Buti P, 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

1Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09

Extended Treatment Duration in Chronic Hepatitis C Genotype 1 Infected Slow-Responders:

Final Results of the SUCCESS Study

M. Buti, Y. Lurie, N.G. Zakharova,N.P. Blokhina, A. Horban, C. Sarrazin,

L. Balciuniene, R. Chen, X. Yu, R. Faruqi,R. Esteban

44th Annual Meeting of the European Association for the Study of the Liver Sunday April 26, 2009; 12:30-12:45, Hall A2

Copenhagen, Denmark

2 Buti P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09

Introduction

Some studies suggest that extending treatment from 48 to 72 weeks could increase SVR in G1 patients who are slow responders1-3

However, definition of slow response varies depending on the study (non-RVR2, partial early virologic response1-3). In addition, the ribavirin dose is suboptimal in many1-2; both factors affect the SVR rate

1. Berg T, et al. Gastroenterology. 2006;130:1086-1097.2. Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460.3. Pearlman BL, et al. Hepatology. 2007;46:1688-1694.


Objectives

Evaluate the efficacy and safety of extended treatment with PEG-IFN alfa-2b plus weight-based RBV in G1 slow responders

• Slow responders are patients with detectable HCV-RNA with ≥2 log viral reduction at TW 12 and undetectable HCV RNA at TW 24

Primary Efficacy End Point

• SVR for slow responders treated for 48 or 72 weeks

Secondary End Points

• Relapse rate

• Safety


Study Design Enrolled 1,428 treatment-naive patients with chronic HCV G1

Week 12 Week 24 Week 48 Week 72

PEG-IFN alfa-2b 1.5 µg/kg/wk + RBV 0.8 1.4mg/d 12 weeks

Tx

HCV-RNA (-) PEG-IFN alfa-2b + RBV :36 weeks Tx

HCV-RNA (+)and <2 log10 ↓

Stop therapy

HCV-RNA (+)and ≥2 log10

PEG-IFN alfa-2b + RBV 12 weeks Tx

HCV-RNA (+) Stop therapy

HCV-RNA (-)

PEG-IFN alfa-2b + RBV :24 weeks Tx

PEG-IFN alfa-2b + RBV:48 weeks Tx

Group CGroup C

Slow Responders

Group A

Group B

118 centers in Europe, Canada, Puerto Rico, and Israel participated in this study.


Key Inclusion Criteria

Age 18–70 years

Treatment-naive

Chronic HCV G1 infection

Detectable HCV-RNA

Elevated serum ALT levels

Liver biopsy (within 18 months) consistent with chronic hepatitis

Compensated liver disease


Patient Disposition Enrolled 1,428 treatment-naive patients with chronic HCV G1

Week 12 Week 24 Week 48 Week 72

PEG-IFN alfa-2b 1.5 RBV 0.8-1.4mg/d: 12

weeks TxN = 1419

HCV-RNA (-) PEG-IFN alfa-2b+ RBV 36 weeks Tx

HCV-RNA (+)and <2 log10 ↓

Stop therapy

HCV-RNA (+)and ≥2 log10

PEG-IFN alfa-2b + RBV 12 weeks T

HCV-RNA (+) Stop therapy

HCV-RNA (-)



Group CGroup Cn = 816 (57.5%)n = 816 (57.5%)

Slow Responders n=159 (11.2%)

Group An = 86

Group B n = 73

Nonrespondersn = 444 (31.3%)

HCV-RNA Central lab Roche TaqMan assay (LLQ = 30 IU/mL)


Patient Demographics

Slow RespondersComplete

EVR

Group A 48 Weeks Tx

(n = 86)

Group B72 Weeks Tx

(n = 73)

Group C48 Weeks Tx

(n = 816)

Age, mean, y (±SD) 44.5 (9.9) 46.5 (11.6) 40.4 (11.4)

Caucasians, n (%) 86 (100) 70 (95.9) 783 (96.0)

Female, n (%) 34 (39.5) 27 (37.0) 309 (37.9)

Weight, mean, kg (±SD) 78.04 (15.20) 77.53 (16.60) 76.45 (14.67)

ALT level, mean, U/L (±SD) 75.88 (48.03) 84.64 (70.68) 99.86 (70.30)

SD = standard deviation.


