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GS-9350: A Pharmacoenhancer Without anti-HIV Activity

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. Potent, irreversible (mechanism-based) inhibition of CYP3A No anti-HIV activity.

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GS-9350: A Pharmacoenhancer Without anti-HIV Activity

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  1. GS-9350: A Pharmacoenhancer Withoutanti-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 mean of 5 experiments mean of > 5 experiments

  3. Greater CYP450 enzyme inhibition specificity Less induction of drug metabolizing enzymes and transporters Keys to Pharmacoenhancement hPXR Activation Induction of Hepatocyte CYP3A4 mRNA 100 120 100 80 80 60 RTV Response (%Emax) % Maximum 60 GS-9350 40 40 20 20 0 0 1 µM 3 µM 10 µM 30 µM Rifampicin 1 10 GS-9350 Concentration (µM) mean ± SD, n=3 mean + SD, n=3 * midazolam 1’-hydroxylase (no preincubation) mean of 3 experiments conducted in duplicate

  4. Reduced potential for lipid abnormalities Improved physicochemical properties Keys to Pharmacoenhancement 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 Pre-treatment safety and PD assessments 100 mg x 14 Days PK/PD 200 mg X 14 Days PK/PD 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 ofEVG/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 EVG/FTC/TDF/GS-9350 150/200/300/150mg FTC + TDF 200mg + 300mg EVG + RTV 150mg + 100mg EVG/FTC/TDF/GS-9350 150/200/300/100mg Real-time GS-9350 & EVG PK analysis Study drugs administered with food

  8. 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 IC95 (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 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

  12. GS-9350 & Ritonavir PK

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