Evaluation of Drug-Drug Interactions Between Sofosbuvir/Velpatasvir/Voxilaprevir and Boosted or Unboosted HIV Antiretroviral Regimens

Transcription

1 Evaluation of Drug-Drug Interactions Between Sofosbuvir/Velpatasvir/Voxilaprevir and Boosted or Unboosted HIV Antiretroviral Regimens Kimberly L. Garrison, Erik Mogalian, Heather Zhang, Grace Ma, Steve West, Hal Martin, Luisa M. Stamm, John Ling, Anita Mathias Gilead Sciences, Foster City, CA IWCPAT 2017, Chicago

2 Disclosures I am an employee of Gilead Sciences, Inc. 2

3 Background SOF Nucleotide polymerase inhibitor VEL NS5A inhibitor Sofosbuvir (SOF)/Velpatasvir (VEL) SOF: nucleotide polymerase inhibitor with activity against HCV genotype (GT) 1 6 GS : predominant circulating metabolite F F O N O O H N N O H N N O O F F O O O S N H VOX NS3/4A PI VEL: 2 nd -generation NS5A inhibitor with picomolar potency against HCV GT 1 6 Approved for use in treatment-naïve, and PEG/RBV- and protease inhibitor (PI) + PEG/RBV-experienced patients Voxilaprevir (VOX) HCV NS3/4A PI with potent antiviral activity against HCV GT 1 6 Favorable resistance profile SOF Nucleotide polymerase inhibitor VEL NS5A inhibitor VOX NS3/4A PI SOF/VEL/VOX Once-daily, oral, fixed-dose combination (400/100/100 mg) Demonstrated high efficacy in Phase 3 clinical trials 1,2 1. Bourlière, et al. NEJM 2017 June 1; 2. Jacobson, et al. Gastroenterology

4 HCV/HIV Co-infection HCV/HIV coinfection is estimated to occur in ~30% of HIV-infected patients 1 Increased risk of more rapid progression of liver disease 2,3 Increased rates of liver-related morbidity and mortality 4 HIV antiretroviral drugs (ARVs) are substrates, inhibitors and/or inducers of Efflux transporters Uptake transporters Metabolizing enzymes Complex drug-drug interactions (DDIs) are possible with HCV direct-acting antivirals due to overlapping mechanisms 1. Sulkowski, 2008, 2. Graham, et al. 2001, 3. Deng, et al. 2009, 4. Myers, et al

5 Potential for Drug-Drug Interactions DDI mechanism SOF 1 VEL 2 VOX 3,4 Drug transporters Drug-metabolizing enzymes VEL is also an inhibitor of OATP2B1. P-gp/ BCRP Substrate Substrate/Inhibitor Substrate / Inhibitor OATP1B Substrate/Inhibitor Substrate/Inhibitor CYP3A4 Substrate Substrate CYP2C8 Substrate CYP2B6 Substrate 1. Kirby, et al. 2015; 2. Mogalian, et al. 2016; 3. Kirby, et al. IWCPHHT 2016, abstr O24; 4. Kirby, et al. IWCPHHT 2016, abstr O25. 5

6 Objectives Primary To evaluate DDIs between SOF/VEL/VOX and boosted- and unboosted-hiv ARV regimens Secondary To evaluate the safety and tolerability of administration of SOF/VEL/VOX with boostedand unboosted-hiv ARV regimens 6

7 Study Design Cohort 1, n=30 SOF/VEL/VOX + DRV 800 mg + RTV 100 mg + FTC/TDF 200/300 mg Cohort 2, n=30 SOF/VEL/VOX + EVG/COBI/FTC/TAF 150/150/200/10 mg Cohort 3, n=30 SOF/VEL/VOX + BIC/FTC/TAF 50/200/25 mg Cohort 4, n=30 SOF/VEL/VOX + FTC/RPV/TAF 200/25/25 mg Phase 1 open-label, randomized, multiple-dose, cross-over studies of 3 treatments (10 days) each, administered under fed conditions to healthy volunteers Additional 100 mg VOX (ie, SOF/VEL/VOX 400/100/100 mg + VOX 100 mg) administered to achieve systemic VOX exposures observed in HCV-infected patients PK Analyses: Steady-state plasma concentrations collected over 24 hours: validated LC/MS-MS assays PK parameters: noncompartmental methods (WinNonlin 6.4) Geometric least-squares mean ratios and 90% confidence intervals (Test: Reference): ANOVA for AUCτ, C max and Cτ; compared against lack of PK alteration boundaries of % AE monitoring, clinical laboratory, physical exam, ECG evaluations AE, adverse event; ANOVA, analysis of variance; AUCτ, area under plasma concentration-time curve over dosing interval; C max, maximal concentration; Cτ, concentration at end of dosing interval; LC/MS-MS, liquid chromatography tandem-mass spectrometry. 7

