FDA Panel Recommends Approval of Simeprevir for Hepatitis C

Troy Brown, RN

October 24, 2013

An advisory committee to the US Food and Drug Administration (FDA) unanimously recommended simeprevir (Janssen) for the treatment of chronic hepatitis C virus (HCV) genotype 1 (GT1) infection, combined with peginterferon alfa and ribavirin in adults with compensated liver disease (including cirrhosis) who are treatment naïve or who have failed previous interferon therapy with or without ribavirin.

Simeprevir is an HCV protease inhibitor, and if approved it will be the third HCV protease inhibitor approved in the US. Boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals, Inc) were approved in 2011, according to background information provided by the FDA. The proposed dose is 150 mg once daily, in combination with peginterferon alfa and ribavirin.

"We clearly need better drugs, and the evidence is strong that this is a better drug than we have," voting member Curt H. Hagedorn, MD, Chief, Medicine Service, at Central Arkansas Veterans Healthcare Service, in Little Rock, Arkansas, noted.

The vote follows a discussion of data from 3 phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in patients with chronic HCV GT1. Patients in the treatment groups (N = 781) were given simeprevir 150 mg daily for 12 weeks plus peginterferon and ribavirin (PR) for 12 weeks, followed by PR only for either 12 or 36 weeks based on the individual's virologic response to therapy. Patients in the control groups (N = 397) were given placebo for 12 weeks combined with PR for 48 weeks.

Those in trials C208 and C216 were treatment-naïve, and those in HPC3007 had received 24 weeks or more of a pegylated interferon-based treatment and had relapsed within 1 year after the last medication dose. Efficacy data from C208 and C216 were pooled because the studies were nearly identical in design.


The trials' primary endpoint was sustained virologic response 12 weeks after the anticipated end of treatment (SVR12), which was defined as an undetectable HCV RNA at treatment end and HCV RNA < 25 IU/mL 12 weeks after the anticipated end of treatment.

The pooled results from C208 and C216 showed an SVR12 rate of 80% in the treatment group and 50% in the control group. For the relapsed patients in HPC3007, the SVR12 rate was 79% in the treatment group and 36% in the control group.

Secondary endpoints for all 3 trials included SVR24 and SVR 72. Both endpoints correlated well with the primary endpoint of SVR12, but data were incomplete at the week 60 data cut-off.

SVR rates were lower in patients with a high baseline viral load, advanced disease on liver histology (bridging fibrosis and cirrhosis), older age, African American ethnicity, and absence of the IL28B CC genetic polymorphism.

The presence of the Q80K HCV GT1a polymorphism (commonly found in GT1a patients in the US) at baseline had a substantial impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. In HPC3007, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group.

In those without the Q80K polymorphism, the SVR12 rates were 84% in the treatment groups vs 43% in the control group for the 2 pooled trials, and 78% in the treatment group vs 24% in the control group for the relapser trial. The committee recommends screening all patients with GT1a infection for the Q80K viral polymorphisms before initiating simeprevir (combined with pegylated interferon and ribavirin) and considering alternative treatment options for those with this polymorphism.

SVR12 rates were significantly higher in the simeprevir arm compared with the placebo arm in all other subgroup analyses.

Mean simeprevir area under the concentration-time curve 24-h postdose (AUC24h) values were 2.4 and 5.2-fold higher, respectively, in HCV-uninfected subjects with moderate or severe hepatic dysfunction compared with healthy controls. Mean simeprevir AUC24h values were also approximately 3.4-fold higher in HCV infected patients of East Asian ancestry compared with the pooled phase 3 population, which was about 91% Caucasian. For this reason, the committee would like to see additional studies in patients of East Asian origin.


A total of 4 deaths occurred in the treatment groups, and they were judged to be unrelated to treatment.

In the pooled analysis, 2% of those in the simeprevir group had serious adverse events, versus 3% of those in the control group during the initial 12 weeks. A total of 3 patients (0.4%) in the simeprevir group had significant adverse events, which were determined to be related to simeprevir by the study investigator; 1 patient experienced major depression and 2 patients experienced photosensitivity reactions.

Other common adverse events were rash (218 [28%] treatment groups; 79 [20%] control groups), influenza like illness (203 [26%] treatment groups; 84 [21%] control groups), pruritis (168 [22%] treatment groups; 58 [15%] control groups), and nausea (173 [22%] treatment groups; 70 [18%] control groups).

"I think this is a great opportunity at treating more HCV infected patients," said voting member Amanda H. Corbett, PharmD, BCPS, FCCP, a clinical associate professor at the University of North Carolina at Chapel Hill's Eshelman School of Pharmacy.

"Efficacy was clearly demonstrated and the safety profile is clearly favorable," explained voting member Thomas P. Giordano, MD, MPH, an associate professor of medicine at Baylor College of Medicine, medical director of HIV services at Harris Health System, and a research scientist at HSR&D Center of Excellence, Michael E. DeBakey VA Medical Center, in Houston, Texas.

Several committee members remarked on the need for postmarketing studies in racial and ethnic minorities, patients coinfected with HIV, and other underrepresented populations. A number of members suggested that the FDA should be more proactive with the pharmaceutical industry at the beginning of the clinical trial process to ensure a more diverse study population that more accurately represents the clinical population being studied.

The committee members have disclosed no relevant financial relationships.

US Food and Drug Administration (FDA)-Antiviral Drugs Advisory Committee Meeting. FDA Briefing, Janssen Briefing


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