AASLD - Drug Combos Hit Hep C Virus Hard

Drug Combos Hit Hep C Virus Hard

By Michael Smith, North American Correspondent, MedPage Today

Published: November 13, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston

Action Points
This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Explain that a trial that included arms with five direct antiviral drugs but no interferon successfully achieved sustained virologic response (SVR) at 12 weeks in hepatitis C-infected patients with genotype 1 infection.

Note that SVR12 response rates were uniformly high, whether patients were treatment-naive or they had failed previous interferon-plus-ribavirin standard therapy

BOSTON – A series of all-oral regimens for hepatitis C -- with four or five drugs each but without interferon -- yielded response rates of greater than 85% in difficult-to-treat patients, a researcher reported here.

For two of the regimens, the so-called sustained virologic response (SVR) 12 weeks after the end of treatment was between 93% and 98%, according to Kris Kowdley, MD, of Virginia Mason Medical Center in Seattle.

Those results were obtained, respectively, in a group of people who failed to respond to previous treatment with pegylated interferon and ribavirin (the standard therapy), and in people who had never been treated for the virus, Kowdley reported in the late-breaker session at the annual meeting of the American Association for the Study of Liver Diseases.

The researchers were studying combinations of three so-called direct-acting agents – they target the hepatitis C virus itself – with or without ribavirin, which interferes with replication of many viruses.
One of the direct-acting agents, dubbed ABT-450, is a protease inhibitor that must be boosted with ritonavir (Norvir), much as some anti-HIV drugs are boosted.

The others are ABT-267, which blocks the viral nonstructural protein NS5A, and ABT-333, a non-nucleoside polymerase inhibitor.

The goal of the industry-sponsored study was to define optimal regimens to treat people with genotype 1 virus who had not previously been treated and those who had not responded to interferon and ribavirin previously.

All told, the study has nine arms, with treatment durations ranging from 8 to 24 weeks, and the primary endpoint is sustained virologic response 24 weeks (SVR₂₄) after the end of treatment.
Sustained virologic response means that the virus is not detectable at the time of the measurement; an SVR₂₄ is widely regarded as a cure.

Kowdley presented the 12-week SVR data – dubbed SVR₁₂ -- for just the arms with treatment lasting 8 and 12 weeks.

"Regardless of treatment assignment," he said, "very high rates of SVR₁₂ were reached across all categories."

Specifically:

• The 8-week arm had 80 treatment-naive patients treated with all five drugs. On an intent-to-treat basis, the SVR₁₂ rate was 87.5%.
• The rate in the five-drug 12-week arm, with 79 treatment-naive patients, was 97.5%.
• Three other 12-week arms (with a total of 199 treatment-naive patients) all included boosted ABT-450, but each dropped one other drug -- ABT-267, ABT-333, or ribavirin. SVR₁₂ rates were 85.4%, 89.9% or 87.3%, respectively.
• In the null responders, treatment with all five drugs yielded an SVR₁₂ rate of 93.3%, while dropping ABT-333 lowered the rate to 88.9%. There were 45 patients in each arm.

When the researchers broke down the data by viral subtype, they found that SVR₁₂ rates were 100% for patients with genotype 1b, except for the 8-week treatment arm, where the rate was 96%.
Genotype 1b is considered easier to treat than 1a but even for patients with the latter genotype, SVR₁₂ rates were still high – ranging from 81% to 98%.

Interestingly, the two highest rates among patients with genotype 1a -- 98% and 89% -- were associated with all five drugs given for 12 weeks in treatment-naive and null responders, respectively, Kowdley reported.

All the regimens were well tolerated, Kowdley reported, and there were no serious adverse events related to the study drugs. The arms without ribavirin had, as expected, significantly smaller declines in hemoglobin.

Phase III trials are planned, he concluded, that will test the three direct-acting agents with or without ribavirin, but to limit the pill burden, three of the drugs – ritonavir, ABT-450, and ABT-267 – will be co-formulated in a single, once-daily pill.

Overall, "the data look very good," commented Paul Pockros, MD, of Scripps Clinic in La Jolla, Calif., who was not involved in the study.
The researchers got good results regardless of several "barriers" that had derailed previous approaches, Pockros told MedPage Today.

For instance, he noted, "efficacy was very, very high" both in hard-to-treat patients with viral genotype 1a and in those with genotype 1b.

In addition, he said, the study had good results in "a very difficult treatment group" -- those who had not responded to previous therapy with interferon and ribavirin.

On the other hand, the regimens in the study had a heavy pill burden. "Five pills is a lot of medicine," Pockros said, especially when some must be given twice a day. But plans to co-formulate some of the drugs into a single pill will eliminate that hurdle, he said.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Kowdley KV, et al "A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) Of 99% in treatment-naïve patients and 93% in prior null responders with HCV genotype 1 infection" AASLD 2012; Abstract LB-1.

The study was supported by Abbott. Kowdley reported financial links with the company, as well as with Boehringer Ingelheim, BMS, Gilead/Pharmasset, Intercept, Janssen, Merck, Mochida, Vertex, and Novartis. Pockros reported financial links with Novartis, Tibotec, GlobeImmune, Genentech, Merck, BMS, Gilead, Vertex, Three Rivers Pharmaceuticals, Debio, Pfizer, Conatus Pharmaceuticals, Abbott, and Mochida Pharmaceutical.

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