October 25, 2013

FDA Issues Revised Draft Guidance on Hepatitis C Drug Development

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The Food and Drug Administration (FDA) has published draft guidance to assist sponsors in the clinical development of direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C (CHC) from the initial pre­-investigational new drug application (pre-IND) through the new drug application (NDA) and postmarketing stages.

You can read the draft guidance at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf

Although comments on guidance may be submitted at any time, to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance, please  submit either electronic or written comments on the draft guidance by December 23, 2013.

Comments may be submitted electronically at http://www.regulations.gov. Alternatively, written comments can be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

This guidance revises the draft guidance for industry entitled “Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment” issued in September 2010. Significant changes in this revision include:

  • Details on phase 2 and phase 3 trial design options for the evaluation of interferon (IFN)-free and IFN-containing regimens in treatment-naïve and treatment-experienced populations, including DAA-experienced populations.
  • Revised primary endpoint to sustained virologic response at 12 weeks post-treatment cessation.
  • Greater emphasis on DAA drug development in special populations including trial design options for human immunodeficiency virus/hepatitis C virus co-infected patients, patients with decompensated cirrhosis, and patients pre- or post-liver transplant.
  • More details on clinical virology considerations for DAA drugs.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

FDA has created a Patient Network web site, designed from the ground up for patients and patient advocates. It provides information on what FDA does, and various topics of interest to patients, including opportunities to comment on a variety of regulatory issues like this one.

A New Day

Hopkins Medicine Magazine Fall 2013


The new therapies are arriving at a crucial time, says Mark Sulkowski. “We’re just now getting into the peak of the impact of hepatitis C in the United States.”

Date: October 1, 2013

One day in late 1995, David Frick began to suffer severe abdominal pain. A few months earlier, he had completed a PhD in biology at Johns Hopkins, and now he was doing a postdoctoral research fellowship on the Homewood campus, studying bacterial enzymes. When the pain hit, his first assumption was that it was appendicitis. He’d go under the knife, be away from his lab bench for a week or so, and then life would return to normal.

Or so he thought. A few days later, the diagnosis arrived: Frick had hepatitis C. He had probably acquired the virus from a contaminated blood product shortly after he was born, when he received transfusions to treat a rare disorder. After 20-odd years of silent destruction, the virus had caused extensive cirrhosis in his liver. He would need a transplant.

Two years later in Boston, where he was doing a postdoc at Harvard, Frick’s liver went into severe failure, and he received his transplant. It was a grueling experience, with long weeks in a hospital bed. “But the transplant year wasn’t the worst year of my life,” Frick says today. “The worst year of my life was the following year, when I went through the treatment for hepatitis C.”

After his transplant Frick needed to try to eradicate the virus from his body, so that hepatitis C wouldn’t ruin his second liver. That meant taking what was, in the late 1990s, the cutting-edge therapy for hepatitis C: 48 weeks of injections with interferon-alfa, a synthetic version of one of the body’s common antiviral proteins. Interferon-alfa carries brutal side effects: fevers, sweats, chills, depression, fatigue. “It felt like I had the flu for nearly an entire year,” Frick says. “I’m glad I did it—I’ve been perfectly fine ever since. But that was very, very tough.”

Frick, who now studies the hepatitis C virus (HCV) at the University of Wisconsin-Milwaukee, vowed to devote the rest of his career to hepatitis C until a more effective and tolerable cure was discovered. That moment appears finally to have arrived—thanks in part to decades of effort by Johns Hopkins researchers.

In the last three years, several new classes of drugs have emerged that directly target enzymes specific to the hepatitis C virus. As early as December 2013, the FDA might approve the first-ever interferon-free therapy for certain hepatitis C patients. Within a few years, says Mark Sulkowski, medical director of the Viral Hepatitis Clinic at Johns Hopkins, the standard treatment for hepatitis C might be just 12 weeks long—or even eight—and involve no interferon. Even better, the new medications appear to be effective for almost everyone, whereas roughly 50 percent of patients have failed to respond to interferon-alfa.

“These have truly been breakthroughs,” says Sulkowski. “The treatment stands to become dramatically simpler, more effective, and easier to tolerate.” Sulkowski has waited a long time to see these victories. For nearly two decades, he has directed clinical trials of hepatitis C medications at Hopkins. While most of those drugs have been brewed in pharmaceutical companies’ private labs, Hopkins researchers have played a central role in testing their safety and efficacy, especially among vulnerable populations such as people co-infected with HIV and HCV.

