RESEARCH B/F/TAF in Treatment-Naïve HIV-1 and HIV-1 RNA Suppressed Switch Patients

Transcription

1 RESEARCH B/F/TAF in Treatment-Naïve HIV-1 and HIV-1 RNA Suppressed Switch Patients Kirsten White Gilead Sciences, Inc., Foster City, CA

2 Background Bictegravir (BIC; B) is a novel, unboosted integrase strand transfer inhibitor (INSTI) Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single tablet regimen (STR) recently approved by the US FDA for treatment of HIV-1 infection in treatment-naïve and virologically suppressed adults without resistance to its components Two Phase 3 studies of treatment-naïve participants (1489 and 1490) Two Phase 3 studies of virologically suppressed participants (1844 and 1878) No development of resistance to B/F/TAF

3 Outline BIC In Vitro Resistance Profile Efficacy Outcomes at Week 48 Pre-Existing Resistance Substitutions and B/F/TAF Treatment Outcomes Future Clinical Trials of B/F/TAF

4 HIV-1 PhenoSense IN Assay with Integrase Site-Directed Mutations Bictegravir has a Favorable Cross-Resistance Profile Single Primary Mutations Fold Change vs WT IN Genotype BIC DTG EVG RAL T66I T66A T66K E92Q E92G T97A F121Y Single Primary Mutations Fold Change vs WT IN Genotype BIC DTG EVG RAL Y143R Y143H Y143C S147G Q148R Q148H Q148K N155H R263K EC 50 Fold Change (FC) vs Reference Wild Type < 2.5 BIC 2.5 to < 10 BIC 10 BIC < 4.0 DTG 4.0 to < 13 DTG 13 DTG < 2.5 EVG 2.5 EVG < 1.5 RAL 1.5 RAL Margot et al.; Submitted

5 HIV-1 PhenoSense IN Assay with Clinical Isolates Bictegravir has a Favorable Cross-Resistance Profile G140A/C/S + Q148H/R/K +/- other IN Genotype Fold Change vs WT DTG BIC G140S,Q148H G140S,Q148H G140S,Q148H G140S,Q148H G140S,Q148H E138K,G140S,Q148H G140S,Q148H G140A/C/S + Q148H/R/K +/- other IN Genotype Fold Change vs WT DTG BIC E138K,G140S,Q148H G140S,Q148H G140S,Q148R E138K,G140C,Q148R L74L/M,G140A,Q148R L74M,G140C,Q148R L74L/M,G140A,Q148R L74M,G140C,Q148R E138A, G140S,Q148H G140S,Q148H G140A/C/S + Q148H/R/K +/- other IN Genotype Fold Change vs WT DTG BIC E138K,G140S,Q148H G140S,Q148H T97A,G140S,Q148H T97A,G140S,Q148H G140S,Q148R E138K,G140A,Q148K BIC has an improved resistance profile compared to DTG (p=0.037) EC 50 Fold Change (FC) vs Reference Wild Type < 2.5 BIC 2.5 to < 10 BIC 10 BIC < 4.0 DTG 4.0 to < 13 DTG 13 DTG < 2.5 EVG 2.5 EVG < 1.5 RAL 1.5 RAL White K, et al., European Workshop HIV & Hep Rome, Italy. Poster O-01. Tsiang M, et al., AAC 2016;60:

6 B/F/TAF Phase 3 Efficacy through Week 48 Study Population Comparator Efficacy Resistance Naïve DTG/ABC/3TC Non-inferior* Naïve DTG+FTC/TAF Non-inferior* Suppressed DTG/ABC/3TC Non-inferior Suppressed Boosted PI + 2 NRTIs Non-inferior Women, Suppressed E/C/F/(TAF or TDF) ATV+RTV + FTC/TDF Non-inferior 0** In five Phase 3 trials of 1,440 patients through Week 48 B/F/TAF had non-inferior efficacy with zero emergent resistance * For ART-naïve studies: Treatment outcomes [between treatment groups] were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count. 6 For virologically suppressed studies: Treatment outcomes between treatment groups were similar across subgroups by age, sex, race, and region. 5,6 One boosted PI regimen participant on DRV+RTV+ABC/3TC developed ABC mutation L74V ** One E/C/F/TAF participant developed FTC mutation M184M/I/V 1. Gallant J, et al. Lancet 2017;390: Sax P, et al. Lancet 2017;390: Molina JM, et al. CROI Boston, MA. Oral Daar E, et al. ID Week San Diego, CA. Oral LB-4 5. Kityo C, et al. CROI Boston, MA. Poster Gilead Sciences. Biktarvy US Prescribing Information. February 2018.

7 P r o p o r tio n w ith H IV -1 R N A < 5 0 c o p ie s /m L (% ) Rapid Suppression of HIV-1 RNA to < 50 copies/ml (Missing = Excluded Approach); 1489 & Week 4 76% 76% 80% Week 8 91% 92% 90% Week 12 96% 96% 95% Week 48 99% B/F/TAF 98% DTG/ABC/3TC 99% DTG+F/TAF B /F /T A F 3 0 D T G /A B C / D T G + F /T A F W e e k B/F/TAF vs. DTG/ABC/3TC or vs. DTG + F/TAF: rapid viral suppression and non-inferior efficacy at Week 48

8 White K, et al. CROI Boston, MA. Poster 532, Andreatta et al, CROI 2018 Boston, MA. Poster 506 Baseline Resistance Testing Screening Retrospective Baseline Testing Tx Naïve PR, RT Genotype GenoSure MG Monogram No IN Genotype PR, RT, IN Deep Sequencing SeqIT, Germany 15% frequency reported Switch Historical Genotype if available PR, RT, IN PR, RT, IN DNA Genotype GenoSure Archive* Monogram *Deep sequencing APOBEC hypermutation filter >15% frequency reported

