Wednesday, October 30, 2013

NATAP-Treatment of Chronic Hepatitis C: The Revolution!

Treatment of Chronic Hepatitis C: The Revolution!

Jules Levin founder and executive director of National AIDS Treatment Advocacy Project (NATAP) reports on the European AIDS Conference which took place in Belgium from October 16-19.

Mr. Levin offers commentary and slides from Dr. Wedemeyer's presentation; Treatment of Chronic Hepatitis C: The Revolution! which reviews data on new HCV oral IFN-free drug regimens and direct acting activirals in clinical development.

Here are a few sample slides and a bit of commentary, view complete presentation @  NATAP

Treatment of Chronic Hepatitis C: The Revolution!

Heiner Wedemeyer
Hannover Medical School

Commentary From Jules Levin:  
The FDA hearings on Oct 24/25 reviewed Simeprevir+PR for 24 weeks and Sofosbuvir +PR for 12 weeks, and as expected the panels voted unanimously to approve both 19-0 & 15-0. This is just the prelude to next year when the first 2 IFN-free regimens will be considered for approval by the FDA in the early part of 2014 & of course approval is expected, they are Gilead's Sofosbuvir+Ledipasvir & Abbvie's ABT450+ABT267+ABT333 both with and/or without RBV, phase 3 studies are......

"All oral therapy will lead to a change in treatment paradigm"
"The number of treatable patients will dramatically increase! Interferon-Free"
"There is an association between SVR & all-cause mortality & liver-related mortality"


Complete Coverage

Hepatitis C - Changes to Incivek (telaprevir) product labeling

Changes to Incivek (telaprevir) product labeling

Source FDA 10/29/2013 Changes to Incivek (telaprevir) product labeling

FDA approved changes to the Incivek (telaprevir) product labeling to include results from trial C211 (OPTIMIZE) to support a twice daily dosing regimen. In addition new contraindications were added for anticonvulsant medications (carbamazepine, phenobarbital and phenytoin) and other revisions to the section 7 Drug Interactions.

Below is a summary of the changes

  • Section 2: Dosage and Administration of telaprevir were updated throughout the label: from 750 mg three times a day to 1125 mg twice daily.
  • The anticonvulsant medications carbamazepine, phenobarbital, and phenytoin were moved from the Drug Interaction section (Section 7, Table 5) to the Contraindications section (Section 4, Table 3)
  • Section 6: Adverse Reactions was updated as follows:
Additional Data from Clinical Trials

In the analysis of an additional study (Trial C211), the safety profile of combination treatment with INCIVEK 1125 mg twice daily was similar to the safety profile for patients receiving combination treatment with INCIVEK 750 mg every 8 hours (q8h) [see Clinical Studies (14.2)]. No new safety findings were identified.

  • The analgesic medications alfentanil and fentanyl were added in section 7 Drug Interactions Table 5 as potential drug interaction drugs when used with telaprevir. Specifically, careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when telaprevir is co-administered with alfentanil or fentanyl, including extended-release transdermal or transmucosal preparations of fentanyl.
  • Section 12 Clinical Pharmacology was updated with information regarding the twice daily dosing regimen.

Telaprevir total exposure (AUC24h,ss) was similar regardless of whether the total daily dose of 2250 mg was administered as 750 mg every 8 hours or 1125 mg twice daily.

Additionally the data from interaction trials with carbamazepine and phenytoin were included.
  • Section 12.4 Microbiology was updated as follows:
In the C211 Phase 3 clinical trial, there were no differences in the types of emerging variants between subjects receiving telaprevir 1125 mg twice daily and subjects receiving telaprevir 750 mg every 8 hours. Similar proportions of subjects in both treatment groups had telaprevir-resistant variants at the time of failure.

  • Section 12.5 Pharmacogenomics was updated to include the sustained virologic response rates at 12 weeks post treatment (SVR12) for the twice daily dosing regimen as follows:
In Trial C211, all subjects were prospectively tested for IL28B variants; there were no clinically relevant differences in SVR12 responses between q8h and twice-daily dosing within the genetic subgroups.

rs12979860 Genotype
SVR, n/N (%)
C211 (treatment-naïve)
T12 Twice Daily/PR
T12 q8h/PR
97/105 (92%)
92/106 (87%)
139/206 (67%)
141/208 (68%)
38/58 (66%)
37/57 (65%)

  • Section 14 Clinical Studies was updated to include results from Trial C211 (OPTIMIZE)
Trial C211 was a randomized, open-label, Phase 3 trial conducted in treatment‑naïve subjects. Enrolled subjects received 12 weeks of either INCIVEK 750 mg every 8 hours [T12 (q8h)/PR] or INCIVEK 1125 mg twice daily [T12 (twice daily)/PR] in combination with peginterferon alfa‑2a and ribavirin. The trial was designed to compare twice-daily dosing [T12 (twice daily)/PR] versus q8h dosing [T12 (q8h)/PR] of INCIVEK. At week 12, INCIVEK dosing ended and subjects continued on peginterferon alfa‑2a and ribavirin treatment. The total treatment duration was determined based on the subjects’ individual on-treatment viral response. If a subject achieved undetectable HCV RNA < 25 IU/mL (target not detected) at week 4, the total treatment duration was 24 weeks. Otherwise, the total treatment duration was 48 weeks.

