Protease inhibitors based triple therapy in patients with advanced fibrosis/cirrhosis

Transcription

1 Protease inhibitors based triple therapy in patients with advanced fibrosis/cirrhosis Michael P. Manns Department of Gastroenterology, Hepatology and Endocrinology White Nights of Hepatology, St. Petersburg, 06 June 2013

2 Acknowledgements Benjamin Maasoumy Markus Cornberg, Heiner Wedemeyer, Sandra Ciesek, Thomas von Hahn HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY

3 Networking in Hepatology German Center for Infection Research: DZIF

4 Milestones in the History of HCV Therapy Past and Future SVR 100% 100% 75% GT1 only! 50% 25% 0%??? ?

5 Milestones in the History of HCV Therapy Past and Future SVR 100% 100% 75% GT1 only! 50% 25% 0%??? ?

6 HCV: Targets of Direct Acting Antiviral Agents...asvir...previr...buvir Manns & Cornberg, Lancet Infectious Diseases 2013

7 Improvement of SVR with HCV protease inhibitors (Boceprevir, Telaprevir) in naive CHC G 1 patients 80 SVR (%) 27-28% % BOCEPREVIR TELAPREVIR 10 0 PR BOC PR TEL PEG-IFN/RBV PEG-IFN/RBV 1. Poordad et al., N Engl J Med 2011;364: Jacobson et al., N Engl J Med 2011;364:

8 SVR in therapy experienced patients 80% 70% 60% 50% 40% 30% 20% 10% 0% 29% Relapser 69% 30-36% 2,6 RGT 75% Partial responders 7% 40% 52% Null responders 2 < 1 log 10 IE/ml HCV RNA decline until week 4 0% 33% 34% 33-45% 7, % 1 RGT RGT P/R BOC/P/R P/R BOC/P/R P/R BOC/P/R 1. Poordad F et al. New Engl J Med McHutchison et al. N Engl J Med ;361(6):

9 1st Generation Protease Inhibitors Advantages 1. Higher SVR in HCV Genotype 1 2. Shorter Treatment Duration

10 HCV and special patient populations Often excluded from RCTs and thus limited efficacy and safety data, i.e. < 10 % Often difficult to treat Cirrhotics HIV HCV coinfection Special patient populations Elderly Liver transplant RCT = randomised controlled trial

11 HCV and special patient populations Often excluded from RCTs and thus limited efficacy and safety data, i.e. < 10 % Often difficult to treat Cirrhotics HIV HCV coinfection Special patient populations Elderly Liver transplant

12 HCV-Cirrhosis Cumulative Incidence A HCC Ascites Jaundice GI--Bleeding Encephalopathia Years Sangiovanni et al. Hepatology 2006; 43:

13 HCV-Cirrhosis A 100 Survival Probability Compensated After first major complication 80 Patients (%) Aszites, SBP, Enzephalopathie, HCC, Ö Varizenblutung 0 Pts at Risk, n Mos Fattovich G, et al. Gastroenterology. 1997;112:

14 A Is SVR relevant for the patient? Elimination of HCV (SVR = Cure) improves hard core endpoints! ALL CAUSE MORTALITY LIVER RELATED MORTALITY Patients: n=530 with F4-F6 Fibrosis Therapies: Interferon alfa, Interferon alfa / Ribavirin, PEG-Interferon alfa / Ribavirin Van der Meer AJ, et al. JAMA 2013

15 Cirrhosis affects treatment outcome in triple therapy Treatment-naive G1 SVR (%) SPRINT2 1 ADVANCE 2 F0 2 F3/4 * * SVR (%) F * F4 * n N P/R P/R + BOC RGT P/R + BOC P/R P/R + BOC RGT P/R + BOC n N P/R TVR12 P/R P/R TVR12 P/R48 * p<0.05 vs. PegIFN alfa/ribavirin G = genotype; P/R = PegIFN alfa/ribavirin 1. Poordad F, et al. N Engl J Med. 2011; 364: ; 2. Jacobson IM, et al. N Engl J Med. 2011; 364:

16 REALIZE (Telaprevir): SVR in relation to fibrosis Relapser Partial responders Null responders Pbo/PR48 SVR (%) Pooled T12/PR48 n/n= 12/38 144/167 2/15 53/62 2/15 48/57 3/17 34/47 0/5 10/18 1/5 11/32 1/18 24/59 0/9 15/38 1/10 7/50 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Zeuzem S, et al. J Hepatol 2011;54(Suppl.):S3

