FDA panel unanimously backs Gilead's hepatitis C drug sofosbuvir

The FDA Antiviral Drugs Advisory Committee  reviewed  Gilead's Sofosbuvir on October 25 and Johnson & Johnson's Simeprevir on October 24.  Both drugs have won support from the committee for approval by U.S. health regulators. The FDA is scheduled to decide whether to approve sofosbuvir by Dec. 8, and simeprevir by Nov. 27.

Panel recommends FDA approve sofosbuvir for hepatitis C

Oct 25

The FDA’s Antiviral Drugs Advisory Committee today recommended approval of sofosbuvir, a first-in-class, once-daily oral nucleotide inhibitor from Gilead Sciences, for treatment of chronic hepatitis C virus genotypes 1, 2, 3 and 4.

The panel voted unanimously and enthusiastically in support of approving sofosbuvir in combination with ribavirin for treatment of HCV GT 2 and 3 in adult patients.

“This is a game-changer,” committee member Marc G. Ghany, MD, MHSc, staff physician with the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said.

The panel also voted 15-0 but offered more reservations in support of approving sofosbuvir in combination with pegylated interferon and ribavirin (PR) for treatment of HCV GT 1 and 4 in treatment-naive patients.

“I was hesitant to give approval for a one-arm study,” committee member Dean Follmann, PhD, chief, biostatistics research branch, National Institute of Allergy and Infectious Diseases, said. “The 90% success rate is what really made me comfortable with this.”

The votes followed a discussion on a series of phase 3 studies of a sofosbuvir-based regimen, generally of 12 to 16 weeks, that demonstrated similar or superior effectiveness to current treatment options at primary endpoint of sustained virologic response (SVR) at 12 weeks.

The committee also discussed, but did not vote, on whether evidence supported sofosbuvir in combination with PR for treatment of chronic hepatitis C in patients with GT 1 infection who are nonresponders to a prior course of PR.

Studies did not directly analyze this patient population, but the FDA presented extrapolated data that suggested about 75% of treatment-experienced patients might respond positively to the therapy.

Several committee members expressed concern over the lack of real data, while others suggested it was a risk worth taking.

Thomas P. Giordano, MD, MPH, associate professor of medicine at Baylor College of Medicine, questioned whether voicing approval was appropriate.

“Clinicians are going to do what they have to do to take care of their patients, but the agency’s responsibility is at a different level,” he said.

On the discussion of whether evidence supported use of sofosbuvir in combination with ribavirin in hepatocellular carcinoma patients meeting Milan criteria awaiting liver transplantation, panel Chairman Yoshihiko Murata, MD, PhD, division of infectious diseases, University of Rochester School of Medicine and Dentistry, said there was a consensus among the panel on the need to treat this population.

“It’s work in progress, but it’s work that has to be done,” Donald J. Alcendor, PhD, associate professor, department of microbiology and immunology at Meharry Medical College, said.
Source - Healio

FDA Advisory Committee Supports Approval of Gilead's Sofosbuvir for Chronic Hepatitis C Infection

Date(s): 25-Oct-2013 4:43 PM

- Final FDA Decision on Sofosbuvir Anticipated by December 8, 2013

FOSTER CITY, Calif.--(BUSINESS WIRE)--Oct. 25, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) has voted unanimously (15-0) that the available data support approval of the once-daily nucleotide analogue sofosbuvir in combination with ribavirin for the treatment of chronic hepatitis C in adult patients with genotype 2 and 3 infection. Committee members also voted unanimously (15-0) that the available data support approval of sofosbuvir in combination with pegylated interferon and ribavirin for the treatment of chronic hepatitis C in treatment-naïve adult patients with genotype 1 and 4 infection.

   
The recommendations of the Advisory Committee are not binding, but will be considered by FDA as the agency completes its review of Gilead's New Drug Application (NDA) for sofosbuvir. Gilead submitted the NDA on April 8, 2013 and was granted a priority review. The FDA also granted sofosbuvir a Breakthrough Therapy designation. The FDA grants Breakthrough Therapy designation and priority review status to drug candidates that may offer major advances in treatment over existing options. A target review date of December 8, 2013 has been set under the Prescription Drug User Fee Act (PDUFA). Applications for marketing approval of sofosbuvir are also pending in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey.
   
