HCV treatment today: pegylated interferons and ribavirin

Transcription

1 HCV treatment today: pegylated interferons and ribavirin

2 Other special patient populations

3 Patients with cirrhosis

4 Higher SVR rates are achieved in patients without cirrhosis Patients without bridging fibrosis/cirrhosis Patients with bridging fibrosis/cirrhosis p=0.011 p= p= SVR (%) n= Genotype 1/4 48 weeks Genotype 2/3 24 weeks Genotype 2/3 16 weeks Bruno S, et al. 43rd EASL 2008; Abstract 774

5 High SVR rates with PEGASYS in cirrhotic patients who achieve an RVR or a cevr G1 patients, 48 weeks PEGASYS 180 μg/wk plus COPEGUS 1000/1200 mg/day G2/3 patients, 24 weeks PEGASYS 180 μg/wk plus COPEGUS 800 mg/day SVR (%) n= RVR cevr Bruno S, et al. 43rd EASL 2008; Abstract 774

6 Younger age and low viral load are predictive of achieving an SVR in patients with cirrhosis Genotype 1/4 patients with bridging fibrosis/cirrhosis treated with PEGASYS 180 μ g/wk plus COPEGUS 1000/1200 mg/day for 48 weeks SVR (%) n= 59 Age <40yrs Age 40yrs 67 Viral load < IU/mL 40 Viral load IU/mL Bruno S, et al. 43rd EASL 2008; Abstract 774

7 On-treatment responses are predictive of SVR in G1/4 patients with advanced fibrosis G1/4 Predictor Baseline factors Higher serum HCV RNA level (per log 10 IU/mL increment) Odds ratio (95% confidence interval) 0.36 ( ) p Baseline and on-treatment factors On-treatment response (RVR or cevr vs. pevr or no EVR) Cumulative ribavirin dose ( 60% vs. <60% of the planned dose) ( ) ( ) < Bruno S, et al. 43rd EASL 2008; Abstract 774

8 On-treatment responses are predictive of SVR in G2/3 patients with advanced fibrosis G2/3 Predictor Baseline factors Baseline and on-treatment factors Higher body weight (per 10 kg increment) Higher serum HCV RNA level (per log 10 IU/mL increment) Higher serum HCV RNA level (per log 10 IU/mL increment) On-treatment response (RVR or cevr vs. pevr or no EVR) Cumulative ribavirin dose ( 60% vs. <60% of the planned dose) Odds ratio (95% confidence interval) 0.84 ( ) 0.46 ( ) 0.67 ( ) ( ) 9.79 ( ) p < < Bruno S, et al. 43rd EASL 2008; Abstract 774

9 Chronic hepatitis C and normal alanine aminotransferase (ALT) levels

10 Chronic hepatitis C and alanine aminotransferase (ALT) Up to 46% of patients with chronic hepatitis C have ALT levels within the currently defined normal range 1 These patients were historically considered healthy or asymptomatic and have not received treatment However, >80% have some degree of liver damage on biopsy 2 Quality of life is significantly impaired in patients with chronic hepatitis C (and elevated or persistently normal ALT) 3 1. Alberti A, et al. Ann Intern Med 2002; 137: Puoti C, et al. J Hepatol 2002; 37: Foster G, et al. Hepatology 1998; 27: 209

11 ALT levels do not always correlate with degree or severity of liver disease Although elevated ALT levels are generally associated with hepatocellular damage, lower levels are not always associated with mild liver disease ALT levels fall as cirrhosis develops Many factors, independent of liver damage, can affect ALT levels ALT levels may fluctuate throughout the course of chronic hepatitis C

12 A single ALT value may not be representative of the true ALT status It is recommended that ALT status be defined by three measurements over a 6-month period 1 However, studies suggest that this time period may not be adequate 2 Patients with ALT levels within the normal range may show further reduction in serum ALT levels following treatment 3 1. Marcellin P, et al. Hepatology 1997; 26: 133S 2. Puoti C, et al. J Hepatol 2002; 37: Di Bisceglie A, et al. Hepatology. 2001; 33: 704

13 77% of patients with normal ALT have some degree of liver damage Portal 26% Bridging 6% Cirrhosis 6% Portal 24% Bridging 16% Cirrhosis 22% No Fibrosis 23% Mild 39% No Fibrosis 19% Mild 19% Normal ALT Elevated ALT Shiffman M, et al. J Infect Dis 2000; 182: 1595

14 Fibrosis progression occurs in patients with normal ALT Cumulative probability of fibrosis (%) p=0.06 Elevated ALT Normal ALT Years Hui C-K, et al. J Hepatol 2003; 38: 511

