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1 FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAÏVE PATIENTS FERENCI P 1, ASSELAH T 2, FOSTER GR 3,

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Presentation on theme: "1 FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAÏVE PATIENTS FERENCI P 1, ASSELAH T 2, FOSTER GR 3,"— Presentation transcript:

1 1 FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAÏVE PATIENTS FERENCI P 1, ASSELAH T 2, FOSTER GR 3, ZEUZEM S 4, SARRAZIN C 4, MORENO C 5, OUZAN D 6, MAEVSKAYA M 7, CALINAS F 8, MORANO LE 9, CRESPO J 10, DUFOURJ-F 11, BOURLIERE M 12, AGARWAL K 13, FORTON D 14, SCHUCHMANN M 15, ZEHNTER E 16, NISHIGUCHI S 17, OMATA M 18, STERN J 19, DATZENKO Y 20, SCHERER J 19, QUINSON AM 19 1 Medical University of Vienna, Vienna, Austria; 2 Hepatology Department, Beaujon Hospital, AP-HP, University Paris Diderot 7 and INSERM U773, CRB3, Clichy, France; 3 Queen Mary, University of London, London, UK; 4 JW Goethe University Hospital, Frankfurt, Germany; 5 Hôpital Universitaire Erasme, Brussels, Belgium; 6 Institut Arnault Tzanck, St Laurent du Var, France; 7 First Moscow State Medical University, Moscow, Russia; 8 Centro Hospitalar de Lisboa Central, Lisbon, Portugal; 9 Hospital Meixoeiro, Vigo, Spain; 10 Hospital Univ. De Valdecilla, Santander, Spain; 11 Universitätsklinik für Viszerale Chirurgie und Medizin, Bern, Switzerland; 12 Hopital Saint Joseph, Marseille, France; 13 King's College Hospital, London, UK; 14 St George's Hospital, London, UK; 15 University Hospital Mainz, Mainz, Germany; 16 Schwerpunktpraxis Hepatologie, Dortmund, Germany; 17 Hyogo College of Medicine, Hyogo, Japan; 18 Yamanashi Central and Kita Hospitals, Yamanashi, Japan; 19 Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA; 20 Boehringer Ingelheim Pharmaceuticals GmbH & Co KG, Biberach, Germany

2 2 Introduction to faldaprevir  Faldaprevir (FDV; BI ) is a potent and selective inhibitor of HCV NS3/4A 1  FDV has antiviral activity against HCV genotypes (GT) 1, 2, 4, 5 and 6 in vitro 1  The pharmacokinetics of FDV allow oral, once-daily administration 1. White PW, et al. Antimicrob Agents Chemother 2010;54:4611–4618; 2. Sulkowski et al Hepatology 2013 Jan 28 (epub)  High efficacy and favourable tolerability was shown in Phase II studies of FDV in combination with pegylated interferon α2a and ribavirin (PegIFN/RBV) 2

3 3 Study design PR Placebo + PR Observation Period Day 1Week 12Week 24Week 48Week 72 Faldaprevir 240 mg QD + PR Observation Period Placebo + PR PRObservation Period ETS No ETS Arm 2 (n=261) Arm 3 (n=262) Arm 1 (n=133) Observation Period Faldaprevir 120 mg QD + PR PR Observation Period ETS No ETS Faldaprevir 120 mg QD + PR Placebo + PR  Patients enrolled from Europe and Japan  Eligibility: Treatment naive, GT1 infection, no HBV or HIV coinfection, adult, platelets >90,000 cells/mm 3  Primary endpoint: SVR 12 weeks after completion of all treatment PR, pegylated interferon α2a 180 µg/week and weight-based ribavirin

4 4 Baseline data a HCV GT-1 subtype analyses by sequencing of NS3 Placebo n= mg FDV n= mg FDV n=261 Male, n (%)75 (57)121 (47)146 (56) Caucasian, n (%)103 (78)203 (78)205 (79) Region, n (%) Japan Europe 24 (18) 108 (82) 52 (20) 207 (80) 50 (19) 211 (81) Mean age, years (SD)46.6 (12.53)47.9 (11.44)48.3 (11.89) Mean BMI, kg/m 2 (SD)24.6 (4.25)24.9 (4.21)25.2 (4.63) HCV GT-1 subtype a, n (%) 1a 1b 45 (34) 86 (65) 87 (34) 171 (66) 90 (34) 171 (66) Median baseline HCV RNA levels, log 10 IU/mL (range) 6.4 (3.4–7.7)6.4 (3.3–7.5)6.4 (3.0–7.4) Baseline HCV RNA, n (%) ≥ IU/mL101 (77)201 (78)185 (71) IL28B (rs ), n (%) CC Non-CC 46 (35) 86 (65) 107 (41) 151 (58) 101 (39) 160 (61) Fibrosis stage, n (%) ≥F325 (19)45 (17)42 (16) Cirrhosis, n (%) Yes8 (6)16 (6)15 (6)