The 740 enrolled subjects had a median age of 51 years (range: 18 to 70); 60% of the subjects were male; 21% had a body mass index ≥ 30 kg/m2; 5% were Black; 2% were Asian; 85% had baseline HCV RNA levels ≥ 800,000 IU/ml; 15% had bridging fibrosis; 14% had cirrhosis; 57% had HCV genotype 1a; and 43% had HCV genotype 1b.

Table 11 shows the response rates for the T12 (twice daily)/PR group and the T12 (q8h)/PR groups by treatment outcomes. The overall SVR rates were similar at 74% [T12 (twice daily)/PR; 274/369] and 73% [T12 (q8h)/PR; 270/371], respectively.  

Table 11:               Response Rates: Trial C211 
Treatment outcome
T12 (twice daily)/PR
N = 369
% (n/N)
T12 (q8h)/PR
N = 371
% (n/N)
74% (274/369)
73% (270/371)
Undetectable HCV RNA (target not detected) at week 4a
69% (256/369)
67% (250/371)
SVR in subjects with undetectable HCV RNA (target not detected) at week 4
86% (221/256)
85% (213/250)
SVR in subjects who did not have undetectable HCV RNA at week 4
47% (53/113)
47% (57/121)
Outcome for Subjects without SVR 
26% (95/369)
27% (101/371)
On‑treatment virologic failureb 
10% (38/369) 
10% (36/371) 
8% (23/300)
6% (19/293)
9% (34/369)
12% (46/371)

T12 (twice daily)/PR: INCIVEK 1125 mg twice daily for 12 weeks with peginterferon alfa‑2a and ribavirin for 24 or 48 weeks; T12 (q8h)/PR: INCIVEK 750 mg every 8 hours for 12 weeks with peginterferon alfa‑2a and ribavirin for 24 or 48 weeks

a   Subjects with planned total treatment duration of 24 weeks.
b   On‑treatment‑virologic failure includes subjects who met a protocol‑defined virologic stopping rule and/or who had detectable HCV RNA at the time of their last dose of study drug and had viral breakthrough.
c   Relapse was defined as having less than 25 IU/mL at the planned end of treatment followed by HCV RNA ≥ 25 IU/ml at the last observation within the SVR follow-up visit window.
d   Other includes subjects with detectable HCV RNA at the planned end of treatment but who did not have viral breakthrough, and subjects with a missing SVR assessment during planned follow-up.

 SVR rates were similar for the T12 (twice daily)/PR and T12 (q8h)/PR groups across subgroups determined by sex, age, race, ethnicity, body mass index, HCV genotype subtype, IL28B genotype, baseline HCV RNA (less than 800,000, greater than or equal to 800,000 IU per mL), and extent of liver fibrosis. However, there were small numbers of subjects enrolled in some key subgroups. 

Fifty-four and 49 subjects in T12 (twice daily)/PR and T12 (q8h)/PR groups, respectively, had cirrhosis at baseline. The SVR rate in these subjects was 54% (29/54) in the T12 (twice daily)/PR group and 49% (24/49) in the T12 (q8h)/PR group. In the T12 (twice daily)/PR group, 52% (28/54) of subjects with cirrhosis achieved undetectable HCV RNA (target not detected) at week 4; their SVR rate was 68% (19/28). In the T12 (q8h)/PR group, 59% (29/49) achieved  undetectable HCV RNA (target not detected) at week 4; their SVR was 59% (17/29). The SVR rate for subjects assigned 48 weeks of treatment was 38% (10/26) in the T12 (twice daily)/PR group and 35% (7/20) in the T12 (q8h)/PR.

Thirty-five subjects were Black/African Americans. The overall SVR among Black/African American subjects was 50% (10/20) in the T12 (twice daily)/PR group and 60% (9/15) in the T12 (q8h)/PR group. Among these subjects, 46% (16/35) were assigned to 24 weeks of treatment and of those 88% (14/16) achieved SVR. 

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Tuesday, October 29, 2013

Estrogen protects women with NASH from severe liver fibrosis

Estrogen protects women with NASH from severe liver fibrosis

New research suggests that estrogen protects women with nonalcoholic steatohepatitis (NASH) from severe liver fibrosis. According to the study published online in Hepatology, a journal of the American Association for the Study of Liver Diseases, men are at higher risk of more severe fibrosis compared to women prior to menopause, but liver fibrosis severity is similar in men and post-menopausal women.

Non-alcoholic fatty liver disease (NAFLD) includes a range of liver disorders from simple fatty liver to inflammation, fibrosis, and cirrhosis. With the rapid rise in obesity, diabetes and metabolic syndrome, the prevalence of NAFLD—the result of insulin resistance—has also steadily increased. In fact, studies suggest that the NAFLD prevalence is 10% to 30%, making it the most common liver disease in the U.S.

"While most NAFLD patients have a mild disease known as fatty liver or hepatic steatosis, some patients present with NASH, which is more severe and increases overall mortality," explains Dr. Ayako Suzuki with the Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences in Little Rock, the lead author of the present study. "Our study aim was to investigate whether gender and menopause significantly impact fibrosis severity among adult patients with NAFLD."

The research team analyzed data from 541 adults with NASH who were seen at Duke University Liver Clinics and the Duke Metabolic and Weight Loss Surgery Program. The mean age of subjects was 48 years, with 35% of the group being men, 28% pre-menopausal women and 37% post-menopausal women.

