1 / 29

Advantages of New Generation Direct Acting Antivirals (DAAs) Tarik Asselah MD, PhD

Advantages of New Generation Direct Acting Antivirals (DAAs) Tarik Asselah MD, PhD Service d ’ Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichy tarik.asselah@bjn.aphp.fr. Where we are : The Present Triple therapy : PI + PEG-IFN + RBV. Increased Efficacy in G1 patients (> 30%)

mahon
Download Presentation

Advantages of New Generation Direct Acting Antivirals (DAAs) Tarik Asselah MD, PhD

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. Advantages of New Generation Direct Acting Antivirals (DAAs) Tarik AsselahMD, PhD Service d’Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichytarik.asselah@bjn.aphp.fr

  2. Where we are : The PresentTriple therapy : PI + PEG-IFN + RBV • Increased Efficacy in G1 patients (> 30%) • G1 naïves • G1 relapsers • Shorten duration (> 50%) • Predictors of non response • Cirrhosis • Subtype 1a • Previous non response

  3. Where we are : The presentLimitations of Triple therapy • Efficacy only in G1 patients • Low SVR in difficult to treat patients • Cirrhosis • Previous null responders • Side Effects • Costs New Generation DAAs

  4. New GenerationDAAs • Introduction : Targets for DAAs • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • IFN free combination • Conclusion

  5. Viral Cycle Asselah T et al. Liver International 2012

  6. Immune Response to HCV Asselah T et al. GUT 2009 Asselah T et al. GUT 2009

  7. Targets for DAAs NS5A Inhibitors Protease Inhibitors Polymerase Inhibitors NS3-4A Protease NS5A NS5B Polymerase Asselah T et al. Liver International 2012

  8. New DAAs 1e.g. PSI-7977, PSI-938; 2e.g. MK-5172, ACH-1625; 3e.g. PPI-461

  9. New drugs

  10. New Agents G1 naïves Not head-to-head comparisons 100 75-86 68-85 65-85 61-84 71-83 42-83 80 53-76 63-75 60 56 38-50 SVR (%) 40 20 0 BOC or TVR [1,2] Filibuvir[8] Vaniprevir[7] Tegobuvir[9] BI 201335[3] TMC435[6] Narlaprevir[5] Danoprevir[4] Alisporivir[11] Daclatasvir[10] Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79. 5. Vierling JM, et al. AASLD 2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5. 7. Manns MP, et al. AASLD 2010. Abstract 82. 8. Jacobson I, et al. EASL 2010. Abstract 2088. 9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011. Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4.

  11. New GenerationDAAs • Introduction : Targets for DAAs • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • IFN free combination • Conclusion

  12. New Generation of DAAs • Proteaseinhibitors • TMC 435 • BI 201335 • Danoprevir • MK 7009 • Polymeraseinhibitors • PSI-7977 • NS5A inhibitor • Daclatasvir

  13. TMC435 (G1 naïves) 100 p = 0,008 p = 0,013 p < 0,001 n.s. SVR (ITT) 90 86 82 81 80 75 70 65 60 50 SVR (%) 40 30 20 10 0 TMC435 75 mg12 wP/R(n = 78) TMC435 75 mg24 wP/R(n = 75) TMC435 150 mg12 wP/R(n = 77) TMC435 150 mg24 wP/R(n = 79) PlaceboP/R(n = 77) Fried et al. AASLD 2011, LB5

  14. BI201335 (G1 naïves) BI 12 weeks BI 24 weeks 100 82 73 72 80 65 60 Patients (%) 40 20 58/81 64/78 53/81 57/78 0 eRVR SVR Dieterich et al. AASLD 2011, A36

  15. A : 300 mg + P/R (n = 72) B : 600 mg + P/R (n = 72) C : 900 mg + P/R (n = 50) 96 100 85 D : Placebo mg + P/R (n = 31) 87 89 88 86 68 79 76 80 74 65 42 60 SVR (%) 40 18 20 7 53 72 63 72 43 50 47 72 57 72 9 50 49 72 61 72 38 50 13 31 41 47 55 57 8 9 2 31 N/A 0 RVR eRVR SVR24 SVR24 Patients eRVR* Danoprevir (DNV, RG7227) (G1 naïves) SVR *Patients RVRe : patients with HCV RNA undetectable from W4 to W20 Terrault et al. AASLD 2011, A79