The new therapies are arriving at a crucial moment, Sulkowski adds. “We’re just now getting into the peak of the impact of hepatitis C in the United States,” he says. Millions of baby boomers are believed to have been exposed to the virus via intravenous drug use, tattooing, and contaminated blood transfusions between 1965 and 1990. (Blood products have been screened for the virus since 1992, so transfusion is no longer a danger.)  Because it takes decades for the virus to do its silent damage to the liver, the national rates of cirrhosis and liver cancer have only recently begun to spike upward. Each year since 2007, hepatitis C has been estimated to kill more Americans than HIV; liver cancer is one of the few types of cancer with a rising mortality rate.

“People say, [the virus] has a very slow progression rate,” Sulkowski says. “And that’s true. It takes decades to progress. But the peak infections in the U.S. occurred 30 or 40 years ago. So, now we’ve reached the time when many people are progressing. This is a major issue right now.”

When david frick received his blood transfusions as an infant in the late 1960s, hepatitis C was an unknown concept. The year 1974 saw the first scientific publication about transfusion-related liver infections that were not caused by the familiar hepatitis A or hepatitis B viruses. But it took another decade and a half until the viral pathogen behind what was then known as “non-A-non-B hepatitis” was finally found. In April 1989, a pair of papers in Science announced the discovery and basic structure of the hepatitis C virus.

A year later, a young physician named David L. Thomas began a fellowship in infectious diseases at Johns Hopkins. Early in his fellowship, he was asked to lead a journal club discussion of the 1989 Science papers. He has been hooked on hepatitis C ever since. “It was a cutting-edge topic,” says Thomas, who is now director of the Division of Infectious Diseases at Hopkins. “But it wasn’t immediately clear what a significant public health challenge hepatitis C would turn out to be.”

Thomas, perhaps more than any other single scientist, helped alert the world to the severity of the hepatitis C problem. “We knew that it was a transfusion issue,” he says. “So it was natural to ask whether the virus could also be transmitted through other blood vectors.”

Sadly, the answer turned out to be yes. Throughout the 1990s, Thomas worked with Hopkins colleagues at the schools of Medicine and Public Health to document the alarmingly high rates of hepatitis C infection among IV drug users in Baltimore and other sites around the world. The team also studied sexual transmission (which turned out not to be a major vector), transmission during childbirth, and needle stick injuries among Johns Hopkins Hospital employees.

Those early needle stick studies became a vital source of information about the virus’s life cycle: Because Thomas and his colleagues knew almost the exact time of transmission, they could draw blood samples from the employees daily to learn how the virus evaded the human immune system during the acute phase of infection.

The studies also allowed Hopkins researchers to examine the mechanisms that allow a lucky minority of people—roughly 20 to 30 percent—to clear the virus from their systems without developing chronic infections. That line of research, which was led by Chloe Thio, an associate professor of medicine, and Priya Duggal, a geneticist at the Bloomberg School of Public Health, has helped lay the groundwork for potential vaccines.

After several years of study, a basic epidemiological portrait emerged. After exposure to the virus, between 70 and 80 percent of patients develop chronic infections. (More than 150 million people internationally, including 3.2 million in the United States, are now estimated to have chronic hepatitis C.) Of those chronic infections, between 15 and 30 percent will eventually cause liver cirrhosis, though that process can take as long as 30 years. And among hepatitis C patients who progress to cirrhosis, between 1 and 3 percent each year will develop liver cancer.

“The most alarming thing is that roughly half of the people with chronic hepatitis C in the United States have not been diagnosed,” says Scott Holmberg, chief of the epidemiology and surveillance branch of the viral hepatitis center at the Centers for Disease Control, which recently recommended that all Americans born between 1945 and 1965 be screened for the virus. “And among those who have been diagnosed, only a relatively small proportion have been treated, in part because the treatments have been so difficult to take.”

That will soon change. While his Hopkins colleagues have analyzed the virus and traced the vectors of public infection, Sulkowski has spent years leading clinical trials of potential new treatments. He has seen firsthand the side effects that made David Frick’s year of treatment so miserable. But in the last two years, Sulkowski’s team has led trials of drugs that appear to radically change the nature of treatment for hepatitis C.

