Reduced Dose and Duration of Peginterferon Alfa

Transcript Reduced Dose and Duration of Peginterferon Alfa

Reduced Dose and Duration of Peginterferon alfa-2b and Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial) Final Analysis

M Manns 1 , S Zeuzem 2 , A Sood 3 , Y Lurie 4 , M Cornberg 1 , H Klinker 5 , I Merican 6 , Y Ilan 7 , T Mueller 8 , R Chen 9 , X Yu 9 , R Faruqi 9 , and H Wedemeyer 1 44th European Association for Study of the Liver Copenhagen 12.00-13.30 Sunday, April 26, 2009. 1 Medical School of Hannover, Hanover, Germany; 2 J.W. Goethe University Hospital, Frankfurt. Germany 3 Dayanand Medical College & Hospital, Ludhiana, India 4 Tel-Aviv Sorasky Medical Center, Tel-Aviv, Israel 5 University of Würzburg Medical Center, Würzburg, Germany 6 Selayang Hospital, Selangor, Malaysia 7 Hadassah Hebrew University Medical Center, Jerusalem, Israel 8 9 University of Munich, Munich, Germany Schering Plough Corp., NJ, USA

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

International Recruitment

Poland Germany Israel India Indonesia Thailand Malaysia Singapore HepNet Cohort (investigator-initiated, 2003-2006) International Cohort (SP sponsored, 2005-2007)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Acknowledgments

HEPNET INVESTIGATORS JC Arnold S Mauss P Buggisch H Cordes U Meyer J Ockenga W Fleig W Gickler J Gottberg K Grungrieff A Heer H Hinrichsen D Hüppe T Käser H Klinker MP Manns R Markus J Pausch T Pohle J Riemann M Rössle A Schober H Steffens A Trein K Wiedmann K Wiegand S Zeuzem INTERNATIONAL INVESTIGATORS S Abu-Mauch Y Lurie D Amarapurkar Z Ben-Ari V Mahachai I Merican C Choudhury A Chutaputti M Goenka W Halota A Horban Y Ilan E Janczewska-Kazek T Piratvisuth D Reddy S Sachithanandan T Safadi S Sarin O Segol PB Setiawan A Konar L Lesmana S Lim A Sood T Tanwandee

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Background

 

PEG-IFN alfa 2b (1.5 µg/kg/wk) + weight-based RBV for 24 weeks is a recommended treatment for patients with genotype 2/3 hepatitis C, but many important clinical questions remain unanswered:

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What is the optimum dose of PEG-IFN alfa-2b?

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Reduced PEG-IFN dose?

1,2 What is the optimum treatment duration?

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24 weeks for all patients?

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Reduced treatment duration for selected patients (<24 weeks 2-6 )? Are separate treatment regimens required for G2 and G3 patients?

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Higher SVR with G2, higher relapse with G3

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Do global/ethnic aspects influence treatment outcomes?

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Asian vs white?

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Prolonged infection leads to high rates of cirrhosis among Asian patients 7 What is the efficacy of standard antiviral treatment in a “real-life” setting 1. Manns et al. Lancet. 2001;358:958-965 2. Mangia et al. N Engl J Med. 2005;352:2609-2617 3. Shiffman et al. N Engl J Med. 2005;357;124-134 4. Lagging et al. Hepatology. 2008;47:1837-1845 5. Dalgard et al.

Hepatology

. 2008;47:35-42 6. von Wagner et al.

Gastroenterology

. 2005;129:522-527 7. D’Souza et al.

Clin Gastroenterol Hepatol

. 2005;3:910-917.

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

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Study Design and Aim

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Study Design

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Open-label, multicenter, randomized, parallel-group study

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Treatment-naive genotypes 2 and 3

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Combination of “real-life” and industry-sponsored study

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Large Asian population

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Aim

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To evaluate the effect of reduced treatment duration or reduced PEG-IFN alfa-2b dosing on SVR and relapse rates among treatment-naive G2/3 patients

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Methods

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Treatment Arms

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A: PEG-IFN alfa 2b (1.5 µg/kg/wk) + RBV (800-1200 mg/d) for 24 weeks B: PEG-IFN alfa 2b (1.0 µg/kg/wk) + RBV (800-1200 mg/d) for 24 weeks