15 Management of asymptomatic HCV patients with persistently normal ALT is evolving Event 1997 NIH Consensus Conference 2002 NIH Consensus Conference 2004 AASLD Practical Guidelines Recommendation Recommended not treating patients with normal ALT outside of controlled clinical trials Recommended that numerous factors (viral and host-specific) be considered when deciding whether to treat and that ALT levels should not be the only criterion Regardless of the serum ALT levels, the decision to initiate therapy should be individualised based on the severity of liver disease by liver biopsy, the potential of serious side effects, the likelihood of response, and the presence of comorbid conditions 1. NIH Consensus Statement NIH Consensus Statement. Hepatology 2002; 36: S3 3. Strader D, et al. Hepatology 2004; 39: 1147

16 PEGASYS plus COPEGUS in patients with normal ALT levels In chronic hepatitis C patients with elevated ALT levels PEGASYS plus COPEGUS therapy shows significant improvement in efficacy and tolerability over conventional interferon-based therapy across all HCV genotypes, irrespective of viral load 1 PEGASYS is the first and only pegylated interferon approved in the European Union for the treatment of patients with ALT levels persistently within the current normal range 1. Fried M, et al. N Engl J Med 2002; 347: 975

17 Zeuzem study: design 440 patients with normal ALT* randomised (3:3:1) PEGASYS plus COPEGUS ** Follow-up PEGASYS plus COPEGUS ** Untreated Study weeks *As determined on three occasions within 6 18 months before baseline **PEGASYS 180 μg/wk; COPEGUS 800 mg/day Zeuzem S, et al. Gastroenterology 2004; 127: 1724

18 PEGASYS plus COPEGUS for 48 weeks is optimal in genotype 1 SVR (%) No untreated patient cleared the virus p< % 13% 10 0 n=144 PEGASYS plus COPEGUS 24 weeks n=141 PEGASYS plus COPEGUS 48 weeks *Intent-to-treat analysis Zeuzem S, et al. Gastroenterology 2004; 127: 1724

19 PEGASYS plus COPEGUS for 24 weeks is optimal in genotype 2/ No untreated patient cleared the virus P= % 72% SVR (%) n=58 PEGASYS plus COPEGUS 24 weeks n=59 PEGASYS plus COPEGUS 48 weeks *Intent-to-treat analysis Zeuzem S, et al. Gastroenterology 2004; 127: 1724

20 No treatment-related ALT flares reported Serum ALT activity (U/L) 24 weeks 36 Patients with an SVR 32 Virological nonresponders Virological relapsers Treatment Follow-up weeks Patients with an SVR Virological nonresponders Virological relapsers Treatment Follow-up Study week Study week indicates the end of treatment Zeuzem S, et al. Gastroenterology 2004; 127: 1724

21 Adverse events in different treatment arms Adverse event (%) PEGASYS 180 μg/wk + COPEGUS 800 mg/day 24 weeks 48 weeks Untreated arm Fatigue Headache Pyrexia Myalgia Insomnia Nausea Depression Zeuzem S, et al. Gastroenterology 2004; 127: 1724

22 Proposed normal ALT treatment algorithm Treat without biopsy Liver biopsy to decide therapy No biopsy / no therapy Follow-up Genotype 2/3 and <45 50 years and highly motivated and no contraindication Genotype 1/4 or years or some contraindication or patient wants to know Genotype 1/4 with HVL and long duration of infection or age >65 years or major contraindication Treat with PEGASYS plus COPEGUS for 24 weeks F2 F0 F1 Avoid alcohol, hepatotoxins, obesity, liver steatosis Treat with Monitor PEGASYS plus COPEGUS for 48 weeks according to genotype Monitor every 6 months Alberti A, et al. J Hepatol 2005; 42: 266

23 HRQL improved in normal ALT responders to PEGASYS plus COPEGUS Adjusted HRQL scores ** 77 SVR No SVR 81 ** ** * 69 0 Pain Index HRQL = health-related quality of life ** p<0.0001; * p<0.05 Higher score indicates better HRQL Vitality Social functioning SF-36 scores General Health Role Physical Arora, S et al. J Gastroenterol Hepatol 2006; 21: 406

24 PEGASYS plus COPEGUS improves health-related quality of life (HRQL) SVR in response to PEGASYS, alone or in combination with COPEGUS, is associated with improved HRQL and less fatigue in patients with chronic hepatitis C and elevated ALT levels 1,2 HRQL was significantly improved in patients with persistently normal ALT who achieved an SVR in response to PEGASYS plus COPEGUS 3 1. Bernstein D, et al. Hepatology 2002; 35: Hassanein T, et al. J Hepatol 2004; 40: Arora S, et al. J Gastroenterol Hepatol 2006; 21: 406

