1. GS-9350: A Pharmacoenhancer Without anti-HIV Activity AA Mathias, P German, M Lee, C Callebaut, L Xu, L Tsai, B Murray, H Liu, K Yale, D Warren and BP Kearney Gilead Sciences Foster City, CA, USA

2. Potent, irreversible (mechanism-based) inhibition of CYP3A No anti-HIV activity Keys to Pharmacoenhancement GS-9350RTV k inact (min -1 )0.440.23 K I (µM)0.940.26 mean of 5 experiments Antiviral Assay EC 50 (  M) GS-9350RTVFold-difference - w/o human serum - 40% human serum > 30 > 90 0.015 0.060 > 2000 > 1500 mean of > 5 experiments

3. Greater CYP450 enzyme inhibition specificity Less induction of drug metabolizing enzymes and transporters Keys to Pharmacoenhancement CYP450 enzyme IC 50 (µM) 1A22B62C82C92C192D63A* GS-9350>252.830>25 9.20.2 RTV>252.95.54.4>252.80.2 * midazolam 1’-hydroxylase (no preincubation) mean of 3 experiments conducted in duplicate

4. Reduced potential for lipid abnormalities Improved physicochemical properties Keys to Pharmacoenhancement Drug Adipocyte Function Assays Inhibition of Normal Lipid Accumulation (EC 50 µM) % Inhibition of Glucose Uptake @ 10µM RTV1655 GS-9350> 309.5 ATV> 301.1 Aqueous Solubility (  g/mL) GS-9350RTVFold-difference pH 7.475~ 2.035 pH 2.2> 65003.1> 2100 mean of 5 experiments /assay mean of 2 experiments conducted in duplicate

5. Study GS-216-0101 Evaluate GS-9350 safety, tolerability, PK and PD (anti-CYP3A activity) – Double-blind, double-dummy, active and placebo controlled study in HIV(-) subjects 3 dose-escalation cohorts: 50, 100 and 200mg tablets (N = 12 /cohort) RTV 100mg & dual placebo (each N = 3 /cohort) –Single and multiple dose PK, safety and tolerability –Steady-state PD: change from pre-treatment PK of “metabolic probe” oral midazolam 50 mg Single Dose PK 50 mg x 14 Days PK/PD 100 mg Single Dose PK 100 mg x 14 Days PK/PD 200 mg X 14 Days PK/PD Pre-treatment safety and PD assessments Study drugs administered with food

6. PK/PD Results GS-9350 exhibited non-linear increases in exposure with dose and time –Time- and dose-dependent PK consistent with mechanism-based inhibition GS-9350 achieved potent inhibition of CYP3A activity –Near-maximal inhibition achieved at ≥ 100mg

7. Study GS-236-0101 Evaluate the relative bioavailability, PK and safety of EVG/FTC/TDF/GS-9350 FDC tablet vs. EVG/r and FTC + TDF –Open-label, partially-randomized, adaptive study design in HIV(-) subjects (N = 44) 100 mg starting GS-9350 dose → 75 or 150 mg GS-9350 containing FDC EVG/FTC/TDF/GS-9350 150/200/300/100mg EVG + RTV 150mg + 100mg FTC + TDF 200mg + 300mg EVG/FTC/TDF/GS-9350 150/200/300/100mg EVG + RTV 150mg + 100mg EVG/FTC/TDF/GS-9350 150/200/300/150mg Real-time GS-9350 & EVG PK analysis Study drugs administered with food

8. Mean (CV%) EVG PK (n = 42) GS-9350 100mg FDCGS-9350 150mg FDCEVG + RTV 100mg AUC tau (ng.hr/mL)21100 (25.4)27000 (29.4)22500 (23.4) C max (ng/mL)2250 (26.3)2660 (27.6)2500 (32.1) C tau (ng/mL)282 (60.4)490 (52.9)409 (40.5) Elvitegravir PK GS-9350 effectively boosts EVG within FDC tablet High EVG trough concentrations maintained w/ GS-9350 150mg –11-fold above the protein binding-adjusted IC 95 (44.5 ng/mL) –Low within-subject variability (15% CV)

9. FTC and TFV exposures clinically equivalent –FTC exposures increased 20% as FDC vs. FTC capsule –TFV AUC bioequivalent as FDC or TDF tablet EVG/FTC/TDF/GS-9350 150 mgFTC + TDF Mean (CV%) PK (n = 42) FTCTFVFTCTFV AUC tau (ng.hr/mL) 11500 (19.3)3010 (20.4)9330 (22.1)2550 (22.6) C max (ng/mL)1850 (22.5)332 (28.9)1600 (26.1)252 (24.9) C tau (ng/mL)101 (26.8)65.0 (26.0)80.1 (25.9)52.0 (25.4) FTC/TDF PK

10. Safety Summary GS-9350 first-in-man, dose-ranging study –Single and multiple doses up to 200 mg well tolerated –No drug-related Grade 3/4 laboratory abnormalities –Single Grade 3 adverse event of discoordination (GS-9350 100mg) –No changes or differences observed in serum lipids across treatments over 14 days Integrase FDC “Quad” tablet study –All treatments well tolerated –Two Grade 3 adverse events Single subject with drug-related ALT elevation (GS-9350 100mg FDC) One subject with acute appendicitis –No other drug-related Grade 3/4 laboratory abnormalities

11. Conclusions GS-9350 is a potent, selective, mechanism-based CYP3A inhibitor that lacks anti-HIV activity and has limited effects on adipocyte function in vitro GS-9350 boosts CYP3A substrates comparable to RTV in humans EVG/FTC/TDF/GS-9350 FDC tablet achieves desired exposures of EVG, FTC and TFV

13. GS-9350 & Ritonavir PK Mean (CV%) PK (n = 42) GS-9350 100mg FDCGS-9350 150mg FDCRTV 100mg AUC tau (ng.hr/mL)5150 (31.7)10400 (35.2)5750 (38.4) C max (ng/mL)855 (27.6)1570 (29.7)1030 (47.8) C tau (ng/mL)7.6 (124)22.7 (107)37.6 (52.2)