Treatment Targets HCV Genotype 1 & PIs Treating HCV G2&3 Future Therapies. Advances in treatment of HCV Dr John F Dillon

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1 Treatment Targets HCV Genotype 1 & PIs Treating HCV G2&3 Future Therapies Advances in treatment of HCV Dr John F Dillon

2 Disclosure slide I have received consulting fees and Honoraria from MSD, Abbott, Roche, Gilead and Janssen My institution has received research support from MSD, Abbott, Roche, Gilead and Janssen Most of what I tell you will be wrong in 24 months

3 Putting Patient treatment in the epidemic TREATMENT TARGETS

4 Living IDUs (thousands) 2008 Modelled prevalent number of HCV infected IDUs in Scotland according to stage of HCV disease, Recovered from HCV Cleared HCV from treatment Mild disease Moderate disease Cirrhosis Calendar year Hutchinson et al. Hepatology 2005

5 Living IDUs with cirrhosis Modelled number of IDUs with cirrhosis in Scotland by different uptake rates of HCV antiviral therapy, Uptake of therapy Uptake of therapy Uptake of therapy by by 225 IDUs per year by 1,000 IDUs per year (up to) 2,000 IDUs per year 0 1,000 2,000 3, ,000 2,000 3, ,000 2,000 3, Cirrhosis prevented from antiviral therapy* Compensated cirrhosis Decompensated cirrhosis HCC * Excludes those prevented from antiviral therapy prior to 2008

6 In the age of PIs HCV GENOTYPE 1 TREATMENT

7 Boceprevir regimen in G1 HCV-infected patients Boceprevir dose must not be reduced or restarted once stopped STOP Treatment-naïve without cirrhosis who achieve undetectable HCV RNA at Weeks 8 and 24 PR lead-in BOC + PR BOC + PR* PR Non-cirrhotic treatment-naïve with detectable HCV RNA at Week 8 but undetectable at Week 24* Non-cirrhotic relapsers and partial responders HCV RNA If 100 IU/mL discontinue all drugs If detectable discontinue all drugs BOC + PR Null responders Patients with cirrhosis Weeks *This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC

8 Telaprevir regimen in G1 HCV-infected patients Telaprevir dose must not be reduced or restarted once stopped Non-cirrhotic naïves and relapsers achieving undetectable HCV RNA at Week 4 and 12 (ervr) STOP Telaprevir + PR PR PR Weeks Non-cirrhotic naïves and relapsers without ervr Partial and null responders Patients with cirrhosis HCV RNA If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36: discontinue PR ervr: extended rapid virologic response Telaprevir EU SmPC

9 SVR (%) SPRINT-2: SVR rates with boceprevirbased therapy versus PR alone * 66 * PR48 BOC RGT BOC44/PR48 n/n = 137/ / /366 *p<0.001 for both boceprevir arms versus PR48 Adapted from Poordad F, et al. N Engl J Med 2011;364:

10 SVR (%) ADVANCE and ILLUMINATE: SVR rates with telaprevir therapy versus PR alone * PR48 T12PR n/n = 158/ /903 *p<0.001 vs PR48 in ADVANCE (75% versus 44%) Sherman KE, et al. Hepatology 2010;52(Suppl.):401A Jacobson IM, et al. N Engl J Med 2011;364: ; Sherman KE, et al. CROI Abstract 957

11 Patients (%) ervr and SVR rates among treatment-naïve and prior relapsers in telaprevir Phase 2/3 trials ADVANCE ILLUMINATE REALIZE n/n = T12PR T12PR24 T12PR T12PR24 T12PR48 ervr+ SVR in ervr+ Naïves Relapsers Adda N, et al. CDDW/CASL 2012: A26 Telaprevir EU SmPC

12 Patients (%) Boceprevir: early viral response can help to motivate patients to stay on therapy (SPRINT-2/RESPOND-2) Naïves RGT arm Relapsers and Partial responders* BOC44/PR48 arm n/n= 162/ /162 84/161 74/84 Week 8-24 undetectable SVR Week 8 undetectable SVR *BOC44/PR48 arm comprised 64% of relapsers and 36% of partial responders Adapted from Poordad F, et al. N Engl J Med 2011;364: and Bacon BR, et al. N Engl J Med 2011;364:

13 Counseling should be provided on potential adverse events that may occur Telaprevir: 1 Anemia Nausea Rash, pruritus Anorectal signs/symptoms Diarrhoea Boceprevir: 2 Anemia Nausea Dysgeusia Neutropenia Headache 1. Telaprevir EU SmPC; 2. Boceprevir EU SmPC

14 SVR (%) SVR rates by degree of adherence to telaprevir in treatment-naïve patients (ADVANCE/ILLUMINATE) >95% adherence to telaprevir 95 adherence to telaprevir N = T12PR T12PR % adherence corresponds to 4.2 days missed doses Adiwijaya BS, et al. HepDART Poster 53