25 PEGASYS plus COPEGUS is cost-effective in patients with normal ALT Genotype 1 PEGASYS plus COPEGUS for 48 weeks No treatment Difference Probability of cirrhosis 19% 32% 13% Life-years Quality-adjusted life years Costs (Euros) PEGASYS plus COPEGUS Other medical costs Cost-effectiveness (Euros) Per life year gained Per quality-adjusted life year gained Hornberger J, et al. J Viral Hepat 2006; 13: 377

26 Normal ALT: conclusions (I) Patients with chronic hepatitis C and persistently normal ALT can have progressive disease PEGASYS plus COPEGUS combination therapy is effective and safe in patients with elevated or persistently normal ALT levels As in patients with elevated ALT, the optimal treatment duration in patients with normal ALT is 24 weeks for genotypes 2 or 3 and 48 weeks for genotype 1

27 Normal ALT: conclusions (II) SVR following PEGASYS plus COPEGUS combination therapy has a positive impact on HRQL in patients with chronic hepatitis C, regardless of ALT levels PEGASYS plus COPEGUS is projected to reduce the incidence of cirrhosis, increase life expectancy, and have an acceptable cost-effectiveness ratio from a societal perspective in patients with normal ALT HRQL = health-related quality of life

28 Treatment and ALT levels Regardless of serum aminotransferase levels, the decision to initiate therapy with interferon and ribavirin should be individualized based on the severity of liver disease by liver biopsy, the potential of serious side effects, the likelihood of response, and the presence of comorbid conditions Strader D, et al. Hepatology 2004; 39: 1147

29 Genotype 4

30 Background Infection with HCV genotype 4 has been historically termed difficult-to-cure due to poor response to conventional IFN-based therapy 1 PEGASYS monotherapy achieves a sustained virological response rate of 45% 2 1. Zylberberg H, et al. Ann Intern Med 2000; 132: Sherman M, et al. Ann Intern Med 2001; 135: 927

31 PEGASYS plus COPEGUS in genotype 4: study objectives To retrospectively study the efficacy and safety of 24 or 48 weeks of treatment with PEGASYS combined with an 800 or mg daily dose of COPEGUS To determine an optimal treatment regimen in chronic hepatitis C patients infected with HCV genotype 4 Diago M, et al. Ann Intern Med 2004; 140: 72

32 PEGASYS 180 μg/wk plus COPEGUS mg/day for 48 weeks is optimal PEGASYS 180 μg plus COPEGUS LD SVR (%) % 63% 79% 24-SD 48-LD 48-SD 20 0% 0 Intent-to-treat analysis. Retrospective analysis of two phase III trials n= LD = RBV 800 mg/day SD = RBV mg/day Diago M, et al. Ann Intern Med 2004; 140: 72

33 Genotype 4: conclusions For patients with HCV genotype 4, both treatment duration and COPEGUS dose affect treatment outcome The optimal treatment regimen is PEGASYS 180 μg/wk plus COPEGUS mg/day for 48 weeks 1 A treatment duration of 24 weeks may now be considered for genotype 4 patients who achieve an RVR (EU only) 2 Using this regimen it is possible to achieve the high SVRs reported for genotypes 2 and Diago M, et al. Ann Intern Med 2004; 140: PEGASYS Summary of Product Characteristics, revised Hadziyannis S, et al. Ann Intern Med 2004; 140: 346

34 African Americans

35 HCV infection and African Americans Antibody to HCV is twice as common 1 Higher prevalence of HCV genotype 1 2 Poor response rate to interferon alfa 2 1. Armstrong G, et al. Ann Intern Med 2006; 144: McHutchison J, et al. Gastroenterology 2000; 119: 1327

36 African Americans have a poor response to IFN-based therapy IFNα-2b for 48 weeks IFNα-2b + RBV for 48 weeks 42% 43% Responders (%) % 16% 17% 10 8% 0 0% African American (n=26) 0% Hispanic (n=17) Caucasian (n=929) Asian (n=13) McHutchison J, et al. Gastroenterology 2000; 119: 1327

37 Higher SVR rates with PEGASYS plus COPEGUS in African Americans Genotype 1; 48-week treatment duration in African Americans Peg-IFNα-2b (12KD) + RBV PEGASYS + COPEGUS SVR (%) % % 28% 26% 31% n= McHutchison 1 0 n= Jeffers 2 Conjeevaram McHutchison Hoofnagle 4 1. McHutchison JG, et al. N Engl J Med 2009: 361: Jeffers M, et al. Hepatology 2004;39: Conjeevaram H, et al. Gastroenterology 2006; 131: Hoofnagle JH, et al. JID 2009; 199: 1112