“The cornerstone of hepatitis C treatment since the late 1990s has been interferon-alfa and ribavirin, a regimen that carries severe side effects,” Sulkowski says. “So what we have had, in effect, is a treatment that’s effective for many people, but toxic. And the special challenge is that hepatitis C is an asymptomatic disease, right up to the time your liver has already sustained severe damage.”

“It can be hard for people to wrap their heads around the idea that they have a potentially fatal illness,” Sulkowski continues. “They feel fine, and now you’re asking them to take medications that will make them feel sick for a year.”

In the last five years, however, several new drugs have emerged that promise radical improvements on the traditional regimen. In 2011, the FDA approved two medications—boceprevir and telaprevir—that target one of the virus’s protease enzymes, much as the cornerstone medications for HIV target that virus’s protease. Taken in combination with interferon and ribavirin, those medications have dramatically improved the proportion of patients who can completely clear the virus from their systems, from roughly 40 percent to roughly 75 percent, according to Sulkowski. But they have only added to the traditional therapy’s burden of side effects.

It is the next generation of medications that most excites Sulkowski, because they promise to do away entirely with interferon injections and ribavirin. These medications target the virus’s polymerase enzyme, which helps to assemble new strands of RNA when the virus replicates, as well as a viral protein known as NS5A. In recent clinical trials, a pair of these new agents—sofosbuvir, a polymerase inhibitor, and declatasvir, an NS5A inhibitor—have demonstrated the ability to clear the virus in almost 100 percent of patients, and they appear to be far better tolerated than the traditional therapies. Sofosbuvir was submitted to the FDA for approval this summer, with a decision expected in December.

“The flu-like symptoms of interferon are gone,” Sulkowski says. “The severe fatigue is gone. Anemia, which has been a consequence of the first protease inhibitors, is no longer a major issue. And the treatment duration has been reduced to, in some cases, 12 weeks, down from 24.”

Because the medications in the pipeline appear so promising, many physicians are urging their patients to defer treatment unless they already show signs of significant liver fibrosis. “I’m encouraging my patients to wait until the new medications come on line,” Thomas says.

“I wouldn’t take any of the old stuff,” says Lynda Dee, a Baltimore attorney who tested positive for hepatitis C several years ago. From firsthand observation of friends and acquaintances, she drew her own conclusion: “Interferon-alfa and ribavirin are a nightmare.” 

Since early tests showed that her liver had not been severely damaged, Dee decided to wait for better treatments to emerge. When she learned last year about the opportunity to participate in a clinical trial of the new antiviral drugs, she chose to sign on. “There’s always a lot of angst associated with something like that,” she says. “But it seems to have worked beautifully.”

Andrew Cameron, who directs the liver transplant program at Hopkins, also sees great promise in the new medications. Among hepatitis C patients whose livers have already deteriorated so badly that they require transplantation, the traditional therapies have usually done poorly, both before and after transplant, Cameron says. People with end-stage liver disease are especially intolerant of interferon’s side effects.

“If we can use easy-to-tolerate drugs to clear the virus or reduce the viral load before surgery, that will make a huge difference,” Cameron says. Among other things, it will broaden the range of livers available to hepatitis C patients. Traditionally, these patients have been restricted to livers from donors younger than 50 or 55, because (for reasons not well understood) the hepatitis C virus tends to roar back and quickly destroy livers from older donors. Since roughly half the transplant pool is from donors older than 55, this has been a major burden for hepatitis C patients. “We might soon be able to open up the entire range of donors to hepatitis C cases,” Cameron says. “That’s very, very exciting.”

Alongside their excitement, hepatitis researchers like Sulkowski also raise four notes of caution about the new wave of medications. One is that the drugs have not been thoroughly tested so far on some of the most medically vulnerable populations, including people who carry both HIV and HCV and those with advanced liver disease. (Clinical trials in that group are presently under way, and Sulkowski says that the early findings are promising.)

A second concern: It’s not known yet whether viral resistance will emerge as these drugs are used in real-world settings. “That’s a question that I don’t think we have much data for yet,” says Susanna Naggie, a Duke University scientist who earned her MD at Hopkins in 2002. “But the early signs are that it probably will matter. Some recent data suggested that of the people who have failed treatment on [the protease inhibitors approved in 2011], half of them have protease-related mutations in the virus.” The solution, Naggie says, will probably be to use combinations of drugs from different classes, as is done in HIV therapy.

