INTERFERON-FREE COMBINATION TREATMENT WITH THE HCV NS3/4A PROTEASE INHIBITOR FALDAPREVIR AND THE NON-NUCLEOSIDE NS5B INHIBITOR BI

Transcription

1 Novel HCV Agents

2 INTERFERON-FREE COMBINATION TREATMENT WITH THE HCV NS3/4A PROTEASE INHIBITOR FALDAPREVIR AND THE NON-NUCLEOSIDE NS5B INHIBITOR BI ± RIBAVIRIN: FINAL RESULTS OF SOUND-C2 AND PREDICTORS OF RESPONSE Stefan Zeuzem 1, Vicente Soriano 2, Tarik Asselah 3, Jean-Pierre Bronowicki 4, Ansgar W. Lohse 5, Beat Müllhaupt 6, Marcus Schuchmann 7, Marc Bourliere 8, Maria Buti 9, Stuart Roberts 10, Ed Gane 11, Jerry O. Stern 12, Richard Vinisko 12, Ivona Herichova 13, Wulf O. Böcher 14, Federico J. Mensa 12 1 Klinikum der J. W. Goethe-Universität, Frankfurt am Main, Germany; 2 Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain; 3 Hôpital Beaujon, Clichy, France; 4 Hôpital de Brabois, Vandoeuvre Cedex, France; 5 University Hospital Hamburg-Eppendorf, Hamburg, Germany; 6 University Hospital of Zurich, Zurich, Switzerland; 7 University Hospital Mainz, Mainz, Germany; 8 Hopital Saint Joseph, Marseille, France; 9 Hospital Vall d Hebron and Ciberehd, Barcelona, Spain; 10 Alfred Hospital, Department of Gastroenterology, Melbourne, Australia; 11 Auckland Clinical Studies, Auckland, New Zealand; 12 Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA; 13 Boehringer Ingelheim Pharma RCV GmbH & Co KG, Vienna, Austria; 14 Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

3 SOUND-C2 Investigators Australia Peter Angus Stuart Roberts Austria Peter Ferenci Michael Gschwantler Andreas Maieron France Tarik Asselah Marc Bourliere Jean-Pierre Bronowicki Dominique Larrey Joseph Moussalli Stanislas Pol Jean-Pierre Zarski Fabien Zoulim Germany Keikawus Arastéh Thomas Berg Michael Geissler Ansgar Lohse Michael Manns Stefan Mauss Marcus Schuchmann Stefan Zeuzem New Zealand Ed Gane Portugal Filipe Calinas Guilherme Macedo Leopoldo Matos Célia Oliveira Cristina Valente Romania Emanoil Ceausu Liliana Preotescu Adrian Streinu-Cercel Spain Maria Buti José Luis Calleja Moises Diago Xavier Forns Javier Garcia-Samaniego Vicente Soriano Switzerland Tilman Gerlach Markus Heim Darius Moradpour Beat Müllhaupt Jürg Reichen

4 Acknowledgments This work was supported by Böehringer Ingelheim. The authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all content and editorial decisions, and were involved at all stages of poster/presentation development. The authors received no compensation related to the development of the poster, but are consultants for BIPI and did receive research grant support for this study. Editorial support, supported financially by Böehringer Ingelheim, was provided by Katharine Howe of Adelphi Communications Ltd.

