1 / 24

Will interferon-free strategies be a reality?

Will interferon-free strategies be a reality?. David Wong, MD University of Toronto TWH Francis Family Liver Clinic TGH Immunodeficiency Clinic SM Positive Care Clinic www.torontoliver.ca . Disclosures. Principal Investigator in multicenter studies HCV (none for IFN-free strategies)

soren
Download Presentation

Will interferon-free strategies be a reality?

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. Will interferon-free strategies be a reality? David Wong, MD University of Toronto TWH Francis Family Liver Clinic TGH Immunodeficiency Clinic SM Positive Care Clinic www.torontoliver.ca

  2. Disclosures • Principal Investigator in multicenter studies • HCV (none for IFN-free strategies) • BI, BMS, Johnson & Johnson, Vertex • HBV • BMS, Gilead • NO involvement in • Advisory Boards, Consultancy roles, Stocks

  3. Outline • IFN free strategies can work • Choosing optimal combinations • Exploring weaknesses of individual agents • Access to treatment • Need for more drugs in each class • Cost of treatment

  4. HCV genomeCombinations for cure Protease Pol Replication Complex

  5. First reportNaïve x 24 weeks • BMS-790052 (Daclatasvir) 60 mg OD • NS5a replication complex inhibitor • BMS-650032 (Asunaprevir) 600 mg BID • NS3 protease inhibitor • PegIFNa2a 180 ug weekly • Weakness: IL28b, cirrhosis (excluded), safety • Ribavirin 1000-1200 mg OD • Weakness: resistance? AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216

  6. Results (SVR) *1 PCR neg 35 days later Resistance Relapse 11 10 11 10 AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216

  7. NS5A + PI • Adding IFN helps • IFN likely small effect (prior null response) • RBV likely even less effect (resistance) AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216

  8. INFORM-SVRTreatment naïve x 24 weeks • Mericitabine (MCB) 1000 mg BID • Polymerase inhibitor • Danoprevir (DNV) 100 mg BID/ ritonavir 100 mg BID • Macrocyclic protease inhibitor - boosted • Ribavirin 1000-1200 mg OD • Treatment naïve • Cirrhotics excluded EJ Gane et al. EASL 2012

  9. Results after 24 weeks • High relapse if • 12 weeks treatment • RBV not included • Adding IFN helps 43 21 15 4 28 17 EJ Gane et al. EASL 2012

  10. PI/r + PolI + RBV • Ribavirin needed • DNV/r + MCB is weak double therapy • Adding another agent (IFN) helps • G1b > 90%, G1a > 70% • Matterhorn Study EJ Gane et al. EASL 2012

  11. Sound-C2/3PI + NNPolI +/- RBV • Faldaprevir (FDV) 120 mg OD • Protease inhibitor (all except 3) • Deleobuvir (DLV) 600 mg BID • Non-Nuc Polymerase Inhibitor • Sound-C21 • 1b >> 1a • IL28b CC and Genotype 1a might respond? • GI side effects: cannot keep pills down • Sound-C32 (learning from our mistakes) • SVR in G1b: 19/20 (95%) • SVR in G1a, IL28b CC: 2/12 (17%) V Soriano et al. EASL 2012 S Zeuzem et al. APASL 2013

  12. PI/r + PolI + RBV • Ribavirin needed • FDV and DLV is weak double therapy • Replacing RBV with another agent will likely help EJ Gane et al. EASL 2012

  13. ABT orals + RBV x 12 weeks in non-cirrhotics (naïve and nulls) • ABT-450/r • Protease inhibitor • ABT-267 • NS5a inhibitor • ABT-333 • Non-Nuc Polymerase Inhibitor KV Kowdley et al. A3. EASL 2013

  14. SVR24 Naïve N=159 Null N=88 % SVR24 81 50 124 42 44 33 33 66 45 3 78 108 35 113 115 56 55 22 41 85 1b >7 log <7 log CC Male Female 1a F0-F1 Non-CC 1b >7 log <7 log F2-F3 CC Male Female 1a F0-F1 Non-CC F2-F3 KV Kowdley et al. A3. EASL 2013

  15. Salvage for BOC/TPV failuresSOF+DCV+/-RBV x 24 weeks • Sofosbuvir (SOF) • Nuc Polymerase Inhibitor • Declatasvir (DCV) • NS5A Replication Complex Inhibitor MS Sulkowski et al. A1417. EASL 2013

  16. SVR12 1 missed is SVR24 % SVR 21 20 21 20 21 20 21 20 21 20 MS Sulkowski et al. A1417. EASL 2013

  17. Gilead Pipeline • Ledipasvir (LDV) • NS5A Replication Complex Inhibitor • GS-9669 • Non-Nuc Polymerase Inhibitor • Gilead plans • SOF + LDV • What about SOF + LDV + GS-9669?

  18. SOF + RBV + (LDV or GS-9669)x 12 weeks Electron Study: EJ Gane et al. A14. EASL 2013

  19. FISSIONG2/3 Treatment naïve x 12 weeks • Sofosbuvir (SOF) 400 mg OD • Polymerase inhibitor • Ribavirin (RBV) 1000-1200 mg OD • Treatment naïve • Cirrhotics included but Plts > 75 • Compared with PegIFN-RBV (800) x 24 weeks E Gane et al. A5. EASL 2013 E Lawitz et al. NEJM 2013;368:1878

  20. SVR12 251 241 250 236 244 224 190 253 243 59 54 11 13 145 139 38 37 Genotype 2 Genotype 3 Fission study: E Gane et al. A5. EASL 2013

  21. FUSIONG2/3 Difficult to treat 1FUSION: DR Nelson et al. A6. EASL 2013 2POSITRON: IM Jacobson et al. A61. EASL 2013 IM Jacobson et al. NEJM 2013;368:1867 • FUSION1 x 12 or 16 weeks • IFN failures • Cirrhosis 33% (Patelets > 50) • POSITRON2 x 12 weeks • IFN intolerant, ineligible or unwilling • Cirrhosis 15% (no platelet restriction)

  22. SVR12SOF + RBV Genotype 3 Prior treatment > 12 weeks 26 23 92 10 9 17 38 40 84 26 23 14 Genotype 2 Genotype 3 1FUSION: DR Nelson et al. A6. EASL 2013 2POSITRON: IM Jacobson et al. A61. EASL 2013 IM Jacobson et al. NEJM 2013;368:1867

  23. SummaryIFN-Free is inevitable • Challenging populations • Cirrhosis • Genotype 3? • Dream combo • Choice of agents to choose from • Ribavirin is weak • Interferon Lambda? • 3 bedroom house • PRT ~ 4 years+ rent • SVR ~ 10 years+ rent

  24. Questions?

More Related