17 Simeprevir with peginterferon-α2a or -α2b and ribavirin in treatment-naïve HCV genotype 1 patients: QUEST-2, a randomised Phase III trial Michael Manns 1, Patrick Marcellin 2, Fred Poordad 3, Evaldo Stanislau Affonso de Araujo 4, Maria Buti 5, Yves Horsmans 6, Ewa Janczewska 7, Federico Villamil 8, Monika Peeters 9, Oliver Lenz 9, Sivi Ouwerkerk-Mahadevan 10, Ronald Kalmeijer 9 and Maria Beumont-Mauviel 9 1 Medizinische Hochschule Hannover, Hannover, Germany; 2 Hôpital Beaujon, Clichy, France; 3 Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA; 4 Hospital das Clinicas of the University of São Paulo School of Medicine, University of São Paulo, Sao Paulo, Brazil; 5 Hospital Vall d Hebron and Ciberhed del Instituto Carlos III, Barcelona, Spain; 6 UCL St Luc, Brussels, Belgium; 7 NZOZ Pol-SaNa-Med. Sp z.o.o., Czeladz, Poland; 8 CIPREC, Buenos Aires, Argentina; 9 Janssen Infectious Diseases BVBA, Beerse, Belgium; 10 Janssen Research & Development, Beerse, Belgium Manns et al, EASL 2013, late breaker session

18 QUEST-2: Baseline demographics and disease characteristics SMV/PR (N=257) Placebo/PR (N=134) Patient demographics Female, % Race, % white Median age, years (range: 18 73) Median BMI, kg/m IL28B genotype, % CC Non-CC Disease characteristics Median baseline HCV RNA, log 10 IU/mL Genotype 1a, % Genotype 1b, % METAVIR score, % F0-F F F F Demographic and baseline disease characteristics were well balanced across both treatment groups BMI, body mass index; PR, PegIFN + ribavirin; SMV, simeprevir Manns et al, EASL 2013, late breaker session

19 QUEST-2: SVR12 by METAVIR score p<0.001 p<0.001 p<0.001 SMV/PR Placebo/PR Proportion of patients (%) 165/195 52/102 24/36 9/17 11/17 6/15 F0-F2 F3 F4 Statistically significantly higher SVR12 rates with SMV/PR compared with placebo/pr, irrespective of METAVIR score Manns et al, EASL 2013, late breaker session PR, PegIFN + ribavirin; SMV, simeprevir

20 QUEST-2: Significantly higher SVR12 with SMV/PR vs PBO/PR in all key subgroups Male Female HCV RNA < IU/mL HCV RNA > IU/mL HCV subtype 1a With baseline Q80K* Without baseline Q80K* HCV subtype 1b IL28B CC IL28B CT IL28B TT METAVIR F0-F2 METAVIR F3 METAVIR F4 Randomised to PegIFNa-2a/RBV Randomised to PegIFNa-2b/RBV PegIFNa-2a/RBV, not randomised N SMV Placebo Difference in proportions and 95% CI Favours PBO Manns et al, EASL 2013, late breaker session *Pooled placebo arm. Differences in proportions and their respective CIs are derived from a logistic regression model including factors for treatment group, baseline HCV RNA (log 10 IU/mL), HCV subtype, IL28B and type of PegIFN 100 Favours SMV

21 SAFETY AND EFFICACY OF BOCEPREVIR/PEGINTERFERON/RIBAVIRIN COMBINATION THERAPY FOR CHRONIC HCV G1 PATIENTS WITH COMPENSATED CIRRHOSIS: A META-ANALYSIS OF FIVE PHASE 3 CLINICAL TRIALS J.M. Vierling, S. Zeuzem, F. Poordad, J.-P. Bronowicki, M.P. Manns, B.R. Bacon, R. Esteban, S.L. Flamm, P.Y. Kwo, L.D. Pedicone, W. Deng, F.J. Dutko, M.J. DiNubile, K.J. Koury, F.A. Helmond, J. Wahl, S. Bruno EASL 2013, Poster 1430, APASL 2013, Manuscript in preparation