38 High SVR rates with PEGASYS plus COPEGUS in African American patients with rapid and early virological responses Genotype 1; 48-week PEGASYS + COPEGUS treatment duration African Americans Non-African Americans SVR (%) n= 92% 77% Undetectable at week 2 or 4 60% 72% Undetectable at week McCone J, et al 59th AASLD Abstract 268: oral

39 Adherence to >60% PEGASYS plus COPEGUS improves SVR in AAs* Cumulative exposure to PEGASYS + COPEGUS 40 >80% 30 29% 30% >60% 80% SVR (%) 20 60% Genotype % 0 0% n= *AAs = African Americans Howell C, et al. J Viral Hepat 2006; 13: 371

40 Significant increase in SVR rates with decreasing fibrosis score in genotype Fibrosis score: SVR (%) PEGASYS 180 μg plus COPEGUS African Americans p= % 25% 25% 20% 0 1 or 2 3 or 4 5 or 6 Caucasian Americans 68% p= % 50% 26% 0 1 or 2 3 or 4 5 or 6 n= Conjeevaram H, et al. 56th AASLD 2005; Abstract 199

41 PEGASYS plus COPEGUS is effective in African Americans SVR of 31% in African Americans with genotype 1 is the highest response seen so far in this patient population Conjeevaram H, et al. Gastroenterology 2006; 131: 470

42 Asians

43 PEGASYS plus COPEGUS in Japanese patients with HCV genotype 1 Treatment naive, genotype 1b n=200 PEGASYS 180 µg/week plus COPEGUS mg/day PEGASYS 180 µg/week Follow-up Follow-up Study week Sakai T, et al. 41st EASL 2006; Abstract 605

44 PEGASYS plus COPEGUS provides highest SVR seen in Japanese genotype 1 patients p<0.001 SVR (%) % 61% 20 0 n= 101 PEGASYS monotherapy 99 PEGASYS plus COPEGUS Sakai T, et al. 41st EASL 2006; Abstract 605

45 PEGASYS plus COPEGUS in Taiwanese patients with HCV genotype 2 Treatment naive, genotype 2 n=150 n=50 n=100 PEGASYS 180 µg/wk plus COPEGUS mg/day PEGASYS 180 µg/wk plus COPEGUS mg/day Follow-up Follow-up Study weeks Yu M-L, et al. Gut 2006, in press Randomisation (1:2) Yu M-L, et al. Gut 2007: 56: 553

46 Abbreviated treatment is as effective as standard treatment in Taiwanese patients achieving an RVR 100% SVR PEGASYS 180 μg plus COPEGUS 80% RVR: YES 87% (130 / 150) 60% 40% 98% 100% 16 weeks 24 weeks 20% All patients (n=150) 0% 100% SVR 80% RVR: NO 13% (20 / 150) 60% 40% 20% 57% 77% 16 weeks 24 weeks RVR: HCV RNA <50 IU/mL at week 4 0% Yu M-L, et al. Gut 2007: 56: 553

47 Patients of Latino origin

48 PEGASYS plus COPEGUS in Latino and non- Latino white patients with HCV G1 infection: study design Multicenter, open-label, non-randomised, prospective study N=569* Latinos: n= 269 Non-Latinos: n=300 Treatment naive, CHC, HCV G1 PEGASYS 180 µg/week plus COPEGUS 1000/1200 mg/day Follow-up Study weeks *All treated patients CHC: chronic hepatitis C infection; HCV G1: hepatitis C genotype 1 Rodriguez-Torres M, et al. N Engl J Med 2009; 360:

49 The Latino study: Baseline characteristics Characteristic * Latino (n=269) Non-Latino (n=300) Males n (%) 183 (68) 192 (64) Age, Mean (years) 45.6± ±8.3 Weight, Mean (kg) 83.2± ±19.0 BMI, Mean >27, n (%) 29.7± (65) 27.9± (51) HCV RNA, IU/mL Mean log ± ±0.8 HCV RNA >400,000 IU/mL, n (%) 229 (85) 254 (85) ALT quotient, Mean 2.2± ±1.8 >3, n(%) 66 (25) 50 (17) Cirrhosis n (%) 36 (13) 29 (10) *All treated patients; plus/minus values are means ±SD. BMI: body-mass index; ALT: alanine aminotransferase. Baseline ALT quotient = ALT/upper limit of normal. Rodriguez-Torres M, et al. N Engl J Med 2009; 360:

50 MLR analysis: Non-Latino ethnic background is a strong predictor of SVR Multiple logistic regression Ethnic group (non-latino vs. Latino) Baseline HCV RNA level ( 400,000 vs. >400,000 IU/mL) Baseline ALT quotient* ( 3 vs. >3) Cirrhosis (no vs. yes) BMI (>27 vs. 27) OR for SVR (95% CI) p-value <0.001 < Worse *ALT quotient = ALT/upper limit of normal. HCV: hepatitis C virus; BMI: body-mass index; OR: odds ratio; CI: confidence interval. Better Rodriguez-Torres M, et al. N Engl J Med 2009; 360:

51 More than one-third of Latino patients infected with HCV G1 achieved an SVR Latinos Non-Latinos 100 p<0.001 p<0.001 p<0.001 Patients with virologic response (%) p= p< Virological response: undetectable serum hepatitis C virus (HCV) RNA level (<28 IU/mL). EOT: end-of-treatment; SVR: sustained virological response Study Week EOT SVR Rodriguez-Torres M, et al. N Engl J Med 2009; 360:

52 Transplant recipients

53 Recurrent hepatitis C in liver transplant (LT) recipients After LT, HCV recurrence is almost universal, with ~10 to 30% of patients developing cirrhosis within 5 years 1,2 Treatment of HCV recurrence after LT is difficult and results are disappointing: 3,4 SVR with combination therapy had been achieved in 21 45% of the cases The risk of treatment-induced rejection ranges from 4 25% Tolerance is poor: 20 43% of patients discontinue treatment 1. Gane E, et al. N Engl J Med 1996; 334: Sanchez-Fueyo A, et al. Transplantation 2002; 73: Samuel D, et al. Gastroenterology 2003; 124: Dumortier J, et al. J Hepatol 2004; 40: 669

54 PEGASYS monotherapy for treatment and prophylaxis of recurrent HCV infection SVR (%) Patients had undergone orthoptic liver transplantation (OLT) % PEGASYS 180 μg/wk monotherapy Prophylaxis 0% Untreated control 12%* PEGASYS 180 μg/wk monotherapy Treatment 0% Untreated control *p=0.03 vs control Chalasani N, et al. Hepatology 2005; 41: 289

55 PEGASYS plus COPEGUS in LT patients with recurrent HCV infection Objectives To test for the efficacy of a 1-year combination therapy with PEGASYS plus COPEGUS in LT patients with established recurrent HCV infection To investigate whether a 1-year maintenance therapy with COPEGUS following a 1-year combination therapy had a positive impact on post-lt HCV recurrence Duvoux C, et al. 41st EASL 2006; Abstract 1

56 Duvoux et al. study design Liver biopsy Liver biopsy Liver biopsy COPEGUS Follow-up PEGASYS plus COPEGUS Stratified by HCV RNA Placebo Follow-up Months End of combination therapy Randomisation Duvoux C, et al. 41st EASL 2006; Abstract 1

57 Excellent virological response following 12 months of PEGASYS plus COPEGUS 80 75% Virological response (%) % 0 60/97 62/83 Intent-to-treat Per protocol 14 patients withdrawn before 12 months Duvoux C, et al. 41st EASL 2006; Abstract 1

58 Keeping in mind the frequent use of growth factors, tolerability was good 22 serious adverse events related to antiviral therapy occurred in 18 patients 2 reversible rejection episodes (2%) Treatment was discontinued in 12 patients, due to serious adverse events: Haematological reasons (n=7) anaemia 6, leucopenia 1 Psychiatric reasons (n=2) Impairment in renal function (n=2) Rejection (n=1) Duvoux C, et al. 41st EASL 2006; Abstract 1

59 Prophylaxis of HCV post-olt: PHOENIX study Post-OLT, n= PEGASYS µg/wk 180 µg/wk plus COPEGUS mg/day (escalated) No treatment Follow-up Follow-up Randomisation 1:1

60 PEGASYS in transplant recipients: conclusion PEGASYS plus COPEGUS combination therapy has shown encouraging results in the treatment of recurrent HCV infection following LT Prophylaxis with PEGASYS monotherapy improves outcomes in patients with recurrent HCV infection following OLT The efficacy of PEGASYS plus COPEGUS combination therapy for the prophylaxis of recurrent HCV infection following OLT is currently being investigated in the PHOENIX trial 1. Duvoux C, et al. 41st EASL 2006; Abstract 1 2. Chalasani N, et al. Hepatology 2005; 41: 289