  16. All 120 * p < 0,001 vs PR Relapsers Partial Responders 100 Breakthroughts 100 100 84,6* 93 Null responders 78* 87 87 86 86 80 83 71,1* 80 66,7* 67 60 60 50 50 40 40 40 37 31 19* 29 20 11 38 39 37 28 39 5 14 7 5 12 16 5 6 10 16 7 16 6 7 10 16 8 5 10 0 0 MK-7009 MK-7009 MK-7009 MK-7009 PR 48 sem 600 mg x 2/j 600 mg x 2/j 300 mg x 2/j 600 mg x 2/j + PR 24 w + PR 48 w +PR 48 w + PR 48 w MK 7009 (G1 experienced) SVR Lawitz et al. AASLD 2011, LB13

  17. Summary: New Generation PI triple therapy (G1 naïves) Fried et al. AASLD 2011 LB5 Sulkowski et al. EASL 2011 USA, A60 Manns et al. AASLD 2010, A82 Terrault et al. AASLD 2011 A79

  18. New Generation of DAAs • Proteaseinhibitors • TMC 435 • BI 201335 • Danoprevir • MK 7009 • Polymeraseinhibitors • PSI-7977 • NS5A inhibitor • Daclatasvir

  19. PSI-7977 (G2 and G3 naïves) PSI-7977 + RBV + PEG-INF n = 11 SVR 12 PSI-7977 + RBV + PEG-INF PSI-7977 + RBV n = 10 SVR 12 PSI-7977 + RBV+ PEG-INF PSI-7977 + RBV n = 9 SVR 12 PSI-7977 + RBV n = 10 SVR 12 W0 W4 W8 W12 W24 Gane et al. AASLD 2011, A34

  20. PSI-7977 (G2 and G3 naïves) *LOD : limit of detection Gane et al. AASLD 2011, A34

  21. RVR RVRe EOT SVR12 (%) 98 98 100 92 91 91 91 88 80 60 50 40 19 20 0 PEG/RBV 200 mg + PEG/RBV 400 mg + PEG/RBV PSI-7977 (G1 naïves) SVR 12 * 50% des patients PR ont atteint la fin de traitement S48 Lawitz et al. AASLD 2011, A225

  22. Quadriple therapy : PEG-IFN+ RBV+ NS5A (Daclatasvir) + PI inhibitors (Asunaprevir)G1 non responders • Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks Japan Study[2] US Study[1] 100 90* 90 Daclatasvir + Asunaprevir 80 Daclatasvir + Asunaprevir + PR 60 SVR24 (%) 36 40 20 N/A 0 *all genotype 1b patients. 1. Lok A, et al. NEJM 2012.2. Chayama K, et al. Hepatology 2012.

  23. New GenerationDAAs • Introduction : Targets for DAAs • Protease inhibitors • Polymerase inhibitors • NS5A inhibitors • IFN free combination • Conclusion

  24. IFN free combination

  25. IFN free combination: Proof of Concept RG7128 and Danoprevir 1 Placebo 0 -1 -2 Réduction ARN VHC -3 -4 1000b/600b-TE 1000b/900b-TE -5 1000b/900b-Na -6 -7 0 2 4 6 8 10 12 14 Days Gane et al. Lancet 2010

  26. BI 201335 + BI 207127 + RBV (G1 naïves) 6/15 6/15 14/17 14/17 10/15 10/15 17/17 17/17 11/15 11/15 17/17 17/17 Zeuzem S, et al. Gatroenterology 2011

  27. Avoid cross resistance : NS3/4A protease inhibitors Ph Halfon, S Locarnini J Hepatol 2011

  28. Where we go : The Future Ten Commandments for the Magic Drug

  29. Where we go : The FutureTen Commandments for the Magic Drug 1 High Efficacy 2 Pan-Genotypic 3 Favorable safety profile 4 Low resistance (high genetic barrier) 5 Oral regimen (IFN free) 6 Once a day (Good pharmacokinetic) 7 Short duration 8 Few drug-drug interraction 9 Available for (ELD) cirrhosis and HIV-HCV 10 Low price (access program)

More Related