22 SVR rates by Metavir fibrosis stage after treatment with BOC/P/R or P/R SVR (%; 95% CI) * BOC/P/R 28 26* P/R 54 * 55 n=1638 n=436 n=107 n=22 n=180 F0-F2 F3 F4 Metavir Fibrosis Score n = Safety & Efficacy of Boceprevir/Peginterferon/Ribavirin for HCV G1 Patients with Compensated Cirrhosis: Meta-Analysis of 5 Phase 3 Trials Vierling et al, EASL, 2013, in preparation

23 SVR According to Virologic Response at Treatment Week 8 Safety & Efficacy of Boceprevir/Peginterferon/Ribavirin for HCV G1 Patients with Compensated Cirrhosis: Meta-Analysis of 5 Phase 3 Trials Vierling et al, EASL, 2013, in preparation

24 Predictors of SVR in F3/F4 Patients Receiving BOC/PR TW8: undetectable vs. detectable HCV RNA TW4: 1log decline vs. <1 log decline Male vs. female ( ); P< ( ); P= ( ); P= Baseline viral load 800,000 IU/mL vs. >800,000 IU/mL G1b vs. G1a Non black vs. black 2.55 ( ); P= ( ); P= ( ); P= Includes patients with F3 and F4 fibrosis in order increase the power to identify predictors of SVR Odds Ratio (95% CI) 9 10 CI = confidence interval; G = genotype; TW = treatment week.

25 Multivariate Logistic Regression Analysis: Predictors of SVR in F3/F4 Patients Receiving BOC/PR Safety & Efficacy of Boceprevir/Peginterferon/Ribavirin for HCV G1 Patients with Compensated Cirrhosis: Meta-Analysis of 5 Phase 3 Trials Vierling et al, EASL, 2013, in preparation

26 Common Adverse Events P/R BOC/P/R F0-2 F3 F4 F0-2 F3 F4 Common Adverse N = 436 N = 22 N = 32 N = 1638 N = 107 N = 180 Event* Any adverse event, n (98) 22 (100) 32 (100) 106 (99) 179 (99) (%) (99) Anemia 124 (28) 6 (27) 7 (22) 786 (48) 49 (46) 100 (56) Fatigue 253 (58) 10 (45) 17 (53) 965 (59) 60 (56) 102 (57) Dysgeusia 72 (17) 5 (23) 4 (13) 627 (38) 39 (36) 75 (42) Nausea 171 (39) 10 (45) 12 (38) 783 (48) 47 (44) 70 (39) Headache 188 (43) 9 (41) 8 (25) 725 (44) 46 (43) 65 (36) Diarrhea 85 (19) 2 (9) 6 (19) 425 (26) 27 (25) 64 (36) Chills 114 (26) 3 (14) 9 (28) 482 (29) 35 (33) 54 (30) Neutropenia 85 (19) 3 (14) 7 (22) 404 (25) 22 (21) 47 (26) Pyrexia 129 (30) 6 (27) 7 (22) 437 (27) 34 (32) 46 (26) BOC = boceprevir; PR = peginterferon and ribavirin 26

27 Conclusions Boceprevir plus P/R is safe and effective in patients with HCV G1 infection and compensated cirrhosis SVR rate was 55% in cirrhotic patients 89% in those with undetectable HCV RNA at TW8 21% in poorly interferon-responsive null responders with <1 log 10 decline at TW4 HCV RNA at TW8 is informative for deciding whether to continue treatment Few hepatic decompensation events Safety events that occurred more frequently with boceprevir + P/R than P/R included: SAEs, transfusions, discontinuation due to an AE, dose modifications due to anaemia, infections, anaemia, thrombocytopenia, dysgeusia, headache and diarrhoea 27 AE = adverse event; HVC = hepatitis C virus; P/R = peginterferon and ribavirin; RNA = ribonucleic acid; SAE = serious adverse event; SVR = sustained virologic response; TW = treatment week.