15 SVR (%) SVR rates by degree of adherence to boceprevir in treatment-naïve patients (SPRINT 2, BOC arms pooled) 80% adherence to boceprevir <80 adherence to boceprevir n/n = 411/589 57/115 BOC arms pooled Data is shown for combined boceprevir arms of SPRINT-2 (n=704); Only patients who took at least one boceprevir dose are included Patients who discontinued during the lead-in were excluded. BOC arms pooled Gordon SC, et al. J Hepatol 2011;54(Suppl. 1):S173

16 Practical dosing and administration considerations with triple therapy Protease inhibitor Protease inhibitor Protease inhibitor or or or 7am 3pm 8pm 11pm Breakfast Ribavirin Dinner Ribavirin

17 SVR (%) Telaprevir (ADVANCE): SVR rates by IL28B genotype CC CT TT n/n= 35/55 38/45 45/50 20/80 43/76 48/68 6/26 19/32 16/22 PR T8/PR T12/PR PR T8/PR T12/PR PR T8/PR T12/PR Samples were available for 454/1088 (42%) patients (Caucasian) enrolled in ADVANCE SVR: sustained virologic response, defined as undetectable HCV RNA 24 weeks after last planned dose Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

18 SVR (%) REALIZE (telaprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV Prior relapsers Prior partial responders Prior null responders Pbo/PR48 Pooled T12/PR48 n/n= 12/38 145/167 2/15 53/62 1/15 48/57 3/17 36/47 0/5 10/18 1/5 11/32 1/18 24/59 0/9 16/38 1/10 7/50 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Pol S, et al. Hepatology 2011;54(Suppl. S1):374A

19 SVR (%) RESPOND-2 (boceprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV Prior relapsers Prior partial responders Prior null responders PR48 BOC RGT BOC44/PR48 Excluded from RESPOND-2 n/n= 12/38 59/79 58/77 2/10 11/22 15/18 2/23 18/38 23/42 0/5 3/10 6/13 Stage No, minimal or portal fibrosis (F0 F2) Bridging fibrosis / cirrhosis (F3/F4) No, minimal or portal fibrosis (F0 F2) Bridging fibrosis / cirrhosis (F3/F4) Bruno S, et al. J Hepatol 2011;54(Suppl. 1):S4

20 Conclusions: first-generation PIs in treatment-naïve patients Improved response rates: telaprevir and boceprevir Could be considered as new standard of care genotype 1 Requires integration into working practice Needs based allocation: advanced fibrosis first? Not freed from disadvantages of interferon Recognise key determinants of response May allow selective treatment with dual therapy with some cost savings in some regions

21 HCV GENOTYPE 2&3

22 HCV treatment for other genotypes Genotype 2 SVR 7-10% better than genotype 3 PegINF and Ribavirin 24 weeks Some evidence for 12 weeks therapy in patients with RVR Genotype 3 PegINF and Ribavirin 24 weeks Some weak evidence for shorter therapy in LVL RVR patients Suggestions of longer therapy for sub-groups, not defined, no evidence of benefit

23 BACK TO THE FUTURE

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25 Whats next? 2nd wave of protease inhibitors TMC435 (simeprevir) next to market (probably) Several others close behind Advantages less anaemia, less rash Fewer interactions OD dosing

26 HCV Antivirals in Development Other HCV Compounds NS5As BMS ATI-0180 PRO 206 FGI ACH 2928 ITX 5061 PF IMO-2125 IFN alpha, Medgenics (Biopump SR) NA-808 IF's BIT-225 BMS PPI-461 EDP-239 AZD-7295 P-1101 MK5172 SCY-635 SPC-3649 CYT-107 Celgosivir Clemizole HDV-IFN (Hepasome) MK-1220 PEG-IL-29 Miglustat CF-102 Golotimod (SCV 07) sc BMS CB-5300 IPH 1101 GI-5005 RG 7348 sr-ifn-alpha (LG Life Sciences) ITCA-638 IFN-alpha-2b-medtronics Debio025 Nitazoxanide IFN-alpha-2b-XL ANA773 Nov-205 Taribavirin NIM-811 Interferon-alpha (buccal lozenge, Amarillo) Albuferon Locteron CR PhI PhIIa PhIIb PhIII VCH-222+ Telaprevir RG7227+RG7128 ABT 450 Telaprevir GS9190+GS9256 Boceprevir SCH BI VX-813 MK-7009 TMC GS 9190 AZD 2795 ABT-333 BI VCH 916 ITMN-191/R7227 R7128 PF VCH 759 AVL-181 VX-985 IDX-184 MK3281 ABT-072 ANA598 IDX-375 VCH-222 VBY376 BMS GS 9256 IDX-320 PSI-7977 BMS PSI-7851 PIs IDX-136 and IDX-316 PHX-1766 ACH-1625 ACH-1095 PSI-938 IDX-102 IDX-189 Non-nuc polymerases TaigGen Bio Nuc polymerases PSI-879 Belerofon Changed/additional info BMS BMS Suspended / Discontinued IDX184+IDX320 Sources: GBI Analysis (August 4, 2010), Pipeline Sources, Company Press Releases, Reuters Knowledge Analyst Reports BI BI20127 Combination Products

