BI 201335 & BI 207127 and ribavirin shows good efficacy, including hepatitis C patients with cirrhosis

Published: 15 May 2012

An interferon-free regimen of the hepatitis C virus (HCV) protease inhibitor BI 201335, the non-nucleoside polymerase inhibitor BI 207127, and ribavirin produced sustained virological response in 68% of previously untreated genotype 1 hepatitis C patients, with favourable safety and efficacy among people with liver cirrhosis, researchers reported at the 47th International Liver Congress (EASL 2012) last month in Barcelona.

The advent of direct-acting antiviral agents for HCV has ushered in a new era of treatment, but many patients and providers continue to wait for interferon-free therapy.

In the Phase 2b SOUND-C2 trial, Stefan Zeuzem (JW Goethe University) and an international team of colleagues evaluated Boehringer Ingelheim's BI 201335 and BI 207127 without pegylated interferon. In a prior Phase 1b study (SOUND-C1), these two drugs plus ribavirin produced high rates of rapid virological response with no serious adverse events.

SOUND-C2 included 362 treatment-naive chronic hepatitis C patients. About half were men, almost all were white, and the average age was approximately 48 years. About 10% had cirrhosis and about one-quarter had the favourable IL28B CC gene pattern; approximately 40% had the more difficult-to-treat HCV subtype 1a, the rest 1b.

Participants were randomly allocated into five treatment arms. All received 120mg once-daily (QD) BI 201335, with varying dosing schedules of BI 207127, with or without 1000 to 1200mg/day weight-adjusted ribavirin:

  • BI 201335 + 600mg three times daily (TID) BI 207127 + ribavirin for 16 weeks;
  • BI 201335 + 600mg TID BI 207127 + ribavirin for 28 weeks;
  • BI 201335 + 600mg TID BI 207127 + ribavirin for 40 weeks;
  • BI 201335 + 600mg twice-daily (BID) BI 207127 + ribavirin for 28 weeks;
  • BI 201335 + 600mg TID BI 207127 with no ribavirin for 28 weeks;

The primary endpoint was sustained virological response, or undetectable HCV RNA (< 15 IU/mL), 12 weeks after completion of therapy (SVR12), which is now regarded as a cure. (4-week SVR results were reported for the 40-week group, which was still being followed for SVR12.)

Results

In an intent-to-treat analysis, SVR12 rates in the five arms were as follows:

  • BI 207127 TID/ribavirin, 16 weeks: 59%;
  • BI 207127 TID/ribavirin, 28 weeks: 61%;
  • BI 207127 TID/ribavirin, 40 weeks: 56%;
  • BI 207127 BID/ribavirin, 28 weeks: 68%;
  • BI 207127 TID, no ribavirin, 28 weeks: 39%.

Stratified by HCV subtype, people with 1b had higher response rates than those with 1a in all arms:

  • BI 207127 TID/ribavirin, 16 weeks: 1a 38% vs 1b 75%;
  • BI 207127 TID/ribavirin, 28 weeks: 1a 44% vs 1b 73%;
  • BI 207127 TID/ribavirin, 40 weeks: 1a 47% vs 1b 63%;
  • BI 207127 BID/ribavirin, 28 weeks: 1a 43% vs 1b 83%;
  • BI 207127 TID, no ribavirin, 28 weeks: 1a 11% vs 1b 57%.

People with the IL28B CC gene pattern likewise responded better in all arms:

  • BI 207127 TID/ribavirin, 16 weeks: non-CC 57% vs CC 67%;
  • BI 207127 TID/ribavirin, 28 weeks: non-CC 57% vs CC 71%;
  • BI 207127 TID/ribavirin, 40 weeks: non-CC 52% vs CC 68%;
  • BI 207127 BID/ribavirin, 28 weeks: non-CC 64% vs CC 79%;
  • BI 207127 TID, no ribavirin, 28 weeks: non-CC 33% vs CC 58%.

After subtracting the patient subgroup with the lowest response – those with HCV subtype 1a and IL28B non-CC – SVR rates for all 1b and 1a CC patients combined were 71, 71, 62, 82 and 53%, respectively. Within this favourable group, viral breakthrough during treatment occurred in 7, 11, 19, 9 and 29%, respectively. In the same group, relapse after completing treatment occurred in 10, 2, 0, 2 and 8%, respectively.