28 Assessment of fibrosis 48 weeks of therapy for all patients with cirrhosis Biopsy: gold standard

29 Assessment of fibrosis 48 weeks of therapy for all patients with cirrhosis Invasive Biopsy: limitations

30 Assessment of fibrosis 48 weeks of therapy for all patients with cirrhosis Invasive Biopsy: limitations Risk of health complications

31 Assessment of fibrosis 48 weeks of therapy for all patients with cirrhosis Invasive Biopsy: limitations Risk of health complications Poor patient acceptance

32 Assessment of fibrosis 48 weeks of therapy for all patients with cirrhosis Invasive Questionable clinical utility Subjective procedure; 25% misclassification, even with optimal biopsy specimen 1 Biopsy: limitations Risk of health complications Poor patient acceptance 1. Bedossa P, et al. Hepatology 2003; 38:

33 Assessment of fibrosis 48 weeks of therapy for all patients with cirrhosis Invasive Questionable clinical utility Subjective procedure; 25% misclassification, even with optimal biopsy specimen 1 Biopsy: limitations Risk of health complications Poor patient acceptance Non-invasive measures include: APRI, FIB-4, Fibroscan, FibroTest, Forns score, HepaScore 1. Bedossa P, et al. Hepatology 2003; 38:

34 Telaprevir Early Access Programm: Testing used to classify liver fibrosis/cirrhosis at baseline Other 12 (2%) * One patient with missing data (n=608) Analysis: 12th October 2012 Colombo et al, AASLD, 2012 Table The FREQ Procedure

35 Triple Therapy in different cohorts French Early Access Program (CUPIC) Only Cirrhotic Only previous non responders Null responders excluded Telaprevir and Boceprevir Real-World Data Hannover Medical School (MHH) Real-World Cohort Telaprevir and Boceprevir Additional Stopping Rule for Null Responders with liver cirrhosis (<1log decline after lead-in) Global Early Access Program (EAP) Only Telaprevir Inclusion/Exclusion criteria No advanced liver disease! Platelets > Hezode et al., AASLD 2012; Maasoumy et al, EASL/AASLD 2012, Plos One 2013 Colombo et al., AASLD 2012

36 PI Therapy in different Patient Cohorts Characteristics CUPIC MHH EAP Patient number Mean Age Male - Female 68% 32% 64% 36% 67% 33% - HCV-1a - HCV-1b - n.d. 36% 52% 11% 30% 67% 2.3% 28% 68% 4.3% - treatment-naïve - treatment-experienced 0% 100% 27% 73% 20% 80% Mean Platelets (/nl) - < n/ a % n/a exluded Liver fibrosis - F0-F2 - F3 - F4 0% 0% 100% 13% 30% 56% 0% 45% 55% Hezode et al., AASLD 2012; Maasoumy et al, EASL/AASLD 2012, Plos One 2013 Colombo et al., AASLD 2012

37 CUPIC Week 16 MHH Week 12 (+/- Personalized lead-in) Patient number SAEs (Patients affected) 40% 19% 14% Death - due to Infection Anemia PI Therapy in different Patient Cohorts Safety 6 (1.2%) 50% 1 (1.2%) 100% 3 (0.5%) 100% EAP Week 16 RBV Dose reduction EPO 12% 51% 36% 0% 28% 24% Blood Transfusion 12% 14% 12% Hezode et al., AASLD 2012; Maasoumy et al, EASL/AASLD 2012, Plos One 2013 Colombo et al., AASLD 2012

38 CUPIC Week 16 MHH Week 12 (+/- Personalized lead-in) Patient number SAEs (Patients affected) 40% 19% 14% Death - due to Infection Anemia PI Therapy in different Patient Cohorts Safety 6 (1.2%) 50% 1 (1.2%) 100% 3 (0.5%) 100% EAP Week 16 RBV Dose reduction EPO 12% 51% 36% 0% 28% 24% Blood Transfusion 12% 14% 12% Predictors for SAEs: CUPIC MHH Platelets < /nl Platelets < /nl Albumin <35g/l Child-Pugh Score >5 EAP: No advanced cirrhosis lower rate of SAEs Hezode et al., AASLD 2012; Maasoumy et al, EASL/AASLD 2012, Plos One 2013 Colombo et al., AASLD 2012

39 PI Therapy in different Patient Cohorts Efficacy CUPIC Week 16 MHH Week 12 (+/- Personalized lead-in) Patient number HCV RNA neg Week 12 Week 16 69% 63% 60% (5% n/a; 7% BLOQ) n/a 79% n/a EAP Week 16 Efficacy high also in difficult-to-treat cohorts (so far: Interim-analysis!) Safety poor in advanced liver disease Hezode et al., AASLD 2012; Maasoumy et al, EASL/AASLD 2012, Plos One 2013 Colombo et al., AASLD 2012