Most Slow Responders Had High Baseline Viral Load

Slow Responders Complete EVR

Baseline Viral Load(IU/mL), n (%)

Group A 48 Weeks Tx

(n = 86)

Group B72 Weeks Tx

(n = 73)

Group C48 Weeks Tx

(n = 816)

Median log IU/mL 6.54 6.64 6.42

≤400,000 3 (3.5) 1 (1.4) 132 (16.2)

400,000–800,000 8 (9.3) 4 (5.5) 90 (11)

>800,000 75 (87.2) 68 (93.2) 594 (72.8)


Treatment Discontinuations

Patient, n (%)Group A

48 Weeks TxGroup B

72 Weeks TxGroup C

Complete EVR

n 86 73 816

Completed study 78 (90.7) 56 (76.7) 716 (87.7)

Withdrew early 8 (9.3) 17(23.3) 100 (12.3)

Due to AE 3 (3.5) 6 (8.2) 39 (4.8)

Lost to FU 2 (2.3) 1 (1.4) 21 (2.6)

No wish to continue 1 (1.2) 6 (8.2) 16 (2.0)

Noncompliance 2 (2.3) 2 (2.7) 16 (2.0)

Others 0 2 (2.7) 8 (1.0)


SVR With 72-Week Treatment Was Not Statistically Superior to 48-Week Treatment in Slow Responders

(ITT Analysis)

79.5

47.943.0

0

20

40

60

80

100

Group A (48 Weeks) Group B (72 Weeks) Group C (48 Weeks)

Pa

tie

nts

, %

P = .6445

P < .0001

———Slow Responders ——— Complete EVR

37/86 35/73 649/816


SVR Was Not Statistically Different Between 72- and 48-Week Treatment Groups in Slow Responders

(Per Protocol Analysis)

48.643.5

0

20

40

60

80

100

Group A (48 Weeks) Group B (72 Weeks)

Pa

tie

nts

, %

Slow Responders

P = .6341

37/85 35/72


SVR was not statistically different between 72-week treatment and 48-week treatment among

80/80/80 Compliance* and Completers†

57,1 57,146,244,3

0

20

40

60

80

100

80/80/80 Completers

Patie

nts

, %

Group A (48 wks)

Group B (72 wks)

P = 0.1952 P = 0.2802

*The subsets of all treated subjects meeting the criteria for fast or slow response and who took at least 80%of the planned dose of each of the study medications (peginterferon and ribavirin) for at least 80% of the assigned treatment duration†The subsets of all treated population meeting the criteria for fast or slow response and who completed the planned course of treatment as per the Case Report Form Subject Status section

n=79 n=56 n=78 n=56


Relapse Rates Were Not Statistically Different Between 72- and 48-Week Treatment Groups in Slow Responders

47.1

10.1

32.7

0

20

40

60

80

100

Group A (48 Weeks) Group B (72 Weeks) Group C (48 Weeks)

*95% CI: 3.3%, 32.1%.†95% CI: 24.9%, 49.0%.

——-Slow Responders —— Complete EVR

Pat

ien

ts, %

P = .1699 14.4%*

P < .0001 37.0%†

Relapse: 32/68 Relapse: 16/49 Relapse: 71/702


Logistic Regression Analysis Weight

• <75 vs >75 kg Age

• 40–60 vs >60 y• <40 vs >60 y

Week 12 HCV-RNA• 50–5000 vs >5000 IU/mL• 50 vs >5000 IU/mL

Baseline Viral Load• ≤ vs > 800,000 IU/mL

Treatment Arm• A vs B

All Analyses NS except for Age <40 vs > 60 y (p = 0.0149)


