Current Treatment Options for HCV Patients. Michael Manns Dept. of Gastroenterology, Hepatology and Endocrinology Hannover Germany

Transcription

1 Current Treatment Options for HCV Patients Michael Manns Dept. of Gastroenterology, Hepatology and Endocrinology Hannover Germany 7th International Congress of Internal Medicine of Central Greece, Larissa, 20 March 2015

2 HEPATITIS C : HCV 185 Mio chronic hepatitis C carriers worldwide No 1 Indication für liver transplantation in EU and US Major cause of liver cancer Death rate due to HCV greater than AIDS No vaccine First curable chronic viral infection Virus elimination prolongs survival

3 Acknowledgements Markus Cornberg Heiner Wedemeyer Thomas von Hahn Sandra Ciesek Benjamin Maasoumy Christoph Hoener zu Siederdissen Thomas Pietschmann

4 Milestones in Hepatitis C Research: A Masterpiece of Translational Research Crystal structure of the HCV NS3 protease Replicon system Nucleic acid test for HCV Discovery of HCV Ribavirin Early IFN in acute HCV prevents chronicity Infectious in vitro HCV system First HCV PI BI 2061 Approval of 1st HCV protease inhibitors : First usage of IFN Optimization of IFN therapy Other IFNs PEG-IFN + RBV IL28B genotype HCV = hepatitis C virus; IFN = interferon; PI = protease inhibitor; Manns, Z. Gastroenterol,

5 Direct Acting Antiviral Agents against Hepatitis C: DAAs...asvir...previr...buvir Abbildung aus: Manns & Cornberg, Lancet Infectious Diseases 2013

6 Main Messages Hepatitis C is curable in almost all patients Cure reduces HCC incidence and overall mortality First generation DAAs (PI) were a major breakthrough but associated with severe problems New DAAs increase SVR to >90% in almost all patients However, It will be important to increase treatment uptake to see an impact on overall mortality and HCC incidence

7 SVR = Cure reduces HCC incidence, liver related mortality and even all cause mortality ALL CAUSE MORTALITY LIVER RELATED MORTALITY Van der Meer AJ, et al. JAMA 2013

8 Patients with SVR have a normal overal survival Van der Meer, AASLD 2013, Abstract 1425

9 Development of HCV therapy 100% 80% 67-81% 89% % 60% 40% 28-36% 42-50% 20% 2-7% 0% Cornberg et al., Hepatology Textbook, 2015

10 ... Efficacy? Tolerability? Effectiveness?

11 N=86 Patients PEG-IFN/RBV plus Telaprevir or Boceprevir 86% F3/F4 fibrosis, 73% experienced 28% serious adverse events 2 patients died (sepsis) 42% SVR Maasoumy et al., PLoS One 2013 Maasoumy et al., European Journal of Gastroenterology & Hepatology 2014

12 Problems of IFN based therapy: low effectiveness of IFN based treatment (P/R/PI) in a real-word setting (referral university center) HCV Patients 50% Treatment Eligible 82%* treatment with triple was started 42%** achieved SVR Represents 17-21% of Total Patients (n=208) (n=105) (n=86) (n=36**) * Others were included in IFN free trials or transferred to local physicians Maasoumy et al., PloS One 2013; Maasoumy et al., European Journal of Gastroenterology & Hepatology 2014

13 The new treatments: DAAs...asvir...previr...buvir Abbildung aus: Manns & Cornberg, Lancet Infectious Diseases 2013

14 IFN-based IFN-free Improved HCV treatments continue to be developed European approvals Interferon Free Protease inhibitor Nuc inhibitors NS5A NS5B inhibitor G2/3 Sofosbuvir + RBV Sofosbuvir+ Ledipasvir FDC* ± RBV Paritaprevir/r* + Ombitasvir* + Dasabuvir* ± RBV Jul Dec Jan Jun Jul Dec Jan Jun Jul Dec Jan Jun Jul Dec Jan Jun Jul Dec Telaprevir Boceprevir Sofosbuvir (G1,4,5,6) Simeprevir (G1, 4) Daclatasvir (G1, 2, 3, 4) Triple therapy Nuc: nucleotide polymerase inhibitor; NS5A: hepatitis C virus non-structural protein 5a protease inhibitor *Not yet approved in Europe

