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AASLD 2011: BI 201335 Performs Well with Standard Therapy

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Once-daily BI 201335 added to pegylated interferon/ribavirin for 24 weeks produced consistently high SVR rates across difficult-to-treat chronic hepatitis C patient subgroups, according to findings from the SILEN-C1 study presented at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) last week in San Francisco. A follow-up study showed that rapid responders did equally well with 12 or 24 weeks of treatment.

The advent of direct-acting antiviral (DAA) agents has begun to revolutionize treatment for chronic hepatitis C, but better therapies are still needed for patient subgroups that do not respond as well to interferon-based therapy, including people with the unfavorable IL28B gene patterns.

Boehringer Ingelheim's Phase 2 SILEN-C trials tested the second-generation HCV NS3/4A protease inhibitor BI 201335 plus pegylated interferon/ribavirin in previously untreated patients.

SILEN-C1

In SILEN-C1, Mark Sulkowski from Johns Hopkins University and colleagues randomly assigned 429 treatment-naive genotype 1 chronic hepatitis C patients to receive 120 mg or 240 mg once-daily BI 201335 with pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day weight-adjusted ribavirin for 24 weeks, continuing on pegylated interferon/ribavirin alone through week 48, or else pegylated interferon/ribavirin standard therapy. In addition, some 240 mg BI 201335 recipients were assigned to start with a 3-day lead-in of pegylated interferon/ribavirin before adding the experimental agent.

The primary analysis showed that 240 mg BI 201335 triple therapy was significantly more effective than pegylated interferon/ribavirin standard therapy, with sustained virological response (SVR) rates of 83% vs 56%, respectively; the lead-in, however, was associated with poorer response (73%).

At AASLD Sulkowski presented a subgroup analysis of 146 people who received 240 mg BI 201335 without the lead-in and 71 pegylated interferon/ribavirin standard therapy recipients.

About half of the participants in this analysis were men, about 80% were white, and the mean age was 46 years. With regard to HCV genotype, 35% in the BI 201335 arm and 45% in the control arm had subtype 1a (which is somewhat more difficult to treat), while 62% and 54%, respectively, had subtype 1b. In addition, 15% in both arms had the favorable IL28B CC gene pattern, 33% and 41%, respectively, had CT or TT (combined), and 52% and 44% were missing data.

Results

  • BI 201335 triple therapy performed significantly better than pegylated interferon/ribavirin in both men and women and in all age groups, with similar SVR rates across the board (81%-87%).
  • Among IL28B CC patients, SVR rates were 100% with BI 201335 vs 82% with standard therapy, not a significant difference.
  • Among IL28B CT and TT patients, SVR rates were 71% vs 41%, respectively, which did reach statistical significance.
  • Among people with HCV genotype 1a, SVR rates were 82% in the BI 201335 arm vs 47% in the standard therapy arm, a highly significant difference.
  • Among people with genotype 1b, SVR rates were 84% vs 66%, respectively, also significant.
  • Among patients with low baseline HCV RNA (<800,000 IU/mL), SVR rates were 91% with BI 201335 vs 67% with standard therapy, which did not reach significance.
  • Among patients with high HCV viral load, SVR rates were 81% vs 57% respectively, which was significant.
  • Among people with normal alanine aminotransferase (ALT) at baseline, SVR rates were 88% vs 46%, while rates for people with ALT above the upper limit of normal were 82% vs 58%, both significant.
  • Among people with normal levels of another liver enzyme, gamma-glutamyl transpeptidase (GGT), SVR rates were 91% vs 67%, respectively, while among people with elevated GGT the corresponding rates were 72% vs 39%, both highly significant.
  • In a multivariate analysis, the only independent predictor of SVR was GGT level.

Based on these findings, the researchers concluded, "SVR rates with BI 201335 240 mg [once-daily] were consistently high across a wide rage of difficult-to-cure subgroups."

Sulkowski suggested that the explanation for the association between SVR and GGT may be that GGT is measuring liver disease parameters that are not picked up by usual histology methods. GGT, which is included in the FibroTest index, may reveal liver damage that has occurred since the last biopsy.