5 5 Primary endpoint SVR12 (ITT) SVR12 rates adjusted for race and genotype ITT, intention-to treat 204/ /261 69/132 SVR12 (%) (∆ = 28.6; 95% CI, 19.0–38.2; p<0.0001) (∆ = 26.7; 95% CI, 17.1–36.3; p<0.0001)

6 6 Early Treatment Success, Week 4 HCV RNA Both FDV groups No ETS ETS, Week 4 <25 IU/mL, detected ETS, Week 4 undetected Early Treatment Success (ETS): HCV RNA <25 IU/mL at Week 4 and undetectable at Week 8; patients with ETS in active treatment arms were eligible to stop all treatment at Week 24

7 7 SVR12 in patients with ETS (received 24 weeks total treatment duration) Proportion of patients (%) ETSETS + SVR12 a ETS, early treatment success: HCV RNA <25 IU/mL (detected or undetected) at Week 4 and <25 IU/mL (undetected) at Week 8. a Denominator = patients with ETS 226/259233/ /226208/233 FDV 120 mgFDV 240 mgFDV 120 mgFDV 240 mg

8 8 SVR12 among ETS patients: BLQ (detected) vs BLD at Week 4 Proportion of patients with SVR (%) 30/39155/17121/29167/178 Week 4 ≤25 IU/mL, detectedWeek 4, undetected FDV 120 mgFDV 240 mgFDV 120 mgFDV 240 mg ETS, early treatment success: HCV RNA <25 IU/mL (detected or undetected) at Week 4 and <25 IU/mL (undetected) at Week 8

9 9 SVR12 according to HCV genotype-1 subtype (ITT) GT-1a 60/87143/17168/90142/171 GT-1b 16/4552/86 Other genotype-1 subtype = one patient in placebo arm and one patient in FDV 240 mg arm. Both achieved SVR12 PlaceboFDV 120 mg FDV 240 mg Placebo SVR12 (%)

10 10 Virological failure GT-1bGT-1a Proportion of patients (%) Placebo FDV 120 mg FDV 240 mg Stopping rules: Null or partial response defined as lack of Early Virological Response, i.e. absence of HCV RNA drop by ≥2 log 10 from baseline at Week 12 Breakthrough indicates confirmed ≥1 log 10 rebound at any time during FDV or PegIFN/RBV treatment Proportion of patients (%)

11 11 FDV 120 mg FDV 240 mg No significant effect of Q80K on SVR12 in GT-1a Q80 wild typeQ80K 23% (49/212) of GT-1a patients had Q80K at baseline SVR12 (%) 56/7542/619/11 16/22

12 12 SVR12 according to IL28B genotype rs (ITT) PlaceboFDV 120 mg FDV 240 mg 96/10785/122 22/2929/46 35/685/1896/101 87/12627/34 PlaceboFDV 120 mg FDV 240 mg PlaceboFDV 120 mg FDV 240 mg CC CT TT SVR12 (%)

13 13 SVR12 for FDV 120 mg vs 240 mg n/N (%)FDV 120 mgFDV 240 mg Genotype 1a 1b 60/87 (69) 143/171 (84) 68/90 (76) 142/171 (83) Race Caucasian Asian 157/203 (77) 44/52 (85) 158/205 (77) 47/51 (92) IL28B CC CT TT 96/107 (90) 85/122 (70) 22/29 (76) 96/101 (95) 87/126 (69) 27/34 (79) Fibrosis stage

14 14 Adverse event summary a DAIDS Grade 2 to 4; protocol defined AEs of special interest DAIDS, Division of AIDS table for grading the severity of adult and pediatric adverse events N (%) Placebo n= mg FDV n= mg FDV n=261 Any AE123 (93)251 (97)253 (97) AEs leading to discontinuation of all medication 5 (4)10 (4)14 (5) AEs leading to discontinuation of FDV or PBO only 02 (1)8 (3) Serious AEs8 (6)17 (7) AEs of at least moderate intensity a 64 (48)134 (52)144 (55) Rash8 (6)21 (8)23 (9) Photosensitivity002 (1) Gastrointestinal4 (3)18 (7)31 (12) Anaemia15 (11)33 (13)32 (12) Jaundice05 (2)7 (3)

