The first major data on interferon-free hepatitis C treatment in people with cirrhosis show that treatment using BI-201335 – now known as faldaprevir – and BI-207127 with ribavirin can be safe, and proved effective in up to 69% of patients, according to results from the SOUND-C2 study presented this week at the 63rd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.
Despite their higher risk of progression to decompensated cirrhosis and liver cancer, most earlier-stage studies of new hepatitis C drugs exclude people with more severe liver damage on the grounds of safety and the unpredictable processing of drugs by a more damaged liver. Moreover, because response rates tend to be poorer in this population, which would make the drug appear to perform poorly in comparison with competitor products, companies are unlikely to risk harming early perceptions of products by recruiting people with cirrhosis into general Phase 2 trials.
Paradoxically, it is likely to be people with cirrhosis and advanced liver disease who will be given priority for treatment with new agents as they become available. Data from earlier stage studies are likely to give people with more advanced disease an earlier indication of whether the chance of curing hepatitis C infection will be greatly improved if they defer treatment until new drugs are available.
The SOUND-C2 study was a Phase 2b safety and efficacy study, comparing the performance of interferon-free combinations containing the hepatitis C protease inhibitor faldaprevir and the non-nucleoside NS5B polymerase inhibitor BI-207127, with or without ribavirin. These direct-acting antivirals are being developed by Boehringer Ingelheim.
Participants were randomised into 5 study arms:
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times daily + ribavirin for 16 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times daily + ribavirin for 28 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times daily + ribavirin for 40 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg twice daily + ribavirin for 28 weeks;
- Faldaprevir 120mg once daily + BI-207127 600mg 3 times daily, with no ribavirin.
A total of 362 people, 33 of them with liver cirrhosis, were recruited to this open-label study. Participants with cirrhosis were not distributed equally across the study arms, and the number of patients with cirrhosis was small, limiting the power of the study to provide evidence regarding the relative performance of different regimens in people with compensated cirrhosis.
Nevertheless, noted Vicente Soriano of Hospital Carlos III, Madrid, presenting the results, this is the first trial to report data on the performance of interferon-free regimens in people with compensated cirrhosis.
In patients with cirrhosis, rates of sustained virologic response 12 weeks after completing treatment (SVR12) ranged between 43% and 80% for people taking ribavirin-containing regimens depending on HCV sub-genotype and IL28B host genotype. Responses were better in people with the IL28B 'CC' host genotype, compared to those who lacked this gene pattern.
The most common side-effects in people with cirrhosis were mild rash and gastrointestinal complaints. Overall, 8% of participants discontinued treatment due to serious adverse events, most of which were not judged to be drug-related.
The investigators emphasised the good response rate seen in people with cirrhosis treated with faldaprevir/BI 207127/ribavirin, as well as the favourable tolerability profile of this combination in this patient group. The combination will continue to be investigated in Phase 3 trials involving patients with cirrhosis.
SOUND-C2: final results
Overall, these interferon-free combinations achieved good results. In a separate presentation, Stefan Zeuzem of Klinikum der J.W. Goethe-Universitat in Frankfurt presented final overall 24-week (SVR24) results of the SOUND-C2 study, showing SVR12 rates of between 52 and 69% in the ribavirin-containing arms and 39% in the ribavirin-sparing arm. (The ribavirin-sparing arm was halted early due to the low efficacy observed in this arm). All patients with SVR12 also went on to achieve SVR24.
Across the study population as a whole three baseline characteristics were strongly predictive of a sustained virological response: HCV genotype 1b (adjusted odds ratio 7.11), IL28B 'CC' host genotype (AOR 4.94) and female sex (AOR 3.94) (all p <0.0001).
Some 80% of participants with genotype 1b infection and the IL28B 'CC' host genotype had a sustained virological response (SVR) at week twelve, as did 50% of those with genotype 1a and the IL28B 'CC' host genotype
When results were stratified according to hepatitis C sub-genotype the best results were seen in people with genotype 1b who received BI-207127 twice daily and ribavirin for 28 weeks (85% achieved SVR12, compared to 43% with genotype 1a), and this dose will now be taken forward for further study in Phase 3 licensing studies. However Dr Zeuzem noted that a treatment duration of greater than 16 weeks did not substantially improve outcomes in people with hepatitis C genotype 1b.
In people with genotype 1a, by comparison, between 38% and 47% taking triple therapy achieved SVR12 according to the dosing regimen. These results reflect the greater potency of both drugs against genotype 1b, Dr Zeuzem commented.
The twice-daily regimen was generally well tolerated, with 12% of participants experiencing severe adverse events and 8% discontinuing treatment for this reason. Only one person developed serious anaemia. Moderately elevated bilirubin was common, however, seen in 26%.
(NOTE: this article has been revised to correct discrepancies between figures reported from conference abstracts and data presented at the meeting).
Soriano V et al. Efficacy and safety of the interferon (IFN)-free combination of BI 201335 + BI 207127 +/- ribavirin in treatment-naïve patients with HCV genotype (GT) 1 infection and compensated liver cirrhosis: results from the SOUND-C2 study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, abstract 84, 2012.
Zeuzem S et al. Interferon (IFN)-free combination treatment with HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS 5B inhibitor BI 207127 +/- ribavirin (R): final results of SOUND-C2 and predictors of response. 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, abstract 232, 2012.