SILEN-C3

In the open-label SILEN-C3 trial, 159 treatment-naive patients with HCV genotype 1 received 120 mg once-daily BI 201335 for either 12 or 24 weeks and pegylated interferon/ribavirin for 24 weeks. Those without extended rapid virological response (eRVR; defined as unquantifiable HCV RNA at week 4 and undetectable at weeks 8-18) continued pegylated interferon/ribavirin alone through week 48. Patients in both groups started with a 3-day pegylated interferon/ribavirin lead-in before adding BI 201335.

About 60% of participants were men, almost all were white, and the mean age was about 46 years. About 12% had liver cirrhosis at baseline; 48% in the 12-week arm and 37% in the 24-week arm had HCV subtype 1a, while 46% and 53%, respectively, had subtype 1b.

Results

  • 72% of participants in the 12-week BI 201335 arm and 82% in the 24-week arm experienced eRVR.
  • 65% and 73%, respectively, achieved SVR, or continued undetectable viral load 24 weeks after completing treatment.
  • 10 people (12%) in the 12-week arm experienced viral breakthrough, compared with 5 people (6%) in the 24-week arm.
  • However, relapse rates among people with undetectable viral load at the end of triple therapy were similar, 11% and 10%, respectively.
  • Among people with undetectable HCV RNA at or before week 8 or week 12, SVR rates were similar with both 12 or 24 weeks of BI 201335, at about 80%.
  • BI 201335 was generally well-tolerated, with 8% in the 12-week arm and 9% in the 24-week arm experiencing severe adverse events.
  • 3 people (4%) in the 12-week arm and 5 people (6%) in the 24-week arm discontinued due to adverse events; 1 person (1%) and 2 people (3%), respectively, did so due to skin rash.

The investigators concluded that "12 and 24 weeks of BI 201 335 had similar efficacy" and "safety and tolerability in both treatment arms were very favorable."

Ongoing Phase 3 studies are further evaluating 120 mg and 240 mg once-daily BI 201335, both without a pegylated interferon/ribavirin lead-in. The new drug is also being studied in HIV/HCV coinfected people.

According to a Boerhinger Ingelheim press release summarizing these findings, "BI 201335 may have the potential to shorten the duration of treatment compared to [pegylated interferon/ribavirin] for a large portion of patients, as well as improve the likelihood of viral cure for patients with characteristics that make their HCV more difficult to treat." 

Investigator affiliations:

SILEN-C1: John Hopkins University, Baltimore, MD; Hôpital Beaujon, Clichy, France; Medical University, Vienna, Austria; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT; Boehringer Ingelheim Pharmaceuticals, Laval, Quebec, Canada; Department of Clinical Research, Boehringer-Ingelheim GmbH, Biberach an der Riss, Germany.

SILEN-C3: Mount Sinai School of Medicine, New York, NY; Hôpital Beaujon, Clichy, France; University of Rennes, Rennes, France; Charité Campus Virchow-Klinikum, Berlin, Germany; "Dr. Victor Babes" Hospital for Infectious and Tropical Diseases, Bucharest, Romania; "Prof. Dr. Matei Bals" Institute of Infectious Diseases, Bucharest, Romania; Internal Medicine 1, University Hospital Mainz, Mainz, Germany; Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; Service d'Hépato-Gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France; Medical University, Vienna, Austria; INSERM632-CIC, Hôpital Saint Eloi, Montpellier, France; Department of Gastroenterology and Hepatology, Elisabethinen Hospital Linz, Linz, Austria; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT; Department of Clinical Research, Boehringer-Ingelheim GmbH, Biberach an der Riss, Germany.

11/15/11

References

M Sulkowski, T Asselah, P Ferenci, et al. Treatment with the second generation HCV protease inhibitor BI201335 results in high and consistent SVR rates -- results from SILEN-C1 in treatment-naive patients across different baseline factors. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 226.

D Dieterich, T Asselah, D Guyader, et al. SILEN-C3: Treatment for 12 or 24 weeks with BI201335 combined with peginterferon alfa-2a and ribavirin (P/R) in treatment-naïve patients with chronic genotype-1 HCV infection. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 36.

Other Source

Boehringer Ingelheim Pharmaceuticals. Sustained Viral Response from Phase 2 Studies of BI 201335, Including Difficult-to-Treat HCV Patient Types. Press release. November 8, 2011.