Patients with both HCV genotype 1a and IL28B non-CC had substantially higher breakthrough and relapse rates, with breakthrough reaching 64% in the BID arm and 91% in the no-ribavirin arm.

The tested regimens were generally well tolerated overall. Discontinuation rates due to adverse events in the five treatment arms were 5, 13, 25, 8 and 11% respectively.

Photosensitivity, skin rash and jaundice were more common in the BI 207127 thrice-daily arms, with very few or no cases in the twice-daily arm. The regimen had a minimal effect on red blood cell count and no effect on white blood cell or platelet counts.

Based on these findings, the researchers concluded that "the interferon-free combination of BI 201335 + BI 207127 + ribavirin demonstrated high efficacy and a good safety profile".

The 600mg twice-daily dosing schedule for BI 207127 was both more effective and better tolerated than thrice-daily dosing. Ribavirin was still needed to enable sustained response. People with HCV subtype 1b and IL28B CC had significantly higher cure rates – an interesting finding since IL28B is known to be associated with interferon responsiveness.

Among patients treated with BI 207127 three times daily, duration of treatment did not have much effect on efficacy, suggesting that 16 weeks might also be feasible with twice-daily dosing. Boehringer Ingelheim is planning further studies of favourable patients (all 1b and 1a CC) using the BID dose.

Cirrhosis

People with advanced liver disease are among the difficult-to-treat patient populations most urgently in need of better treatment options. Study investigators therefore performed a sub-analysis of 37 SOUND-C2 participants with confirmed compensated cirrhosis by biopsy or transient elastometry (Fibroscan). Within this group, about 65% were men, the mean age was about 52 years, 25 had HCV 1b, and 30 had the IL28B CC gene pattern.

SVR12 rates were 57% with BI 207127 TID/ribavirin (all durations combined), 54% with BI 207127 BID/ribavirin, and 33% with no ribavirin. Looking again at HCV subtype, SVR12 rates for people with genotype 1b were 64, 71 and 33%, respectively, compared with 43, 33 and 0% for those with HCV 1a.

Looking at treatment failure, rates of viral breakthrough were 19% in the BI 207127 TID/ribavirin groups, 38% with BI 207127 BID/ribavirin, and 67% with no ribavirin. A single patient in the thrice-daily group relapsed after finishing treatment.

Although this patient subgroup had advanced liver disease, overall safety and tolerability were "favourable" in the twice-daily BI 207127/ribavirin arm, the researchers concluded, with 15% experiencing serious adverse events and one person discontinuing due to adverse events. Tolerability was poorer, however, for people taking thrice-daily BI 207127 with ribavirin, with a serious adverse event rate of 19% and six people stopping treatment early, mostly due to photosensitivity, rash or jaundice.

"These are the first data from an interferon-free regimen in a population with compensated HCV cirrhosis and they support further evaluation of this regimen for chronic HCV genotype 1 infection including patients with cirrhosis," the researchers concluded.

References

Zeuzem S, Soriano V, Asselah T et al. SVR4 and SVR12 with an interferon-free regimen of BI201335 and BI207127, +/- ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: interim results of SOUND-C2. 47th International Liver Congress (EASL 2012), Barcelona, abstract 101, 2012. See the abstract here.

Soriano V, Gane E, Angus P et al. The efficacy and safety of the interferon-free combination of BI201335 and BI207127 in genotype 1 HCV patients with cirrhosis - interim analysis from SOUND-C2. 47th International Liver Congress (EASL 2012). Barcelona, abstract 1420, 2012. See the abstract here.

Boehringer Ingelheim Phase 2b study of Boehringer Ingelheim’s interferon-free hepatitis C treatment shows undetectable virus in HCV genotype-1 patients 12 weeks after treatment ended (SVR12). Press release, 19 April 2012.

Boehringer Ingelheim First ever data investigating interferon-free treatment in hepatitis C patients who have liver cirrhosis shows high viral cure rate. Press release, 19 April 2012.

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