8 Subject Enrollment and Demographics by Cohort *4 subjects discontinued due to withdrawal of consent. Boosted HIV ARV Regimens DRV + RTV + FTC/TDF SOF/VEL/VOX plus Unboosted HIV ARV Regimens EVG/COBI/ FTC/TAF BIC/FTC/TAF FTC/RPV/TAF Enrolled/completed, n 30 / 28* 30 / 28* 30 / / 30 Mean age, y (range) 35 (20, 43) 34 (19, 45) 35 (28, 42) 34 (19, 45) Mean BMI, kg/m 2 (range) 26 (21, 30) 26 (19, 30) 27 (20, 30) 27 (21, 30) Sex (male / female), n 21 / 9 20 / / / 15 Race, n (%) White 25 (83) 21 (70) 17 (57) 20 (67) Black or African American 3 (10) 9 (30) 12 (40) 10 (33) Other 2 (7) 1 (3) Ethnicity, n (%) Hispanic/Latino 27 (90) 23 (77) 18 (60) 23 (77) 8

9 Results: Safety Subjects by Cohort, n (%) Boosted HIV ARV Regimens DRV + RTV + FTC/TDF SOF/VEL/VOX plus Unboosted HIV ARV Regimens EVG/COBI/ FTC/TAF BIC/FTC/TAF FTC/RPV/TAF AEs 8 (27) 11 (37) 9 (30) 16 (53) Grade 3 4 AE Serious AE Treatment D/C due to AE AEs >10% overall Headache* 2 (7) 0 3 (10) 11 (37) Grade 3 4 laboratory abnormality 2 (7) 2 (7) 2 (7) 5 (17) *All AEs of headache were Grade 1 or 2; All laboratory abnormalities were Grade 3, and included elevated LDL and occult blood in urine. D/C, discontinuation. 9

10 SOF or GS GMR% (90% CI) (FDC + ARV)/FDC Effect of HIV ARV Regimens on SOF and GS PK 250 SOF GS SOF GS SOF GS SOF GS AUCτ C max DRV + RTV + FTC/TDF EVG/COBI/FTC/TAF BIC/FTC/TAF FTC/RPV/TAF No clinically relevant changes to SOF or GS PK Minor changes in SOF exposure with boosted ARV regimens Mechanism for minor increase in renally-eliminated GS with EVG/COBI/FTC/TAF is unclear GMR, geometric least-squares mean ratios 10

11 VEL GMR% (90% CI) (FDC + ARV)/FDC Effect of HIV ARV Regimens on VEL PK AUCτ C max 143 Cτ DRV + RTV + FTC/TDF EVG/COBI/FTC/TAF BIC/FTC/TAF FTC/RPV/TAF No clinically relevant changes to VEL PK No alteration in VEL exposure with the exception of a minor increase in VEL Cτ with EVG/COBI/FTC/TAF 11

12 VOX GMR% (90% CI) (FDC + ARV)/FDC Effect of HIV ARV Regimens on VOX PK 500 AUCτ C max 300 Cτ DRV + RTV + FTC/TDF EVG/COBI/FTC/TAF BIC/FTC/TAF FTC/RPV/TAF VOX exposure is higher with boosted ARV regimens Explained by VOX being a substrate of transporters and enzymes Not clinically relevant based on exposure-safety evaluation in Phase 3 SOF/VEL/VOX studies 12

13 ARV GMR% (90% CI) (ARV + FDC)/ARV Effect of SOF/VEL/VOX on HIV ARV PK DRV RTV EVG COBI BIC RPV 500 AUCτ C max 300 Cτ DRV + RTV + FTC/TDF EVG/COBI/FTC/TAF BIC/FTC/TAF FTC/RPV/TAF No clinically relevant changes to DRV, RTV, EVG, COBI, BIC, or RPV PK Minor changes in DRV, RTV and EVG/COBI No change in BIC or RPV Lack of change in BIC, a CYP3A and UGT1A1 substrate, supports use of SOF/VEL/VOX with DTG and RAL UGT1A1, uridine diphosphate glucuronosyltransferase 1A1. 13

14 ARV GMR% (90% CI) (ARV + FDC)/ARV Effect of SOF/VEL/VOX on HIV ARV PK 250 TFV TAF TFV TAF TFV TAF TFV 200 AUCτ C max Cτ 0 DRV + RTV + FTC/TDF EVG/COBI/FTC/TAF BIC/FTC/TAF FTC/RPV/TAF Changes in TFV and/or TAF PK were consistent with P-gp/BCRP inhibition Small increase in exposure of TFV (~40 %) within DRV + RTV + FTC/TDF Moderate increases in exposures of TAF (~50 to 60 %) and TFV (~70 to 80 %) within unboosted ARV regimens Not considered clinically significant based on established exposure-safety relationships No change in FTC PK (data not shown) 14

15 Conclusions Study treatments were generally safe and well tolerated PK data support coadministration of SOF/VEL/VOX in HCV/HIV-coinfected patients on the following agents: NRTI NNRTI Integrase inhibitor Protease inhibitor PK booster FTC, TAF, TDF RPV BIC, DTG, EVG, RAL DRV COBI, RTV 15

16 Acknowledgments We extend our thanks to the study participants and study teams. These studies were funded by Gilead Sciences, Inc. 16