By John Gever, Deputy Managing Editor, MedPage Today
Published: April 25, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
AMSTERDAM -- Treatment-naive patients with hepatitis C virus (HCV) infection showed high viral cure rates when treated with simeprevir, an investigational once-daily oral drug, along with standard therapy, researchers said here.
Sustained 12-week virologic responses (SVR12), defined as viral loads too low to be measured, occurred in eight out of 10 patients with HCV genotype 1 receiving simeprevir in two identical, placebo-controlled phase III trials conducted in the U.S. and Europe, according to presentations at the annual meeting of the European Association for the Study of the Liver.
All patients in these trials also received standard anti-HCV treatment with pegylated interferon and ribavirin for 24 or 48 weeks. SVR12 rates in the trials' placebo groups were 50% in both cases (P<0.001 versus the simeprevir groups).
Simeprevir is an orally active, second-generation inhibitor of the HCV NS3/4A protease. Two first-generation products, boceprevir (Victrelis) and telaprevir (Incivek), were approved in 2011. Both have significant disadvantages: they must be taken three times a day, and telaprevir has been linked to life-threatening skin rashes while boceprevir can cause serious anemia.
As a result, drug firms have been working to develop HCV protease inhibitors with better safety profiles and that can be given just once a day.
Each of the phase III simeprevir studies randomized approximately 400 treatment-naive HCV patients in a 2:1 ratio to 150 mg of the drug or placebo in addition to peginterferon and ribavirin.
Both trials were designed to use "response-guided therapy," under which patients achieving viral loads of less than 25 IU/mL at week four and and below detection limits at week 12 had the peginterferon and ribavirin stopped at week 24. Those showing responses short of these standards continued on treatment through week 48.
Patients with poor responses (less than a two-log reduction in HCV viral loads by week 12 or confirmed loads of at least 25 IU/mL at weeks 24 or 36) were taken off the study.
Results of the U.S. trial, called QUEST-1, were reported by Ira Jacobson, MD, of Weill Cornell Medical College in New York City, and colleagues. Not only did simeprevir meet the study's primary endpoint of superiority over placebo in SVR12 rates, but it also was highly effective against the hard-to-treat genotype 1a form of the virus.
Additionally, it was better than placebo in patients with all three IL28B genotypes, although response rates were especially high with the drug in patients with the TT and CT forms of the gene. Responses to simeprevir were also equally good irrespective of METAVIR score, which measured liver fibrosis and inflammation.
The only subgroup for whom simeprevir was not more effective than placebo was patients with genotype 1a and the so-called Q80K polymorphism, Jacobson and colleagues indicated.
Results were closely similar in the European QUEST-2 trial, according to data reported at a press conference prior to the study's formal presentation later this week.
Adverse events in both trials were similar in number in the active-drug and placebo groups. In QUEST-2, rates of skin rash and photosensitivity were somewhat higher with simeprevir versus placebo, but those events were not increased with the drug in QUEST-1.
Conversely, anemia, neutropenia, and elevated bilirubin appeared more common with simeprevir in QUEST-1, but not in QUEST-2.
Other efficacy data from QUEST-1 were as follows:
- Patients taken off study for poor virologic response: 7% simeprevir, 66% placebo
- Simeprevir patients qualifying for shortened peginterferon/ribavirin treatment: 85%
- Patients with undetectable virus at week four: 80% simeprevir, 12% placebo
Jacobson and colleagues also reported that SVR12 rates were nearly as great in patients with HCV genotype 1a as in those with the more responsive 1b genotype. However, most of the responses in the 1a patients occurred in those without the Q80K polymorphism, for whom the SVR12 rate was the same with simeprevir as with placebo.
Relatively poor simeprevir responses were also seen in patients with emergent mutations in the Ns3 protease at position 155 in genotype 1a and at position 168 in genotype 1b.
Press briefing co-moderator Mark Thursz, MD, of St. Mary's Hospital in London, commented that the data suggest that simeprevir and other second-generation products have succeeded in surpassing boceprevir and telaprevir.
"With the new protease inhibitors, [the side effect profile] seems to be better, more patients get shorter periods of treatment, and more patients get cured," he said.
A third trial of simeprevir in HCV patients previously treated with other drugs is ongoing, Jacobson and colleagues indicated.
The drug's manufacturer, the Janssen unit of Johnson & Johnson, applied last month for U.S. marketing approval of simeprevir to be given with peginterferon and ribavirin. It also has applications in the works in Japan and the European Union.
Both studies were funded by Johnson & Johnson's Janssen unit.
Study authors declared that they had relationships with unspecified commercial entities that could be perceived as having a connection to the studies. Both included investigators who were Janssen employees.
Primary source: European Association for the Study of the Liver
Source reference:
Jacobson I, et al "Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1, a phase III trial" EASL 2013; Abstract 1425.
Additional source: European Association for the Study of the Liver
Source reference:
Manns M, et al "Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial" EASL 2013; Abstract 1413.
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