Rates of Adverse Events Were Similar Among Treatment Groups

Slow RespondersComplete

EVR

Adverse Event, n (%)

Group A 48 Weeks Tx

(n = 86)

Group B72 Weeks Tx

(n = 73)

Group C48 Weeks Tx

(n = 816)

At least one 83 (96.5) 71 (97.3) 792 (97.1)

Treatment-related 82 (95.3) 69 (94.5) 787 (96.4)

Serious 6 (7.0) 6 (8.2) 57 (7.0)

Leading to early withdrawal 3 (3.5) 6 (8.2) 41 (5.0)


Summary

This, the largest prospective study among naïve G1 slow responders, demonstrated no statistically significant differences in SVR or relapse rates between 48 and 72 weeks of treatment when ribavirin is adjusted according to body weight

However there is a numerical trend toward improved SVR and reduced relapse rates for the 72 wks therapy


Summary

No unexpected safety concerns were reported

Higher discontinuation rates may be associated with extended treatment period

Among Complete EVR patients, 80% achieved SVR similar to those observed in the IDEAL study


Study InvestigatorsFrank H AndersonJose D Pedreira AndradeJoachim C ArnoldLigita BalciunieneSimon Bar-Meir Harry P Bassaris Manuel Garcia Bengoechea Thomas Berg Frieder Berr Marc Bilodeau Natalia P Blokhina Danielle Botta-Fridlund Marc Bourliere Peter Buggisch Mads R Buhl Patrice Cacoub Jose Luis Calleja Andreas Cerny Janusz Cianciara Matthew CrampAntonio CraxiJens EnckeLajos DalmiJean DelwaideDimitrios DimitroulopoulosHalyna DubynskaMartti FarkkilaSaya Victor FeinmanJon FlorholmenManuel Rodriguez GarciaCornelia Gelbmann

Guido GerkenJudit GervainAndrzej GietkaAndrzej GladyszTobias GoeserOlga A GolubovskaJean-Jacques GonversMichael GschwantlerNatalya B GubergritsRainer GuntherDominique GuyaderWaldemar HalotaMarkus H HeimVaclav HejdaBorys A HerasunChristophe HezodeNir HilzenratAndrzej HorbanDominika IpatovaAlgimantas IrniusViktor JancsikJacek JuszczykKelly KaitaLars N KarlsenNatalya V KharchenkoHartwig KlinkerJohn KoskinasTomas KrechlerDominique LarreyMark LevstikAlfredo Juan Lopez-Morante

Yoav Lurie Spilios ManolakopoulosJose Maria Oscar Nunez MartinezRafael Barcena MaruganPhilippe MathurinLeopoldo MatosStefan MaussEhud MelzerLarysa V MorozViatcheslav G MorozovBeat MullhauptRafael Esteban MurFrederik NevensAssy NimerBlai Dalmau ObradorRicardo Moreno OteroDenis OuzanCourt PedersenGiovambattista PinzelloViver Pi-SunerVladimir V RafalskyMaria Raptopoulou-GigiJens RasenackJose Aguilar ReinaHelmer Ring-LarsenMario RizzettoFederico Rodriguez-PerezJose Such RondaFernando Pons RomeroSiegbert Rossol

Stephen RyderJose Sanchez-TapiasRui Sarmento e Castro Christoph SarrazinJordi Ortiz SeumaStephen ShafranDaniel ShouvalEmanuel SikulerManfred V SingerJan SperlZilvinas SukysJolanta SumskieneGerlinde TeuberValentyn TopolnytskyyAlbert TranChristian TrepoPetr Urbanek Jose M Zozaya UrmenataOla R WeilandJohan WestinKarl H WiedemannFlorence Wong Cristina ValenteJean-Pierre VinelZhanna I VozianovaEric YoshidaReinhart ZachovalNatalia G ZakharovaJean-Pierre ZarskiEli Zuckerman

Documents

Buti P, 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