Third, scientists hope that the apparent success of the new drugs will not slow down funding of vaccine development for hepatitis C. Andrea Cox, an associate professor at Hopkins, is currently conducting a clinical trial of a potential vaccine [see sidebar].

Finally, researchers foresee difficult conflicts ahead about how many people should be offered the new medications, which are expected to carry a price tag of tens of thousands of dollars, at least initially. Should the drugs be given to the millions of people who are HCV-positive, or only to those who have already suffered actual liver damage? Should some patients be asked to wait until the drugs get cheaper? “I don’t know of any precedent for this kind of thing in the history of medicine,” says Hopkins virologist Stuart Ray. “This won’t be an easy ethical decision.” Recall that only 15 to 30 percent of chronic hepatitis C infections are estimated to result in full-blown liver cirrhosis. If you’re an HCV-positive individual, you might understandably feel that it’s worth $70,000 to reduce that risk to zero. But will private insurance companies and Medicare agree?

Even with all of those cautions in mind, these scientists seem palpably joyous about the imminent transformation of hepatitis C therapy.  “It was completely unimaginable a decade ago, or even two years ago, that we would have these kinds of treatment advances,” Sulkowski says. “Soon we’ll be able to tell patients that they’ll only have to take one pill, once or twice a day, for 12 weeks.”

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Canada falling behind in tackling hepatitis C

Hepatitis C symposium highlights need for national action plan

Toronto, ON (October 25, 2013) – Today, international researchers will present a compelling case for government action on hepatitis C. The disease can now effectively be screened, diagnosed, treated and often cured. Unfortunately, progress has hit a critical moment; in order to prevent thousands of unnecessary deaths and to avoid soaring acute care costs, Canada needs a national action plan to identify, treat and cure more patients with hepatitis C.

“We have the knowledge, the diagnostic tests and an ever-improving crop of therapies that we can use to treat patients,” says Dr. Morris Sherman, chairman of the Canadian Liver Foundation. “However, our ability to help people is hampered by our lack of resources. We have to find innovative and affordable ways to bring advancements to patients; otherwise we will waste the efforts of researchers in Canada and around the world.”

During Hepatitis C Virus: From Discovery to Cure, a symposium jointly presented by the Gairdner Foundation and the Canadian Liver Foundation, Dr. Harvey Alter and Dr. Daniel Bradley, both winners of the prestigious 2013 Canada Gairdner International Award, will recount their ground-breaking work in isolating and identifying the hepatitis C virus. This research led to the development of the first screening tests for the virus.

Leading Canadian and American specialists will join Dr. Alter and Dr. Bradley, highlighting the ongoing challenges in measuring the current and future burden of hepatitis C and in overcoming the social, financial and administrative barriers standing between patients and the care they need.

“It’s incredible how far we’ve come and how much we’ve learned in the last 20 years,” says Dr. Gary Levy, former director of the Multi-Organ Transplant Program at the University Health Network in Toronto and one of the organizers of the symposium. “Hepatitis C is the leading cause of liver transplantation in this country, but with advances in treatment it doesn’t have to be. Transplants are, and always should be, a last resort, but we are often left with no choice because patients already have advanced forms of the disease by the time they are diagnosed. We should be using what we know to identify patients and intervene long beforehand.”

At Toronto General Hospital, which has the largest transplant program in the country, about 35 per cent of liver transplants performed each year are for patients living with hepatitis C.

Sergeant Lance Gibson was diagnosed with hepatitis C in January 2009 and discovered he had been living with the virus for 28 years after receiving blood products as a teenager. While in the process of being released from the Canadian Armed Forces (CAF), his medical examination revealed that he had the disease. As a result, he had to turn down a lucrative civilian position and stay in the CAF for treatment. He received a liver transplant in May 2012.

“While I’m grateful to the donor and the doctors who saved my life, I don’t think that liver transplants should be the answer,” says Lance. “If doctors were routinely testing for hepatitis C, mine might have been identified much earlier and I might have had more options for treatment.”

