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First Interferon-Free HCV Regimen Gets Unanimously Positive Vote

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By Catherine Shaffer
Staff Writer

The FDA’s Antiviral Drugs Advisory Committee voted 15 – 0 to recommend approval of Gilead Sciences Inc.’s sofosbuvir for genotype 2 and 3 hepatitis C virus (HCV) patients and for treatment-naïve genotype 1 and 4 patients.

The history-making vote for the first interferon-free HCV regimen passed with very little fireworks, as the committee agreed Gilead had done its homework in showing the drug was safe and effective for its intended use.

The Foster City, Calif.-based company supported its application with four Phase III studies of the drug in combination with ribavirin or with ribavirin and pegylated interferon in patients with six different genotypes of virus. The agency’s questions for the committee include straightforward discussion and voting questions related to safety and efficacy of the drug in the various trials, and whether postmarketing studies are needed for its optimal use.

Interferon-free regimens for HCV have been hotly pursued due to the side effects of interferon. The standard treatment for HCV for many years has been pegylated interferon-alpha and ribavirin. The therapy, often given over a period of many months, only cures about 50 percent of patients. In 2011, the FDA approved two new protease inhibitor therapies, Johnson & Johnson’s Incivek (telaprevir) and Victrelis (boceprevir, Merck & Co. Inc.), and although those drugs were approved for use in combination with interferon and ribavirin, the introduction of a new class of therapeutics was considered an important step toward the ultimate goal of an all-oral, interferon-free regimen.

And yet, after two years’ intense competition, preparation and analysis, the big moment was nearly anticlimactic, as the committee handed in its recommendation with very little debate or question.

The discussion focused mainly on pre-transplant patients and extrapolation of sustained viral response (SVR) rates from genotype 1 treatment-naïve patients from Gilead’s NEUTRINO trial to genotype 1 treatment-experienced patients, because the panel lacked data for the latter group.

“Our patients have been waiting for this for a long time,” said panel member Curt H.Hagedorn, a gastroenterologist and professor of medicine from the University of Arkansas, as the yes votes racked up.

On the second voting question, for use of the drug in treatment-naïve genotype 1 and 4 patients, some panel members voted yes, but expressed some hesitation over approval of the drug in that indication on the basis of a single, one-arm study. However, the data from that study were unusually strong.

In that Phase III, open-label trial (NEUTRINO) in 327 patients with genotypes 1, 4, 5 or 6 HCV, 90 percent achieved SVR after 12 weeks (SVR12).

Worldwide, about 210 million people are infected with HCV, and more than 350,000 die from HCV-related liver disease each year. The World Health Organization classifies HCV into 11 major genotypes, plus a number of subtypes. Genotypes 1-3 are widespread globally. Types 1a and 1b are most common, accounting for about 60 percent of all infections.

Sofosbuvir was granted fast track designation and priority review status from the FDA. The drug is widely expected to be a blockbuster.

Other entrants in the race to develop interferon-free HCV regimens have suffered setbacks recently. The FDA imposed a partial clinical hold on an ongoing Phase II study of Vertex Pharmaceuticals Inc.’s HCV candidate VX-135, due to observations of elevated liver enzymes in patients receiving the highest dose of 400 mg. Vertex was able to continue its trial of VX-135 at the 100 mg dose, however. (See BioWorld Today, July 29, 2013.)

Achillion Pharmaceuticals Inc. also was sidelined by a clinical hold on its HCV drug, sovaprevir, due to elevated liver enzymes. The company is moving forward with its other oral HCV combinations. (See BioWorld Today, Oct. 1, 2013.)

Sofosbuvir to Line Up Against Simprevir

The decision on sofosbuvir follows a 19 – 0 vote in favor of approval of Janssen Pharmaceutical Co.’s application for simeprevir on Thursday. Simeprevir is an NS3/4A protease inhibitor developed for treatment of HCV genotype 1 infection.

The committee agreed that the benefits of simeprevir outweighed its risks, and that it is an improvement over currently available therapies, including boceprevir and telaprevir.

Because simeprevir’s safety profile includes rash and photosensitivity reactions, the committee advised that a recommendation should be included in the drug labeling for sun protection. Panel members were uncertain whether treatment should be discontinued in the event of a photosensitivity reaction, and agreed therefore that that decision should be left to physician and patient.

The committee also endorsed the FDA’s plan to recommend screening of all subjects with genotype 1a infection for the Q80k viral polymomrphism before initiating simeprevir therapy.

Simeprevir and sofosbuvir are expected to compete in the marketplace, but simeprevir’s weakness in the Q80k mutation may give the edge to sofosbuvir. “Regardless of whether the label contains a contraindication against using simeprevir in Q80K or just a recommendation to consider other options, and regardless of exactly how prevalent the polymorphism is globally, the fact that there exists a reasonably sized group that derives considerably less efficacy from simeprevir-based regimens we believe still confers an advantage to GILD’s sofosbuvir – which should have no such liabilities/pre-screening requirements,” wrote Wells Fargo analyst Brian Abrahams in a research note.

Shares of Gilead (NASDAQ:GILD) closed Friday at $69.68, down 15 cents.