5 Disclosures Stefan Zeuzem has served as a consultant for Abbot, Achillion, AstraZeneca, BMS, Böehringer Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, and Vertex; and has served on speakers bureaus for BMS, Böehringer Ingelheim, Gilead, MSD, Roche, and Janssen. Vicente Soriano has received grants from Gilead, Janssen, and Merck; has served on speakers bureaus for BMS, Böehringer Ingelheim, Gilead, Janssen, and Merck; and has received compensation for educational presentations from Abbott, Gilead, Janssen, and Merck. Tarik Asselah has served as a consultant, advisory board member, and/or speaker for Böehringer Ingelheim. Jean-Pierre Bronowicki has served as a consultant and received grants from Böehringer Ingelheim. Ansgar W. Lohse has received grants from Gilead, Janssen, and Merck; has served on speakers bureaus for BMS, Böehringer Ingelheim, Gilead, Janssen, and Merck; and has received compensation for educational presentations from Abbott, Gilead, Janssen, and Merck. Beat Müllhaupt has served as a consultant for Abbott, Bayer, Gilead, GSK, MSD, and Roche; and has served on speakers bureaus for AstraZeneca, Bayer, Gilead, MSD, and Roche. Marcus Schuchmann has received editorial assistance from Böehringer Ingelheim.

6 Disclosures (continued) Marc Bourliere has served as a board member for Abbott, BMS, Böehringer Ingelheim, Gilead, GSK, Janssen, MSD, Roche and Vertex. Maria Buti has served on speakers bureaus for Gilead, MSD, and Novartis. Stuart Roberts has served as an advisory board member for Janssen and Roche. Ed Gane has served as an advisory board member for Abbott, Gilead, Janssen, and Novartis; and on speakers bureaus for Gilead, Novartis, and Roche. Jerry O. Stern is an employee of Böehringer Ingelheim Pharmaceuticals, Ridgefield, CT. Richard Vinisko is an employee of Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT. Ivona Herichova is an employee of Boehringer Ingelheim Pharma RCV GmbH & Co KG, Vienna, Austria. Wulf O. Böcher is an employee of Böehringer Ingelheim Pharma, Biberach, Germany. Federico Mensa is an employee of Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT

7 Background Faldaprevir BI Second-generation linear tripeptide NS3/4A protease inhibitor Nanomolar potency EC nmol/l vs GT-1a in vitro EC nmol/l vs GT-1b in vitro PK profile supports QD dosing Non-nucleoside thumb pocket 1 NS5B inhibitor Nanomolar potency EC nmol/l vs GT-1a in vitro EC nmol/l vs GT-1b in vitro PK profile supports BID dosing

8 Study design (n=81) Faldaprevir 120 mg QD BI mg RBV Follow-up (n=80) Faldaprevir 120 mg QD BI mg RBV Follow-up (n=77) Faldaprevir 120 mg QD BI mg RBV Follow-up (n=78) Faldaprevir 120 mg QD BI mg BID RBV Follow-up (n=46) Faldaprevir 120 mg QD BI mg, no RBV Follow-up Day 1 Week 16 Week Week Phase IIb, multicenter, open-label, randomized (1:1:1:1:1) a Treatment-naïve patients with chronic HCV GT-1 Stratified by GT-1 subtype (1a vs 1b) and ILB (CC vs non-cc) Compensated cirrhosis included, years of age, HCV RNA > IU/mL Stopping rule: HCV RNA detectable between Weeks 6 and 8 Primary endpoint: SVR 12 weeks after treatment completion a Randomization to the non-rbv arm stopped early (FDA request based on perceived increased risk of breakthrough with other interferon-free and RBV-free combinations). First dose of faldaprevir = 2 mg and BI = 1200 mg. RBV dose, 1000 mg/day (<75 kg body weight) or 1200 mg/day ( 75 kg body weight) BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; SVR, sustained virologic response;, three-times daily