15 EMA Label Sofosbuvir (D) IFN intolerant patients Sofosbuvir RBV 24 weeks Experience in Hannover since 1/2014

16 1st gen PI-based therapy SOF-based therapy HCV patients N = 208* 100% N = 207** 100% Eligible for treatment 50% 74% Treatment adherence 49% >95% SVR 42% SVR 70%* Cure 21% 52% **SVR not availbale for all patients * Maasoumy B et al., PlosONE 2013, Maasoumy B et al., Eur J Gastroenterol Hepatol ** Höner zu Siederdissen et al., Liver Int. 2014, Höner zu Siederdissen et al., GASL 2015

17 Improvement of albumin during the first 12 weeks of therapy 160 p = 0, N=84 (87% F3/F4), 57% Albumin <35 g/l p < p = 0, Baseline Woche p = 0, p = 0, Albumin ALT Quick Thrombozyten Bilirubin Höner zu Siederdissen et al., GASL 2015

18 new kids on the block step by step to an ideal HCV therapy*...asvir Daclatasvir Ledipasvir Ombitasvir Elbasvir...previr Simeprevir Paritaprevir/r Grazoprevir...buvir Sofosbuvir (NI) Dasabuvir (NNI) Baclabuvir (NNI) *Cornberg & Manns. The Lancet 2014; doi: /s (14)

19 What is possible now (Germany 03/2015)?...asvir Daclatasvir Ledipasvir Ombitasvir...previr Simeprevir Paritaprevir/r...buvir Sofosbuvir Dasabuvir Abbildung aus: Manns & Cornberg, Lancet Infectious Diseases 2013

20 SOFOSBUVIR & SIMEPREVIR Daclatasvir SOF 400 mg daily SIM 150 mg daily Week 12 Simeprevir Sofosbuvir 92-94% SVR in G1 with SIM/SOF weeks 1 12 weeks without Ribavirin sufficient (limited number of patients) Phase II data 1 Lawitz et al., Lancet Jul 26. pii: S (14) Fachinformation Olysio

21 Target September 2014 TARGET: real life US and Beyond 2185 Patients - 97 from German sites 51 % SOF/SMV 24 % SOF/PEG/RBV 15 % SOF/SMV/RBV 10% SOF/RBV

22 SOFOSBUVIR & DACLATASVIR Daclatasvir % SVR in G1 with SOF/DCV±RBV weeks 1 P/R/PI failures: % SVR with SOF/DCV±RBV 24 weeks 1 Simeprevir Sofosbuvir G2/3: % SVR in G2/3 with SOF/DCV±RBV 24 weeks 1 Phase II data 1 Sulkowski et al. N Engl J Med 2014;370:

23 ALLY Phase 3 Program. DACLATASVIR All-Oral DCV + SOF in Patients With High Unmet Medical Need ALLY-1 N = 113 Patients with cirrhosis or post-liver transplant GT 1 to 6 DCV + SOF + RBV, 12 weeks ALLY-2 N = 203 Patients with HIV coinfection GT 1 to 6 DCV + SOF, 8 or 12 weeks ALLY-3 N = 152 Patients with GT 3 infection Treatment-naive or treatment-experienced DCV + SOF, 12 weeks Nelson et al, AASLD

24 ALLY-3: Study Design GT 3 Treatment-naive N = 101 Treatment-experienced N = 51 DCV 60 mg + SOF 400 mg QD DCV 60 mg + SOF 400 mg QD Follow-up Day 1 Week 12 Week 24 Week 36 Primary endpoint: SVR12 SVR12 HCV RNA < lower limit of assay quantitation (LLOQ) at posttreatment Week 12 a Eligible patients Age 18 years with chronic GT 3 infection and HCV RNA 10,000 IU/mL Treatment-naive or -experienced (prior treatment failures), including patients with cirrhosis Those who received prior treatment with NS5A inhibitors were excluded a Assessed using the Roche HCV COBAS TaqMan Test v2.0 (LLOQ 25 IU/mL). Nelson et al, AASLD

