Estimate of total patient exposure to Descovy® 45 11.2 Description of adverse effects/reactions 45 11.3 Renal safety profile 46 11.3.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – renal safety 46 11.3.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – renal safety 48 11.3.3 Phase 3 switching study to EVG/COBI/FTC/TAF – GS-US-292-0109 – renal safety 49 11.3.4 Phase 3 switching study from FTC/TDF to FTC/TAF – GS-US-311-1089 – renal safety 49 11.3.5 Phase 3 switching study from FTC/TDF to FTC/TAF in renal impairment – GS- US-292-0112 – renal safety 50 11.3.6 Phase 3 switching study to FTC/TAF in multi-drug resistant HIV-infected adults – GS-US-292-0119 – renal safety 51 11.4 Bone safety profile 52 3 Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 11.4.1 Phase 3 registration studies in treatment-naïve subjects – GS-US-292-0104 and GS-US-292-0111 – bone safety 52 11.4.2 Phase 3 studies in treatment-naïve adolescents – GS-US-292-0106 and GS- US-236-0112 – bone safety 53 11.4.3 Phase 3 switching study to EVG/COBI/FTC/TAF – GS-US-292-0109 – bone safety 54 11.4.4 Phase 3 switching study from FTC/TDF to FTC/TAF – GS-US-311-1089 – bone safety 56 11.4.5 Phase 3 switching study from FTC/TDF to FTC/TAF in renal impairment – GS- US-292-0112 – bone safety 57 11.5 Lipid safety profile 57 11.6 Drug–drug interactions 58 12. Summary of available data on comparative cost and cost-effectiveness within the pharmacologic class or therapeutic group ............................................................... 62 12.1 Range of costs of the proposed medicine 62 12.1.1 Europe 62 12.1.2 Developing countries 63 13. Summary of regulatory status of the medicine Descovy® ................................. 63 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) ....................................................... 63 14.1 Specifications of Descovy® tablets 63 15. Proposed (new/adapted) text for the WHO Model Formulary ........................... 64 15.1 Other antivirals 64 16. References .................................................................................................. 66 Appendix 1. Descovy® Access PI 72 4 Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 1. Summary statement of the proposal for inclusion The fixed dose, once-daily combination of emtricitabine (FTC) and tenofovir alafenamide (TAF) – Descovy® – is proposed for inclusion in the WHO Model List of Essential Medicines as a treatment for HIV-1 infection in adults and children aged 12 years (≥35 kg) and older when used in combination with other antiretroviral agents [Descovy® 200 mg/10 mg film coated tablets Summary of Product Characteristics (SmPC), 2016; Descovy® 200 mg/25 mg film coated tablets SmPC, 2016]. The principal reasons for requesting this inclusion are as follows: As one of the preferred backbones of HIV combination therapy, tenofovir (as tenofovir disoproxil fumarate [TDF]) in combination with FTC continues to underpin much of the treatment of HIV infection [DHHS, 2016; EACS, 2016; WHO, 2016] FTC/TDF as the fixed dose combination tablet Truvada® is listed in the WHO EML as a treatment for HIV-1 infection in adults and children aged 12 years and older when used in combination with other antiretroviral agents. Truvada® (FTC/TDF) in combination with efavirenz (as the fixed combination Atripla®) is listed in the consolidated WHO treatment guidelines as preferred first-line treatment of HIV infection [WHO, 2016] Current estimates of 13.3 million patient-years of experience with TDF-based regimens in 2016 is testament to its efficacy and safety in people living with HIV [Gupta et al, 2016] While TDF-based therapy is generally well tolerated, chronic use is known to have adverse renal effects that in rare instances can include Fanconi’s syndrome [Herlitz et al, 2010; Rodriguez-Novoa et al, 2010; Poizot-Martin et al, 2013]. It is also associated with a decrease in bone mineral density and an increased risk of fragility fractures, which people with HIV are vulnerable to [Grant & Cotter, 2016] Earlier initiation of antiretroviral therapy (ART) together with a long duration of therapy due to an ageing HIV population demands efficacious antiretroviral drugs 5 Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 with improved safety and tolerability for life-long administration [Negin & Cumming, 2010] Life-long adherence to ART is also critical to prevent the emergence of antiretroviral drug resistance In older HIV patients, some antiretroviral drugs have side effects that overlap the complications associated with ageing [Deeks et al, 2013] TAF is a novel prodrug of tenofovir that is converted intracellularly to tenofovir diphosphate, allowing for significantly higher drug concentrations in peripheral blood cells and lower plasma levels of the pharmacologically active metabolite than its predecessor TDF [Bonora et al, 2016; Ray et al, 2016] Because of its unique metabolic pathway, TAF achieves a 91% reduction in plasma levels of tenofovir while maintaining similar intracellular concentrations [Zack et al, 2016] Preferential accumulation of tenofovir diphosphate in immune cells following administration of TAF means that much smaller doses can be used in comparison with TDF (10–25 mg versus 300 mg per day, respectively). This translates into smaller pills and easier co-formulation with other antiretroviral drugs Tenofovir diphosphate is eliminated via the kidneys. The reduced systemic exposure associated with TAF administration reduces the risk of renal and bone toxicity compared with TDF [Ray et al, 2016; Zack et al, 2016] TAF, first formulated in a fixed dose combination with FTC, cobicistat and elvitegravir (Genvoya®), has been evaluated for efficacy and safety in four separate populations of people living with HIV as follows: o Treatment-naïve adults o Treatment-naïve adolescents o Treatment-experienced adults o Adults with renal impairment Overall, results from clinical studies in these patient populations have shown that regimens containing TAF were as efficacious as those containing TDF and had an improved safety profile with respect to kidney function and bone health 6 Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 These