April 11, 2014

'3D' HCV Combo Almost Perfect

Published: Apr 11, 2014

By Michael Smith, North American Correspondent, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor,
Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Note that 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.
  • The combination of a protease inhibitor (ABT-450) and a drug that delays its degradation (ritonavir), plus two inhibitors of hepatitis C virus replication (ombitasvir and dasabuvir) achieved high SVR12 rates with low rates of treatment discontinuation in treatment-experienced, noncirrhotic HCV genotype 1-infected patients, including prior null responders.

LONDON -- An investigational drug combination cured almost all patients with the form of hepatitis C (HCV) that is most common in North America, researchers said.

In two major phase III studies, cure rates after 12 weeks of treatment with the so-called 3D combination ranged from 95.3% to 100% depending on patient subgroups, investigators reported here at the annual meeting of the European Association for the Study of the Liver and online in the New England Journal of Medicine.

Cure rates -- with a cure defined as no detectable HCV RNA 12 weeks after the end of treatment, or SVR12 -- appeared to be independent of patient and viral characteristics in the industry-supported trials.

The results are highly promising and likely to hold up in clinical practice, once the combination is approved, according to William Carey, MD, of the Cleveland Clinic.

But, Carey told MedPage Today, the studies included only patients with HCV genotype 1. Although that accounts for about 70% of the cases in North America, "that means there's 30% of people who have a different genotype and these results are not directly applicable" to them, he said.

The combination until recently has been known by its nickname 3D -- or by a soup of numbers and letters -- because the drugs involved had yet to be named by the manufacturer, AbbVie of North Chicago, Ill.

Two of them now have names -- ABT-267, an NS5A inhibitor, is now ombitasvir and the non-nucleoside polymerase inhibitor ABT-333 is now called dasabuvir. The as-yet-nameless third drug is ABT-450, a protease inhibitor boosted with ritonavir (Norvir).

The combination is given with ribavirin, a nonspecific antiviral drug.

With cure rates approaching 100%, the combination is one of the stars of this meeting, with two plenary session presentations and a late-breaker oral talk, as well as others, devoted to it.

The Sapphire I and Sapphire II studies are parallel randomized placebo-controlled trials that tested the combination in patients with genotype 1 HCV who did not have cirrhosis.

Sapphire I, led by Jordan Feld, MD, of the University of Toronto in Canada, looked at outcomes in patients who had not been previously treated. Sapphire II, led by Stefan Zeuzem, MD, of Johann Wolfgang Goethe University in Frankfurt, Germany, studied patients who had failed earlier therapy.

Sapphire I enrolled 631 patients and assigned three-quarters of them to the active drug, while the remainder were given matching placebo for 12 weeks, after which they were switched to the active regimen for an open-label study.

The primary endpoint was a comparison with outcomes from historical trials involving telaprevir (Incivek) with pegylated interferon-alfa and ribavirin, where the SVR12 was 78%, Feld reported.

The SVR12 rate in the active treatment arm was 96.2% overall, which was superior to the historical control rate, he reported. Nor was there little difference by subgenotype -- 95.3% among patients with genotype 1a and 98.0% among those with genotype 1b.

Rates were similarly high in all subgroups, including those defined by sex, race, age, fibrosis score, and HCV RNA level.

Few patients stopped therapy because of adverse events -- 0.6% in each study group, but those in the active treatment arm had significantly more nausea, pruritus, insomnia, diarrhea, and asthenia than placebo patients (P<0.05 for all comparisons).

Grade 1 declines in hemoglobin occurred in 47.5% of patients in the 3D arm; grade 2 drops occurred in 5.8%, Feld reported. In contrast, 2.5% of placebo patients had grade 1 declines.

"I would say this was a highly, highly effective regimen," commented Alessio Aghemo, MD, PhD, of the University of Milan and a member of the association's governing board.

The design of Sapphire II was similar, except that patients had to have failed a previous attempt at treatment with peginterferon and ribavirin.

Zeuzem and colleagues enrolled 394 patients, including 115 who had relapsed after previous therapy, 86 who had had only a limited response, and 193 who had not responded at all.

Again three-quarters were assigned to the 3D combination for 12 weeks, while the rest got a matching placebo before being switched to the active treatment in an open-label, 12-week extension.

Results were also similar to those seen in Sapphire I and, if anything, a little better: an overall SVR12 rate of 96.3%, with 96% in genotype 1a and 96.7% in genotype 1b, Zeuzem reported.

The type of previous failure did not seem to matter: 95.3% among patients with a prior relapse, 100% among patients with a prior partial response, and 95.2% among patients with a prior null response.

As in Sapphire I, SVR12 rates were high and similar across subgroups.

The SVR12 rates were superior to the historical comparison rate of 65% among treatment failures who had been retreated with telaprevir, peginterferon, and ribavirin.

Pruritus occurred more frequently in 13.8% of 3D patients, which was significantly different (at P=0.03) from the 5.2% among placebo patients.

Three patients in the active-regimen group dropped out owing to adverse events including one patient with a serious renal adverse event that investigators thought was not related to the study drugs, Zeuzem reported.

Hemoglobin declines of grade 2 (from 8 to less than 10 grams per deciliter) and grade 3 (6.5 to less than 8) were observed in 4.7% and 0.3% of 3D patients, respectively, but none stopped treatment owing to anemia, he said.

"It's a very important study," Aghemo told reporters, "because it shows that previous treatment failure can be overcome with the 3D regimen with "incredibly high SVR rates (and) an excellent safety profile."

Both studies were supprted by AbbVie.

Feld disclosed relevant relationships with the company, as well as with Boehringer Ingelheim, Gilead Sciences, Vertex Pharmaceuticals, Achillion Pharmaceuticals, Bristol-Myers Squibb, Idenix Pharmaceuticals, Janssen Pharmaceuticals, Merck, Roche, and Santaris Pharma.

Zeuzem disclosed relevant relationships with the company, as well as with Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Vertex Pharmaceuticals, Idenix Pharmaceuticals, Janssen Pharmaceuticals, Merck, Roche, Novartis, and Santaris Pharma.

Aghemo disclosed relevant relationships with Gilead, AbbVie, Janssen, Merck, and Roche.

Primary source: New England Journal of Medicine
Source reference: Feld JJ, et al "Treatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin" N Eng J Med 2014; DOI: 10.1056/NEJMoa1315722.

Additional source: New England Journal of Medicine
Source reference:Zeuzem S, et al "Retreatment of HCV with ABT-450/r–ombitasvir and dasabuvir with ribavirin" N Eng J Med 2014; DOI: 10.1056/NEJMoa1401561.


Also See: AbbVie to Present Detailed Phase III Results from SAPPHIRE-I and SAPPHIRE-II Studies in Chronic Hepatitis C Patients at the 2014 International Liver Congress™

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