Findings indicate that 22% of the cohort had advanced fibrosis. After adjusting for known predictors of fibrosis, the risk for greater fibrosis severity in post-menopausal women and men vs. pre-menopausal women was 1.4-fold and 1.6-fold, respectively. Furthermore, when dividing the cohort at age 50, which is the average age at menopause in the US, the risk for greater fibrosis severity in men vs. women before age 50 was 1.8-fold, while after the age 50 the risk was reduced to 1.2-fold.

"Our findings suggest a protective effect from estrogen against development of severe fibrosis," concludes Dr. Suzuki. "Further study of the impact of estrogen on fibrosis progression in NASH patients is needed."
More information: "Gender and Menopause Impact Severity of Fibrosis Among Patients with Nonalcoholic Steatohepatitis." Ju Dong Yang, Manal F Abdelmalek, Herbert Pang, Cynthia D Guy, Alastair D Smith, Anna Mae Diehl and Ayako Suzuki. Hepatology; (DOI: 10.1002/hep.26761) Published online: October 1, 2013.
Journal reference: Hepatology      
Provided by Wiley

This study was funded by grants from the National Institute on Alcohol Abuse and Alcoholism (5RC2 AA019399), and the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) (U01-DK57149 and K23-DK062116).

Photo Credit - 

Newly Approved Ultrasound Device Eliminates Risks and Pain of Liver Biopsy

MRE - Liver Imaging Test Detects Pediatric Liver Disease Without Need for Needle Biopsy

FDA Approves FibroScan for Noninvasive Liver Diagnosis
A painless alternative to liver biopsy for evaluating the stage of liver fibrosis.

Newly Approved Ultrasound Device Eliminates Risks and Pain of Liver Biopsy

At the annual meeting of the American Association for the Study of Liver Disease being held in Washington, DC, a multi-center study will be presented Monday, Nov. 4, which "confirms that (Fibroscan®) very accurately assesses presence of cirrhosis in patients with chronic type B and C viral hepatitis."

DETROIT, Oct. 29, 2013 /PRNewswire/ -- Henry Ford Hospital is the first in Michigan to use a pioneering ultrasound device that can help patients with liver disease avoid invasive biopsies to manage their disorders.

FibroScan® replaces repeated and sometimes painful liver biopsies for patients with chronic hepatitis C and B, fatty liver diseases and other hepatic disorders with a quick and painless procedure similar to the familiar ultrasound tests used to track pregnancy and diagnose internal diseases.

The device is based on a technology called transient elastography, which measures liver "stiffness" to assess disease and guide ongoing treatment.

"FibroScan® is designed to measure liver fibrosis using a painless, non-invasive method of assessing many of the same conditions measured with biopsy," says Stuart Gordon, M.D., Director of Hepatology at Henry Ford Hospital. "It's an outpatient procedure taking less than 15 minutes."

At the annual meeting of the American Association for the Study of Liver Disease being held in Washington, DC, a multi-center study will be presented Monday, Nov. 4, which "confirms that (Fibroscan®) very accurately assesses presence of cirrhosis in patients with chronic type B and C viral hepatitis."

Henry Ford Hospital was one of the seven U.S. institutions that conducted the study.

The patient feels only a slight vibration on the skin, the results are immediate and, because it does no harm, the procedure can be safely repeated as often as necessary.

About 150,000 people in the U.S. are diagnosed with chronic liver disease annually, about a fifth of them with cirrhosis, a scarring of the liver.

By one conservative estimate, more than 30,000 liver biopsies are performed in the U.S. each year, a number that led to medical discussions and calls for ways to make the procedure more "acceptable" to patients.

Cirrhosis and other diseases of the liver result from or cause hepatic fibrosis, in which fibrous scars develop as part of the liver's mechanism to heal its own damage.

Sometimes it's beneficial because the scar tissue surrounds and blocks off the cause of the damage. But often this scarring develops to the point that it interferes with liver function, as in cirrhosis.

For decades, a liver biopsy has been considered the "gold standard" for assessing liver disease. In most cases, the biopsy involves using a needle inserted through the skin and underlying tissue and into the liver to collect a sample of tissue. It's widely regarded as safe, but because it is invasive, it carries risks ranging from bleeding to rare instances of death. In addition, a proportion of liver biopsy patients complain of severe pain during the procedure.

Using FibroScan ®, the skin in the area of the liver is first coated with a water-based gel. The doctor then passes an ultrasound sensor over the area to take 10 consecutive readings. The sensor produces vibrations that create a low-frequency seismic wave sent between the ribs and into the liver. The speed of the wave as it passes through the liver is used to determine the hardness or stiffness of the organ – the faster the wave, the harder the tissue.

The data collected during the readings are collected and analyzed in the console connected to the sensor, and provides immediate results on the presence and severity of liver fibrosis.

FibroScan® is produced by Paris-based Echosens, entered the European market in 2003 and was already being used in more than 70 countries worldwide when it received approval by the U.S. Food and Drug Administration in April.

