Boehringer Ingelheim’s interferon-free all-oral hepatitis C treatment+ shows up to 85% viral cure in Phase IIb study including patients with advanced liver disease

Final results from the Phase IIb study, SOUND-C2, confirmed that up to 85 percent of hepatitis C (HCV) patients infected with the most prevalent type of HCV globally, genotype-1b (GT-1b), achieved and subsequently sustained viral cure with Boehringer Ingelheim’s interferon-free regimen, when measured 12 and 24 weeks (SVR12 & SVR24) after treatment. This high cure rate was achieved following just 28 weeks of treatment with the highly effective polymodal* therapy, faldaprevir (BI 201335)+, a potent next wave once daily protease inhibitor, and BI 207127+, a potent non-nucleoside polymerase inhibitor, plus ribavirin.1

These full results from the largest interferon-free trial of its kind to be concluded to date, include patients with advanced liver disease that are more challenging to cure. Boehringer Ingelheim’s rigorous HCV development programme aims to include a diverse population that reflects the type of patients that physicians see in clinical practice. Through its comprehensive study programme, Boehringer Ingelheim aims to deliver an all-oral interferon-free therapy that would enable more patients to achieve a viral cure with shorter treatment duration and an improved side-effect profile, compared to current-interferon based treatments.

Results are being presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November in Boston, MA. Building on this success, the pivotal Phase III clinical trial programme for this all-oral interferon-free HCV regimen will be initiated shortly.

“Eliminating interferon-alfa is a critical goal in hepatitis C. These Phase IIb results bring us a step closer to an interferon-free anti-HCV treatment for many patients,” said Stefan Zeuzem, M.D., Chief of the Department of Medicine and Professor of Medicine at the Goethe University Hospital in Frankfurt, Germany. “We included a broad spectrum of patients in SOUND-C2, reflecting those that we see day-to-day in our clinics, including patients with cirrhosis, who desperately need an effective alternative treatment option to interferon-based therapies.”

The Phase IIb study included 362 treatment-naïve patients with genotype-1 HCV (both GT-1a and GT-1b infection). When looking at all patients collectively, inclusive of the most challenging to cure, a viral cure was achieved for 69 percent, compared with 85 percent seen in the prevalent GT-1b patient subgroup. 9 percent of the total population had liver cirrhosis (severe scarring of the liver), an advanced form of liver disease and achieved viral cure rates of up to 67 percent.2 This represents a population with high unmet need, urgently requiring more effective and better tolerated treatment.3 Interferon is a central component of existing treatment, however, it can be difficult for patients to take due to long treatment duration and often severe side-effects.4,5 Interferon containing regimens are not an option for up to 50 percent of patients.6

“Based on the high viral cure rates seen in the Phase IIb studies for our novel hepatitis C compounds faldaprevir and BI 207127, we are optimistic in being able to deliver new treatment options in response to the high unmet medical need in HCV,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim. “We are proud to announce the initiation of our robust Phase III interferon-free trial programme in HCV. We continue to pursue our goal of delivering an all-oral, highly effective polymodal therapy without interferon, to provide more hepatitis C patients with a viral cure, following a shorter treatment, and reduce harsh side-effects.”

The most common adverse events (AEs) in SOUND-C2 were mild skin changes (itchy skin, rash or photosensitivity) or gastrointestinal (GI) disorders and transient indirect hyperbilirubinemia which sometimes presented as jaundice.1 36 percent of patients experienced some form of side-effect, 12 percent of these were considered severe and eight percent led to discontinuation of treatment.1 This compares with approximately 25 percent discontinuation due to adverse events associated with interferon and ribavirin treatment.7

Comprehensive results from SOUND-C2 will be presented at AASLD:

• An oral presentation of final results from the SOUND-C2 study, including an analysis of predictors of treatment response will be presented on Tuesday, November 13 (ID# 232) 1
• An oral presentation of results from a sub-analysis of patients with compensated liver cirrhosis from the SOUND-C2 study will be presented on Sunday, November 11 (ID# 84) 2
• A poster presentation of a comparison of SVR4, SVR12 and SVR24 results from SOUND-C2 will be presented on Sunday, November 11 (ID#778) 7
• A poster presentation of: HCV NS3 and NS5B variants that emerged in patients with virologic breakthrough and relapse from the Phase IIb SOUND-C2 trial will be presented on Sunday, November 11 (ID#788) 8

Other Boehringer Ingelheim data being presented at the meeting include:

• A poster presentation of: Pharmacokinetics of the interferon-free combination of BI 207127 and BI 201335 plus ribavirin in treatment naïve patients with genotype (GT) 1 HCV: Results from the SOUND-C1 study will be presented on Sunday, November 11 (ID#777) 9
• A poster presentation of: Analysis of baseline polymorphisms and persistence of emergent variants from Phase Ib and II trials evaluating the HCV NS3 protease inhibitor BI 201335 will be presented on Sunday, November 11 (ID#785) 10
• A poster presentation of: Addition of the NS5B polymerase inhibitor BI 207127 to pegylated interferon and ribavirin (PegIFN/RBV) for 4 weeks followed by PegIFN/RBV for 44 weeks improves SVR24 rates in treatment-naïve patients with HCV genotype (GT) 1 and is well tolerated will be presented on Sunday, November 11 (ID#767) 11

About SOUND-C21,2

SOUND-C2 is an open-label, randomised, Phase IIb study that enrolled 362 treatment-naïve HCV genotype-1 (GT-1) patients into one of five treatment arms. The study evaluated the safety and efficacy of Boehringer Ingelheim’s interferon-free polymodal therapy of faldaprevir and BI 207127, with and without ribavirin.