61 Patients with renal impairment

62 HCV in patients with renal impairment HCV is a significant cause of liver disease leading to morbidity/mortality in HCV-infected end-stage renal disease (ESRD) patients 1 HCV-infected ESRD patients show increased mortality on haemodialysis 2 and increased risk of mortality and graft loss after transplantation 3 Eradication of HCV can increase eligibility for kidney transplantation and improve outcomes 4,5 1. Pereira BJG, et al. Kidney Int 1998; 53: Butt AA, et al. J Viral Hepat 2007; 14: Fabrizi F, et al. Am J Transplant 2005; 5: Martin P, Fabrizi F, et al. J Hepatol 2008; 49: Kamar N, et al. Transplantation 2006; 82: 853

63 Prevalence of HCV in end-stage renal disease patients Higher prevalence of HCV infection in ESRD patients compared with the general population 1,2 HCV infects about 10% of ESRD patients undergoing haemodialysis in the US 2 Higher prevalence in developing countries 2 Infection of dialysis patients via nosocomial transmission 2 1. Dienstag JL, McHutchison JG, Gastroenterology 2006; 130: Fabrizi F, et al. Hepatology 2002; 36: 3

64 HCV treatment in end-stage renal disease ESRD patients have impaired drug absorption, distribution, metabolism and clearance leading to: Increase in adverse events 1 High discontinuation rates 1 Interferon-based therapies may require dose adjustment due to alterations in clearance 1 Reducing doses of peginterferon and/or RBV may allow safe treatment of ESRD patients on dialysis 2 4 RBV should not be administered to patients with creatinine clearance <50 ml/min 5 1. Fabrizi F, et al. Hepatology 2002; 36: 3 2. Rendina M, et al. J Hepatol 2007, 46: Bruchfeld A, et al. J Viral Hepat 2006; 13: Sikole A et al. Renal Failure 2007; 29: COPEGUS SPC

65 PEGASYS can be safely administered in patients with renal impairment Mean PEGASYS concentration (ng/ml) *Shaded area denotes concentration of PEGASYS in subjects with normal renal function for both doses PEGASYS 135 μg/week (n=6) PEGASYS 180 μg/week (n=6) Time (hours) Single dose Lamb M, et al. Hepatology 2001; 34: 326A

66 HELPS (Haemodialysis patients: Efficacy with Low-dose PEGASYS ) Multinational, randomised, open-label clinical study Primary endpoint: SVR Patients (N=85): non-cirrhotic, interferon naive, ESRD, CHC PEGASYS 135 µg/week PEGASYS 90 µg/week Follow-up Follow-up 6 weeks screening Study weeks Randomisation (stratified by country and HCV genotype [1 vs. non-1]) Peck-Radosavljevic M, et al. 43rd EASL 2008; Abstract 999

67 HELPS: SVR rates achieved with PEGASYS in ESRD patients 100 PEGASYS 135 µg/week PEGASYS 90 µg/week 80 SVR (%) p= % 35% 61% 57% 31% 38% 20 0 All patients Patients with BL HCV RNA < IU/mL G1 patients Peck-Radosavljevic M, et al. 43rd EASL 2008; Abstract 999

68 HELPS: week 12 response with PEGASYS 135 µg/week highly predictive for SVR PEGASYS 135 µg/week (n=38) <50 IU/mL at week 12: YES 61% (23/38) 100% 80% 60% 40% 20% 0% 100% 61 14/23 SVR 39 9/23 No SVR 92 PPV: 61% <50 IU/mL at week 12: NO 32% (12/38) PPV: positive predictive value NPV: negative predictive value 80% 60% 40% 20% 0% 8 1/12 SVR 11/12 No SVR NPV: 92% Peck-Radosavljevic M, et al. 43rd EASL 2008; Abstract 999

69 HELPS: week 12 response with PEGASYS 90 µg/week highly predictive for SVR PEGASYS 90 µg/week (n=43) <50 IU/mL at week 12: YES 37% (16/43) 100% 80% 60% 40% 20% 0% 100% 98 14/16 SVR 12 2/16 No SVR 96 PPV: 88% <50 IU/mL at week 12: NO 63% (27/43) 80% 60% 40% 20% 0% 4 1/27 26/27 SVR No SVR NPV: 96% PPV: positive predictive value NPV: negative predictive value Peck-Radosavljevic M, et al. 43rd EASL 2008; Abstract 999