Note: To access Fibroscan® a patient needs a physician referral. The cost is $200. Email:
SOURCE Henry Ford Hospital

Hepatitis C: Faldaprevir regimen is effective as first treatment for genotype 1

Faldaprevir regimen is effective as first treatment for HCV genotype 1
SAN DIEGO – A regimen containing the oral investigational protease inhibitor faldaprevir is efficacious and safe as initial treatment for chronic hepatitis C virus genotype 1, a randomized phase III trial showed.
A team led by Dr. Christophe Moreno, a gastroenterologist at the Erasme Hospital, Université Libre de Bruxelles, Brussels, conducted the trial, known as STARTverso 1, among 652 patients in Europe and Japan.  
Dr. Christophe Moreno
More than three-fourths of patients given a faldaprevir-containing interferon-based regimen had achieved a sustained virologic response at 12 weeks after the end of treatment (SVR12), Dr. Moreno reported. This compared with only about half of patients given a placebo-containing regimen.

A low dose of faldaprevir worked just as well as a high one. In addition, most faldaprevir-treated patients met criteria for early treatment success and were therefore able to stop treatment after half the full duration.
The rate of serious adverse events was similarly low across treatment groups, and rates of most laboratory abnormalities were comparable.
"Faldaprevir is highly efficacious in European and Japanese patients infected with HCV [hepatitis C virus] genotype 1. Almost 90% of patients treated with faldaprevir were eligible for a shortened treatment duration of 24 weeks," Dr. Moreno commented. "Faldaprevir was well tolerated with few discontinuations due to adverse events at both dosages."
"Since this was primarily a European and Japanese study, there were no patients from this country [the United States], with African American ethnicity, which is one of the negative predictors of response," noted session comoderator Dr. Zobair N. Younossi, executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va.
Dr. Zobair N. Younossi 

"Do you think that that would change [the results], if you ran the trial in this country and had 20%-30% of patients with African American ethnicity?" he asked.

Two-thirds of the patients in the trial had HCV genotype 1b, Dr. Moreno replied. "As genotype 1a is more frequent in the U.S. and African Americans, we can suppose that maybe the results would be quite different.

"There is another trial, STARTverso 2, which is evaluating the efficacy of faldaprevir in patients from the U.S., Canada, and also other countries," he added. 

The investigators enrolled in STARTverso 1 patients with treatment-naive HCV genotype 1and randomized them in 1:2:2 ratio to 24 weeks of pegylated interferon alfa-2a and ribavirin plus placebo for 24 weeks (arm 1), plus faldaprevir 120 mg once daily for 12 or 24 weeks depending on response (arm 2), or plus faldaprevir 240 mg once daily for 12 weeks (arm 3).

Patients meeting criteria for early treatment success (HCV RNA less than 25 IU/mL at week 4 and undetectable at week 8) in arms 2 and 3 stopped treatment at week 24. Patients who did not meet these criteria and all patients in arm 1 received interferon and ribavirin out to 48 weeks.
The main trial results showed that the rate of SVR12 was higher in both the high-dose faldaprevir group (80%) and the low-dose faldaprevir group (79%) than in the placebo group (52%, P less than .0001 for both comparisons).
Fully 87% of patients treated with low-dose faldaprevir and 89% treated with high-dose faldaprevir achieved early treatment success and therefore qualified for the shortened treatment duration of 24 weeks. Among these patients, 86% and 89%, respectively, achieved SVR12.
Just 1% of all patients treated with faldaprevir had a primary nonresponse. About 4%-10% of patients had a viral breakthrough, and 6%-15% had a relapse.
"Common baseline polymorphisms were not found to affect the efficacy of faldaprevir," Dr. Moreno commented. In particular, the drug worked equally well in the 23% of patients with genotype 1a who had the Q80K polymorphism, which has been found to reduce the efficacy of other protease inhibitors.
"The high dose of faldaprevir showed no benefit over the 120-mg dose in any subgroup analyzed," he added.
The rate of serious adverse events was 7% with both doses of faldaprevir and 6% with placebo. Moderate or worse gastrointestinal adverse effects were more common with faldaprevir (7%-12%) than with placebo (3%).
Rates of grade 3 or higher laboratory abnormalities were largely the same. The faldaprevir groups had a higher rate of hyperbilirubinemia (12%-53% vs. 1%); however, "bilirubin elevations were benign and transient," Dr. Moreno noted.
Compared with placebo, faldaprevir was not associated with an increase in the incidence of anemia, one of the leading adverse effects of first-generation protease inhibitors.
Dr. Moreno disclosed that he is a board member for Janssen, Gilead, MSD, and Bristol-Myers Squibb; is a consultant for Janssen and MSD; receives grants from Janssen, MSD, Roche, and Novartis; is on the speakers’ bureau for MSD, Janssen, and BMS; and receives travel support from Janssen, Gilead, MSD, and Novartis. The trial was sponsored by Boehringer Ingelheim Pharmaceuticals. Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

Study questions FDA's shorter drug approval times

WASHINGTON | Tue Oct 29, 2013 12:54am EDT

(Reuters) - New drugs that receive expedited review by the Food and Drug Administration are being tested on fewer patients, leaving many safety questions unanswered even after they are approved, a study released on Monday in the Journal of the American Medical Association found.

Study authors Thomas Moore of the Institute for Safe Medication Practices and Dr Curt Furberg, a professor at Wake Forest School of Medicine, examined the development times, clinical testing and risks associated with 20 new drugs approved in 2008. Eight were given expedited review and 12 standard review.

It found that expedited drugs underwent a median of 5.1 years of clinical testing before being approved, compared with 7.5 years for those that underwent a standard review. But in many cases safety monitoring trials that were supposed to be conducted after the products were approved were either not conducted, not completed, or not submitted to the FDA.