9 Baseline characteristics 16W W W BIDW W-NR (n=81) (n=80) (n=77) (n=78) (n=46) Male, n (%) 45 (56) 41 (51) 36 (47) 41 (53) 24 (52) White, n (%) 79 (98) 78 (98) 76 (99) 77 (99) 46 (100) Mean age, years (SD) 48.6 (11.3) 47.3 (11.2) 48.9 (10.7) 47.9 (11.1) 45.3 (13.0) Mean BMI, kg/m 2 (SD) 25.3 (4.1) 25.5 (4.1) 24.8 (3.8) 25.0 (3.6) 25.5 (3.8) Liver cirrhosis, n (%) 9 (11) 7 (9) 5 (7) 9 (12) 3 (7) ILB a CC, n (%) 21 (26) 21 (26) 19 (25) 19 (24) 12 (26) HCV GT-1a b, n (%) 34 (42) 32 () 34 (44) 30 (38) 18 (39) HCV GT-1b b, n (%) 47 (58) 48 (60) 43 (56) 48 (62) (61) Baseline HCV RNA c, n (%) IU/mL 70 (86) 66 (83) 67 (87) 66 (85) 36 (78) a ILB SNP rs b HCV GT-1 subtype analyses by sequencing of NS3 and NS5B regions c Plasma HCV RNA was measured using the Roche COBAS TaqMan HCV/HPS assay v2.0, with a lower limit of quantification of 25 IU/mL and a lower limit of detection of approximately 15 IU/mL

10 SVR12 (%) 100 Primary endpoint: SVR12 (ITT) BI dosing Duration (weeks) RBV ITT n/n 48/81 47/80 /77 54/78 18/46 16 BID - ITT, intention to treat All groups received faldaprevir 120 mg QD for the same duration as BI (16,, or weeks)

11 SVR12 (%) Primary endpoint: SVR12 (ITT and PP) 100 ITT PP BI dosing Duration (weeks) RBV PP n/n 48/73 47/68 /58 54/75 18/41 16 BID - PP, per-protocol All groups received faldaprevir 120 mg QD for the same duration as BI (16,, or weeks)

12 SVR12 (%) SVR12 according to HCV subtype (ITT) GT-1a GT-1b ITT n/n BI dosing Duration (weeks) RBV 13/34 35/47 14/32 33/48 16/34 24/43 13/30 41/48 2/18 16/ 16 BID 11 - ITT, intention-to-treat All groups received faldaprevir 120 mg QD for the same duration as BI (16,, or weeks)

13 SVR12 (%) SVR12 according to ILB genotype (ITT) Non-CC CC rs ITT n/n BI dosing Duration (weeks) RBV 34/60 14/21 32/58 14/21 /58 12/19 38/59 16/19 11/33 7/12 16 BID - ITT, intention-to-treat All groups received faldaprevir 120 mg QD for the same duration as BI (16, or weeks)

14 Regressional analyses: baseline parameters and SVR12 Univariate Multivariate p-value p-value Age 1.03 p= p=0.08 Gender (F:M) 3.76 p< p< HCV subtype (1a:1b) 5.59 p< p< ILB genotype (CC:non-CC) 2.93 p= p< Cirrhosis (Y:N) 1.08 p=0.87 Baseline HCV group (< :> IU/mL) Baseline ALT (>ULN:normal) p=0.06 p=0.48 Baseline GGT (>ULN:normal) 2.73 p< p=0.016 BMI (<25: 25 kg/m 2 ) 1.14 p=0.60 Diabetes (Y:N) 1. p= Odds ratio Odds ratio Analysis from per-protocol population

15 Failure Rate (%) Virologic failures by HCV subtype Breakthrough a Met futility rule b Relapse c 100 Genotype 1a Genotype 1b BI dosing Duration (weeks) RBV BID BID - a Increase in HCV RNA: 25 IU/mL after previously undetectable and 1 log 10 IU/mL after previously detectable; b HCV RNA detectable between Week 6 and 8; c Values are for patients with undetectable HCV RNA at the end of the assigned treatment.