9 White K, et al. CROI Boston, MA. Poster 532 Studies 1489 & 1490: B/F/TAF vs DTG-containing Regimens in Treatment-Naïve Adults Baseline Resistance-Associated Substitutions & FDA Snapshot Outcome Resistance Class Number of Participants, n (%) B/F/TAF n=634 Week 48 HIV-1 RNA <50 c/ml With Data 634 (100%) 576/634 (91%) Primary INSTI-R 6 (1.0%) 6/6 (100%) T97A 5 (0.8%) 5/5 (100%) Q148H (+G140S) 1 (0.2%) 1/1 (100%) Primary NRTI-R 16 (2.5%) 14/16 (88%) Any TAM 16 (2.2%) 14/16 (88%) Primary NNRTI-R 76 (12%) 68/76 (90%) K103N/S 41 (6.5%) 38/41 (93%) E138A/G/K/Q 24 (3.8%) 21/24 (88%) Primary PI-R 16 (2.5%) 15/16 (94%)

10 B/F/TAF Patient With Transmitted Resistance: Baseline White K, et al. CROI Boston, MA. Poster 532

11 P la s m a H IV -1 R N A (c o p ie s /m L ) B/F/TAF Patient with Transmitted Resistance: Baseline (2.5 10) B /F /T A F This is the first case of an ART-naïve patient with transmitted integrase resistance (G140S + Q148H) on B/F/TAF Virologic suppression was rapid and maintained from Week 4 to V is it D a te (W e e k s ) Baseline Genotype: NRTI: K70R NNRTI: K103N PI: none INSTI: G140S, Q148H

12 Andreatta K, et al. CROI Boston, MA. Poster 506 Studies 1844 & 1878: Suppressed Adults Switched from ABC/3TC/DTG or Boosted PI Baseline Resistance Data Resistance Class Number of Participants, n (%) B/F/TAF n=572 PR/RT Baseline Data 405 (71%) Historical Genotype 280 (49%) Baseline DNA Genotype 149 (26%) IN Baseline Data 170 (30%) Historical Genotype 23 (4%) Baseline DNA Genotype 149 (26%)

13 Andreatta K, et al. CROI Boston, MA. Poster 506 Studies 1844 & 1878: Suppressed Adults Switched from ABC/3TC/DTG or Boosted PI Baseline Resistance-Associated Substitutions & FDA Snapshot Outcome Resistance Class Number of Participants, n (%) B/F/TAF n=572 Week 48 HIV-1 RNA <50 c/ml Primary INSTI-R 1 (1.0%) 1/1 (100%) T97A 1 (1.0%) 1/1 (100%) Primary NRTI-R 52 (13%) 49/52 (94%) K65R 5 (1%) 5/5 (100%) M184V/I 30 (7%) 28/30* (93%) Any TAM 29 (7%) 28/29 (97%) Primary NNRTI-R 73 (18%) 71/73 (97%) K103N/S 46 (11%) 44/46 (96%) Primary PI-R 25 (6%) 25/25 (100%) M184V/I: 1 discontinued with HIV-1 RNA <50 c/ml at Week 4 and 1 had rebound at Week 8 and no detectable BIC in the plasma

14 Study 4030: B/F/TAF vs DTG + F/TAF or F/TAF in Suppressed Adults 4030 Study Design Phase 3, randomized, double-blind, multicenter, active-controlled study HIV-Suppressed Adults DTG + F/TDF or F/TAF Treatment HIV-1 RNA Naïve < 50 Patients c/ml Study egfr 102 and 103 CG 30 ml/min 1:1 N=260 N=260 B/F/TAF QD DTG + F/TAF Placebo QD DTG + F/TAF QD B/F/TAF Placebo QD ClinicalTrial.gov: NCT Key inclusion criteria Any NRTI, NNRTI or PI resistance are permitted HIV-1 <50 c/ml 6 months if documented or suspected NRTI resistance HIV-1 <50 c/ml 3 months if no NRTI resistance suspected or documented No documented resistance to INSTI or confirmed virologic failure (2 consecutive HIV-1 RNA 50 c/ml after achieving < 50 c/ml while on an INSTI-containing regimen) HBV and/or HCV coinfections allowed Primary Endpoint HIV-1 RNA 50 copies/ml at Week 48 by modified FDA-defined snapshot algorithm (4% non-inferiority margin) Week 48 Primary Endpoint

15 Conclusions ARV-naïve: Treatment with B/F/TAF, DTG/ABC/3TC, or DTG + F/TAF was highly efficacious through Week 48 Rapid viral load suppression by Week 4 Pre-existing drug resistance did not affect efficacy outcome One patient with transmitted INSTI resistance at G140S+Q148H treated with B/F/TAF achieved HIV-1 RNA was < 50 copies/ml at Week 4 and maintained suppression through Week 96 ARV Suppressed Switch: Switch to B/F/TAF from DTG +ABC/3TC or Boosted PI was highly efficacious through Week 48 Pre-existing drug resistance did not affect efficacy outcome High maintenance of suppression with M184V/I or 1-2 TAMs No patient developed resistance to study drugs on B/F/TAF or a DTG-based regimen Further studies of bictegravir and B/F/TAF in patients with virologic resistance are warranted

16 Acknowledgements Patients and their families Study Investigators and Site Staff Gilead Sciences B/F/TAF Team, Erin Quirk, Hal Martin, Devi Sengupta, Hiba Graham, Sean Collins, Huyen Cao, Tariro Makadzendge Clinical Virology: Rima Acosta, Kristen Andreatta, Madeleine Willkom, Danielle Porter, Nicolas Margot Seq-IT: Martin Daümer, Alex Thielen Monogram: Tim Persyn 16