"The testing of new drugs has shifted from a situation in which most testing was conducted prior to initial approval to a situation in which many innovative drugs are more rapidly approved after a small trial in a narrower patient population with extensive additional testing conducted after approval," the authors said.

At the urging of patient groups, Congress and the drug industry, the FDA over the past decade has introduced multiple mechanisms for speeding new products to the market. While patient groups and drug companies applaud these measures, saying they get much-needed medication into the hands of patients more quickly, critics say the agency is approving products before they have been fully vetted.

Of the drugs studied by Moore and Furberg in 2008, the FDA required 85 follow-up trials to monitor for safety. By 2013, only 40 percent of those studies had been completed.

The FDA said in a statement that it will review the article in more detail but that on the surface "it shows that the expedited development programs are working as intended by getting promising new drugs to patients more quickly."


The FDA has traditionally required two controlled clinical trials to prove that a drug is safe and effective. Over time the agency has relaxed the evidence it is willing to accept for certain products.

In some cases the FDA will accept data from a single trial and success may be judged on the basis of a surrogate measure - such as tumor shrinkage - that may or may not translate into a concrete measure such as increased survival.

"In situations of serious and life-threatening diseases with unmet medical need, patients and physicians who treat them have told us repeatedly that they are willing to accept greater uncertainty about risk in order to have access to the hope of improved treatment today," the FDA said in its statement.

The FDA is discussing additional measures to speed the drug development process, including the use of "enriched" trials that would select patients based on certain demographic or genetic characteristics in order to increase the chance of a trial's success.

The idea is to direct treatment to patients for whom it will be most effective or who are most likely to respond.

But in a commentary published alongside the study, Daniel Carpenter, a professor of government at Harvard University, said the FDA has put few measures in place to ensure that drugs that are approved based on limited populations are only marketed to those limited groups.

"The current system of accelerating drug approval in the United States can be described as a growing hodgepodge of exceptions to the rule of rigorous premarket review," he said.

The FDA said it has a "robust program for postmarketing surveillance and ensuring the completion of required post-approval trials."

"We believe that we have set the bar for the balance between pre-approval testing and early availability of promising new drugs to treat serious and life-threatening diseases in the right place."

(Reporting by Toni Clarke in Washington; editing by Matthew Lewis)

Monday, October 28, 2013

FDA Hepatitis Update - Revised draft guidance on clinical development of treatment for chronic hepatitis C‏

FDA Hepatitis Update - Revised draft guidance on clinical development of treatment for chronic hepatitis C‏

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 here

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 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

Hepatitis C Drug Sofosbuvir Still Effective at 24 Weeks

Hepatitis C Drug Sofosbuvir Still Effective at 24 Weeks

Jim Kling

October 28, 2013

SAN DIEGO, California — New data from 4 phase 3 trials with the hepatitis C (HCV) drug sofosbuvir (SOF) and ribavirin (RBV) show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. Twenty-four-week sustained virologic response (SVR) is essentially identical to 12-week SVR, bolstering confidence that the drug combination represents a cure. Those with genotype 3 infections are better served with a 16-week course of treatment.

The new work extends the results of the studies out to 24 weeks after treatment cessation. Twenty-four weeks was the traditional milestone for HCV treatments, but in recent years, the US Food and Drug Administration and industry have gravitated toward the 12-week time point. However, with new drugs set to greatly affect HCV treatment, it is important to consider this older benchmark, according to Kris Kowdley, MD, director of the Liver Center of Excellence at the Digestive Disease Institute at the Virginia Mason Medical Center in Seattle, Washington, who presented the research here at the American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course.

"We're in a brave new world of hepatitis C treatments, and we're very quickly reaching all oral, interferon-free, short-duration regimens, so I think it remains valuable to continue following patients to 24 weeks, and possibly 48 weeks, posttreatment to see if the assumption [of a cure] really holds up. We can also learn more about late relapses and possible questions about resistance," Dr. Kowdley told Medscape Medical News.

The research drew from 4 phase 3 studies: Sofosbuvir With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naive Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection (NEUTRINO), which enrolled treatment-naive patients with genotype (GT) 1, 4, 5, and 6 infection, each of whom received 12 weeks of SOF, peg-interferon (PEG), and ribavirin (RBV); Phase 3 Study of Sofosbuvir and Ribavirin (FISSION), which enrolled treatment-naive GT 2/3 patients to receive either 12 weeks of SOF+RBV or 24 weeks of PEG+RBV; GS-7977 + Ribavirin for 12 Weeks in Subjects With Chronic Genotype 2 or 3 HCV Infection Who Are Interferon Intolerant, Interferon Ineligible or Unwilling to Take Interferon (POSITRON), which enrolled GT 2/3 patients unable or unwilling to receive interferon, who were randomly assigned to receive 12 weeks of SOF+RBV or placebo; and Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection (FUSION), which enrolled treatment-experienced GT2/3 patients who received 12 or 16 weeks of SOF+RBV.

For all studies, the primary end point was sustained virologic response (HCV RNA < 25 IU/mL) at 12 weeks posttreatment (SVR12).

In the studies, participants had a mean age of 53 years (range, 19 - 77 years) and a mean body mass index of 28 kg/m2 (range, 17 - 56 kg/m2). Demographics were consistent with those of the HCV-infected population in the United States. Six percent of the participants were receiving opioid replacement therapy.