15 15 Rash N (%) Placebo n= mg FDV n= mg FDV n=261 N (%) of patients with event* 29 (22)83 (32)86 (33) Mild Moderate Severe Potentially life-threatening 21 (16) 6 (5) 2 (2) 0 62 (24) 19 (7) 2 (1) 0 63 (24) 21 (8) 2 (1) 0 N (%) of patients who discontinued due to event 1 (1)3 (1)2 (1) *All events resolved

16 16 Grade ≥3 lab abnormalities during first 24 weeks of treatment *Laboratory value categories based on the DAIDS grading system N (%) Placebo n= mg FDV n= mg FDV n=261 White blood cells <1,499/mm 3 4 (3)10 (4)11 (4) Platelets <49,999/mm 3 4 (3)4 (2)7 (3) Neutrophils <749/mm 3 24 (18)53 (20)31 (12) Lymphocytes <499/mm 3 15 (11)49 (19)48 (18) ALT >5.1 x ULN 4 (3)5 (2)2 (1) Total bilirubin >2.6 x ULN 1 (1)29 (12)138 (53)

17 17 Changes in haemoglobin N (%)Placebo n= mg FDV n= mg FDV n=261 Anaemia adverse event38 (29)64 (25)57 (22) Led to permanent RBV D/C0 (0)3 (1)2 (1) Led to RBV dose reduction32 (24)44 (17)39 (15) Received blood transfusion 1 (1)2 (1) Received EPO 4 (3)10 (4)12 (5)

18 18 Bilirubin changes over time

19 19 Summary and conclusions  FDV is highly efficacious in European and Japanese patients infected with HCV GT-1  Almost 90% of FDV-treated patients were eligible for shortened treatment  The 240 mg dose showed no benefit over 120 mg for any subgroup  FDV was well tolerated with few discontinuations due to AEs at both dosages  No incremental haemoglobin reduction was observed with FDV and PegIFN/RBV compared with PegIFN/RBV alone  Bilirubin elevations were benign and transient

20 20 Acknowledgements Boehringer Ingelheim for sponsoring the study and their clinical and statistical teams for study monitoring, data collection, and analysis Editorial support provided by Katharine Howe of Adelphi Communications Ltd and funded by Boehringer Ingelheim The patients enrolled in the STARTVerso1 trial Study investigators : AustriaRainer GüntherYoshinori Sakai Spain Peter FerenciDieter HäussingerYoshiyuki Sakai Javier Crespo Michael Gschwantler Dietrich Hüppe Yasuhito Tanaka Moises Diago Hermann Laferl Dietmar Klass Kunihiko Tsuji Jaime Enriquez Andreas Maieron Ansgar Lohse Yoshiyuki Ueno Luis Enrique Morano Belgium Stefan Mauss Hiroshi Yatsuhashi Jose Domingo Pedreira Jean DelwaideMarcus Schuchmann Osamu Yokosuka Manuel Romero Yves Horsmans Jürgen SieblerHirohito Yoneyama Ricard Solá Peter Michielsen Ulrich SpenglerPortugal Vicente Soriano Christophe Moreno Christian TrautweinFilipe CalinasSwitzerland Frederik Nevens Elmar ZehnterArmando CarvalhoAndreas Cerny Hans Van Vlierberghe Stefan ZeuzemTiago Bana e CostaJean-François Dufour FranceJapanGuilherme MacedoDaniel Genné Armand AbergelAkihiro DeguchiLeopoldo MatosBeat Müllhaupt Tarik AsselahYukio GiboCélia OliveiraDavid Semela Marc BourliereYuichi HiroseJosé PresaUnited Kingdom Jean-Didier GrangéTatsuya IdeLuís TavaresKosh Agarwal Dominique GuyaderTakafumi IchidaRomaniaJane Collier Christophe HezodeShogo IwabuchiFlorin CaruntuFiona Gordon Dominique LarreyMichio KatoEmanoil CeausuDaniel Forton Victor LedinghenNorifumi KawadeLiliana PreotescuGraham R. Foster Philippe MathurinYasuteru KondoAdrian Streinu-CercelMark Nelson Sophie MétivierMakoto KubokiRussiaStephen Ryder Denis OuzanHitoshi Mochizuki Pavel Bogomolov Javier Vilar Vlad RatziuMitsuhiko Moriyama Marina Maevskaya Mark Wright Albert TranKazuyoshi Nagayama Vadim Pokrovsky Alison Uriel Germany Yoichi Nishigaki Olga Sagalova Keikawus Arastéh Shuhei Nishiguchi Alexey Yakovlev Thomas Berg Kazunori Noguchi Natalia Zakharova Johannes BognerMasao Omata


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