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C: PEG-IFN alfa 2b (1.5 µg/kg/wk) + RBV (800-1200 mg/d) for 16 weeks

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Co-primary End Points

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Compare standard regimen of PEG-IFN alfa 2b (1.5 µg/kg/wk) + RBV with a lower dose PEG-IFN alfa 2b (1.0 µg/kg/wk) + RBV regimen (A vs B) Compare 24-week vs 16-week regimen of PEG-IFN alfa 2b (1.5 µg/kg/wk) + RBV (A vs C)

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Noninferiority criteria (p<0.025 required)

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Period of Enrollment

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HepNet cohort: July 2003 to March 2006

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International cohort: January 2005 to March 2007

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No Interim Analysis per Protocol

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First presentation of results from REDD 2/3

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Patient Population

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Key Inclusion Criteria

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Adult patients with chronic hepatitis C and compensated liver disease (Child-Pugh score <7)

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Genotype 2 or 3

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Treatment-naive

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At least 1 abnormal ALT level in previous 12 months

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Key Exclusion Criteria

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HIV or hepatitis B coinfection

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Causes of liver disease other than hepatitis C

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Evidence of advanced liver disease

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Preexisting psychiatric condition

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Alcohol/substance abuse

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Patient Demographics

Age, y, mean (SD) Male, n (%) Body weight, kg (SD) Time since infection, y (SD) Genotype, n (%) 2 3 Baseline HCV RNA, n (%) ≥600,000 IU/mL <600,000 IU/mL Group A PEG 1.5/R (24 wk) n = 230 38.8 (10.2) 139 (60.4) 73.7 (15.2) 7.3 (7.04) 38 (16.5) 192 (83.5) 119 (51.7) 109 (47.4) Group B PEG 1.0/R (24 wk) n = 224 39.9 (11.2) 146 (65.2) 72.8 (13.7) 7.6 (7.49) 49 (21.9) 175 (78.1) 120 (53.6) 103 (46.0) Group C PEG1.5/R (16 wk) n = 228 39.7 (11.1) 148 (64.9) 72.5 (15.0) 7.3 (8.02) 48 (21.1) 180 (78.9) 123 (53.9) 103 (45.2) Total n = 682 39.5 (10.9) 433 (63.5) 73.0 (14.6) 7.4 (7.52) 135 (19.8) 547 (80.2) 362 (53.1) 315 (46.2) 8

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

HepNet vs International Cohort Patient Demographics

Age, y, mean (SD) Male, n (%) Body weight, kg (SD) Years since HCV exposure, y (SD) HCV genotype, n (%) 2 3 Baseline HCV-RNA, n (%) ≥600,000 IU/mL <600,000 IU/mL HepNet Cohort n = 347 38.8 (10.9) 207 (59.7) 74.4 (14.6) 4.7 (5.01) 84 (24.2) 263 (75.8) 171 (49.3) 171 (49.3) International Cohort n = 335 40.2 (10.8) 226 (67.5) 71.6 (14.6) 11.4 (8.71) 51 (15.2) 284 (84.8) 191 (57.0) 144 (43.0) 9

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

100 75

SVR by Treatment Regimen

A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 66.5 64.3

a 56.6

b 58.6 60.0

47.4

74.6

68.8

66.1

50 25 0 All Patients (n = 682) HepNet Cohort (n = 347) International Cohort (n = 335) All Randomized and Treated Patients Treatment differences (one-sided 95% CI): a Grp A – Grp B: -0.02 (-0.10); P = .041.

b Grp A – Grp C: -0.10 (-0.17); P = .495.

Noninferiority not achieved for all patients and individual cohorts.

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

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100

SVR by Treatment Regimen

A: PEG 1.5/R (24 weeks) Real-life setting 67.1% completers vs. 85.7% in clinical setting B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 74.6

68.8

66.1

75 66.5 64.3

a 56.6

b 58.6 60.0

47.4

b Grp A – Grp C: -0.10 (-0.17); P = .495.

Noninferiority not achieved for all patients and individual cohorts.

