Antiviral Therapy 2013; 18:1015–1019 (doi: 10.3851/IMP2567) Short communication Faldaprevir (BI 201335), deleobuvir (BI 207127) and ribavirin oral therapy for treatment-naive HCV genotype 1: SOUND-C1 final results Stefan Zeuzem1*, Tarik Asselah2, Peter Angus3, Jean-Pierre Zarski4, Dominique Larrey5, Beat Müllhaupt6, Ed Gane7, Marcus Schuchmann8, Ansgar W Lohse9, Stanislas Pol10, Jean-Pierre Bronowicki11, Stuart Roberts12, Keikawus Arasteh13, Fabien Zoulim14, Markus Heim15, Jerry O Stern16, Gerhard Nehmiz17, George Kukolj18, Wulf O Böcher17, Federico J Mensa16 1JW Goethe University Hospital, Frankfurt am Main, Germany 2Service d’Hépatologie, Hôpital Beaujon, Université Diderot-Paris 7, INSERM U773, CRB3, Clichy, France 3Austin Hospital, Heidelberg, Victoria, Australia 4Hôpital Albert Michallon, Grenoble, France 5Département d’Hépato-Gastroentérologie-CIC-IRB INSERM 1040, Hôpital Saint-Eloi, Montpellier, France 6University Hospital of Zürich, Zürich, Switzerland 7Auckland City Hospital, Auckland, New Zealand 8University Medical Center Mainz, Mainz, Germany 9University Hospital Hamburg-Eppendorf, Hamburg, Germany 10Université Paris Descartes, INSERM U1016 et APHP, Hôpital Cochin, Paris, France 11INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France 12Alfred Hospital, Melbourne, Victoria, Australia 13Epimed GmbH, Berlin, Germany 14Hepatology Department, Hospices Civils de Lyon, Lyon University, Lyon, France 15University Hospital Basel, Basel, Switzerland 16Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA 17Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany 18Boehringer Ingelheim (Canada) Ltd, Laval, QC, Canada *Corresponding author e-mail: [email protected] Background: Faldaprevir (BI 201335) and deleobuvir was reported in one patient and re-increase of HCV (BI 207127) are direct-acting antiviral agents under RNA in one patient. Both patients were successfully development for the treatment of chronic HCV infection. treated with interferon-containing therapy. The rate of This article describes the final results of the Phase Ib sustained virological response 24 weeks after comple- SOUND-C1 study that evaluated the interferon-free oral tion of treatment was 73% (11/15) in the deleobuvir combination of faldaprevir, deleobuvir and ribavirin in 32 400 mg group and 94% (16/17) in the 600 mg group. treatment-naive patients infected with HCV genotype 1. During faldaprevir plus pegylated interferon-a2a/ Methods: Patients were randomized to receive deleobuvir ribavirin treatment, the most common adverse events 400 mg (n=15) or 600 mg (n=17) three times daily plus were pruritus (38% of patients), rash (31%) and asthe- faldaprevir 120 mg once daily and weight-based ribavi- nia (31%); these were severe in approximately 3% of rin for 4 weeks. Interferon-free therapy was followed by patients. response-guided faldaprevir plus pegylated interferon- Conclusions: Potent antiviral activity and favourable a2a/ribavirin to week 24 or 48. safety of the treatment regimen were demonstrated. Results: At week 4, 73% (11/15) and 100% (17/17) of Furthermore, the results suggest that patients with patients in the deleobuvir 400 mg and 600 mg groups breakthrough at week 4 may be rescued with an inter- achieved HCV RNA<25 IU/ml, respectively. During feron-containing regimen. Clinical trials.gov number interferon-free treatment, virological breakthrough NCT01132313. ©2013 International Medical Press 1359-6535 (print) 2040-2058 (online) 1015 S Zeuzem et al. Introduction Figure 1. Virological response rates according to deleobuvir (BI 207127) treatment group Many patients with chronic HCV infection cannot be 400 mg three times daily treated due to intolerance or contraindications to inter- 600 mg three times daily feron (IFN), a component of all approved treatment regimens. Trials with new direct-acting antiviral agents 100 100 94 94 (DAAs) aim to improve IFN-containing regimens and 80 to introduce IFN-free therapy. DAAs under develop- 80 73 73 ment include faldaprevir (BI 201335), a potent, selec- % tive non-covalent linear NS3/4A protease inhibitor [1], 60 and deleobuvir (BI 207127), a non-nucleoside NS5B 40 polymerase thumb pocket 1 inhibitor [2]. We recently Patients, reported interim (week 4) results of the Phase Ib, mul- 20 ticentre, open-label, randomized SOUND-C1 study of 11/15 17/17 12/15a 16/17b 11/15 16/17c a novel IFN-free combination [3]. We now report the 0 Wk 4 VR EOT SVR 24 final SOUND-C1 results, including the sustained viro- logical response (SVR) rate 24 weeks after completion aIncludes one patient who switched to pegylated interferon/ribavirin (PEG-IFN/ of treatment (SVR24) and safety data. RBV). Two patients had viral load data missing at end of treatment (EOT). bOne patient had viral load data missing at EOT. cRemaining patient achieved sustained virological response 12 weeks after completion of treatment (SVR12), Methods but was subsequently