Hep Talk by Larry Buhl
New direct-acting antivirals cross a major hurdle
The Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) in October gave unanimous recommendations for approval of two next-generation direct-acting antivirals (DAAs) for hepatitis C, Janssen’s simeprevir (Johnson & Johnson), and Gilead Science’s sofosbuvir.
The FDA committee approved sofosbuvir, a nucleotide inhibitor, as both an interferon add-on and for use in an interferon-free regimen for people with easier-to-treat HCV genotypes 2 or 3, which would make it the first approved interferon-free regimen and an option for patients who are ineligible, intolerant or unwilling to take interferon-based regimens.
Simeprevir, a protease inhibitor, was approved for use only in interferon-based therapy, at a dose of 150 mg once-daily for genotype 1 hep C patients, either treatment-naive or prior non-responders, with compensated liver disease including cirrhosis.
Approval for simeprevir was supported by data from the pivotal Phase 3 QUEST-1 and QUEST-2 trials in treatment-naive patients and PROMISE in patients who relapsed after prior interferon-based therapy, as well as data from the Phase 2b ASPIRE study in prior non-responders. Simeprevir is less effective among people with subtype 1a HCV carrying the Q80K mutation.
The committee’s sofosbuvir recommendation covers both use with interferon-based therapy for treatment-naive people with HCV genotypes 1 or 4 and use in dual therapy with ribavirin for people with genotypes 2 or 3 with the HCV NS5A inhibitors daclatasvir and ledipasvir.
However, neither drug was considered for use in interferon-free regimens for people with HCV genotype 1, the most common genotype for those with HCV.
Simeprevir and sofosbuvir have their strengths and weaknesses, and both companies are saying the drugs will not be going head-to-head in the battle to treat HCV.
A background report submitted to the FDA Antiviral Drugs Advisory Committee concluded that simeprevir in combination with pegylated interferon-alpha and ribavirin was superior to placebo in achieving a sustained virologic response in treatment-naive patients with HCV. But the report also concluded that a subpopulation of HCV patients—those with genotype 1a and a Q80K polymorphism—responded similarly to controls in the late-stage study. When data from two Phase 3 trials were pooled together, patients with the Q80K polymorphism didn’t benefit from simeprevir, according to the advisory committee meeting materials. Specifically, the sustained viral response over twelve weeks, or SVR12, for Q80K patients was a statistically insignificant fifty-eight percent versus fifty-five percent for the control arm. That could mean that simeprevir will be able to treat fewer people than originally thought.
Across Gilead’s trials, twelve-week dosing of simeprevir wasn’t as successful in patients with genotype 3 as those with genotype 2. However, in Gilead’s FUSION Phase 3 trial, extending treatment to sixteen weeks produced a much better outcome, with the SVR jumping to sixty-two percent at week 16 from thirty-eight percent at week twelve. That means HCV3 patients treated with sofosbuvir will likely have a longer treatment period.
One drug expert, Todd Campbell of the Motley Fool, gives sofosbuvir a competitive advantage over simeprevir once they’re commercialized, due to simeprevir’s Q80K difficulties, and the ability of sofosbuvir to treat a lest some patients as part of an all-oral therapy.
“The absence of peg-interferon injections marks a big step forward in removing significant hurdles faced by patients who are either unwilling, or unable, to tolerate interferon,” he said.
Then again, most people with hepatitis C—including the common HCV 1 genotype—will still have to rely on peg-interferon no matter which DDA they choose. Even so, their treatment duration is expected to drop to twelve weeks when peg-interferon is combined with either sofosbuvir or simeprevir. That’s good news, because a shorter treatment time will help mitigate some of the serious side effects.
Final decisions from the full FDA about approval of simeprevir and sofosbuvir are expected by the end of the year. Although the FDA is not required to follow its advisory committees’ recommendations, it almost always does so.
That would mean simeprevir and sofosbuvir shortly join two DDAs, boceprevir (Victrelis) and telaprevir (Incivek), by early next year. Victrelis and Incivek have been available for almost two years and, when used with pegylated interferon and ribavirin, have dramatically shortened treatment duration and raise sustained virological response rates—even though they do come with side effects.
Several next-generation DAAs in the pipeline (see Hep Talk, October 2012) promise to be even more effective, more convenient and better tolerated. While the earliest such drugs will still be used as add-ons to interferon-based therapy, all-oral, interferon-free regimens are expected to become available within the next couple of years. That’s excellent news for the big and growing pool of people with HCV. The World Health Organization estimates around 170 million are infected worldwide with 2.7 million chronic cases in the U.S. Roughly 20,000 to 30,000 new cases are diagnosed in the U.S. each year.
Larry Buhl is a radio news reporter, screenwriter, and novelist living in Los Angeles. His young adult novel, The Genius of Little Things, debuted in January 2013.