§ Subjects who would be eligible to receive the drug if approved for the proposed indication. ‡ And adolescents if applicable.
None of the pharmacodynamic studies had deficiencies that excluded their results from consideration.
For further details of the clinical evaluation of pharmacodynamics please see Attachment 2.
Evaluator’s conclusions on pharmacodynamics
TAF showed broad anti HIV activity in human PBMCs against all HIV-1 groups and potent antiviral activity against HIV-2. TAF also has shown potent antiviral activity against HIV-1 isolates resistant to other ARV drug classes (that is, NNRTI-resistant (NNRTI-R), protease inhibitor-resistant (protease inhibitor-R) and INSTI-resistant (INSTI-R) mutants and combination NRTI-R + NNRTI-R or NRTI-R + NNRTI-R + protease inhibitor -R mutants).
The PK/PD profiles of E/C/F/TAF and its components have been well established in HIV-1 infected subjects and certain special populations. No clinically relevant differences in the PK/PD of the E/C/F/TAF FDC were observed with respect to demographic variables. The PK/PD of the individual components of E/C/F/TAF in adolescents were consistent with the range of exposures associated with antiviral activity of E/C/F/TAF in adults, which supports the extrapolation of efficacy data from paediatrics to adult subjects and the use of E/C/F/TAF in patients > 12 years.
Based on PK/PD analysis for efficacy parameters, the exposure associated with TAF 25 mg (or ECFTAF 10 mg) is expected to provide near maximal activity.
Dosage selection for the pivotal studies
The dose for the pivotal studies was the approved FDC Stribild as the comparator with the same components as the approved FDC, with TAF 10 mg substituted for TDF 300 mg in Stribild.
The proposed commercial E/C/F/TAF FDC tablet contains EVG 150 mg, COBI 150 mg, FTC 200 mg, and TAF 10 mg. The 150 mg dose of EVG is 1 of the 2 marketed doses of the product as a single agent (85 mg is the other dose). The 150 mg boosting dose of COBI is the marketed dose of COBI as a single agent, and the dose associated with boosting of the 150 mg dose of EVG. The 200 mg dose of FTC represents the marketed dose.
Cumulative assessment of exposure: response data from proof of concept Study GS‑US‑120-0104 indicated that TAF 25 mg exposure provided potent and near maximal antiviral activity. Relative to TDF 300 mg, TAF 25 mg demonstrated no loss in efficacy, but 90% reduction in TFV plasma levels that potentially translates into an improvement in off-target side effects. Pharmacokinetic data from Studies GS-US-292-0101 and GS‑US‑311‑0101 indicated that TAF exposure from an 8 to 10 mg dose in combination with COBI (single agent or as E/C/F/TAF) were comparable with that from TAF 25 mg administered alone. Cumulative results from Studies GS-US-120-0104, GS-US-292-0101, and GS-US-311-0101 were used in selecting a 10 mg TAF dose for clinical development within the E/C/F/TAF FDC.
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.