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

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The duration of exposure to study drug was similar between the 2 treatment groups (Table 10). Median (Q1, Q3) exposure was as follows: E/C/F/TAF 48.1 weeks (45.4, 60.1); Stribild 48.3 weeks (44.4, 60.1). However, the distributions of time to premature discontinuation of study drug between the treatment groups as measured by the KM estimates were different, mainly due to more subjects discontinuing study drug in the Stribild group (p = 0.04).

Table 10. GS-US-292-0111: Duration of exposure to study drug (safety analysis set)

Safety issues with the potential for major regulatory impact

The primary safety analyses for these studies focussed on renal and bone mineral toxicity. The primary safety outcomes were specified as hip bone mineral density (BMD); spine BMD, serum creatinine and treatment emergent proteinuria.

For a full evaluation of the results of the studies see Attachment 2.

Post-marketing data

There is no post-marketing experience as this FDC is not available in any market globally.

Evaluator’s conclusions on safety

Statistically significant differences favouring E/C/F/TAF over Stribild or TDF containing regimens were observed at Week 48 for all key secondary safety endpoints in both ART naive and virologically suppressed subjects: mean percentage changes from baseline in hip BMD (p < 0.001 for both ART naive and virologically suppressed subjects) and spine BMD (p < 0.001 for both ART naive and virologically suppressed subjects), mean change from baseline in serum creatinine (p < 0.001 for both ART naive and virologically suppressed subjects), change from baseline in treatment emergent proteinuria (ART naive subjects, p = 0.022), and change from baseline in EFV related symptom assessment composite score (virologically suppressed subjects; p < 0.001).

The clinical relevance of improving BMD is unquestionable in terms of potentially reducing fractures. It is not possible to determine if the 48 week follow-up period is long enough. However statistically significant differences between Genvoya and Stribild were observed by 48 weeks. There is no reason to assume these differences will be reduced following longer term observation as the pharmacokinetics of TDF and TAF should remain consistent.

There appears to be a positive benefit of Genvoya in terms of renal toxicity, compared with Stribild and also when patients were switch to Genvoya from a TDF containing regimen. There were no untoward adverse reactions to Genvoya, in cohorts of either naive or treatment experienced patients. There were no untoward AEs or SAEs in adolescents or patients who had baseline mild to moderate renal impairment.

The overall safety profile of Genvoya is a significant improvement over the safety profile of Stribild.

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