June 2016 Australian Public Assessment Report for Elvitegravir / Cobicistat / Emtricitabine / Tenofovir alafenamide (as fumarate) Proprietary Product Name: Genvoya Sponsor


Evaluator’s conclusions on efficacy



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Evaluator’s conclusions on efficacy


Evaluator’s conclusions on clinical efficacy for the treatment of HIV-1 infection in adults and paediatric patients 12 years of age and older.

The sponsor has submitted at least ten separate clinical trials, involving more than 2,500 patients in more than 40 countries. The clinical efficacy objective of these studies was to confirm that TAF is equivalent to TDF when combined in an FDC tablet with EVG, COBI and FTC. The single parameter of efficacy has been defined as achieving an HIV-1 RNA viral load of less than 50 copies per mL. These studies universally confirm that TAF, as a component of Genvoya, is clinically equivalent to TDF as a component of Stribild (or QUAD), which has been approved. The equivalence of TAF with TDF is supported by the comprehensive pharmacokinetics data submitted by the sponsor. The PK studies provide data to demonstrate that TAF at a dose of 10 mg, boosted by COBI 150 mg, results in the equivalent intracellular levels of the active substance TFV, as a dose of 300 mg of TDF. The sponsor provides further data to conclude that, in the short to medium term this lower dose requirement of TAF will result in a lower rate of adverse renal and bone density effects. This observation will be detailed in the section on clinical safety.

The pivotal efficacy studies in this submission are GS-US-292-0104 and GS-US-292-0111. These are the studies that have been pooled for analysis. The data shows that the FDC containing TAF (Genvoya) resulted in equivalent viral suppression when compared with the FDC containing TDF (Stribild), both achieving > 90% of patients with an HIV-1 RNA viral load of < 50 copies per mL. Virological failure was infrequent in both groups (3.6% and 4.0% respectively). It was observed that the TAF combination appeared to be significantly better for women and for those with a baseline viral load of < 100,000 copies per mL. The TAF group also appeared to have a significantly higher CD4 increase when compared with the TDF group. Other parameters such as age, ethnicity, area of residence and mild to moderate renal and hepatic abnormality did not have an effect on the efficacy outcomes. Study GS-US-292-0109 provided data on both HIV-1 treatment naive patients and patient who switched from a regimen containing TDF to one containing TAF. This study with more than 1,400 patients also showed that suppression of HIV‑1 RNA viral load was maintained when patients switched to the TAF containing regimen.

It is the opinion of the evaluator that the Genvoya FDC provides a non-inferior viral suppression single tablet regimen to an already approved FDC.


Safety

Studies providing safety data


The sponsor has submitted 20 separate clinical studies that, in some aspects address the safety of TAF, either as a separate tablet or in combination with E/C/F as the compound Genvoya, which is submitted for assessment. As the current application for TAF is not as a separate tablet, the assessor has considered the safety of TAF in combination with E/C/F. The pivotal safety data provided by the sponsor are GS-US-292-0104 and GS-US-292-0111 which were the pivotal efficacy studies. The key safety data for this submission is the documented renal and bone mineral density toxicity reported for the Stribild and due to the TDF component. The sponsor’s submission states that this toxicity is due to the TDF component because it is in plasma for an extended period before being incorporated into PBMCs. The sponsor’s submission is intended to show that, because TAF is incorporated into PBMCs at a much more rapid rate than TDF the effects on renal and bone mineral function will be much ameliorated.
Pivotal studies that assessed safety as a primary outcome

The three studies regarded as the most important in relation to safety are GS-US-292-0104, GS-US-292-0111 and GS-US-292-0109. The first two studies have been pooled as their design, implementation and analysis frameworks are identical.
Pivotal studies that assessed safety as a secondary outcome

Studies GS-US-292-0104, GS-US-292-0111, GS-US-292-0106, GS-US-292-0109, GS‑US‑292‑0102 were pivotal studies that assessed safety as a secondary outcome in parallel with their primary outcome of efficacy (equivalence between E/C/F/TAF and E/C/F/TDF). These studies are described below. Study GS-US-292-0112 is relevant, although not a pivotal safety study as it is a Phase III open label study of patients treated with E/C/F/TAF who have mild to moderate renal impairment. This study is important in consideration of the impact of TAF on renal function.

Patient exposure

GS-US-292-0104

The duration of exposure to study drugs was similar between the 2 treatment groups. Median (Q1, Q3) exposure was as follows: E/C/F/TAF 60.0 weeks (48.0, 71.3); Stribild 59.4 weeks (48.0, 65.1). The majority of subjects in each treatment group had received study drugs for ≥ 48 weeks at the time of the Week 48 data cut date (E/C/F/TAF 78.9%, 343 subjects; Stribild 76.6%, 331 subjects). There was no statistically significant difference between groups in the overall Kaplan-Meier (KM) estimate of time to premature discontinuation.

Table 9. GS-US-292-0104: Duration of exposure to study drug (safety analysis set)







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