Efficacy and safety of switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the single-tablet regimen (STR) of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in virologically suppressed, HIV-1-infected adults through 24 weeks: EMERALD Study Jean-Michel Molina1, Joel Gallant2, Chloe Orkin3, Eugenia Negredo4, Laveeza Bhatti5, Joseph Gathe6, Erika Van Landuyt7, Erkki Lathouwers7, Veerle Hufkens7, Simon Vanveggel7, Magda Opsomer7 Department of Infectious Diseases, St-Louis Hospital, University of Paris Diderot, Paris, France; 2Southwest CARE Center, Santa Fe, New Mexico, USA; 3 Barts and Health NHS Trust, London, UK; 4Germans Trias i Pujol University Hospital, Badalona, Spain; 5AIDS Healthcare Foundation, Beverly Hills, California, USA; 6Therapeutic Concepts, Houston, Texas, USA; 7 Janssen Pharmaceutica NV, Beerse, Belgium 1 Molina J-M, et al. 9th IAS 2017. Abstract TUAB0101 D/C/F/TAF: The First Once-Daily STR in Development Containing Darunavir Boosted darunavir (DRV) 800mg: High, durable virologic response High barrier to development of resistance 14 Recommended in EACS (any booster) and DHHS (DRV/r) guidelines 5,6 Tenofovir alafenamide (TAF), prodrug of tenofovir, vs TDF: Similar efficacy at 1/10 dose Improved renal and bone safety profile710 D/C/F/TAF: DRV (D, 800mg), cobicistat (C, 150mg), emtricitabine (FTC, F, 200mg) and TAF, 10mg 7 Being investigated in EMERALD and AMBER EMERALD (NCT02269917) and AMBER (NCT02431247) 1. Cahn P, et al. AIDS 2011;25:92939 2. Mills AM, et al. AIDS 2009;23:167988 3. Flynn P, et al. PIDJ 2014;33:9405 4. Lathouwers E, et al. CROI 2017. Abstract 505 5. DHHS guidelines. July 14, 2016 6. EACS Guidelines, Version 8.2. January 2017 7. Mills A, et al. J Acquir Immune Defic Syndr 2015;69:43945 8. Ruane PJ, et al. J Acquir Immune Syndr 2013;63:44955 9. Custodio JM, et al. ASCPT 2015. Abstract PI-052 10. De Clercq E. Biochem Pharmacol 2016 pii:S0006-2952(16)300697
2 EMERALD: Open-label, Randomised, Multicentre, Parallel-group, Non-inferiority Phase III Trial Screening phase 30 days prior to baseline Extension phase Treatment phase Randomisation* 2:1 N=1149 Roll-over phase D/C/F/TAF D/C/F/TAF D/C/F/TAF Continue bPI + F/TDF Baseline Week 24 Week 48 Interim analysis Primary endpoint Week 96 Objective: Non-inferiority and safety of switching to D/C/F/TAF vs continuing bPI + FTC/TDF regimens in virologically suppressed HIV-1-infected adults at Week 48 Key inclusion criteria: Previous ART VF allowed
Absence of history of VF on DRV, and if historical genotype available, absence of DRV RAMs Viral load (VL) <50 c/mL for 2 months before screening; one VL50 and <200 c/mL within 12 months prior to screening allowed Creatinine clearance (by Cockcroft-Gault) 50 mL/min *Stratified by bPI (protease inhibitor boosted with low-dose ritonavir or cobicistat) at screening; DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V (IAS-USA) 3 Primary Endpoint Proportion of patients with virologic rebound, cumulative through Week 48 Virologic rebound definition: Confirmed VL50 c/mL* or Premature discontinuations (irrespective of reason), with last (single) VL50 c/mL through Week 48 Statistical analysis: Stratified MH difference (95% CI) between D/C/F/TAF and control Non-inferiority margin: upper limit of 95% CI <4% at Week 48 *Single VL >50c/mL at Week 48 also considered as a rebounder MH = Mantel-Haenszel test adjusting for bPI at screening CI = confidence interval 4 Baseline Demographics and Disease Characteristics D/C/F/TAF QD N=763 Control N=378 Median (range) age, years 46 (1975) 45 (2078)