Table 1. 12-Week SVR Rates

Compensated cirrhosis at baseline was found in 17% of patients in the NEUTRINO study, 21% in FISSION, 18% in POSITRON, and 33% in FUSION.

In all studies, SVR12 was higher in patients without cirrhosis. Patients with GT 2 experienced higher SVR12 rates than those with GT 3.

SVR 24 rates were similar to SVR 12 rates.

Table 2. SVR12 vs SVR24
 SVR12 SVR24
Treatment-naïve patients  
GT 1, 4, 5, 6 overall91%91%
GT 190%90%
GT 496%96%
GT 5 and GT 6100%100%
Treatment-naive and experienced GT 2, 3 patients  
Interferon unable78%78%
Previously treated (12 week regimen)51%50%
Previously treated (16 week regimen)73%72%

The additional data back up the 12-week SVR. "In all the studies, the 24-week results are almost identical [to the 12-week SVR]. We detected durability of that response," said Dr. Kowdley. The studies also suggest that interferon is not needed to achieve SVR in genotypes 2 and 3, although Dr. Kowdley said that trials of interferon-sparing regimens are underway.

The results further underscore the anticipation that physicians have toward sofosbuvir and other new drugs. "I think 2 years ago there was a standing-room only meeting in San Francisco, where Pharmasset (which originally developed sofosbuvir), dropped just unbelievable results, and we all thought this was too good to be true," Tim Little, MD, a physician with Puget Sound Gastroenterology in Seattle, Washington, who attended the presentation, told Medscape Medical News.

"I don't know that there's anything incredibly new about (this study), but it's confirmation that this dramatic result that this very small group of investigators presented is actually real, and I think we can all understand that this is as good as they said it was going to be, or almost as good," Dr. Little said.

On October 25, an FDA advisory committee unanimously recommended approval of sofosbuvir based on the 12-week results. The FDA is expected to make a decision by December 8.

The research was funded by Gilead Bioscences, which is sponsoring sofosbuvir. Dr. Kowdley has received research funding from Gilead and is a member of the company's advisory committee. Dr. Little has disclosed no relevant financial relationships.
American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course: Abstract 38. Presented October 15, 2013.

Medscape Medical News from the:
American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course

Hepatitis C - Pregnant women may pass heartier viral strain to newborns

Pregnant women with hepatitis C may pass heartier viral strain to newborns, study suggests

Infants who get hepatitis C from their mothers during childbirth may inherit a viral strain that replicates more quickly than strains found in non-pregnant hosts, according to a new study published Oct. 27 in Nature Medicine. The findings, from a team in The Research Institute at Nationwide Children's Hospital, are the first to describe how a virus that has infected 180 million people worldwide takes advantage of immune changes during pregnancy.

About 1 percent of all pregnant women worldwide have hepatitis C, caused by a highly adaptable virus known as HCV that infects liver cells. In 3 to 5 percent of these pregnancies, the virus is passed to the newborns, accounting for the majority of new childhood HCV infections. Between 15 and 45 percent of people infected with HCV are able to mount an immune response sufficient to eradicate the virus. But in most cases, the virus eludes immunity, leading to a chronic infection that increases the risk of liver failure or liver cancer.

As part of a larger study of HCV in pregnant women and infants, researchers at Nationwide Children's followed two women with hepatitis C over a five-year period. Both women had two children during this time, and researchers were able to track the virus before, during and after pregnancy. Their analysis revealed surprising changes in HCV genomes that not only allowed the virus to thrive, but also ensured that the strain passed on by one of the women during childbirth was particularly good at replication, says Jonathan R. Honegger, MD, an infectious disease specialist and principal investigator in the Center for Vaccines and Immunity at Nationwide Children's.

"We found that better replicating versions of the virus emerged during pregnancy, and these 'fit' viruses were passed to the babies." Dr. Honegger says. "The findings actually provide unique insight into the impact of pregnancy on the mothers' control of viral infections, and also a striking illustration of this virus' ability to adapt to changing environmental pressures."

HCV persists in the general population, in part, because the virus outwits the immune system with mutations that can render it undetectable to CD8+ T-cells, important weapons in the body's antiviral immune arsenal. Although these viral variations—called immune escape mutations—protect the virus from attack by T-cells, they sometimes slow the virus replication machinery.

During pregnancy, T-cells are restrained to prevent the body from attacking the fetus as foreign tissue. Viral levels of HCV have also been known to increase during pregnancy, but whether this was related to changes in T-cell function was unknown. Working closely with Chris Walker, director of the Center for Vaccines and Immunity, and colleagues at Emory University and the University of North Carolina, Dr. Honegger found that during pregnancy, certain T-cell escape mutations were lost, resulting in a virus that could replicate far more quickly.

"This surprised us because the virus' immune escape mutations are usually stable in a patient," Dr. Honegger says. "The loss of these immune escape mutations from HCV during pregnancy provided strong evidence that the immune changes of pregnancy, intended to protect the fetus, significantly impaired the ability of CD8+ T-cells to exert pressure on the virus."

Loss of the escape mutations also meant that the babies got a version of the virus that was optimized for viral replication, Dr. Honegger adds. In the children they studied, the virus persisted and did not mutate in a way to suggest that it was under significant attack by their CD8+ T-cells.

