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AASLD 2012: Interferon-free Faldaprevir + BI 207127 Safe and Effective for Hepatitis C Patients with Cirrhosis

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The first major data on interferon-free hepatitis C treatment in people with cirrhosis shows 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 American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) in Boston.

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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 cirrhotic patients into general Phase 2 trials.

Paradoxically, it is likely to be patients with cirrhosis and advanced liver disease that 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 HCV 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 randomized into 5 study arms:

  • Faldaprevir 120 mg once daily + BI-207127 600 mg 3 times daily + ribavirin for 16 weeks;
  • Faldaprevir 120 mg once daily + BI-207127 600 mg 3 times daily + ribavirin for 28 weeks;
  • Faldaprevir 120 mg once daily + BI-207127 600 mg 3 times daily + ribavirin for 40 weeks;
  • Faldaprevir 120 mg once daily + BI-207127 600 mg twice daily + ribavirin for 28 weeks;
  • Faldaprevir 120 mg once daily + BI-207127 600 mg 3 times daily, with no ribavirin.

A total of 362 patients, 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 patients with compensated cirrhosis.

Nevertheless, noted Vicente Soriano of Hospital Carlos III in Madrid, presenting the results, this is the first trial to report data on the performance of interferon-free regimens in patients with compensated cirrhosis.

In patients with cirrhosis, sustained virological response rates 12 weeks after completing treatment (SVR12) ranged between 43% and 80% for patients taking ribavirin-containing regimens, depending on HCV subtype and IL28B host genotype. Responses were better in patients with the IL28B CC host genotype compared to those who lacked this gene pattern.  

The most common side effects in patients 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 emphasized the good response rate seen in patients with cirrhosis treated with faldaprevir/BI 207127/ribavirin, as well as the favorable 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, in people with and without cirrhosis, the interferon-free Boehringer Ingelheim combinations achieved good results. In a separate presentation, Stefan Zeuzem of Klinikum der J.W. Goethe-Universitat in Frankfurt presented final overall 24-week results from SOUND-C2, showing SVR12rates 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. All patients with SVR12 also went on to achieve SVR24.

Across the study population as a whole, 3 baseline characteristics were strongly predictive of a sustained virological response: HCV sub-genotype 1b, IL28B CC host genotype, and female sex (all statistically significant).

Some 80% of patients with HCV subtype 1b and the IL28B CC host genotype had SVR12, as did 50% of those with genotype 1a and the IL28B CC host gene pattern.

When results were stratified according to HCV subtype the best results were seen in genotype 1b patients who received BI 207127 twice daily with ribavirin for 28 weeks: 85% achieved SVR12, compared to 43% with genotype 1a. This dose regimen will now be taken forward for further testing in Phase 3 licensing studies.

The twice-daily regimen was generally well tolerated, with 12% of participants experiencing severe adverse events and 8% discontinuing treatment for this reason. Only 1 person developed serious anemia. Moderately elevated bilirubin was common, however, seen in 26%.

Zeuzem noted that treatment duration of greater than 16 weeks did not substantially improve outcomes in patients with HCV subtype 1b. In genotype 1a patients, by comparison, between 38% and 47% taking triple therapy achieved SVR12, increasing with longer dosing. These results reflect the greater potency of both faldaprevir and BI 207127 against HCV 1b, Zeuzem commented.

11/17/12

References

V Soriano, E Gane, P Angus, 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 (AASLD 2012). Boston, November 9-13, 2012. Abstract 84.

S Zeuzem, V Soriano, T Asselah,et al. Interferon (IFN)-free combinationtreatment 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 (AASLD 2012). Boston, November 9-13, 2012. Abstract 232.

Other Source

Boehringer Ingelheim.Phase 2b Data of Boehringer Ingelheim’s Interferon- Free Hepatitis C Treatment Show Viral Cure Achieved in Up to 85% of Treatment-Naive Patients. Press release. November 10, 2012.