30 (7.9) 107 (14.0) 65 (17.2) 107.5 (30.56) 107.0 (30.29) Race, n (%) Asian/other races Median (range) CD4+ cell count, cells/mm3 Median (range) time since diagnosis, years On first ARV regimen, n (%) Prior VF, n (%) Boosted PI at screening, n (%) Cobicistat, n (%) Mean (SD) eGFR creatinine (Cockcroft-Gault) 5 Week 24 Efficacy 0.8% (95% CI: 1.7%, 3.3%) 80 % confirmed virologic rebound cumulative through Week 24 60 40 0.3% (95% CI: 2.0%, 1.5%) 20 100 96.3 95.5 Proportion of patients (%) Proportion of patients (%)
100 80 60 40 20 (n=735) 0 0 180.00% 210.00% DCFTA... Contro... % response and virologic failure at Week 24 (FDA snapshot) (n=361) Virologic success 0.5 0.8 Virologic failure 3.1 3.7 No virologic data VF (50c/mL) at W24 defined as last VL in W24 window 50c/mL, or premature discontinuations ( AE/death), with last (single) VL 50c/mL
Most rebounders (10/14 D/C/F/TAF and 5/8 control) resuppressed (<50c/mL) by Week 24 No confirmed rebounds 200 c/mL No discontinuations for VF No DRV/primary PI or NRTI RAMs were observed (2 patients genotyped in each group) 6 Adverse Events Through 24 Weeks Parameter, n (%) 1 AE, any grade, regardless of causality 1 grade 34 AE related to study drug 1 serious AE Total discontinuations 1 AE leading to permanent discontinuation Discontinuations due to renal AEs Deaths Most common AEs (5% both arms) Nasopharyngitis Upper respiratory tract infection Vitamin D deficiency D/C/F/TAF QD N=763 543 (71.2) 9 (1.2) 19 (2.5) 22 (2.9) 10 (1.3) 1 (0.1)a 0 Control N=378 265 (70.1) 2 (0.5) 12 (3.2) 11 (2.9) 4 (1.1) 2 (0.5)b 0 58 (7.6) 48 (6.3) 42 (5.5) 25 (6.6) 24 (6.3)
19 (5.0) Worsening of a pre-existing chronic kidney disease (Grade 2, non-serious); toxic nephropathy (Grade 4, non-serious) and one renal tubular disorder (Grade 1) a b One 7 Grade 3 or 4 Laboratory Abnormalities Through Week 24 D/C/F/TAF QD N=763 Control N=378 Creatinine clearancea (<60 mL/min) 31 (4.1) 12 (3.2) Fasting LDL-C (4.90 mmoL/L) 23 (3.0) 2 (0.5) Parameter, n (%) Phosphate (<0.65 mmoL/L) Creatinine kinase (10 x ULN) Total bilirubin (2.6 x ULN) 15 (2.0) 15 (4.0) 10 (1.3) 8 (2.1) 1 (0.1)
16 (4.3) Worst grade, treatment-emergent Grade 3 or 4 events occurring in 2% of patients in either arm No clinically or statistically significant difference between arms in median change from baseline to Week 24 in TC/HDL-C ratio (D/C/F/TAF 0.2 vs control 0.1; p=0.288*) Cockcroft-Gault; *Assessed by van Elteren test, controlling for bPI at screening; ULN = upper limit of normal a 8 Changes in eGFR Through Week 24 Estimated GFR based on Serum Creatininea Mean (SE) change from baseline in eGFR (mL/min/1.73m2) 3 D/C/F/TAF (N=735) Estimated GFR based on Cystatin Ca 3 Control (N=362) 2 D/C/F/TAF (N=734) 2 p=0.118* 1 Control (N=360) p=0.026* 1 0
0 -1 -1 -2 -2 -3 0 2 4 8 12 24 -3 0 2 Time (weeks) 4 8 12 24 Time (weeks) Results are consistent with the known effect of cobicistat on inhibition of tubular secretion of creatinine Based on serum levels and CKD-EPI formula *Between treatment comparison assessed by van Elteren test, controlling for bPI at screening a 9
Changes in BMD Through Week 24 Hip Control (N=108) 2 1 0.6 -0.3 0 -1 p<0.001* -2 D/C/F/TAF (N=209) Mean (SE) % change from baseline in BMD Mean (SE) % change from baseline in BMD D/C/F/TAF (N=209) Spine Control (N=108) 2 1.2 1 -0.3 0 -1 -2 p<0.001* D/C/F/TAF
Control D/C/F/TAF Control 3% increase 9.8% 5.4% 24.0% 9.3% 3% decrease 4.3% 7.5% 6.8% 15.5% *Assessed by van Elteren test, controlling for bPI at screening; BMD, bone mineral density 10 EMERALD Week 24 Analysis: Conclusions Through Week 24, switching from bPI + FTC/TDF to D/C/F/TAF resulted in: Low virologic rebound rate cumulative through 24 weeks (1.8%) High virologic suppression rate (96.3%) No discontinuations for VF No resistance to any study drug Few serious AEs and discontinuations due to AEs D/C/F/TAF bone, renal and lipid safety vs control were consistent with known profiles of TAF and cobicistat D/C/F/TAF combines the safety advantages of TAF and DRV, with the known efficacy and high genetic barrier to resistance of DRV, in an STR 11