40 Clinical Trials vs Real Life Treatment-naive Clinical trials (including cirrhotics) Treatment-experienced Real world (cirrhotics only) Treatment-experienced 49% Patients with serious AEs (%) 9% 7% 9 12% 12% 10 14% 9% 5% 5% 38% Telaprevir PegIFN/RBV Boceprevir

41 CUPIC: real-life cohort of patients with cirrhosis SVR12 rates in CUPIC n N Fontaine

42 Optimal Patient Selection Real Life Eligibility for Triple Therapy 208 patients with chronic HCV GT1 infection referred to hepatitis outpatient clinic of Hannover Medical School between June 1st and November 30th 2011 were evaluated for triple therapy Real Life Phase-3 trials: F3/F4: 64%; platelets <90/nl: 16%, treatment-experienced: 60% Therapyassociated Safety Concerns Poor Chance for SVR Decision: No Triple Therapy n=103 Regularly multiple reasons influenced the final decision Almost 50% (n=103) not treated Low Treatment Urgency: Wait for better Options Nonmedical Patient related Reasons: i.e. Patients Wish Real Life Maasoumy et al, PLoS One 2013, AASLD 2012 Maasoumy B, et al. PLOSOne 2013; 8: e55285

43 Real-world data: safety concerns of triple therapy in patients with cirrhosis Safety profile after 12 weeks of triple therapy in 86/208 HCV G1 patients treated in a real-world setting Treated patients with advanced liver fibrosis (F3/4): 86% N=86 Anaemia <10 g/dl 37% <8.5 g/dl 14% Blood transfusions 14% RBV dose reduction due to anaemia 36% Hospitalisations related to antiviral therapy 19% Symptomatic anaemia 62% Infections 14% Hepatic decompensation 14% Hospitalised patients had more advanced liver disease: higher MELD score (9.6 vs. 7.3) and lower platelet count (107.5 vs /nL) Maasoumy B, et al. PLOSOne 2013; 8: e55285

44 Safety and efficacy stratified by risk profile in real-life cirrhotic patients (N=48) Group A Platelets <110/nL and Child-Pugh Score >5 n=7 Group B Platelets <110/nL or Child-Pugh Score >5 n=16 Group C Platelets 110/nL and Child-Pugh Score 5 n=20* Treatment failure 100% (7/7) 69% (11/16) 30% (6/20) SAE 57% (4/7) 63% (10/16) 25% (5/20) SAE or treatment failure 100% 94% 50% 96% of patients (22/23) with Child-Pugh Score >5 and/or baseline platelets <110/nL (Group A/B) experienced treatment failure or 1 SAE (up to EOT) The remaining patient relapsed during follow-up * Five patients with platelets 110/nL but no accessible Child-Pugh Score were excluded Maasoumy B, et al. J Hepatol 2013; 58(s1): s351 [abstract 857]

45 Predictors for SAEs and death in the CUPIC cohort Albumin Platelets > 100,000/nL < 100,000/nL 35 g/dl 3.4% 4.3% < 35 g/dl 7.1% 44.1% *Presence of portal hypertension HVPG 10 mmhg, low albumin, low platelets Hezode C et al. J Hepatol 2013, in press

46 Summary HCV Triple Therapy in Cirrhosis 1. HCV protease inhibitor based triple therapy increases SVR in cirrhotic and non cirrhotic patients 2. SVR is reduced in cirrhosis, in particular in previous null responders 3. Limited experience in pivotal trials, cirrhotic patients in pivotal trials with thrombocytes > or according to PEG- IFN label 4. Increased rates of severe adverse events (SAE) in real world experiences such as CUPIC and MHH

47 Conclusion HCV Triple Therapy in Cirrhosis Careful individual benefit / risk assessment in particular in treatment experienced cirrhotic patients with thrombocytes < /mm³ and serum albumin < 35 g/l

48 Careful patient selection and monitoring

49 Outcomes in patients with cirrhosis who achieve SVR SVR patients 27.4 Non-SVR patients Patients (%) All-cause mortality 1.9 Liver-related mortality or liver transplant 10-year cumulative occurrence rate van der Meer A, et al. JAMA 2012; 308: HCC 2.1 Liver failure

50 Thank you for your attention