Each treatment group included 120mg BI 201335 once daily but with different dosing and treatment durations of BI 207127:

• BI 201335 120mg (once-daily) QD + BI 207127 600mg (three times daily) TID + RBV for 16 weeks;
• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 28 weeks;
• BI 201335 120mg QD + BI 207127 600mg TID + RBV for 40 weeks;
• BI 201335 120mg QD + BI 207127 600mg BID (twice daily) + RBV for 28 weeks;
• BI 201335 120mg QD + BI 207127 600mg TID without RBV for 28 weeks.

A sub-analysis of the SOUND-C2 study includes 37 patients (9 percent) with compensating liver cirrhosis across all arms of the study.2

* Polymodal therapy = combining different modes of action for positive effect – as seen with faldaprevir (BI 201335), a potent next wave once daily protease inhibitor, and non-nucleoside polymerase inhibitor BI 207127, plus ribavirin

+ Faldaprevir and BI 207127 are investigational compounds and not yet approved. Their safety and efficacy have not yet been fully established

References

1. Zeuzem S. et al Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the nonnucleoside NS5B inhibitor BI 207127 ± ribavirin (R): Final results of SOUND-C2 and predictors of response. Abstract#232 presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November
2. Soriano V. et al. Efficacy and safety of the interferon (IFN)-free combination of BI 201335 + BI 207127 ± ribavirin (RBV) in treatment-naïve patients with HCV genotype (GT) 1 infection and compensated liver cirrhosis: Results from the SOUND-C2 study. Abstract#84 presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November
3. Bota S. et al. Response to standard of care antiviral treatment in patients with HCV liver cirrhosis – a systematic review. Journal of Gastrointestinal and Liver Diseases 2011; 20:293-8
4. National Institutes of Health; US Department of Health and Human Services. Chronic Hepatitis C: Current Disease Management. Bethesda, MD: National Institutes of Health; 2010. NIH Publication 10-4230 4.
5. World Health Organisation. Hepatitis C. 2012 http://www.who.int/csr/disease/hepatitis/Hepc.pdf [Last accessed on 25/09/12]
6. Kramer JR. et al. Gaps in the achievement of effectiveness of HCV treatment in national VA practice. J Hepatology 2012; 56:320-5
7. Gaeta G.B. et al. Premature discontinuation of interferon plus ribavirin for adverse effects: a multicentre survey in real worldpatients with chronic hepatitis C. Aliment Pharmacol Ther 2002; 16: 1633–1639
8. Zeuzem S. et al SOUND-C2: SVR4, 12, and 24 concordance in genotype (GT) 1 HCV patients receiving interferon (IFN)-free treatment with the HCV NS3/4A protease inhibitor BI 201335 and the NS5B polymerase inhibitor BI 207127. Abstract#778 presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November
9. Côté-Martin A. et al. HCV NS3 and NS5B variants that emerged in patients with virologic breakthrough and relapse from the Phase II SOUND-C2 trial investigating interferon-free BI 201335 and BI 207127 therapy ± ribavirin. Abstract#788 presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November
10. Sabo J. et al Pharmacokinetics of the interferon-free combination of BI 207127 and BI 201335 plus ribavirin in treatment naïve patients with genotype (GT) 1 HCV: Results from the SOUND-C1 study. Abstract#777 presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November
11. Berger K. et al. Analysis of baseline polymorphisms and persistence of emergent variants from Phase Ib and II trials evaluating the HCV NS3 protease inhibitor BI 201335. Abstract#785 presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November
12. Lohse A. et al. Addition of the NS5B polymerase inhibitor BI 207127 to pegylated interferon and ribavirin (PegIFN/RBV) for 4 weeks followed by PegIFN/RBV for 44 weeks improves SVR24 rates in treatment-naïve patients with HCV genotype (GT) 1 and is well tolerated. Abstract#767 presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 9 – 13 November
13. World Health Organisation. Hepatitis C. 2012 http://www.who.int/csr/disease/hepatitis/Hepc.pdf [Last accessed on 25/09/12]
14. National Digestive Disease Information Clearing House, NIH. Chronic Hepatitis C Current Disease Management. NIH Publication No. 10-4230. January 2010
15. Soriano, Vincent et al. New Therapies for Hepatitis C Virus Infection. Clinical Infectious Disease, February 2009