Daniel M. Keller, PhD

November 13, 2012

BOSTON — A phase 2b trial of an oral, interferon-free regimen of 3 direct-acting antiviral drugs (DAAs) has shown very good efficacy in the treatment of hepatitis C virus (HCV) infection in both treatment-naive patients and null responders.

Speaking here at Liver Meeting 2012: American Association for the Study of Liver Diseases 63rd Annual Meeting, lead author Kris Kowdley, MD, of the Liver Center of Excellence in the Digestive Disease Institute at Virginia Mason Medical Center and a clinical professor of medicine at the University of Washington in Seattle, said that because of the high pill burden, 2 of the drugs (with ribavirin) will be formulated into a single tablet for phase 3 trials.

The all-oral treatment regimen consisted of ABT-450 (a daily NS3/4A protease inhibitor) boosted with ritonavir (ABT-450/r), ABT-267 (a daily NS5A inhibitor), and ABT-333 (a twice-daily nonnucleoside polymerase inhibitor) with or without ribavirin. Eligible patients (N = 448) were aged 18 to 70 years, had chronic HCV genotype 1 (GT1) infection regardless of IL28B host genotype, were noncirrhotic, were either treatment-naive or had not responded to prior treatment with peg-interferon and ribavirin (null responders), and were not coinfected with either HIV or hepatitis B virus.

All groups of patients were about 55% to 62% male (except 1 group, which was 44% male), predominantly white, and about 50 years old on average. Of the treatment-naive patients, 26% to 29% were of IL28B CC genotype, whereas only 2% to 4% of the null responders were. In all the treatment groups, 59% to 71% of the patients were infected with HCV genotype 1a, and mean baseline log10 HCV RNA levels were about 6.6.

Treatment was for 8, 12, or 24 weeks with ABT-450/r with various combinations of the other ABT drugs, with or without ribavirin for treatment-naive patients. Null responders received all 3 drugs or ABT-450/r and ABT-267 for 12 weeks, or all 3 drugs for 24 weeks, always with ribavirin.

The primary and secondary efficacy endpoints were sustained viral response at 24 weeks (SVR24). Those results will be presented at a later time. Dr. Kowdley presented sustained viral response at 12 weeks (SVR12) here.

Very High Response Rates, Especially With Ribavirin

For the 8- and 12-week groups, "regardless of treatment assignment, very high rates of SVR12 were reached across all categories both in the treatment-naive and nonresponder [null responder] categories," Dr. Kowdley reported. "But in particular, the group receiving 3 DAAs and ribavirin showed the highest SVR12 rates."

Treatment-naive patients treated for either 8 or 12 weeks achieved 85.4% to 97.5% SVR12 on an intent-to-treat basis, with the highest response rates achieved with 12-week regimens of ABT-450/r, ABT-267, and ribavirin (89.9%) or ABT-450/r, ABT-267, ABT-333, and ribavirin (97.5%).

For null responders treated for 12 weeks, the SVR12 response rate was 88.9% with ABT-450/r, ABT-267, and ribavirin and 93.3% with all 3 DAAs plus ribavirin. Null responders have historically been resistant to retreatment, with only about 30% responding to peg-interferon and ribavirin.

Treatment-naive patients with HCV GT1a treated for 12 weeks responded only slightly less well (82% - 98%) than the GT1b-infected patients (100% SVR12 regardless of drug combination). GT1a null responders had 81% to 89% responses, but 100% of the GT1b-infected null responders achieved an SVR12.

The safety and tolerability of the regimens were excellent. One percent of the 448 patients in the trial discontinued it because of adverse events (AEs). Of 5 serious AEs, 1 case of arthralgia was possibly related to study drugs. The most common AEs were fatigue, headache, nausea, and insomnia affecting treatment-naive patients and null responders. Of 2 patients whose study drugs were discontinued by an investigator because of AEs attributed to the drugs, the AEs resolved, and both patients achieved a sustained viral response.