Acknowledgements We thank the patients and their families for their participation and support during the study, the EMERALD study team, site staff and the principal investigators: Belgium: S De Wit, E Florence, M Moutschen, E Van Wijngaerden, L Vandekerckhove, B Vandercam; Canada: J Brunetta, B Conway, M Klein, D Murphy, A Rachlis, S Shafran, S Walmsley; France: F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah; Poland: J Gasiorowski, W Halota, A Horban, A Piekarska, A Witor; Spain: JR Arribas, J Berenguer, J Casado, JM Gatell, F Gutierrez, MJ Galindo, MDM Gutierrez, JA Iribarren, H Knobel, E Negredo, JA Pineda, D Podzamczer, J Portilla Sogorb, F Pulido, C Ricart, A Rivero, I Santos Gil; Sweden: A Blaxhult, L Flamholc, M Gissln, A Thalme; Switzerland: J Fehr, A Rauch, M Stoeckle; UK: A Clarke, BG Gazzard, MA Johnson, C Orkin, F Post, A Ustianowski, L Waters; US: J Bailey, P Benson, L Bhatti, I Brar, UF Bredeek, C Brinson, G Crofoot, D Cunningham, E DeJesus, C Dietz, R Dretler, J Eron, F Felizarta, C Fichtenbaum, J Gallant, J Gathe, D Hagins, S Henn, WK Henry, G Huhn, M Jain, C Lucasti, C Martorell, C McDonald, A Mills, J Morales-Ramirez, K Mounzer, R Nahass, H Olivet, O Osiyemi, D Prelutsky, M Ramgopal, B Rashbaum, G Richmond, P Ruane, A Scarsella, A Scribner, P Shalit, D Shamblaw, J Slim, K Tashima, G Voskuhl, D Ward, A Wilkin, J de Vente The authors would also like to thank Bryan Baugh, Maria Blanca Hadacek, Kimberley Brown, Julia Sugumar and Eric Y. Wong from Janssen for their important contributions to the presentation. 12 Disclosures J-M Molina has participated in advisory boards for Merck, Gilead Sciences, Janssen, ViiV, Bristol-Myers Squibb (BMS) and Teva and a Speakers Bureau for Gilead. He has received research grants from Merck and Gilead Sciences. J Gallant has received consulting fees or advisory board honoraria from BMS, Gilead Sciences, Merck, ViiV and Theratechnolgies, and research grants from AbbVie, BMS, Gilead Sciences, Janssen Therapeutics, Merck, Sangamo Biosciences and ViiV/GSK. C Orkin has received speaker honoraria or consulting fees for attending Speaker's Bureaus or advisory boards and research grants from Janssen, Merck, ViiV and Gilead Sciences. E Negredo has received personal fees from ViiV, Merck, Janssen Cilag, BMS, Gilead Sciences and AbbVie. L Bhatti has received payment for lectures (including Speakers Bureaus) from BMS, Janssen, Merck and ViiV, holds stock in Gilead Sciences and has served on advisory boards for BI, BMS, Genentech and Gilead Sciences. J Gathe has been a consultant or speaker in conferences supported by AbbVie, BMS, GSK, ViiV, Janssen, Merck, and Gilead Sciences; is affiliated with an institution that received research grants from AbbVie, BMS, GSK, ViiV, BI, Pfizer, Janssen, Merck, Gilead Sciences, and Janssen Therapeutics; has served an investigator for Abbott Laboratories, Avexa, BI, Gilead Sciences, GSK, Merck, Pfizer, Roche Laboratories, Parexel, Hiesped, and Janssen Therapeutics; and his institution has received honoraria for speaking or chairing engagements from Abbvie, BMS, GSK, Gilead Sciences, Merck, Pfizer, and Janssen Therapeutics. E Van Landuyt, E Lathouwers, V Hufkens, S Vanveggel and M Opsomer are all full-time employees of Janssen and potential stockholders of Johnson and Johnson. This study was sponsored by Janssen. Medical writing support was provided by Ian Woolveridge from Zoetic Science, Macclesfield, UK, an Ashfield Company. Support for medical writing assistance was provided by Janssen. 13
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