Canada needs a national action plan for hepatitis C

Earlier this year, the Canadian Liver Foundation’s report – Liver Disease in Canada: A Crisis in the Making – highlighted the gaps in knowledge, care and resources for all forms of liver disease. For hepatitis C, the report called for widespread screening of adults born between 1945 and 1975. This recommendation was supported by Canadian specialists in a recently published Canadian Medical Association Journal (CMAJ) article1. The report also recommended changes to how hepatitis care is funded and managed as well as how patients qualify for treatment reimbursement.

“We estimate that only two per cent of the more than 300,000 Canadians living with hepatitis C have undergone treatment,” says Dr. Sherman. “We recognize the financial implications of diagnosing and treating each Canadian with the disease, but if we don’t figure out a strategy now, we will end up spending even more in acute care costs or resorting to transplants to save the lives of patients that could have otherwise been cured.”

About the Canadian Liver Foundation
Founded in 1969 by a group of doctors and business leaders concerned about the increasing incidence of liver disease, the CLF was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease.

Media contact:
Melanie Kearns
416-491-3353 x4923

Additional resources:
B-roll is available for download here.

Canadian Liver Foundation’s Report, Liver Disease: A Crisis in the Making can be accessed here.

Canadian Liver Foundation’s Position Statement on Hepatitis C Testing can be accessed here.

1 Canadian Medical Association Journal. A Canadian screening program for hepatitis C: Is now the time? H. Shah, J. Heathcote, J. Feld http://www.cmaj.ca/content/early/2013/09/30/cmaj.121872.extract


FDA Panel Backs Sofosbuvir for Hepatitis C– (Excellent breakdown of the studies presented) – From Medscape

Troy Brown, RN
October 25, 2013

An advisory committee to the US Food and Drug Administration (FDA) voted unanimously (15-0) to recommend sofosbuvir (Gilead Sciences, Inc) in combination with ribavirin for the treatment of adults with chronic hepatitis C virus (HCV) genotypes (GT) 2 and 3 infections.

The committee also recommended (15-0) sofosbuvir in combination with pegylated interferon and ribavirin for treatment of chronic HCV in treatment-naïve adults with GT 1 and 4 infections.

Sofosbuvir is an NS5B polymerase inhibitor and the first drug in this class to be reviewed in the US. It is intended to be administered as a 400-mg oral dose once daily in combination with other drugs. The approval is momentous because it provides the first interferon-free regimen for adult patients with HCV GTs 2 and 3.

"This is a tremendous advance for patients, and I think both the sponsor and the FDA should be applauded for having gotten us here," said voting member Elizabeth Connick, MD, a professor of medicine at University of Colorado Denver, Division of Infectious Diseases, in Aurora, Colorado.

The vote follows a discussion of 4 pivotal phase 3 trials:

In patients with HCV GT 2 or 3:

· P7977-1231 (FISSION) evaluated sofosbuvir + ribavirin (SOF + RBV) treatment for 12 weeks in treatment-naïve patients (499 patients: 256 in the SOF + RBV group; 243 in a pegylated interferon + ribavirin [PEG + RBV] group);

· GS-US-334-0107 (POSITRON) evaluated SOF + RBV for 12 weeks in patients who were interferon intolerant, ineligible, or unwilling to take interferon (278 patients: 207 in the SOF + RBV group; 71 in the placebo group);

· GS-US-334-0108 (FUSION) evaluated SOF+RBV for 12 or 16 weeks in treatment-experienced patients (201 patients: 103 in the SOF+RBV 12-week group; 98 in the SOF+RBV 16-week group).

In patients with HCV GT 1, 4, 5, or 6:

· GS-US-334-0110 (NEUTRINO), evaluated SOF (400 mg once daily) + PEG (180 μg/week) + RBV (1000 or 1200 mg/day) for 12 weeks in treatment-naïve patients (N = 327).


For all 4 trials, the primary endpoint was sustained virologic response (SVR), defined as HCV RNA less than the lower limit of quantification (LLOQ) 12 weeks after stopping active treatment (SVR12).


In FISSION, the overall SVR12 rate was 67% for both groups. When they looked at the subgroups (by genotype) of the SOF+ RBV group, the SVR12 rate was 95% in the subgroup of HCV genotype 2 subjects, and 56% in the subgroup of genotype 3 subjects.

In the PEG + RBV group, SVR12 rates were 78% in those with HCV GT2 and 63% in those with HCV GT3.