25 SVR12, % SVR12 in Patients With Cirrhosis Overall Treatment-naive Treatment-experienced Absent Present Absent Present Absent Present Cirrhosis a,b Among patients with cirrhosis, 34% (11/32) had baseline platelet counts < 100,000/mm 3 a Cirrhosis status determined in 141 patients by liver biopsy (METAVIR F4), FibroScan (> 14.6 kpa), or FibroTest score 0.75 and APRI (aspartate aminotransferase to platelet ratio index) > 2. b Cirrhosis status for 11 patients was inconclusive (FibroTest score > 0.48 to < 0.75 or APRI > 1 to 2). 25

26 Chronic Hepatitis C Genotype 1: 6x New England Journal of Medicine (April 2014) Sofosbuvir 400 mg 1/d Ledipasvir 90 mg 1/d ± Ribavirin 8-24 weeks 96,4% SVR 12 Paritaprevir/r 150/100 mg 1/d Ombitasvir 25 mg 1/d Dasabuvir 250 mg 2/d ± Ribavirin weeks Cirrhosis: n=604 P/R exerienced: n= SOF/LDV: Kowdley et al., NEJM 2014; Afdhal et al., NEJM 2014; Afdhal et al. NEJM D: Feld et al., NEJM 2014; Poordad et al., NEJM 2014; Zeuzem et al., NEJM 2014

27 11/2014 1/2015 Sofosbuvir 400 mg 1/d Ledipasvir 90 mg 1/d Paritaprevir/r 150/100 mg 1/d Ombitasvir 25 mg 1/d Dasabuvir 250 mg 2/d >95% SVR GT-1

28 Effectivness of treatment = Efficacy of treatment x Diagnosis x Treatment uptake

29 OLD PEG-IFN/RBV 90% SVR 90% SVR Higher Treatment Uptake All HCV PATIENTS 100% 100% 100% TREATMENT UPTAKE 10% 10% 90% CURE 5% 9% 81%

30 Strategies to manage hepatitis C virus (HCV) disease burden Old standard Peg-IFN/RBV SVR 90% SVR 90%, Increase of Treatment uptake by 75% Wedemeyer, Duberg, Buti et al., Journal of Viral Hepatitis pages 60-89, 8 APR 2014

31 HCV-associated complications until 2030 Razaiv, Waked, Sarrazin et al., J Viral Hepatitis 2014

32 How to increase treatment uptake if treatment is expensive? Risk for endpoints (cirrhosis and HCC) Side effects and tolerability Efficacy of treatment Costs and availability

33 SVR should be >90% in 2015 (G1, 2, 4) Ideally treatment duration should be 12 weeks 90% with 12 weeks or? 95% with 24 weeks Treatment i.e. 50,000 Euro for 12 weeks Cure with 12 weeks: 56,000 Euro Cure with 24 weks: 105,000 Euro

34 Treatment weeks SOF/LDV (RBV *,# ) Naïve, no cirrhosis, < 6 Mio IU/ml HCV RNA Naïve with or without cirrhosis Treatment experienced without cirrhosis Treatment experienced with cirrhosis* Treatment weeks OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV GT1b, no cirrhosis GT1b, cirrhosis GT1a, no cirrhosis GT1a, cirrhosis*

35 LDV/SOF ± RBV: Compensated Cirrhosis Results: SVR12 by Treatment Regimen Overall SVR wk wk Duration 24 wk Treatment Naïve 98% 97% 99% Treatment Experienced 95% 94% 98% Regimen LDV/SOF LDV/SOF + RBV 96% 99% 95% 96% LDV/SOF 12 wk 96% 90% Duration/ ± RBV LDV/SOF + RBV 12 wk LDV/SOF 24 wk 98% 97% 96% 98% LDV/SOF + RBV 24 wk 100% 100% Among TE cirrhotic patients, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone Bourliere, AASLD, 2014, Oral #82 35