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

100 75

SVR: Completers Analysis

A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 81.5 79.9

a 67.6

b 80.0 80.5

59.3

82.5 79.4

74.5

50 25 0 All Patients HepNet Cohort International (N = 520) (n = 233) Cohort (n = 287) Completers Treatment differences (one-sided 95% CI): a Grp A – Grp B: -0.02 (-0.09); P = .024.

b Grp A – Grp C: -0.14 (-0.21); P = .798.

Noninferiority not achieved for all patients and individual cohorts.

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

100 75

SVR by Genotype

A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 77.8

61.3

53.8

72.7

66.7

72.7

52.8

59.5

45.6

74.8

69.2

64.4

50 25 0 HepNet Cohort (n = 84) International Cohort (n = 51) HepNet Cohort (n = 263) International Cohort (n = 284) Genotype 2 Genotype 3

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

100 75

SVR According to Race

A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 75.4

69.5

65.6

73.7

68.0 66.7

58.6 60.0

47.4

50 25 0 International Cohort (n = 177) Asian HepNet Cohort (n = 347) White International Cohort (n = 158)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

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Lower Relapse Rates With 24 Weeks of Therapy

A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 34.2

29.3

c 25.5

25 17.8

a 16.3

b 18.8

14.3

17.0 18.0

0 All Patients (N = 496) HepNet Cohort (n = 219) International Cohort (n = 277) All Randomized and Treated Patients Rate d (two-sided 95% CI): a 0.18 (0.12, 0.24) b 0.16 (0.11, 0.22) c 0.29 (0.22, 0.36)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

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Most Common Treatment-Emergent Adverse Events

a Adverse Event, % Pyrexia Fatigue Headache Alopecia Asthenia Myalgia Influenza-like illness Pruritus Weight decrease Anorexia Nausea Injection-site erythema Depressed mood Arthralgia Anemia Diarrhea Dry skin Group A: PEG 1.5/R (24 wk) N = 230 37.8

22.6

20.9

19.1

15.2

12.6

12.2

11.7

11.3

10.9

10.0

9.6

5.7

Group B: PEG 1.0/R (24 wk) N = 224 37.1

22.3

25.4

16.1

27.7

12.1

9.4

19.6

10.7

4.9

11.6

13.8

7.1

7.6

4.9

12.1

11.2

Group C: PEG1.5/R (16 wk) N = 228 44.3

15.8

25.4

13.6

19.7

14.9

10.1

13.6

9.6

14.0

7.5

8.3

10.5

11.0

7.0

6.6

a Occurring at a frequency >10% in any treatment arm

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Serious Adverse Events and Discontinuations

Treatment-emergent SAE, n (%) Treatment-emergent severe/life threatening AEs, n (%) Deaths, a n (%) AE causing discontinuation of treatment, n (%) Group A PEG 1.5/R (24 weeks) n = 230 14 (6.1) 16 (7.0) 2 (<1) 3 (1.3) Group B PEG 1.0/R (24 weeks) n = 224 11 (4.9) 10 (4.5) 1 (<1) 3 (1.3) Group C PEG1.5/R (16 weeks) n = 228 7 (3.1) 12 (5.3) 0 (0) 5 (2.2) 17 a All 3 deaths were considered unlikely to be related to study medication AE, adverse event; SAE, serious adverse event.

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Conclusions

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Statistically unable to demonstrate that lower dose PEG-IFN alfa 2b (1.0 ug/kg/wk) regimen is noninferior to standard dose PEG-IFN alfa-2b (1.5 ug/kg/wk) regimen.

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PEG-IFN alfa 2b 1.5 µg/kg/wk and 1.0 µg/kg/wk in combination with weight-based ribavirin have similar tolerability profiles

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24 weeks of therapy is the appropriate treatment duration for G2/3

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Higher relapse rate with shorter duration treatment

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SVR rates were similar in Asian and white patients

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This is the largest study to date in Asian G3 patients

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Results from REDD 2/3 are similar to those reported in other large prospective clinical trials of PEG-IFN alfa plus RBV 1-4 1. Manns et al. Lancet. 2001;358:958-965.

2. Fried et al. N Engl J Med. 2002;347:975-982. 3. Shiffman et al. N Engl J Med. 2007;357:124-134.

4. Mangia et al. N Engl J Med. 2005;352:2609-2617.

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.

04/28/09

Reduced Dose and Duration of Peginterferon Alfa

Transcript Reduced Dose and Duration of Peginterferon Alfa