"We don't yet know whether getting the fast-replicating, immune-susceptible version of the virus would be an advantage for the baby or the virus," says Dr. Honegger, who also is an assistant professor of pediatrics at The Ohio State University. "We suspect that if the baby doesn't mount a swift and strong immune response, then fast viral replication may increase the risk of persistent infection in the baby."

On the other hand, viral loads in the mothers dropped more than 1,000 fold by 12 weeks after delivery and viral genetic analysis showed that immune escape mutations had returned. "We interpreted this to mean that T-cell activity against hepatitis C in the liver increased sharply after delivery," Dr. Honegger says.

Researchers now are following a larger group of pregnant women with HCV, hoping to learn more about how viral mutations affect the way the body controls hepatitis C in pregnant women and infants.

"We believe that better understanding of the natural history of the infection in these patients will be critical for designing rational strategies to treat or prevent HCV in these populations."


Full citation: Honegger JR, Kim S, Price AA, Kohout JA, McKnight KL, Prasad MR, Lemon SM, Grakoui A, Walker CM. Loss of Immune Escape Mutations During Persistent HCV Infection in Pregnancy Enhances Replication of Vertically Transmitted Viruses. Nature Medicine. 2013 Oct 27. doi: 10.1038/nm.3351 [Epub ahead of print]

Funding: This work was supported by the US National Institutes of Health (R37-AI47367 to C.W, R56-AI096882 and R01-AI096882 to C.W and J.H., RO1-DA024565 and R01-AI95690 to S.L., R01-AI070101 and R01-DK083356 to A.G., T32-HD043003 and K12-HD043372 to J.H., and the Yerkes Research Center Base Grant P51RR-000165 (A.G.)), The Research Institute at Nationwide Children's Hospital (C.W. and J.H.), and the University of North Carolina University Cancer Research Fund (S.L.).

Nationwide Children's Hospital
2013 Oct 27. doi: 10.1038/nm.3351. [Epub ahead of print]
Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.
1] The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio, USA. [2] Department of Pediatrics, The Ohio State University School of Medicine, Columbus, Ohio, USA.

Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8+ cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.

Sofosbuvir - Novel antiviral for chronic hepatitis C backed for approval

Oct 25 - Related @ Family Practice News Digital Network
FDA panel backs approval of new protease inhibitor for hepatitis C
A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C........
Infectious Diseases

Novel antiviral for chronic hepatitis C backed for approval
October 28 2013
By: ELIZABETH MECHCATIE, Family Practice News Digital Network

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.
Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.
Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.
Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.
The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.
The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.
The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

AASLD 2013 - Hepatitis C to Take Center Stage at the Liver Meeting

Hepatitis C to Take Center Stage at the Liver Meeting
Miriam E. Tucker
October 28, 2013

With its major focus on hepatitis C screening and treatment, perhaps it's fitting that the Liver Meeting 2013 is taking place in Washington, DC, for the very first time, where just last week an advisory panel to the US Food and Drug Administration (FDA) voted in favor of licensing 2 direct-acting antiviral agents — sofosbuvir and simeprevir — that represent major advances in hepatitis C treatment.

"We're excited about it," American Association for the Study of Liver Diseases (AASLD) president J. Gregory Fitz, MD, told Medscape Medical News. "This is the 64th meeting of the organization, and the first time in Washington. So far, the attendance looks like it's going to set new records."

The projected attendance, some 10,000 liver specialists from more than 50 different countries, "reflects the excitement in the field," said Dr. Fitz, "but also the needs in the field and the searching for answers."

This summer, the US Preventive Services Task Force for the first time recommended hepatitis C screening for all baby boomers.

The Liver Meeting's scientific program committee chair Gary Davis, MD, said, "I think most people at both this meeting and the European meeting are most fascinated by what's happening with hepatitis C because that's an area that is changing so fast right now."

With the FDA's antiviral drugs advisory committee's endorsement of the NS5B polymerase inhibitor sofosbuvir, hepatologists are now excitedly looking toward a new era of all-oral, interferon-free regimens that are expected to successfully treat a greater proportion of infected patients with lower toxicity.

Dr. Davis told Medscape Medical News that the abstracts at the meeting will pick up where the data submitted to the FDA left off, with studies looking at more potential uses for sofosbuvir and other direct-acting antiviral agents in various drug combinations. "Some of the abstracts that are being presented are giving us a peek at what the next incremental steps are likely to be, and those are coming soon," he said.

Still, not everything at the conference will be about hepatitis C. Other hot topics include nonalcoholic fatty liver disease, which is an outgrowth of the obesity epidemic, prevention of acute-on-chronic liver failure in cirrhosis patients, drug-induced hepatotoxicity, and the recent rise in the incidence of liver cancer at a time when other cancer rates in the United States are declining.

In all, Dr. Fitz told Medscape Medical News, liver disease is now the eighth leading cause of death in the United States. "Despite huge progress in the field, the burden of diseases continues to increase."

Attendees looking for a broad overview of the very latest trends in their specialty can attend the AASLD Postgraduate Course on New Treatments in Liver Disease. The course, which will be held on Friday afternoon, will cover new diagnostic approaches, including genetic testing, noninvasive alternatives to biopsy, and new biomarkers for hepatocellular carcinoma.