36 Genoytpe 1a and Cirrhosis: 12 or 24 weeks treatment? viekirax + exviera + RBV 12 weeks viekirax + exviera + RBV 24 weeks EOTR Baseline values: α-fetoprotein < 20 ng/ml Platelets 90 x 10 9 /l Albumin 35 g/l All parameter fulfilled 1% (1/87) 0% (0/68) At least one parameter not fulfilled 21% (10/48) 2% (1/45) Fachinformation viekirax, Stand Januar 2015 Fachinformation exviera, Stand Januar 2015

37 Conclusion Hepatitis C ist curable in >90% of patients Cure reduces HCC incidence and overall mortality IFN free therapies are possible for most of the patients Costs are the main obstacle to start treatment in all patients It will be important to increase treatment uptake to have an impact on overall mortailty and HCC incidence

38 25 years of HCV GT 1 Therapy: from 0 to 100 % *trials with treatment-naive genotype 1 infection Cornberg et al, Der Internist, 2014

39 Open issues / problems Decompensated cirrhosis Liver transplantation (treatment before or after Tx)? Genotype non-1 Renal insufficiency / dialysis Access to therapy

40 Data for SOF/NS5A combi in G3 SOF/DC V SOF/ LDV SOF/DC V SOF/ LDV Without cirrhosis 12 weeks No Ribavirin 94-97% 64%* Ribavirin?% % 24 weeks?%?% 89%?% cirrhosis No Ribavirin Ribavirin 12 weeks 58-69%?%?% 73% 24 weeks?%?%?%?% * some patients with cirrhosis were included Gane et et al., EASL 2014; Gane et al., AASLD 2014; Nelson et al., AASLD 2014; Sulkowski et al., NEJM 2014

41 EMA Label Sofosbuvir/NS5A for G3 (D) Difficult to treat: cirrhosis, nonresponder SOF/LDV Sofosbuvir 400 mg 1/d Ledipasvir 90 mg 1/d Ribavirin 24 weeks N=0 SOF/DCV Sofosbuvir 400 mg 1/d Dacalatsvir 60 mg/d Ribavirin 24 weeks

42 Improvement of liver function with SOF/LDV in patients with advanced liver cirrhosis Sofosbuvir 400 mg 1/d Ledipasvir 90 mg 1/d ± Ribavirin Wochen Flamm et al., AASLD 2014

43 Improvement of liver function with SOF/LDV in patients with advanced liver cirrhosis SOF based therapies: GFR > 30 3DAA Sofosbuvir regimen 400 mg 1/d not approved for decomp Ledipasvir 90 mg 1/d cirrhosis ± Ribavirin Wochen Flamm et al., AASLD 2014

44 IFN-based IFN-free Improved HCV treatments continue to be developed European approvals Interferon Free Protease inhibitor Nuc inhibitors NS5A NS5B inhibitor Sofosbuvir + RBV Jul Dec Jan Jun Jul Dec Jan Jun Jul Dec Jan Jun Jul Dec Jan Jun Jul Dec G2/3 Paritaprevir/r* + Ombitasvir* + Dasabuvir* ± RBV Sofosbuvir+ Ledipasvir FDC ± RBV Asunaprevir* + Daclatasvir* ± Baclabuvir* Sofosbuvir+ GS-5816 Pan GT FDC* MK-5172* MK-8742* MK-3682*? Telaprevir Boceprevir Sofosbuvir (G1,4,5,6) Simeprevir (G1, 4) Daclatasvir (G1, 2, 3, 4) Triple therapy Nuc: nucleotide polymerase inhibitor; NS5A: hepatitis C virus non-structural protein 5a protease inhibitor *Not yet approved in Europe

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