30 1,507 NC 5.14/NC 100 7,397 NC 25.24/NC 2 years (TDF) (carcinogenicity) 600 44,300 NA 151.19/NA Females 50,900 NA 173.72/NA Rat (SD) 6 months (TAF) Males 5 740 NA 2.52 25 3,530 NA 12.05 100 15,930 NA 54.37 Females 5 600 NA 2.05 25 4,000 NA 13.65 100 15,140 NA 51.67 2 (TDF) (carcinogenicity) Males 10/300 16,690 NA 56.96/NA 30 2,700 NA 9.22/NA 100 6,600 NA 22.53/NA Females 10/300 15,720 NA 53.65/NA 30 3,060 NA 10.44/NA 100 7,460 NA 25.46/NA Dog (Beagle) 9 months (TAF) Males 2 1,300 90 4.44/0.44 6 3,890 1290 6.25/6.26 18/12 14,900 2160 13.28/10.48 Females 2 1,070 60 3.65/0.29 6 5010 780 17.10/3.79 18/12 12,570 1750 42.90/8.50 Monkey (Rhesus) 4 (TAF) Combined 3 350 NC 1.19/NA 30 5,870 1030 20.03/5.0 Human (healthy volunteers) steady state (TAF) – (10 mg) 293* 206* – * Mean steady AUCSS in pivotal studies for TFV (GS-US-292-0104 and GS-US-292-0111); ** = animal: human plasma AUCss 0–24h NC = not calculated, NA = not applicable
ongoing safety concerns, to be reflected accordingly in the revised ASA. this population (see dosage and administration)’. Furthermore a similar situation is observed with the use of Genvoya in hepatic impairment and it is noted that the missing information: ‘Safety in patients with severe hepatic impairment (CPT score C)’ is included in the summary of safety concerns for Genvoya. Consequently it is recommended that the missing information: ‘Safety in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute)’ should be included in the summary of safety concerns for Genvoya. It is acknowledged that routine risk minimisation is already applied for this new missing information and monitoring by routine pharmacovigilance will be sufficient. The ASA need only be revised accordingly, preferably before this application is approved. The sponsor should provide an assurance that the draft protocol for the planned clinical study of E/C/F/TAF in ARV HIV-1 infected patients from 6 to < 18 years of age will be attached to the ASA once it becomes available. The sponsor advises that the planned clinical study GS-US-292-0113 has been renumbered as Study which is enrolling virologically suppressed, HIV-infected adolescents 12 to < 18 years of age only. Virologically suppressed, HIV-infected children 6 to < 12 years of age are now being enrolled into Cohort 2 of the ongoing, paediatric Study rather than Study GS-US-292-0113. The protocols for Studies GS-US-292-0106 and are attached to the ASA. This is acceptable. Section 4: ‘Summary of the RMP’ of the ASA contains 6: ‘summary table of risk minimization measures’. This table summarises the pharmacovigilance and risk minimisation activities for Australia. Consequently this table should be renamed accordingly. Furthermore all the additional pharmacovigilance The sponsor states: ‘Gilead has renamed the and revised the classification of pharmacovigilance activities accordingly’. This is acceptable.
Open label phase: mg) Phase III Commenced Randomised, double multicentre, active controlled study HIV-infected ART naive adults 867 mg) + Stribild OR Stribild + 96 weeks of randomised, blinded treatment, optional rollover extension to 48 week data presented only Commenced 2013 Randomised, double blind, multicentre, active controlled study HIV-infected ART adults 866 mg) + Stribild OR Stribild + 96 of randomised, blinded treatment, optional rollover extension to 48 week data presented only Commenced 2013 Randomised, open label multi centre, active controlled Virologically suppressed HIV infected adults 1,436 Treatment Group 1: Switch to = 1,000) Treatment Group 2: Stay on pre-existing FTC/TDF+3rd Agent regimen (Stribild, ATR, ATV/co+TVD, or ATV/r+TVD (n = 500) 96 weeks for comparative phase, option to continue treatment until it becomes commercially available or until development is terminated. 48 week data presented only
Table 15. GS-US-292-0104 and GS-US-292-0111. Common adverse events (all grades) in ≥ 5% of patients Elvitegravir, COBI, emtricitabine, tenofovir alafenamide (n=866) Elvitegravir, COBI, emtricitabine, tenofovir disoproxil fumarate (n=867) Diarrhoea 147 (17%) 164 (19%) Nausea 132 (15%) 151 (17%) Headache 124 (14%) 108 (13%) Upper respiratory tract infection 99 (11%) 109 (13%) 78 (9%) 80 (9%) Fatigue 71 (8%) 71 (8%) Cough 67 (8%) 60 (7%) Vomiting 62 (7%) 54 (6%) Arthralgia 61 (7%) 39 (5%) Back pain 60 (7%) 57 (7%) Insomnia 57 (7%) 48 (6%) Rash 55 (6%) 46 (5%) Pyrexia 45 (5%) 41 (5%) Dizziness 44 (5%) 37 (4%) Results for the other studies are described in Attachment 2 Deaths and SAEs Seven subjects died during the EVG/COBI/FTC/TAF Phase II and Phase III studies: 5 subjects in Studies GS-US-292-0104 and GS-US-292-0111, and 2 subjects in Study GSUS292-0109 None of the events that resulted in death were considered related to study drug by the investigator. Serious AEs were reported for a similar percentage of subjects in both treatment groups in the comparative Studies (GS-US-292-0104, GS-US-292-0111 and GS-US-292-0109) and < 10% in the EVG/COBI/FTC/TAF group in each study. No individual SAE occurred in ≥ 1% of subjects in either treatment group. Among virologically suppressed subjects in Study GS-US-292-0109, subjects who switched to EVG/COBI/FTC/TAF had a higher incidence of any AE considered by the investigator as