A summary of the clinical findings is presented in this section. Further details of these clinical findings can be found in Attachment 2.
Standard of care for the treatment of HIV-1 infection uses combination antiretroviral therapy (ART) to suppress viral replication to below detectable limits, increase CD4 cell counts, and stop disease progression. For ART naive HIV infected patients, current treatment guidelines suggest that initial therapy consist of 2 nucleos(t)ide reverse transcriptase inhibitors (N(t)RTI) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a boosted protease inhibitor, or an integrase strand transfer inhibitor (INSTI).
The success of potent and well tolerated ART means that morbidity and mortality in the HIV infected population is increasingly driven by non-acquired immunodeficiency syndrome (AIDS) associated comorbidities. Clinical attention has become more focused on the optimization of tolerability, long-term safety, and adherence to potent ART regimens. There remains a significant medical need for new, effective therapies that take into consideration the non HIV comorbidities; demographics of the aging HIV infected population, antiretroviral (ARV) resistance, and regimen simplification. Chronic kidney disease is important, since observational studies have demonstrated a relationship between kidney disease and progression to AIDS and death. Moreover, HIV associated nephropathy present in up to 30% of patients is a common cause of end stage renal disease (ESRD) requiring dialysis. Antiretroviral therapy with proven efficacy and safety in the both elderly and young patients is important; limited data and treatment options are available in both populations. The elderly have increased risks for comorbidities, including those related to renal and bone. There are specific and complex challenges for the treatment of adolescents, who also represent the population that will require ART for the longest time.
Given the duration for which a newly diagnosed person with HIV may take an ART regimen throughout his or her lifetime, the E/C/F/TAF FDC tablet may provide the longevity of a single treatment that optimises tolerability, long-term safety, and durable efficacy. For HIV infected, ART naive patients, E/C/F/TAF may have advantages over the existing marketed product of Stribild, specifically less proteinuria, less need for renal monitoring, and less impact on bone mineralization relative to TDF treatment. The relatively low dose of TAF (10 mg versus TDF 300 mg) that is used in the E/C/F/TAF FDC also allows for co-formulation with multiple other third ARV agents. This will allow HIV infected, virologically suppressed patients to convert from a TDF based regimen to receive a TFV prodrug co-formulated with 2 active agents without any diminution of efficacy, but with renal and bone safety advantages. E/C/F/TAF can potentially provide a lifelong treatment option that can minimise impact on non AIDS comorbidities that may be more important than AIDS related opportunistic infections.
Contents of the clinical dossier
The submission contained the following clinical information:
In total, the sponsor has submitted clinical trial data, in addition to clinical discussion papers. Many of these studies overlap in terms of their objectives and therefore cannot be clearly categorised as, efficacy, safety or pharmacokinetics/pharmacodynamics. The evaluator has focussed on the most relevant and pivotal studies for review as many of the studies submitted have identical designs, methodologies and analytical frameworks and geographic locations.
15 Phase I and Phase II studies of clinical pharmacology, including 10 that provided PK data and 5 that provided pharmacodynamic data.
2 pivotal efficacy/safety studies GS-US-292-0104 and GS-US-292-0111. Both studies are randomised; double blind trials conducted in HIV-1 positive, antiretroviral treatment naive adults and provide a direct comparison of E/C/F/TAF (Genvoya) with E/C/F/TDF (Stribild), the currently approved and marketed FDC.
Additional studies include GS-US-292-0109; a Phase III, open label study to evaluate the potential renal and/or bone benefits of switching from a TDF based regimen to the Genvoya in virologically-suppressed HIV-1 positive subjects; GS-US-292-0112; an open label study of Genvoya in patients with mild to moderate renal impairment and GS-US-292-0106; an open label study of Genvoya in HIV infected treatment naive adolescents.
Clinical overview, summary of clinical efficacy, summary of clinical safety and literature references.
The submission included paediatric pharmacokinetic /pharmacodynamic /efficacy /safety data for HIV infected treatment naive adolescents 12 years old or greater (GS-US-292-0106).
Good clinical practice
The clinical studies reviewed in this evaluation were in compliance with CPMP/ICH/135/95 Note for Guidance on Good Clinical Practice.
Studies providing pharmacokinetic data
Table 6 shows the studies relating to each pharmacokinetic topic.
† Bioequivalence of different formulations. § Subjects who would be eligible to receive the drug if approved for the proposed indication.
None of the pharmacokinetic studies had deficiencies that excluded their results from consideration.
For further details on the evaluation of the pharmacokinetic studies please see Attachment 2.
Evaluator’s conclusions on pharmacokinetics
The new drug for which the sponsor seeks approval is TAF. This compound is intended as a replacement component for TDF in the single tablet regimen which is currently approved as Stribild (also referred to as QUAD). The other three components of this single tablet regimen (EVG/COBI/FTC) have been extensively assessed and approved, both individually and in combination. Their formulations and dosages in the applicant single tablet regimen will remain the same as in Stribild. TAF is a prodrug of tenofovir (TFV) which is metabolised intracellularly by Cat A to tenofovir diphosphate (TFV-DP), the form that has anti-viral activity. The reason the sponsor is applying to replace TDF with TAF is that TDF has higher and more prolonged plasma circulating levels of TFV which is associated with an increased risk of renal and bone toxicity. The PK studies submitted by the sponsor indicate that TAF at a dose of 10 mg in the single tablet regimen (boosted by COBI) or 25 mg (un boosted) have a circulating level of TFV that is 90% less than the current dose of TDF 300 mg, which is the approved dose component of Stribild. The sponsor has submitted an extensive number of studies to support this application which indicate that the pharmacokinetics of TAF are not affected by race, mild to moderate hepatic failure, renal failure or age (for teenagers more than 12 years of age). Specifically the clinical trial with Japanese subjects GS-US-292-0108 demonstrated no PK effect of Japanese origins. PK studies conducted as a part of the pivotal efficacy/safety clinical trial, GS-US-292-0104 and GS-US-0111 show that the AUCtau of E/C/F/TAF was 91% lower than tenofovir exposure compared with E/C/F/TDF and the PBMC AUCtau was 4.1 times higher with administration of E/C/F/TAF compared with E/C/F/TDF.
Figure 6. Plasma TVF and Intracellular TFV-DP
There are limited data on subjects of advanced ages. All studies in healthy subjects and in the target populations have been designed and analysed according to standardised procedures and all data are available for assessment. There are no specific interactions between TAF and other drugs commonly used by patients with HIV, although there are many drug interactions associated with the Genvoya FDC. These are primarily due to the COBI component and have been described in detail in previous assessments of Stribild and of COBI. As TAF is not available as a single agent and the sponsor has applied for TAF to be included only as a component of the FDC, the evaluator did not consider the interaction of TAF, as a single agent, with other HIV antiretroviral agents. It is the opinion of the evaluator that the sponsor has adequately covered issues of the PK of TAF in the dossier.