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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).

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

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  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

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