Infectious Disease
Published: Oct 23, 2013
By Michael Smith, North American Correspondent, MedPage Today
An FDA advisory committee is set to debate the merits of two new agents that act directly against hepatitis C (HCV) -- the first such agents to come before the agency since 2011.
Simeprevir and sofosbuvir are also the first in an anticipated wave of second-generation, direct-acting agents for the disease, which chronically afflicts about 3.2 million Americans.
The agency's Antiviral Drugs Advisory Committee will vote on whether to recommend approval of simeprevir on Thursday and sofosbuvir on Friday.
For many years, the standard therapy for hepatitis C was a combination of peginterferon-alfa and ribavirin, drugs that are regarded as both difficult and dangerous to take.
In 2011, the FDA approved the first agents that act directly against the virus itself -- the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).
Simeprevir, another protease inhibitor, would be the third drug in the class if it passes the advisory committee's scrutiny. The FDA usually follows the guidance of its advisory committees but is not bound to do so.
Sofosbuvir, on the other hand, is a member of another class -- the nucleotide analog NS5B polymerase inhibitors. It would be the first in its class to get the nod, if the FDA approves it.
The makers of simeprevir, Janssen Research and Development, are asking for an indication to use the drug, in combination with peginterferon and ribavirin, in HCV genotype-1 patients who are either treatment-naive or who have failed previous interferon-based therapy.
The application is based on efficacy results from three placebo-controlled phase III trials, two in treatment-naive patients and one in patients who've relapsed. The primary endpoint in all three studies was the proportion of patients with undetectable virus 12 weeks after the end of therapy -- the so-called SVR12.
In pooled data for treatment-naive patients, the SVR12 rate was 80% among those getting all three drugs and 50% among those in the control group, who got placebo along with interferon and ribavirin.
In the trial among relapsers, the SVR12 rates were 79% in the simeprevir group and 36% among placebo patients.
In patients with genotype-1a, however, the presence of a relatively common genetic variant -- the Q80K polymorphism in the viral protease -- reduced the efficacy of the drug to the point where it was no longer statistically better than placebo.
The FDA reviewers recommended that if the drug is approved, prospective patients with genotype-1a disease should be screened for the variant and treated with other drugs if they have it. The efficacy of both telaprevir and boceprevir is unimpaired by the Q80K polymorphism.
FDA reviewers were also concerned about reports of photosensitivity and rash among patients taking the drug.
Gilead Sciences, the developer of sofosbuvir, is seeking an indication to use the drug, in combination with either ribavirin or with peginterferon and ribavirin, in patients with genotypes 1 through 6 of the HCV, as well as in adult patients awaiting liver transplant.
FDA staff reviewers said available data support a favorable benefit-risk assessment for sofosbuvir as part of a combination regimen for HCV. Also, the reviewers noted that the drug could form the basis, for the first time, of all-oral regimens for HCV.
There were no major safety issues associated with sofosbuvir, they concluded.
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