16 Regimen Concordance between SVR12 and SVR24 Patients with SVR12 who had a measurement at the SVR24 time point Patients who relapsed between SVR12 and SVR24 time points PPV of SVR12 SVR24 16W W W BIDW W-NR Concordance between SVR12 and SVR24 was 100% SVR12 SVR48 164/207 patients who achieved SVR12 have reached the SVR48 timepoint One patient relapsed between SVR24 and SVR48 Male, 66 years old, non-cirrhotic, BMI of 21.8 kg/m 2, ILB non-cc, infected with HCV GT-1b, and with a baseline HCV RNA of 6.4 log 10 IU/mL Phylogenetic analysis indicates relapse not reinfection PPV, positive predictive value Zeuzem et al AASLD 2012 Poster 778

17 Adverse events 16W (n=81) W (n=80) W (n=77) BIDW (n=78) W-NR (n=46) Moderate AEs 27 (33) 32 () 34 (44) (36) 18 (39) Nausea 2 (3) 10 (13) 5 (7) 6 (8) 2 (4) Vomiting 4 (5) 10 (13) 3 (4) 3 (4) 2 (4) Asthenia 6 (7) 10 (13) 15 (20) 8 (10) 0 Fatigue 2 (3) 1 (1) 8 (10) 3 (4) 2 (4) Rash 4 (5) 2 (3) 2 (3) 0 (0) 7 (15) Severe AEs 1 (1) 8 (10) 12 (16) 9 (12) 4 (9) Anemia 0 1 (1) 0 1 (1) 0 Dehydration 0 1 (1) 0 1 (1) 0 Vomiting (5) 0 1 (2) Rash 1 (1) 1 (1) 3 (4) 0 1 (1) Photosensitivity reaction 0 1 (1) 2 (3) 0 0 Asthenia (1) 2 (3) 0 D/C due to AEs 4 (5) 10 (13) 19 (25) 6 (8) a 5 (11) Vomiting 1 (1) 2 (3) 5 (6) 0 0 Photosensitivity 2 (2) 0 4 (5) 0 0 Rash 2 (2) 3 (4) 5 (6) 0 4 (9) Asthenia (8) 0 0 a Reasons for discontinuation: anemia, febrile neutropenia, dehydration, myocardial infarction, diarrhea, mucosal inflammation Moderate AE = occurring in >10% of patients in any treatment arm; severe AE = occurring in 2 patients; discontinuation (D/C) due to AEs = occurring in >5% of patients in any treatment group

18 Worst grade 3 and 4 laboratory abnormalities on treatment 16W (n=81) W (n=80) W (n=77) BIDW (n=78) W-NR (n=46) Hemoglobin Grade (3) 3 (4) 1 (1) 0 Grade (1) 0 Leukocytes Grade Grade Platelets Grade Grade ALT Grade 3 1 (1) a (1) a 0 Grade Total bilirubin b Grade 3 33 (41) 15 (19) 20 (26) 20 (26) 6 (13) Grade 4 4 (5) 10 (13) 5 (7) 10 (13) 0 a Isolated grade 3 elevations of ALT that normalized on treatment without concomitant conjugated bilirubin increase b All patients had a predominance of unconjugated bilirubin (UGT 1A1 inhibition) Gradings based on (Division of AIDS (DAIDS) gradings for laboratory abnormalities

19 Conclusions Faldaprevir plus BI plus RBV achieved SVR rates of up to 69% in this study, including patients with compensated cirrhosis SVR12 rates up to 85% in GT-1b with BI BID SVR12 successfully predicted SVR24 with this interferon-free regimen BI BID had the most favorable tolerability profile with a low rate of discontinuation and no moderate or severe skin reactions In GT-1b patients receiving the (RBV) regimens, treatment durations >16 weeks did not increase SVR GT-1a patients had lower SVR12 rates than GT-1b patients, possibly due to the lower activity of BI in this population 1,2 GT-1a patients also had a lower barrier to resistance than GT-1b patients 3 RBV remains a necessary component of treatment Phase III studies evaluating the combination of faldaprevir 120 mg QD and BI mg BID with RBV began in Larrey et al., Hepatology 2009;50(Suppl 4): 267A 2 Beaulieu et al., J Hepatol 2012;56(Suppl 2): S321 3 Sarrazin et al., Gastroenterol 2010;138:447 62