In POSITRON, the overall SVR12 rate was 78% in the SOF + RBV group and 0% in the placebo group. In the SOF + RBV group, SVR12 rates were 93% in those with HCV GT2 and 61% in those with HCV GT3.

Relapse was the reason for most treatment failures (HCV GT3, 38%; HCV GT2, 5%). No patients in the placebo group achieved SVR.


In FUSION, the SVR12 rate was higher in the SOF + RBV16 week group (71%) than the SOF + RBV12 week group (50%). Each of these was significantly higher ( P < .001), when compared with the null rate of 25%. When treatment duration was increased by 4 weeks in the 12-week group, SVR12 rates in those with HCV GT2 increased from 82% to 89%, and in those with HCV GT3, SVR12 rates increased from 30% to 62%.


In NEUTRINO, overall, SVR12 was achieved by 90% of subjects compared with a historical SVR12 rate of 60%, and this was statistically significant (P < .0001). The overall relapse rate was 9%.

The SVR12 rate in those with GT1 (N = 292) was 89% (GT1a-92%; GT1b 82%). In those with GT4 (N = 28) the SVR12 rate was 96%. Too few subjects with GT5 and GT6 were in the clinical trial to allow for definitive dosing recommendations for those groups.


No serious or severe cardiac adverse events occurred in sofosbuvir-treated patients, and no treatment discontinuations occurred due to cardiac adverse events. Palpitations were the only Grade 2 event found in the SOF + RBV group. Eleven patients in the SOF + RBV group experienced Grade 1 events including palpitations, tachycardia, sinus bradycardia, extrasystoles, and ventricular extrasystoles.

"It's a great step forward," noted voting member Lawrence S. Friedman, MD, chair of the department of medicine at Newton-Wellesley Hospital, Massachusetts, assistant chief of medicine at Massachusetts General Hospital, a professor of medicine at Harvard Medical School, and a professor of medicine at Tufts University School of Medicine, in Boston.

"I was particularly impressed by the very favorable resistance data," said voting member Russell B. Van Dyke, MD, a professor of clinical pediatrics and head of the Section of Pediatric Infectious Diseases at Tulane University School of Medicine, New Orleans, Louisiana.

The committee was largely supportive of offering sofosbuvir in combination with pegylated interferon and ribavirin to adults with GT1 infection who are nonresponders to a previous course of pegylated interferon and ribavirin. Several members would like to see additional studies including those on long-term effects of treatment and management of complex patients.

The FDA is expected to make a decision by December 8.

The advisory committee members reported no relevant financial relationships.

US Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee meeting October 25, 2013. FDA Briefing, Gilead Briefing


Panel recommends FDA approve sofosbuvir for hepatitis C – (Excellent summary from Healio)

Provided by Healio

October 25, 2013

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.


Hepatitis C: CHMP Backs 'Compassionate Use' of Sofosbuvir

International Approvals > Medscape Medical News

Miriam E. Tucker

October 25, 2013

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.


Also See: European Medicines Agency advises on compassionate use of sofosbuvir

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

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

FOSTER CITY, Calif., Oct 25, 2013 (BUSINESS WIRE) -- 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-naive 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.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)


Gilead sweeps FDA panel vote for pioneering hep C drug sofosbuvir

Provided by FierceBiotech

October 25, 2013 | By John Carroll

There were no big surprises for Gilead's $11 billion hepatitis C drug sofosbuvir at today's FDA panel review. The therapy, which promises to help create an entirely new standard of care for the millions of people afflicted with the virus, won a clear endorsement from agency experts. And now it's likely headed for a near-term approval as the FDA formally considers the application.

The panel voted unanimously that the drug and various combinations should be approved for all four basic genotypes. Sofosbuvir was endorsed in combination with ribavirin for genotypes 2 and 3, and in genotypes 1 and 4 in combination with ribavirin as well as in combination with interferon for treatment-naive patients.

The agency already signaled its views in an internal review released earlier this week which heralded the therapy as the first interferon-free drug that clearly demonstrated its efficacy and safety among important groups of hep C patients.


FDA panel unanimously backs Gilead's hepatitis C drug sofosbuvir

WASHINGTON | Sat Oct 26, 2013 12:25am IST

WASHINGTON (Reuters) - A federal advisory panel recommended on Friday that U.S. health regulators approve Gilead Sciences Inc's experimental hepatitis C drug sofosbuvir.