27 PROTON: PSI-7977 (nuc): G1, treatment-naïve Double-blind, placebo-controlled study in treatment-naïve patients N=48 PSI mg QD + PR PR Stop Non-eRVR PR SVR24 N=47 PSI mg QD + PR PR Stop Non-eRVR PR SVR24 N=26 PR SVR24 Wk Lawitz E, et al. Hepatology 2011;54(Suppl. S1): Abstract 225

28 ITT responders (%) PROTON (PSI-7977): virologic response 40 60% RVR ervr EOT SVR12 200mg + PR n <LOD ITT % ITT mg + PR PR <50 ITT: all dosed patients; EOT: end of treatment; LOD: limit of detection Lawitz E, et al. Hepatology 2011;54(Suppl. S1): Abstract 225

29 AI44-017: BMS (PI) + BMS (NS5A) Daclatasvir (BMS ) + Asunaprevir (BMS ) (N=10) Follow-up x 24 weeks Week 4 (RVR) Week 12 (cevr) Week 24 (EOT) Post-treatment Week 12 (SVR12) Post-treatment Week 24 (SVR24) Non-cirrhotic Japanese adults with HCV genotype 1b infection, HCV RNA >10 5 IU/mL and prior null response to PR Dual oral treatment with daclatasvir and asunaprevir for 24 weeks Daclatasvir 60mg once daily Asunaprevir initially 600mg twice daily, subsequently reduced to 200mg twice daily due to elevated transaminases at 600mg in a concurrent dose-ranging study Chayama K, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-4

30 Proportion of patients with undetectable HCV RNA (%) AI (BMS /BMS ): virologic response 4/10 9/10 9/10 9/10 Week 4 Week 12 EOT SVR24 One patient discontinued at Week 2; HCV RNA was undetectable after 24 weeks follow-up Chayama K, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-4

31 Alisporovir but.. - Cases of severe pancreatitis - Whole trial programme suspended on the advice of FDA. - Many drugs never get to the market EASL 2012

32 Nucleotide analogues Polymerase is essential enzyme for HCV replication Nucleos(t)ide analogues (NUCs) are chain-terminators Nuc polymerase inhibitors NUC Chain-terminator 5 Primer strand G C C A Nuc RNA chain cannot be elongated 3 C G G U G A C G 5 Template strand active against ALL genotypes HIGH barrier to resistance

33 GS-7977 (Sofosbuvir) Specific nucleotide analogue (chain terminator) Potent antiviral activity 5 log reduction by D7 across genotypes Well tolerated Once daily, no food effect No drug interactions No safety signals in all studies High barrier to resistance No virologic breakthrough to date

34 GS-7977 ELECTRON Study Design for Arms 1-4 Treatment-naïve, non-cirrhotic, age 18 years Allowed concurrent methadone use Randomized 1:1:1:1 into IFN-sparing or IFN-free Wk 0 Wk 4 Wk 8 Wk1 2 n= 10 GS RBV n= 9 n= 10 GS PEG + RBV GS PEG + RBV GS RBV GT 2/3 Tx-naive n= 11 GS PEG + RBV Gane E, et al. Hepatology 2011; 54: 377A

35 % undetectable HCV RNA GS-7977/RBV IFN 100% Cure 7977/RBV+12wks PEG 7977/RBV+8wks PEG 7977/RBV+4wks PEG 7977/RBV+no PEG 100% 80% 82% 88% 89% 80% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 60% 40% 20% 0% 2 weeks 4 weeks End of Treatment 24 weeks post-rx Gane E, et al. Hepatology 2011; 54: 377A

36 GS-7977 ELECTRON Study Design for Arm 5 Exploratory arm of monotherapy in GT2/3 Determine role of ribavirin 4/10 relapsed Geno 1 Rx naïve and null responders 100% EOT response Relapses occurred and common in null responders

37 % undetectable HCV RNA Sulkowski M, et al. J Hepatol 2012; 56: S1422 NUC NS5B inhibitor GS-7977 plus 2 nd DAA Daclatasvir RBV (geno 1, n =45) 100% 80% 60% 40% 20% GS7977/daclatasvir 79% 77% 67% GS7977/daclatasvir/RBV 100% 100% 100% 100% 100% 93% 93% 0% 2 weeks On Rx 4 weeks On Rx 12 weeks On Rx 24 weeks End of Rx 12 weeks post-rx

38 Cure rate 100% 75% 50% 25% 0% IFN-α 24 weeks 4% Success of HCV Therapy IFN-α 48 weeks 9% IFN/RBV 48 weeks 27% yrs 2004 PEG/RBV 48 weeks 45% Triple Rx Protease inhibitor + PEG/RBV 24 weeks % Combo DAA Nuc + 2 nd DAA 12 wks No IFN No RGT % 2013

39 New Therapies for Hepatitis C 2012 a great year with HCV cure rates over 70% By 2014 will be >90% Tablet taken once per day Well tolerated Low risk of viral resistance complex hospital based monitoring and support no longer needed Community based treatment programmes Justifies population screening The futures bright..but expensive

40 The Future Health Service criminally culpable For any patient with HCV listed for liver transplant? HCV within 40 years of discovery becomes extinct!! Martin, NK. et al. (2011) J. Hepatol. 54(6):