70 HELPS: safety and tolerability 135 μg/week (n=38) n (%) PEGASYS 90 μg/week (n=43) n (%) Patients with 1 serious AEs 14 (36.8) 14 (32.6) Withdrawal for safety reasons AEs/intercurrent illness Death Dose modifications for AEs or lab abnormalities AE Laboratory abnormality Neutropenia Thrombocytopenia 5 (13.2) 1 (2.6) 4 (10.5) 10 (26.3) 9 (23.7) 3 (7.9) 0 3 (7.9 ) 3 (7.0) 3 (7.0) 0 12 (27.9) 9 (20.9) 4 (9.3) 2 (4.7) 3 (7.0) Laboratory abnormalities Haemoglobin <8.5 g/dl Neutrophils 0.5 <0.75 x 10 9 /L Platelets 20 <50 x 10 9 /L Median cumulative dose administered, µg/kg (range) 10 (26.3) 1 (2.6) 4 (10.5) (13 144) 9 (20.9) 4 (9.3) 2 (4.7) 59 (22 123) Peck-Radosavljevic M, et al. 43rd EASL 2008; Abstract 999

71 Pharmacokinetics (PK) of RBV in CHC patients with renal impairment Renal excretion is a major elimination route of RBV and patients with renal impairment are at risk of RBV toxicity RBV is not recommended in CHC patients with creatinine clearance <50 ml/min 1 A study by Wang et al. examined the multiple-dose PK of RBV in CHC patients with renal impairment 2 Secondary objectives of the study included the evaluation of safety and tolerability of RBV and PEGASYS combination therapy in these patients 1. COPEGUS SPC 2. Wang K, et al. 59th AASLD 2008; Abstract 1864

72 Pharmacokinetics (PK) of RBV in CHC patients with renal impairment: study design Screening Day -35 to -1 PK and safety assessments Weeks 1 12 Treatment extension and safety assessments Additional 12 or 36 weeks* Follow-up Patients (N=63) CHC, Renal impairment A B C D Moderate renal impairment PEGASYS 180 µg/week plus ribavirin 600 mg daily Severe renal impairment PEGASYS 180 µg/week plus ribavirin 400 mg daily End-stage renal disease PEGASYS 135 µg/week plus ribavirin 200 mg daily Normal renal function PEGASYS 180 µg/week plus ribavirin* Within 1 week of completion or d/c of treatment Study weeks *G2/G3 patients received a total of 24 weeks treatment plus 800 mg RBV G1/G4 patients received a total of 48 weeks treatment plus 1000/1200 mg RBV Wang K, et al. 59th AASLD 2008; Abstract 1864

73 Lowest multiple-dose exposure of RBV at week 12 in patients with ESRD RBV AUC 0-12 * (ng h/ml) Individual patient value Mean Median 0 A (n=9) B (n=9) C (n=12) D (n=12) * AUC 0-12 : area under the plasma concentration-time curve A, Moderate renal impairment; B, Severe renal impairment; C, End-stage renal disease; D, Normal renal function Wang K, et al. 59th AASLD 2008; Abstract 1864

74 Lower apparent clearance of RBV at week 12 in patients with impaired renal function RBV CL/F* (L/h) Individual patient value Mean Median A (n=9) B (n=8) C (n=7) D (n=12) * CL/F: apparent total body clearance A, Moderate renal impairment; B, Severe renal impairment; C, End-stage renal disease; D, Normal renal function Wang K, et al. 59th AASLD 2008; Abstract 1864

75 Wang study: safety Treatment group Group A (n=17) Group B (n=14) Group C (n=18) Group D (n=13) Any AE, n (%) 17 (100) 14 (100) 17 (94) 13 (100) Related AE* 17 (100) 14 (100) 17 (94) 13 (100) Serious AEs, n (%) 4 (24) 5 (36) 7 (39) 1 (8) Related serious AEs* 1 (6) 3 (21) 3 (17) 0 (0) Deaths, n (%) 0 (0) 1 (7) 1 (6) 0 (0) Premature discontinuations for AEs or lab abnormalities, n (%) RBV 4 (24) 8 (57) 3 (17) 0 (0) PEGASYS 0 (0) 5 (36) 3 (17) 0 (0) *Judged by the investigator A, Moderate renal impairment; B, Severe renal impairment; C, End-stage renal disease; D, Normal renal function Wang K, et al. 59th AASLD 2008; Abstract 1864

