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LIVER CENTRE Toronto Western Site David Wong, MD University of Toronto TWH Francis Family Liver Clinic TGH Immunodeficiency Clinic SM Positive Care Clinic.

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Presentation on theme: "LIVER CENTRE Toronto Western Site David Wong, MD University of Toronto TWH Francis Family Liver Clinic TGH Immunodeficiency Clinic SM Positive Care Clinic."— Presentation transcript:

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

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

3 LIVER CENTRE Toronto Western Site Outline IFN free strategies can work IFN free strategies can work Choosing optimal combinations Choosing optimal combinations Exploring weaknesses of individual agents Exploring weaknesses of individual agents Access to treatment Access to treatment Need for more drugs in each class Need for more drugs in each class Cost of treatment Cost of treatment

4 LIVER CENTRE Toronto Western Site HCV genome Combinations for cure Protease Pol Replication Complex

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

6 LIVER CENTRE Toronto Western Site Results (SVR) 11101110 *1 PCR neg 35 days later ResistanceRelapse AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216

7 LIVER CENTRE Toronto Western Site NS5A + PI Daclatasvir (DCV)Asunaprevir (ASV) Genotypic coverageBroadG1 and 4 G1b SVR in 2/2Works G1a SVR in 2/9Weak?Weakness ResistanceWeakness CirrhosisNot tested Adding IFN helps Adding IFN helps IFN likely small effect (prior null response) IFN likely small effect (prior null response) RBV likely even less effect (resistance) RBV likely even less effect (resistance) AS Lok et al. A60. EASL 2011 AS Lok et al. NEJM 2012;336:216

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

9 LIVER CENTRE Toronto Western Site Results after 24 weeks High relapse if 12 weeks treatment RBV not included Adding IFN helps 43211542817 EJ Gane et al. EASL 2012

10 LIVER CENTRE Toronto Western Site PI/r + PolI + RBV Danoprevir (DNV)/rMericitabine (MCB) Genotypic coverage1, 4 and 6Broad? G1b SVR > 70%Works but moderate G1a SVR ~ 25%Weakness ResistanceWeakness CirrhosisNot tested Ribavirin needed Ribavirin needed DNV/r + MCB is weak double therapy DNV/r + MCB is weak double therapy Adding another agent (IFN) helps Adding another agent (IFN) helps G1b > 90%, G1a > 70% G1b > 90%, G1a > 70% Matterhorn Study Matterhorn Study EJ Gane et al. EASL 2012

11 LIVER CENTRE Toronto Western Site Sound-C2/3 PI + NNPolI +/- RBV Faldaprevir (FDV) 120 mg OD Faldaprevir (FDV) 120 mg OD Protease inhibitor (all except 3) Protease inhibitor (all except 3) Deleobuvir (DLV) 600 mg BID Deleobuvir (DLV) 600 mg BID Non-Nuc Polymerase Inhibitor Non-Nuc Polymerase Inhibitor Sound-C2 1 Sound-C2 1 1b >> 1a 1b >> 1a IL28b CC and Genotype 1a might respond? IL28b CC and Genotype 1a might respond? GI side effects: cannot keep pills down GI side effects: cannot keep pills down Sound-C3 2 (learning from our mistakes) Sound-C3 2 (learning from our mistakes) SVR in G1b: 19/20 (95%) SVR in G1b: 19/20 (95%) SVR in G1a, IL28b CC: 2/12 (17%) SVR in G1a, IL28b CC: 2/12 (17%) V Soriano et al. EASL 2012 S Zeuzem et al. APASL 2013

12 LIVER CENTRE Toronto Western Site PI/r + PolI + RBV Faldaprevir (FDV)Deleobuvir (DLV) Genotypic coverage1b>1a, not 3Broad? G1b SVR > 90%Works G1a SVR ~ 17%Weakness ResistanceWeakness CirrhosisWorks but moderate Ribavirin needed Ribavirin needed FDV and DLV is weak double therapy FDV and DLV is weak double therapy Replacing RBV with another agent will likely help Replacing RBV with another agent will likely help EJ Gane et al. EASL 2012

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

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

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

16 LIVER CENTRE Toronto Western Site SVR12 % SVR 21 20 21 20 21 20 21 20 21 20 MS Sulkowski et al. A1417. EASL 2013 1 missed is SVR24

17 LIVER CENTRE Toronto Western Site Gilead Pipeline Ledipasvir (LDV) Ledipasvir (LDV) NS5A Replication Complex Inhibitor NS5A Replication Complex Inhibitor GS-9669 GS-9669 Non-Nuc Polymerase Inhibitor Non-Nuc Polymerase Inhibitor Gilead plans Gilead plans SOF + LDV SOF + LDV What about SOF + LDV + GS-9669? What about SOF + LDV + GS-9669?

18 LIVER CENTRE Toronto Western Site SOF + RBV + (LDV or GS-9669) x 12 weeks Electron Study: EJ Gane et al. A14. EASL 2013 N=25N=10N=25N=9N=25N=3 IL28b CC44%20%36%028%13% Geno 1b12%10%20%11%16%90%

19 LIVER CENTRE Toronto Western Site FISSION G2/3 Treatment naïve x 12 weeks Sofosbuvir (SOF) 400 mg OD Sofosbuvir (SOF) 400 mg OD Polymerase inhibitor Polymerase inhibitor Ribavirin (RBV) 1000-1200 mg OD Ribavirin (RBV) 1000-1200 mg OD Treatment naïve Treatment naïve Cirrhotics included but Plts > 75 Cirrhotics included but Plts > 75 Compared with PegIFN-RBV (800) x 24 weeks Compared with PegIFN-RBV (800) x 24 weeks E Gane et al. A5. EASL 2013 E Lawitz et al. NEJM 2013;368:1878

20 LIVER CENTRE Toronto Western Site SVR12 251250244253241236224190243 591114538541313937 Genotype 2Genotype 3 Fission study: E Gane et al. A5. EASL 2013

21 LIVER CENTRE Toronto Western Site FUSION G2/3 Difficult to treat FUSION 1 x 12 or 16 weeks FUSION 1 x 12 or 16 weeks IFN failures IFN failures Cirrhosis 33% (Patelets > 50) Cirrhosis 33% (Patelets > 50) POSITRON 2 x 12 weeks POSITRON 2 x 12 weeks IFN intolerant, ineligible or unwilling IFN intolerant, ineligible or unwilling Cirrhosis 15% (no platelet restriction) Cirrhosis 15% (no platelet restriction) 1 FUSION: DR Nelson et al. A6. EASL 2013 2 POSITRON: IM Jacobson et al. A61. EASL 2013 IM Jacobson et al. NEJM 2013;368:1867

22 LIVER CENTRE Toronto Western Site SVR12 SOF + RBV Genotype 2Genotype 3 26231093840262392178414 Genotype 3 Prior treatment > 12 weeks 1 FUSION: DR Nelson et al. A6. EASL 2013 2 POSITRON: IM Jacobson et al. A61. EASL 2013 IM Jacobson et al. NEJM 2013;368:1867

23 LIVER CENTRE Toronto Western Site Summary IFN-Free is inevitable Challenging populations Challenging populations Cirrhosis Cirrhosis Genotype 3? Genotype 3? Dream combo Dream combo Choice of agents to choose from Choice of agents to choose from Ribavirin is weak Ribavirin is weak Interferon Lambda? Interferon Lambda? 3 bedroom house PRT ~ 4 years+ rent SVR ~ 10 years+ rent

24 LIVER CENTRE Toronto Western Site Questions?

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