The 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 would be the first all-oral treatment for genotypes 2 and 3.

The panel also voted unanimously to approve the drug in patients with genotype 1 and genotype 4 variants in combination with ribavirin and the injectible drug 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.

(Reporting by Toni Clarke in Washington; Editing by Gerald E. McCormick)


Will New Hepatitis C Treatments Alter the Outlook for These Companies?

Provided by The Motley Fool

By Leo Sun | More Articles
October 25, 2013 

This week, Gilead Sciences (NASDAQ: GILD ) and Johnson & Johnson (NYSE: JNJ ) received positive news from the Food and Drug Administration regarding their new hepatitis C treatments. The FDA issued a positive review for Gilead's sofosbuvir, and an FDA advisory panel voted unanimously to recommend the approval of J&J's simeprevir.

What do these two victories mean for Gilead and J&J, which are competing against other major companies to usher in the next generation of hepatitis C treatments?

What an approval would mean for Gilead
The FDA stated that Gilead's sofosbuvir cured 90% of patients with the most common form of hepatitis C within their first 12 weeks of treatment.

If approved, Gilead's drug will mark the first major step forward for hepatitis C drugs in two years. The last major advance in hepatitis C treatments was made by Merck (NYSE: MRK ) and Vertex Pharmaceuticals in 2011. Merck and Vertex's drugs raised the average cure rate from approximately half to 65% and 75%, respectively, when administered with other treatments.

Gilead's sofosbuvir is a once-daily, orally administered treatment, whereas older treatments were either injected or required multi-pill cocktails. In addition, it does not contain interferon, a protein frequently used in older hepatitis C treatments that can cause flu-like symptoms.

Gilead is seeking approval of sofosbuvir for the treatment of all six genotypes of the hepatitis C virus, since treatment for the type 1,4,5, and 6 genotypes still require the drug to be administered with a dose of pegylated interferon, such as Merck's Pegintron or Roche's Pegasys, along with ribavirin, an older hepatitis C drug.

Therefore, if approved, sofosbuvir only drastically improves the lives of patients with genotypes 2 and 3, who will only need to take the pill once a day with ribavirin. The type 1 genotype is currently the most common form of hepatitis C in the United States.

Nonetheless, Wall Street believes sofosbuvir has blockbuster potential -- analysts polled by Bloomberg expect the drug to generate up to $6.03 billion in annual revenue for Gilead by 2016, and analysts at Morningstar believe it could hit peak sales of $8 billion by 2022 -- equivalent to 80% of Gilead's revenue in 2012.

Diversification and growth beyond HIV treatments
For Gilead, the success of sofosbuvir is the key to growing the company beyond its current portfolio of HIV treatments, which generated 86% of its total product sales last quarter.

The main weakness in Gilead's portfolio of HIV treatments is that they are all combination treatments built on top of a single treatment, Viread, which will face its first patent expirations in 2017.

Gilead's top seller, Atripla, is a combination of Viread and another antiviral drug, Emtriva. Its second best-selling drug, Truvada, is a triple combination ("triple pill") of Viread, Emtriva, and Merck's Sustiva. Its newest HIV drug, Stribild, is a four-way combination ("quad pill") of Viread, Emtriva, the HIV drug EVG, and cobicistat, a medication that inhibits liver enzymes from metabolizing HIV medications.

It's a clever strategy that allows Gilead to maximize sales of HIV treatments as long as it can, especially if its newer triple and quad pills are considered more convenient and effective treatments. However, there are also concerns that generic versions of Viread could simply bring the whole house down.

Therefore, sofosbuvir's approval could help Gilead enter a new phase of growth by diversifying its drug portfolio away from HIV treatments. Gilead is already testing its combo drug strategy on sofosbuvir with two new combination hepatitis C treatments -- one which combines sofosbuvir with another new hepatitis C drug ledipasvir, and another triple pill which combines that combination pill with ribavirin.

What an approval would mean for Johnson & Johnson
Johnson & Johnson, on the other hand, is far less ambitious with simeprevir than Gilead is with sofosbuvir.

J&J is only seeking the approval of the treatment for hepatitis C patients with the type 1 genotype. Like sofosbuvir for type 1 hepatitis C patients, simeprevir must be administered with an injection of pegylated interferon and a dose of ribavirin. However, the treatment might not benefit 48% of patients with the type 1 genotype who have a particular polymorphism known as Q80K -- which narrows down the potential market for simeprevir even further.