The sofosbuvir NDA is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, in which 12 or 16 weeks of sofosbuvir-based therapy was found to be superior or non-inferior to currently available treatment options or historical controls, based on the proportion of patients who had a sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). During the review, data from an additional Phase 3 study, VALENCE, were filed to the NDA. In this study, patients with genotype 3 HCV infection were treated with sofosbuvir and ribavirin for 24 weeks. Patients who achieve SVR12 are considered cured of HCV.
   
About Sofosbuvir
Sofosbuvir is a nucleotide analogue inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. Sofosbuvir is a direct-acting agent, meaning that it interferes directly with the HCV life cycle by suppressing viral replication. Sofosbuvir is an investigational product and its safety and efficacy have not been established.
   
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.
   
Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that FDA, EMA and other regulatory agencies may not approve sofosbuvir in the currently anticipated timelines or at all, and that any marketing approvals, if granted, may have significant limitations on their use. In addition, future studies of sofosbuvir, including in combination with other products, may not produce favorable results. Further, even if approved, Gilead may not be able to successfully commercialize sofosbuvir, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
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FDA panel unanimously backs Gilead's hepatitis C drug sofosbuvir

By Toni Clarke

WASHINGTON Oct 25 (Reuters) - A federal advisory panel recommended on Friday that the U.S. Food and Drug Administration approve Gilead Sciences Inc's experimental hepatitis C drug sofosbuvir, paving the way for a treatment that is more effective than current therapies and takes less time.

The FDA advisory panel voted 15 to 0 in favor of approval of the drug in patients with two variants of the liver-damaging disease - genotype 2 and genotype 3 - in combination with an existing treatment, ribavirin.

If approved, it will be the first all-oral treatment for genotypes 2 and 3, obviating the need for the injectable drug interferon, which can cause debilitating side effects. Panelists called the vote "historic" and a "game-changer."

"Our patients have been waiting for this for a long time," said Dr. Curt Hagedorn, chief of medicine service at the Central Arkansas Veterans Healthcare Service.

The panel also voted unanimously to approve the drug in patients with genotype 1 and genotype 4 variants in combination with ribavirin and interferon in patients who have not received prior therapy.
Genotype 1 accounts for roughly 70 percent of hepatitis C cases. The FDA is not bound to follow the advice of its panels but typically does so.

"We'd already built in 100 percent chance of approval into our valuation for the company," said Karen Andersen, an analyst at Morningstar. "Gilead is still really in the prime position looking ahead in the hepatitis C market."

Panelists also appeared to support the use of sofosbuvir in patients who failed prior treatment, even though the company has little hard data to support such a claim.
"I did think there was a surprise upside result by the end of the panel," said Michael Yee, an analyst at RBC Capital Markets.

Bristol-Myers Squibb Co and Abbvie Inc have advanced all-oral clinical trial programs in late-stage development, using a variety of so-called direct acting antivirals, which directly interfere with the virus's ability to replicate. But Gilead is widely seen to be in the lead.

Chronic hepatitis C affects at least 3 million people in the United States, according to the U.S. Centers for Disease Control.

Analysts on average expect Gilead's drug to generate sales of $1.73 billion in 2014, according to Thomson Reuters data.

Current standard treatments for genotype 1 often include a protease inhibitor. These are oral drugs that include Merck & Co Inc's Victrelis and Vertex Inc's Incivek.
Gilead acquired sofosbuvir, known as a nucleotide analogue inhibitor, with its $11 billion purchase of Pharmasset Inc in 2012.

Panelists urged Gilead to make the drug available to other companies to study in combination with other oral regimens waiting in the wings.
Bristol-Myers is expected to present data from a late-stage clinical trial of its interferon-free treatment of genotype 1 patients at next month's meeting of the American Association for the Study of Liver Diseases in Washington, D.C.

The FDA is due to rule on whether to approve the drug by Dec. 8.
http://www.reuters.com/article/2013/10/25/gilead-hepatitisc-idUSL1N0IF1JN20131025

Hepatitis C: CHMP Backs 'Compassionate Use' of Sofosbuvir

Miriam E. Tucker

The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) has issued a "compassionate use" opinion for Gilead Sciences Inc's antiviral drug sofosbuvir in patients who have chronic hepatitis C virus (HCV) infection and who are awaiting a liver transplant or have already received one.

This is the third time the CHMP has used the compassionate use designation for a drug. Set up at the national level, compassionate use programs aim to give patients with life-threatening, chronic, or seriously disabling disease who do not have other treatment options access to drugs that are still under development or consideration and that have not yet been authorized for wider use.