76 Patients with ESRD treated with 200 mg/day RBV are able to maintain exposure Treatment group Daily RBV dose (mg) Time treated with assigned dose of RBV* A (n=17) 600 B (n=14) 400 C (n=19) 200 D (n=13) 1000 or 1200 According to genotype 40% of study duration, n (%) 3 (30) 2 (50) 9 (100) 9 (100) 60% of study duration, n (%) 2 (20) 1 (25) 9 (100) 9 (100) 80% of study duration, n (%) 1 (10) 0 (0) 8 (89) 9 (100) *Evaluated in 10 patients of Group A, four patients of Group B, nine patients of Group C, and nine patients of Group D who received 80% of assigned dose of PEGASYS. Maximum study duration was 168 days for HCV genotype 2- or 3-infected patients and 336 days for HCV genotype 1- or 4-infected patients. A, Moderate renal impairment; B, Severe renal impairment; C, End-stage renal disease; D, Normal renal function Wang K, et al. 59th AASLD 2008; Abstract 1864

77 Patients with renal impairment: conclusions CHC patients with ESRD can achieve an SVR with PEGASYS A week 12 response is highly predictive of SVR in ESRD patients PEGASYS doses of 135 and 90 μg/week were well-tolerated and showed similar safety profiles PEGASYS 135 µg/week plus daily RBV 200 mg/day was well-tolerated among patients with ESRD Adherence to therapy was similar between patients with ESRD and patients with normal renal function

78 Children and adolescents

79 Chronic hepatitis C in children and adolescents The prevalence of HCV in children is approximately: 0.2% in those younger than 12 years old 1 0.4% in those between 12 and 19 years old 1 The main route of transmission of HCV in children is blood transfusion 2 Of those infected, 30-60% will develop chronic HCV infection 1 Children with HCV respond better to IFN than adults: Sustained response rates in patients with HCV genotype 1 infection: 27% vs. 8 10% for children and adults respectively 3 1. Mushtaq M et al. Curr Pediatr Res 2009; 13 (1 & 2): El-Raziky MS et al. World J Gastroenterol 2007; 13(12): Jacobson IM et al. J Pediatr Gastroenterol Nutr Jan; 34(1): 52

80 CHIPS study: PEGASYS plus COPEGUS in children and teenagers with chronic HCV infection PEGASYS 100 µg/m 2 /wk plus COPEGUS 15 mg/kg/day Treatment naive, HCV - infected children, ages 6 18 (n=65) Group A Group B Genotype 2/3 Genotype 1/4/5/6 Follow-up Follow-up Study weeks Design: Prospective, open-label, multicentre, pilot study CHIPS=Chronic Hepatitis C International Paediatric Study PEGASYS SPC 2009

81 PEGASYS plus COPEGUS in children and adolescents Efficacy results were similar to those reported in adults Preliminary data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection PEGASYS SPC 2009

82 PEDS-C study: assessing safety and efficacy of PEGASYS plus COPEGUS in children and adolescents with chronic HCV infection Treatment-naive, (HCV -infected children, ages 5-17 (n=114) PEGASYS 180 µg/1.73 m 2 /week plus COPEGUS 15 mg/kg/d PEGASYS 180 µg/1.73 m 2 /week plus placebo Follow-up Follow-up 0 24 Study weeks Design: US multicentre, randomised, placebo-controlled trial Randomisation Schwarz KB, et al. 59th AASLD 2008: Abstract 242

83 PEDS-C study: higher SVR rates with PEGASYS plus COPEGUS PEGASYS 180 µg/1.73 m 2 /week plus RBV 15 mg/kg/d PEGASYS 180 µg/1.73 m 2 /week plus placebo 100 p<0.001 p=0.003 p= SVR (%) Overall Genotype 1 Genotype 2/3 Schwarz KB, et al. 59th AASLD 2008: Abstract 242

84 PEDS-C study: lower relapse rates with PEGASYS plus COPEGUS PEGASYS 180 µg/1.73 m 2 /week plus RBV 15 mg/kg/d PEGASYS 180 µg/1.73 m 2 /week plus placebo Relapse rate (%) /35 10/22 Schwarz KB, et al. 59th AASLD 2008: Abstract 242

85 PEDS-C study: similar rates of adverse events with mono and combination therapy Adverse events related to therapy (%) Flu PEGASYS 180 µg/1.73 m 2 /week plus RBV 15 mg/kg/d PEGASYS 180 µg/1.73 m 2 /week plus placebo Headache GI symptoms Injection site rx Joint aches Irritability Rash Anorexia Depression Schwarz KB, et al. 59th AASLD 2008: Abstract 242

86 PEDS-C Study: conclusions Higher SVR rates achieved with PEGASYS plus COPEGUS compared with PEGASYS monotherapy SVR rates in children and adolescents treated with PEGASYS plus COPEGUS are similar to those reported in adult patients PEGASYS plus COPEGUS was generally well tolerated in children and adolescents Side effects were similar to those observed in adult patients Schwarz KB, et al. 59th AASLD 2008: Abstract 242