1 / 28

Direct Acting Antivirals: What are they? What is their place in HCV management?

Direct Acting Antivirals: What are they? What is their place in HCV management? . Mark Sulkowski, MD Associate Professor of Medicine Johns Hopkins University School of Medicine . Limitations of PegIFN + Ribavirin (with or without protease inhibitors).

nantai
Download Presentation

Direct Acting Antivirals: What are they? What is their place in HCV management?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Direct Acting Antivirals: What are they? What is their place in HCV management? Mark Sulkowski, MD Associate Professor of Medicine Johns Hopkins University School of Medicine

  2. Limitations of PegIFN + Ribavirin (with or without protease inhibitors) • Antiviral activity is host + virus genotype dependent • IL28B CC genotype > TC and TT • Safety and tolerability risk outweighs treatment benefit for some individuals • “IFN unwilling and/or unable” • Finite number of expert healthcare providers • Cost

  3. Therapeutic Targets for DAAs • Prevent viral entry • Polyclonal and monoclonal antibodies • SRB1 receptor blockers • Prevent translation of viral RNA • NS3/4 protease inhibitors • Inhibit HCV-RNA polymerase • Nucleoside analogue NS5B polymerase inhibitors • Non-nucleoside analogue NS5B polymerase inhibitors • NS5A inhibitor • Cyclophilin B inhibitors • Viral assembly/release Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.

  4. Direct Acting Antivirals for Hepatitis C Nature Reviews Drug Discovery10, 93-94 (February 2011) | doi:10.1038/nrd3361

  5. New Targets • Peginterferon lambda (PegIL-29) • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • Cyclophilin inhibitors • DAA Combinations

  6. Peginterferon lambda + RBVVirologic response by IL28BGenotype in patients with HCV Genotypes 1, 4 Solid bars: CC Hatched bars: CT/TT RVR cEVR 100 90 80 70 60 Percentage of patients ± 95% CI 50 40 30 20 10 0 120 μg 180 μg 240 μg PegIFN-λ 120 μg 180 μg 240 μg PegIFN-λ 180 μg PegIFN-α-2a 180 μg PegIFN-α-2a n = 19 46 22 38 17 40 18 57 19 46 22 38 17 40 18 57 Zeuzem et al. EASL 2011

  7. Changes in Hematologic Parameters Over Time and Hematology-associated PegIFN and RBV Dose Reductions PegIFN-λ 120 µg PegIFN-λ 180 µg 150 PegIFN-λ 240 µg PegIFN-α-2a 140 Hemoglobin (g/L) 130 120 LLN 0 2 4 6 8 10 12 5 4 TotalNeutrophils (GI/L) 3 LLN 2 1 0 2 4 6 8 10 12 300 250 Platelets (GI/L) 200 150 LLN 0 2 4 6 8 10 12 Study Week Zeuzem et al EASL 2011

  8. New Targets • Peginterferon lambda (PegIL-29) • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • Cyclophilin inhibitors • DAA Combinations

  9. PILLAR Study: TMC435 + PegIFN/RBV PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4 and 12 Week 4 Week 12 *** *** *** *** *** *** *** *** Fried et al. AASLD 2010 Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.

  10. PILLAR Study: Role of IL28B Genotype PILLAR Week 24 Analysis: Mean Change in HCV RNA from Baseline According to IL28B Genotype* Placebo 0 -2 CC CT TT -4 -6 0 4 8 12 16 20 24 Week Mean(+/- SE) Change in Plasma HCV RNA(log10 IU/mL) from Baseline All TMC 435 (75 mg) All TMC 435 (150 mg) 0 0 -2 -2 -4 -4 -6 -6 0 0 4 4 8 8 12 12 16 16 20 20 24 24 Week Week Fried et al. AASLD 2010 Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.

  11. SILEN-C1: BI-1335 + PegIFN/RBV with or without 3-day lead-in Sulkowski et al. EASL 2011

  12. New Targets • Peginterferon lambda (PegIL-29) • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • Cyclophilin inhibitors • DAA Combinations

  13. Mericitabine + PegIFN/RBV for HCV genotype 1 patients 0 *Roche COBAS® HCV Test; LLOD = 15 IU/mL ITT population, n=408 Jensen DM, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. 81.