Sofosbuvir, an NS5B polymerase inhibitor, is currently under evaluation by the EMA for wider use in patients with chronic HCV. In the meantime, Sweden had requested a CHMP opinion for use of the antiviral in combination with other agents specifically in patients before or after liver transplantation.

In the United States, sofosbuvir is being discussed today at a US Food and Drug Administration advisory committee hearing for the treatment of chronic HCV infection in combination with other agents in adult patients with genotypes 1 to 6 and/or adult patients awaiting liver transplantation.

HCV infection occurs in 0.4% to 3.5% of the population in different EU member states and is the most common single cause of liver transplantation in the European Union. There is currently no standard therapy for patients with chronic HCV who are awaiting transplantation or who have already received a liver transplant, and there are no approved treatments for most of these patients.

"Many patients with HCV infection in the pre- and post-transplant setting are therefore in urgent medical need of therapy to prevent graft reinfection or to treat recurrent HCV infection in the graft," the EMA said in a statement.

The CHMP opinion is intended to ensure a common approach for member states that are considering setting up a compassionate use program. It is not mandatory. An assessment report and conditions of use of sofosbuvir in this setting will be published shortly on the agency's Web site, the EMA says.
Medscape Medical News

FDA Panel Backs HCV Drugs

Published: Oct 25, 2013

By Michael Smith, North American Correspondent, MedPage Today

An FDA committee has unanimously supported approval of both simeprevir and sofosbuvir, drugs that act directly against hepatitis C (HCV).

The Antiviral Drugs Advisory Committee voted 19-0 to recommend approval of simeprevir, in combination with pegylated interferon and ribavirin, as suitable for treatment of patients with genotype 1 HCV.

The committee voted 15-0 to support approval of sofosbuvir in combination with ribavirin for treatment of patients with genotype 2 and 3 HCV.
And, by the same margin, the committee supported approval of the drug, in combination with pegylated interferon and ribavirin, for patients with genotype 1 and 4 infection.
If the agency agrees with the advice, simeprevir and sofosbuvir will be the first new HCV drugs approved since 2011.

The FDA is not bound to take the advisory committee's advice but usually does so.
The two drugs are the first in an anticipated wave of second-generation, direct-acting agents for the disease, which chronically afflicts about 3.2 million Americans.

For years, the standard therapy for hepatitis C was a combination of pegylated interferon-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, while sofosbuvir -- a nucleotide analog NS5B polymerase inhibitor -- would be the first in its class to get the nod.
The simeprevir application was based on efficacy results from three placebo-controlled phase III trials, two in treatment-naive patients and one in patients who had relapsed after interferon-based therapy.

In all three trials, the primary endpoint was the proportion of patients with undetectable virus 12 weeks after the end of therapy -- the so-called SVR₁₂.
Among 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.
Among relapsers, the SVR₁₂ rates were 79% in the simeprevir group and 36% among placebo patients.

In genotypes 2 and 3, regarded as relatively easy to treat, the sofosbuvir application was based on several studies of the drug in combination with ribavirin, a general anti-viral medication.
In some cases, the study evaluated efficacy over different treatment durations, while in others, the combination was compared with placebo or peginterferon and ribavirin.
An open-label trial evaluated the drug in patients with other genotypes, including the difficult-to-treat genotype 1, using sofosbuvir in combination with ribavirin and peginterferon, an immune system booster.

FDA reviewers, summarizing the data for genotypes 2 and 3 in briefing documents before the advisory committee meeting, said the combination of sofosbuvir and ribavirin was both efficacious and safe and would be the first all-oral, interferon-free treatment for HCV, if approved.

As well as efficacy, the combination offers a shorter treatment duration and improved safety profile compared with interferon-based regimens, the current standard of care, the reviewers concluded.
On the other hand, sofosbuvir appeared to offer better efficacy in patients with genotype 2 than in those with genotype 3, they noted.

It would also address an unmet need -- therapy for patients ineligible for, intolerant of, or unwilling to take interferon-based regimens.

Among those with HCV genotypes 1 and 4, the reviewers argued, sofosbuvir plus pegylated interferon and ribavirin would offer increased efficacy and shorter treatment than currently approved regimens.

But the available data were not sufficient to make definite dosing recommendations for patients with genotypes 5 or 6, the reviewers concluded.
Source

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FDA Revised Draft Guidance on Hepatitis C Drug Development
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