Very few clinical chemistry or hematologic abnormalities occurred. The most common ones were transient indirect bilirubin increases twice the upper limit of normal or greater in 6.7% and 12.2% of the treatment-naive patients and null responders, respectively. As expected, there was significantly less decrease in hemoglobin in the ribavirin-free regimens.

Drug Combination Can Overcome Barriers to Effective Treatment

In summary, Dr. Kowdley said the 12-week, 3-DAA regimens with ribavirin showed the greatest efficacy in both treatment-naive patients and null responders, for both GT1a and GT1b infections, and across all IL28B host genotypes. All of the drug combinations were well tolerated in the 8- and 12-week treatment groups.

The 3-DAA regimen with and without ribavirin will move into phase 3 testing with a coformulated tablet of ABT-450/ritonavir/ABT-267 to reduce the pill burden, Dr. Kowdley said.

Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College, London, UK, and secretary general of the European Association for the Study of the Liver, commented to Medscape Medical News that the data from the trial is "impressive both in naive patients and in patients who were previous null responders."

He said 2 important points to note are that IL28 host genotype does not appear to matter, "as there were good responses in all 3 genotypes." Second, "the combination appears to be equally effective against HCV GT1a and 1b whereas 1a has been a problem in other studies."

But Dr. Thursz pointed out that on the downside, patients have to take 5 medications to get the best efficacy from these drugs. "Also worth noting is that SVRs were less frequent in the 8-week treatment arms vs the 12 weeks," he said. "As with many other [interferon] regimens, 12 or 24 weeks' treatment seems to be a requirement."

Paul Pockros, MD, director of the Liver Disease Center and senior consultant in the Division of Gastroenterology/Hepatology at Scripps Clinic in La Jolla, California, commented to Medscape Medical News that the data from this study look very good and show that the drug combination can overcome some long-standing barriers to effective treatment.

"Before, many of the regimens [containing DAAs] we've seen have all been more effective in genotype 1b than 1a, so genotype 1a was a barrier, and in this study they overcame that. The efficacy was very, very high in both 1a and 1b," he said.

"Number 2, they were able to shorten therapy to 12 weeks." Dr. Pockros said the drugs' developer is also going to explore an even shorter regimen of 8 weeks.

"Number 3, they overcame the barrier of nonresponse, so they had true null responders" in the study, defined as patients who did not have a 2-log10 drop in HCV RNA with 12 weeks of peg-interferon/ribavirin. "That's a difficult treatment group, and with telaprevir, their SVR rates are only 30% or 35%, same with boceprevir," he said. "So this overcame that barrier, and the SVR rates were [93.3%] in the null responders with an intention-to-treat analysis, so that's really great data."

Dr. Pockros expressed concern about a burden of 5 pills a day but noted that with a reformulated pill containing ABT-450/r/ABT-267, "that's going to be 1 pill, and that's no longer a deal breaker," taken with ABT-333 and maybe with ribavirin.

"There may be patients you can just give that to as a single capsule, which would make them very competitive with [a combination treatment from] Gilead, for instance, if they have a single-formulated compound," he predicted.

The next key step will be to do the same study in a population of cirrhotic patients, which investigators will initiate soon. Dr. Pockros said that if patients with cirrhosis could achieve an 80% SVR rate, "that would be a win."

The study was supported by Abbott Laboratories. Dr. Kowdley has research support from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead/Pharmasset, Intercept, Janssen, Merck, Mochida, Vertex, Scientific Consulting, and Novartis. He is on advisory boards for Abbott, Gilead, Merck, and Vertex. Dr. Pockros does studies for Gilead, BMS, and Abbott, is a speaker for BMS, and is an advisor to all 3.

The Liver Meeting 2012: American Association for the Study of Liver Diseases 63rd Annual Meeting. Abstract LB-1. Presented November 12, 2012.

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