AbbVie All-oral Combination Cures Most Hepatitis C Patients in Phase 2 Study

An all-oral regimen of AbbVie's experimental HCV drugs ABT-450, ABT-333, and ABT-367 plus ribavirin was well-tolerated and cured 88% of genotype 1 hepatitis C patients with only 8 weeks of therapy, rising to 95% with 12 weeks, according to a report in the January 16, 2014, New England Journal of Medicine.

Direct-acting antiviral agents have started to revolutionize hepatitis C treatment, but many people with hepatitis C and their providers are still waiting for all-oral regimens that avoid the difficult side effects of interferon.

Kris Kowdley from Virginia Mason Medical Center and colleagues conducted a study to evaluate various interferon-free combinations containing the HCV protease inhibitor ABT-450 boosted with ritonavir, the non-nucleoside HCV polymerase inhibitor ABT-333, the NS5A inhibitor ABT-267, and/or ribavirin.

This open-label Phase 2b trial enrolled a total of 571 genotype 1 chronic hepatitis C patients. It included both 438 treatment-naive participants and 133 people who were non-responders to a prior course of interferon-based therapy. About 60% were men, most were white, and the average age was approximately 50 years. About 65% had harder-to-treat HCV subtype 1a. About 30% of treatment-naive patients and almost none of the treatment-experienced patients had the favorable IL28B CC gene variant. About 30% of naive and half of experienced patients had moderate or worse fibrosis (stage >F2), but not cirrhosis.

Participants were randomly allocated to 14 treatment subgroups receiving ABT-450 (100, 150, or 200 mg plus 100 mg ritonavir once-daily) plus ABT-333 (400 mg twice-daily) or ABT-267 (25 mg once-daily) or both. All but 1 of the subgroups also received 1000-1200 mg/day weight-based ribavirin. Treatment lasted for 8, 12, or 24 weeks. The primary endpoint was sustained virological response, or continued undetectable HCV RNA, at 24 weeks post-treatment (SVR24).

Results

• Across all treatment subgroups,sustained virological response rates ranged from 83% to 100%.
• Among previously untreated participants taking 3 direct-acting antivirals (using the 150 mg ABT-450 dose) plus ribavirin, the SV24 rate was 88% among those treated for 8 weeks and 95% among those treated for 12 weeks, a non-significant difference.
• SVR24 rates were similar in an analysis comparing the 100 mg and 150 mg doses of ABT-450 (both approximately 94%).
• With these ABT-450 dose groups combined, SVR24 rates ranged from 83% to 96% for treatment-naive patients and from 89% to 95% for prior non-responders.
• While SVR24 rates were highest in the groups receiving 4-drug regimens, rates were also good for 3-drug combos:

o   ABT-450 + ABT-333 + ribavirin: 83% for treatment-naive;

o   ABT-450 + ABT-267 + ribavirin: 89% for both naive and experienced;

o   ABT-450 + ABT-333 + ABT-267: 89% for treatment-naive.

• SVR24 was higher among previously untreated patients who took the 4-drug regimen for 12 versus 8 weeks (96% and 88%), but the difference was not significant.
• Relapse rates for treatment-naive patients treated for 8, 12, or 24 weeks were 12%, 1%, and 2%, respectively.No relapses occurred among prior non-responders treated for either 12 or 24 weeks.
• Sustained response rates were high and similar regardless of IL28B status, HCV subtype, race, or baseline HCV RNA level.
• All the oral regimens were generally safe and well-tolerated.
• 8 participants (1%) experienced serious adverse events, and the same percentage discontinued treatment early due to adverse events.
• The most frequent side effects were fatigue, headache, nausea, and insomnia, which occurred with similar frequency across treatment arms.

"In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy," the researchers concluded. "These preliminary data suggest that a 12-week regimen of three direct-acting agents plus ribavirin is efficacious in patients without cirrhosis who either had not received treatment previously or had not had a response to prior therapy."

"Among previously untreated patients, the rate of treatment failure was lower among those receiving 3 direct-acting agents plus ribavirin for 12 weeks than among those who received the same regimen for only 8 weeks and among those who received fewer agents; extending the treatment to 24 weeks offered no further benefit. However, no differences in the rates of sustained virologic response reached statistical significance," they explained in their discussion.

Nevertheless, "[t]he higher number of relapses among patients in the 8-week treatment group...and the absence of resistance-associated variants in most patients who had a relapse in the 8-week treatment group suggest that 8 weeks of treatment might not be sufficient to eradicate the susceptible HCV population in these patients," they continued.

Based on these findings, AbbVie's regimen of 3 direct-acting antivirals (dubbed "3D") with or without ribavirin has been designated as a "breakthrough therapy" by the U.S. Food and Drug Administration, intended to expedite development and review of drugs for serious or life-threatening conditions.

The 3D plus ribavirin combo -- featuring a coformulation of ABT-450/ritonavir/ABT-267 -- is now undergoing Phase 3 trials in more than 2000 patients, using a 12-week duration for non-cirrhotic patients and comparing 12 vs 24 weeks for people with cirrhosis, according to AbbVie.

So far, data from the SAPPHIRE-I trial have demonstrated SVR12 rates of 95% for previously untreated non-cirrhotic patients with HCV subtype 1a and 98% for those with subtype 1b, while data from the SAPPHIRE-II trial showed an SVR12 rate of 96% for treatment-experienced patients without cirrhosis, with similar response rates for subtypes 1a and 1b.

1/16/14

Reference

KV Kowdley,E Lawitz, FPoordad, et al. Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1. New England Journal of Medicine 370(3):222-232. January 16, 2014.