  14. PSI-7977 Phase 2b Study GT-1 treatment-naïve Weeks 72 48 24 12 0 STOP PSI-7977 200 mg QD + PEG-IFN -2a+ RBV PEG-IFN -2a+ RBV N=50 Non-RVR PEG-IFN -2a+ RBV SVR Follow-Up RG7128 400 mg QD + PEG-IFN -2a+ RBV PEG-IFN -2a+ RBV STOP N=50 Non-RVR PEG-IFN -2a+ RBV PEG-IFN -2a+ RBV N=25 GT-2/3 treatment-naïve open-label PSI-7977 400 mg QD + PEG-IFN -2a+ RBV SVR Follow-Up N=25 “12+0” • 150 patients GT-1, 2 & 3, treatment-naïve • Response-guided • IL28B stratified (GT-1, 125 patients) • Primary efficacy endpoint : Safety and tolerability Lalezari et al. EASL 2011

  15. PSI-7977 + PegIFN + RBV • 121 patients with HCV genotype 1 • 41% IL28B CC • No viral breakthrough observed • No safety signal detected

  16. New Targets • Peginterferon lambda (PegIL-29) • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • Cyclophilin inhibitors • DAA Combinations

  17. BMS-790052 Replication Complex Inhibitor: Change in HCV RNA after administration of single dose M Gaoet al. Nature000, 1-5 (2010) doi:10.1038/nature08960

  18. NS5A replication complex inhibitor + PegIFN/RBV Pol et al. EASL 2011

  19. New Targets • Peginterferon lambda (PegIL-29) • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • Cyclophilin inhibitors • DAA Combinations

  20. Alisporivir (DEB025): Oral cyclophilin B inhibitor • Synthesized from cyclosporin A • No immunosuppressive activity; Potent Cyp inhibition • Active all HCV genotypes • In vitro resistance in the NS5A region • Also active against HIV Flisiak et al. Hepatology. 2009 May;49(5):1460-8.

  21. Alisporivir + PegIFN/RBV in HCV genotype 1, treatment naïve patients Flisiak R et al. EASL 2011

  22. New Targets • Peginterferon lambda (PegIL-29) • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • Cyclophilin inhibitors • DAA Combinations

  23. INFORM-1: RG7128 + RG7227 1st clinical trial to investigate the combination of DAA in the absence of interferon and ribavirin Assessed safety and antiviral activity of RG7128 + RG7227 x13d Rx-naïve, null and relapser GT-1 HCV patients (N ~90) No evidence of resistance breakthrough in any cohort Gane et al. TheLancet 15 Oct 2010

  24. Telaprevir + VX-222 with or with PegIFN/RBV

  25. SOUND C-1: PI (1335) + non-nucleoside polymerase (7127) + RBV HCV RNA < 25 IU/mL, undetectable Two genotype 1a patients in the low dose group had viral rebound during treatment Zeuzem S., et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-7.

  26. PI + NS5A inhibitor ± PegIFN/RBV in prior null responder ↓ Indicates Initiation of PegIFN/RBV ↓ ↓ ↓ LOQ 26 IU/mL LOD < 10 IU/mL LOQ LOQ LOQ 26 IU/mL LOD < 10 IU/mL LOD LOD Lok AS, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-8.

  27. PI + NS5A inhibitor ± PegIFN/RBV in prior null responder • No PegIFN/RBV • 4/11 patients had SVR-12 with no PegIFN/RBV • 1a, 2/3 SVR with 1 relapse; 1b; 2/2 • 6/11 patients had breakthrough with PegIFN/RBV added  4 achieve undetectable HCV RNA (treatment ongoing) • QUAD therapy (PegIFN/RBV) • 10/10 patients had SVR-12 Lok AS, et al. EASL; Berlin, Germany 2011

  28. Future HCV therapies • Multiple agents in phase 2 or later development • Effective across viral genotypes and subtypes • Different resistant variants • Improved safety and tolerability • Oral (with the exception of IFN λ) • Less frequent dosing • Increase HCV treatment rates with IFN alfa free regimens

More Related