Date: 2013-06-13
Type of information: Presentation of results at a congress
phase: 2b
Announcement: presentation of results at the APASL Liver Week in Singapore
Company: Boehringer Ingelheim (Germany)
Product: protease inhibitor BI 201335 (faldaprevir) and polymerase inhibitor BI 207127 (deleobuvir)
Action mechanism:
Disease: hepatitis C
Therapeutic area: Infectious diseases
Country:
Trial
details: In this open-label Phase 2b study, 362 treatment-naive GT1 HCV patients were randomized into five interferon-free treatment groups, each with 120 mg BI 201335 QD, but with different dosing of BI 207127 and treatment durations. The randomization was stratified by HCV genotype (1a or 1b) and patient IL-28B genotype, with 41 percent of patients being GT1a and 75 percent being IL-28B CT or TT.
Latest
news: SOUND-C2 Trial Design and Interim Results BI 201335 BI 207127 RBV Treatment SVR12 A N=81 120 mg QD 600 mg TID Y 16 wks 48 (59%) B N=80 120 mg QD 600 mg TID Y 28 wks 49 (61%) C N=77 120 mg QD 600 mg TID Y 40 wks N/A* D N=78 120 mg QD 600 mg BID Y 28 wks 53 (68%) E N=46 120 mg QD 600 mg TID N 28 wks 18 (39%) * SVR12 data for the 40 week arm of SOUND-C2 is not available due to treatment duration Investigators reported breakthrough broken out by genotype and IL-28B status. In GT1b and GT1a-CC patients, breakthrough occurred in 7 percent of patients in Arm A, 11 percent of patients in Arm B, 19 percent of patients in Arm C, 9 percent of patients in Arm D, and 29 percent of patients in Arm E (no RBV arm). In GT1a non-CC patients, breakthrough occurred in 40 percent of patients in Arm A, 50 percent of patients in Arm B, 25 percent of patients in Arm C, 64 percent of patients in Arm D, and 91 percent of patients in Arm E (no RBV arm). In this study, the most common adverse events (AEs) were skin (photosensitivity, rash), gastrointestinal (GI) disorders (vomiting, diarrhea), and jaundice due to unconjugated hyperbilirubinemia. Treatment discontinuations due to AEs correlated with increased dosing frequency and treatment duration, with discontinuations ranging from 4.9 percent in Arm A (16 weeks) to 24.7 percent in Arm C (40 weeks). In the arm with BID dosing of BI 207127 (Arm D), discontinuations were 7.7 percent. BID dosing of BI 207127 is planned for Phase 3 investigation.* On June 20, 2014, Boehringer Ingelheim has re-evaluated its strategy in hepatitis C, and as a result the company has decided not to move forward in this therapeutic area. The HCV treatment environment has significantly and rapidly evolved since the submission of the faldaprevir marketing applications to regulatory bodies around the world. There are now several new treatment options available for patients and additional all-oral options are expected to be approved in 2014. This decision was taken as there is no longer an unmet medical need for the faldaprevir interferon-based regimen that was the subject of the application. Boehringer Ingelheim will withdraw all pending marketing applications for faldaprevir worldwide and is discontinuing further development.
* On June 13, 2013, new data from Boehringer Ingelheim’s interferon-free SOUND-C3 study were presented during the APASL Liver Week in Singapore. The Phase IIb study investigated the efficacy and safety of faldaprevir+ and deleobuvir+ (BI 207127) plus ribavirin in treatment-naïve patients with genotype-1b (GT-1b) hepatitis C virus (HCV),1 one of the most common types of HCV globally.
Results showed that 95% of genotype-1b (GT-1b) infected patients (19/20) who received BI’s interferon-free combination therapy achieved viral cure after 16 weeks of treatment.1 20% (4/20) of GT-1b patients in the study had liver cirrhosis (an advanced form of liver disease), all of whom achieved viral cure.1 Viral cure was defined as a sustained viral response 12 weeks after completion of treatment (SVR12).1 In contrast, patients with genotype-1a (GT-1a) infection and host IL28b type CC (n=12) had a lower viral response of 17% SVR12 (2/12), suggesting a need for treatment of greater intensity for this population and confirming the decision to focus on GT-1b patients in Phase III trials.
In SOUND-C3, optimising treatment (by removing a deleobuvir+ first day loading dose and reducing treatment duration to 16 weeks) for GT-1b-infected patients resulting in higher efficacy compared with SOUND-C2. The SOUND-C2 study, presented in November 2012 at the AASLD Congress, showed viral cure rates of up to 85% with different interferon-free regimens of faldaprevir, deleobuvir+ and ribavirin in HCV GT-1b infected patients.3
Overall tolerability in the SOUND-C3 trial was good with three patients (9%) discontinuing treatment due to intolerance, and mild rash or nausea being the most common side-effects.1 Adverse events of a moderate or higher intensity were rare, with anaemia (16%), fatigue (9%), vomiting (9%) and nausea (9%) being the most frequent adverse events.1
Boehringer Ingelheim‘s pivotal Phase III interferon-free HCVerso™ programme includes three trials aiming to enrol approximately 1,100 treatment-naïve HCV GT-1b patients.4,5,6 The trial programme includes patients who are interferon ineligible and those with liver cirrhosis; results are expected in Q2 2014.
* On April 19, 2012, Boehringer Ingelheim has announced that new data from a pre-specified interim analysis of the Phase 2b SOUND-C2 study show that 68 percent of genotype-1 (GT1) hepatitis C virus (HCV) patients achieved sustained viral response 12 weeks after the end of treatment (SVR12) with its investigational direct-acting antiviral compounds – the protease inhibitor BI 201335 and polymerase inhibitor BI 207127 – plus ribavirin (RBV), without interferon. SVR12 has been highly correlated with SVR24, which is a recognized indicator of viral cure. These patients received combination therapy with BI 201335 once-daily (QD), BI 207127 twice-daily (BID) and RBV for 28 weeks. The SOUND-C2 study investigated interferon-free treatment in HCV GT1 patients, the most difficult genotype to treat, regardless of IL-28B status. Among study participants, 10 percent had compensated liver cirrhosis. Furthermore, a separate arm of the SOUND-C2 study showed that after 16 weeks of interferon-free treatment, SVR12 was achieved in 59 percent of patients. Investigators presented relapse data broken out by genotype and IL-28B status. The rate of relapse in the treatment arms ranged between 2 and 10 percent for GT1b and GT1a-CC patients. There was a higher rate of relapse in GT1a non-CC patients, with relapse ranging from 0 to 40 percent. The full results from this interim analysis of SOUND-C2 are being presented on Saturday, April 21, at the International Liver Congress, the 47th Annual Meeting of the European Association of the Study of the Liver (EASL 2012) in Barcelona, Spain (Abstract #101). Planning of the interferon-free Phase 3 clinical trial program is underway.
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