Due to its narrower appeal, sales estimates for simeprevir are considerably lower that sofosbuvir, with analysts at Bernstein estimating $400 million in peak annual sales by 2016.

Yet for J&J, gaining a new hepatitis C treatment isn't a top priority for the company, which generates the majority of its pharmaceutical revenues from the blockbuster rheumatoid arthritis treatment Remicade, which accounted for 24% of the segment's top line last quarter.

Instead, J&J has plenty of other more exciting treatments to keep an eye on, such as ibrutinib, a blood cancer treatment that it is co-marketing with Pharmacyclics, and Invokana, a first-in-class diabetes treatment which helps diabetics excrete excess blood sugar through the urine.

Although the approval of simeprevir would be an added bonus for J&J, don't expect $400 million in annual peak sales to mean much for a company whose pharmaceutical business generated $25.4 billion in sales in 2012.

Don't forget about AbbVie
Last but not least, AbbVie's (NYSE: ABBV ) combination hepatitis C treatment should not be overlooked.

Like Gilead, AbbVie is looking toward hepatitis C treatments for diversification. One of the most common criticisms of AbbVie, which was spun off of Abbott Laboratories last year, is that it is far too dependent on its blockbuster rheumatoid arthritis drug, Humira, which generated 55% of its revenue last quarter.

AbbVie's treatment is also orally administered, but it requires four pills -- three in the morning and one at night -- and is only being tested on the type 1 genotype, on which it has demonstrated similar cure rates as sofosbuvir. Back in June, AbbVie declared that it could possibly beat Gilead to a market approval, although the company has remained relatively quiet on the issue ever since.

The Foolish takeaway
There is certainly plenty of hype about the next generation of hepatitis C treatments, but investors should cut through the headlines to better understand what each upcoming treatment means for each company.

Companies like Gilead and AbbVie have the most to gain if their treatments succeed, due to their need for diversified growth. For larger companies like Johnson & Johnson, a new hepatitis C treatment is just another brick in the wall.

However, all of these treatments are scientifically significant, since they represent higher cure rates, shorter treatment times, and easier methods of administration, which could substantially improve the quality of lives for patients.


European Medicines Agency advises on compassionate use of sofosbuvir



Conditions of use defined for patients with chronic hepatitis C infection before or after liver transplantation

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has given an opinion on the use of sofosbuvir, a medicine for chronic (long-term) hepatitis C virus (HCV) infection, in a compassionate-use programme. It is the third time a compassionate-use programme has been assessed at the European Union (EU) level.

Such programmes, set up at the national level, are intended to give patients with a life-threatening, long-lasting or seriously disabling disease who have no available treatment options access to treatments that are still under development and that have not yet been authorised. An application for authorisation of sofosbuvir was submitted by Gilead in April 2013. While it is currently under evaluation by the CHMP, Sweden has requested a CHMP opinion on the conditions under which early access to sofosbuvir in combination with other agents could be given specifically for patients before or after liver transplantation.

HCV infection is a major European public health challenge. It occurs in between 0.4% and 3.5% of the population in different EU Member States and is the most common single cause of liver transplantation in the EU.

There is currently no standard-of-care therapy available for patients with chronic HCV infection awaiting liver transplantation or for those who have undergone liver transplantation. For most of these patients, there are currently no approved treatment options. 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 opinion concerns the use of sofosbuvir as part of a compassionate-use programme, for the treatment of adults infected with chronic HCV who are also:

  • actively on the waiting list for liver transplantation and require treatment to prevent graft reinfection with HCV;
  • or who have undergone liver transplantation and have aggressive, recurrent HCV infection resulting in progressive and worsening liver disease and are at high risk of death or decompensated liver failure within 12 months if left untreated.

The aim of the CHMP assessment and opinion on a compassionate-use programme of new medicinal products is to ensure a common approach, whenever possible, regarding the criteria and conditions of use under Member States' legislation. The opinion provides recommendations to the EU Member States that are considering setting up such a programme, and its implementation is not mandatory. In addition to describing which patients may benefit from the medicine, it explains how to use the medicine and gives information on safety. The assessment report and conditions of use of sofosbuvir in this setting will be published shortly on the Agency’s website.

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