State-of-the-Art Hepatology
A Friday evening course, entitled Old Diseases, New Treatments, will revisit conditions such as primary sclerosing cholangitis and iron overload. The course will devote entire sessions on Saturday morning to current and future management of viral hepatitis and fatty liver disease.

Previous meetings have featured the postgraduate course, but this year's will be particularly clinical, Dr. Davis, the former director of liver diseases at Baylor University Medical Center in Dallas, told Medscape Medical News.

"It will address a lot of questions and will reference many of the abstracts. In many areas, like hepatitis C, it's about incremental changes."

State-of-the-art lectures, from Sunday through Tuesday, will feature cutting-edge topics such as regenerative medicine, alpha-1 antitrypsin deficiency (a novel treatment strategy 50 years after discovery), acetaminophen and the liver, and hepatitis C therapeutics in the postinterferon era.

"I think the state of the arts this year are really great," Dr. Davis said, noting that he's particularly excited about the regenerative medicine talk Sunday morning by Anthony Atala, MD, director of the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, who will discuss building organs from stem cells. "It will be a fascinating talk."

Both Dr. Davis and Dr. Fitz told Medscape Medical News they're looking forward to the president's choice lecture by Bruce Beutler, MD, winner of the Nobel Prize in physiology or medicine. Dr. Beutler, from the University of Texas Southwestern in Dallas, shared the Nobel for discoveries concerning the activation of innate immunity.

Dr. Fitz pointed out that Dr. Beutler's work relates to "pathways that are fundamental to almost all causes of liver diseases, so the lecture will be of interest to both the scientists and clinicians."

Younger faces are expected at this year's meeting because the society has made an effort to bring in more trainees, Dr. Fitz told Medscape Medical News.

"We've gone out very specifically to try to identify younger physicians and scientists who are interested in the liver and bring them to the meeting and get them engaged and show them what the future might look like. I'm looking forward to having everyone interact with these younger people and hearing their thoughts."

Dr. Fitz said that free time will be an important facet of the meeting to encourage such exchanges. "That's really important to the success of the meeting — to have the unstructured time for the right kind of interactions necessary for collaborations and future plans."

Many of those social interactions are likely to take place at the Saturday evening cocktail reception, where alcohol will be served. "Even liver doctors drink wine," he said. "Alcohol continues to be a very important cause of liver disease around the world, but all things in moderation. AASLD definitely has an antiexcess alcohol stance, but we're not going back to the prohibition era."

Dr. Fitz has disclosed no relevant financial relationships. Dr. Davis serves on data safety and monitoring boards for the Duke Research Institute and for Bristol-Myers Squibb for a nonhepatology drug.

Medscape Medical News from:

The Liver Meeting 2013: American Association for the Study of Liver Diseases (AASLD)    

This coverage is not sanctioned by, nor a part of, the American Association for the Study of Liver Diseases.


Sunday, October 27, 2013

Treat Hepatitis C Now or Later? Expert Guidance for Individual Scenarios

HCV TimingHCV Timing

Expert Guidance on Timing of Treatment for HCV

Treat Now or Later in HCV?
Expert Guidance for Individual Scenarios

Hello everyone, welcome to another Sunday afternoon. Hope you're enjoying this lovely weekend. I wanted to point our readers to a new "treat or wait" HCV activity launched Friday over at Clinical Care Options (CCO).

Quick Summary

You won't want to miss this learning experience designed to help healthcare professionals (or patients?) decide the best time to initiate hepatitis C therapy. Participants will be asked a series of questions to help determine individual patient characteristics. These characteristics include HCV genotype, previous treatment history, fibrosis level (F0-Decompensated Cirrhosis), and disease progression.
After completing the activity and all data is entered, five HCV experts offer recommendations on whether to treat now or wait for future therapies.

If nothing else folks this program is helpful for anyone interested in knowing more about hepatitis C or treatment. 


This Interactive Decision Support Tool provides recommendations from HCV experts Ira M. Jacobson, MD; Paul Y. Kwo, MD; Andrew J. Muir, MD, MHS; Mark Sulkowski, MD; and Norah Terrault, MD, MPH, on optimal timing of HCV therapy in a variety of clinical scenarios. You will be asked to provide specific patient characteristics, including:

Liver fibrosis stage
Stability of liver disease
HCV genotype
Previous treatment history
Interferon willingness and eligibility

Based on the patient characteristics you enter, you will receive an Expert Insight of recommended management approaches from the 5 experts who assessed the same patient characteristics (see the “About” tab for more information). After viewing the answers from the Expert Insight panel, you will have an opportunity to record whether the experts’ recommendations either confirmed or changed your treatment choices.

These recommendations are based on the assumption that this is a “standard” patient, meaning the patient is healthy enough to tolerate selected treatment (interferon tolerability will be directly assessed in the tool); the patient does not have renal insufficiency, HIV coinfection, or another significant comorbidity; the patient has not received a transplantation; and the patient is not a pregnant woman or woman who wishes to become pregnant in the near future. The liver fibrosis stage of the patient must be generally known. The experts who have participated in this tool have made their choices based on what they would recommend for most patients who have health insurance.
Table of Contents
Interactive Virtual Presentation (Coming soon)

Present Approaches to HCV Therapy (Coming soon)
*As with any CME free registration is required 

Friday, October 25, 2013

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, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
For a complete listing of our news releases, please click here

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.

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.

Related Links:
Download FDA Review Information For Sofosbuvir And Simeprevir.

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