unavailable for testing and SVR24 assessment was missing. Wk 4 VR, virological response after 4 weeks of treatment (HCV RNA<25 IU/ml). In SOUND-C1, 32 treatment-naive patients with chronic HCV genotype 1 (GT-1) infection were randomized to receive 4 weeks’ treatment with deleobuvir 400 mg or of patients achieved undetectable HCV RNA in the 600 mg three times daily plus faldaprevir 120 mg once deleobuvir 400 mg and 600 mg groups, respectively daily and weight-based ribavirin (RBV), followed by (Figure 1). The SVR24 rate was 73% (11/15) in the faldaprevir 120 mg once daily plus pegylated interferon- deleobuvir 400 mg group and 94% in the 600 mg a2a (PEG-IFN) and RBV for 20 weeks. Depending on group (16/17; one patient was missing the SVR24 extended rapid virological response (HCV RNA<25 IU/ assessment but achieved SVR12). ml at week 4 and undetectable at weeks 5–18), patients During the 4-week IFN-free phase, one patient expe- stopped treatment at week 24 or continued PEG-IFN/ rienced viral breakthrough (≥1 log10 IU/ml rebound in RBV through week 48 (Additional file 1) [3]. HCV RNA from a quantifiable nadir) and another experienced a re-increase in HCV RNA (0.7 log10 IU/ Results ml; Additional file 2). Both were HCV GT-1a-infected patients and received deleobuvir 400 mg. Their viral As previously reported, most baseline characteristics variants have been described previously [3]. After were well balanced between the deleobuvir 400 mg switching on day 29 to PEG-IFN/RBV, the patient three times daily (n=15) and 600 mg three times daily with breakthrough achieved HCV RNA<25 IU/ml by (n=17) groups [3]. More patients had HCV GT-1a week 28, but died shortly thereafter in a road traf- infection in the 400 mg group (67%, 10/15) than in the fic accident. The patient with re-increase achieved 600 mg group (47%, 8/17). Patients (GT-1a or GT-1b) SVR24 after treatment with faldaprevir plus PEG- showed an initial rapid and steep decline in HCV RNA IFN/RBV during weeks 5–24 followed by PEG-IFN/ levels (median HCV RNA decay 3.4 log10 IU/ml in both RBV through week 48. No cases of viral break- groups at day 2), followed by a slower second-phase through or rebound occurred during faldaprevir plus decline until the end of 4 weeks of IFN-free treatment. PEG-IFN/RBV treatment. Two patients with HCV At week 4, 73% (11/15) and 100% (17/17) of patients GT-1a in the deleobuvir 400 mg group (one with in the deleobuvir 400 mg and 600 mg groups achieved and one without prolonged treatment) relapsed after HCV RNA<25 IU/ml, respectively. scheduled EOT (Additional file 2); both patients had Virological response continued after the switch emergent NS3 R155K variants and no known NS5B from IFN-free treatment to faldaprevir plus PEG-IFN/ resistance-associated variants. RBV on day 29. At week 24, 47% (7/15) of patients in There were no severe or serious adverse events (AEs) the deleobuvir 400 mg group and 71% (12/17) in the and no premature treatment discontinuations due 600 mg group stopped treatment; the remainder con- to AEs during IFN-free treatment; the most common tinued PEG-IFN/RBV through to week 48. At the end AEs during this period were mild-to-moderate nausea of treatment (EOT), 80% (12/15) and 94% (16/17) (47%), vomiting (38%), diarrhoea (22%), asthenia 1016 ©2013 International Medical Press HCV genotype 1 oral therapy: SOUND-C1 results (28%), pruritus (28%), rash (16%) and photosensitiv- viral breakthrough or rebound during faldaprevir plus ity (19%) [3]. One patient in the deleobuvir 400 mg PEG-IFN/RBV suggests an effective barrier to resist- group experienced anaemia on day 22 and the RBV ance. The safety and tolerability of IFN-free treatment dose was reduced on day 25. The patient achieved SVR were favourable and consistent with Phase II studies following 20 weeks’ faldaprevir plus PEG-IFN/RBV of faldaprevir plus PEG-IFN/RBV [4,5] and a Phase Ib plus a further 24 weeks’ PEG-IFN/RBV alone. study of deleobuvir plus PEG-IFN/RBV (in which rash From week 5 to EOT during faldaprevir plus PEG- was also observed) [6]. Faldaprevir plus PEG-IFN/ IFN/RBV treatment, the most common AEs were pru- RBV and PEG-IFN/RBV alone were generally well- ritus (38%), rash (31%) and asthenia (31%); these tolerated when given after the IFN-free regimen; 13% were severe in approximately 3% of patients during of patients (4/32) discontinued because of severe AEs this period. Three patients discontinued all drugs due and the predominant AEs – gastrointestinal symptoms, to severe AEs: pancytopenia (one patient: haemo- asthenia and dermatological events, including rash – globin 8.1 g/dl, platelets 58×109/l and white blood were consistent with the Phase II studies mentioned cells 1.9×109/l); eczema and pruritus (one patient) above [4,5]. Changes in haemoglobin and platelets and maculopapular rash, pruritus and eye swelling were consistent with known effects of PEG-IFN/RBV (one patient).