Simeprevir (TMC435) - Janssen Submits New Drug Application to U.S. FDA

Janssen Submits New Drug Application to U.S. FDA for Simeprevir (TMC435) for Combination Treatment of Adult Patients with Genotype 1 Chronic Hepatitis C

-- Filing Based on Phase 3 Data in Treatment-Naïve and Treatment-Experienced Patients with Compensated Liver Disease --

RARITAN, N.J., March 28, 2013 /PRNewswire/ -- Janssen Research & Development, LLC (Janssen) today announced it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for simeprevir (TMC435), an investigational NS3/4A protease inhibitor, administered as a 150 mg capsule once daily with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients. 

"Hepatitis C is a complicated disease and genotype 1 hepatitis C can be particularly difficult to cure. Given the complexity and diversity of the patient population, physicians need multiple options to provide their patients a chance at treatment success," said Wim Parys , Global Head of Development, Infectious Diseases and Vaccines, Janssen. "The U.S. filing represents an important step forward in bringing simeprevir to market and in helping to battle this challenging disease."

Hepatitis C virus (HCV) is a blood-borne infectious disease of the liver that affects approximately 3.2 million people in the United States. When left untreated over time, HCV can cause significant damage to the liver, including cirrhosis.

The regulatory submission for simeprevir is supported in part by data from three pivotal Phase 3 studies: QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In each study, participants were treated with one 150 mg simeprevir capsule once daily for 12 weeks plus pegylated interferon and ribavirin for 24 or 48 weeks. Primary efficacy data from the Phase 3 studies will be presented at an upcoming medical meeting.

About Simeprevir

Simeprevir (TMC435) is an investigational NS3/4A protease inhibitor jointly developed by Janssen and Medivir AB for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease. Simeprevir is believed to work by blocking the protease enzyme that enables the hepatitis C virus to survive and replicate in host cells.

For additional information about simeprevir clinical studies, please visit www.clinicaltrials.gov.

About Hepatitis C

Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is the focus of a rapidly evolving treatment landscape. Approximately 150 million people are infected with hepatitis C worldwide - including approximately 3.2 million people in the United States - and 350,000 people per year die from the disease globally. When left untreated, HCV can cause significant damage to the liver including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which can include liver failure.

About Janssen Research & Development, LLC

Janssen Research & Development, LLC is headquartered in Raritan, N.J. and has affiliated facilities in Europe, the United States and Asia. Janssen Research & Development is leveraging a combination of internal and external innovation to discover and develop novel medicines and solutions in five distinct therapeutic areas: Neuroscience, Oncology, Immunology, Infectious Diseases and Vaccines, and Cardiovascular and Metabolism. For more information about Janssen Research & Development, LLC visit www.janssenrnd.com.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2012. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither Janssen Research & Development, LLC nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)

SOURCE
Janssen Research & Development, LLC
RELATED LINKS
http://www.janssenrnd.com

Related-
Feb 22 2013
Simeprevir (TMC435) Regulatory Application has now been filed in Japan for the treatment of genotype 1 hepatitis C patients
Medivir AB (STO:MVIR-B) today announced that its partner Janssen now has submitted a regulatory application to the Japanese Ministry of Health &Welfare authorities seeking approval for simeprevir, administered with pegylated interferon (Peg-IFN) and ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C patients who are treatment naïve, prior non responders or relapsed following treatment with Peg-IFN with or without RBV. Simeprevir, an investigational NS3/4A protease inhibitor, is administered as a single once-daily pill for 12 weeks.The regulatory submission in Japan is supported by data from four Japanese phase III clinical studies of once-daily simeprevir administered with Peg-IFN and RBV.......

Watch - Dentist's office a 'perfect storm' for HIV, hepatitis exposure, health official says

Dentist's office a 'perfect storm' for HIV, hepatitis exposure, health official says

By Mariano Castillo, CNN
updated 1:43 PM EDT, Fri March 29, 2013

 













(CNN) -- About 7,000 patients who visited a suburban Tulsa, Oklahoma, dentist in the past six years may have been exposed to HIV and hepatitis, health investigators say.

Investigators were left grasping for words to describe what they found inside W. Scott Harrington's dental practice: Assistants did techniques that only a dentist should, and sterilization procedures and needles were handled improperly.

"I will tell you that when ... we left, we were just physically kind of sick," said Susan Rogers, executive director of the Oklahoma Board of Dentistry. "I mean, that's how bad (it was), and I've seen a lot of bad stuff over the years."

Read more @  CNN

Watch - Miravirsen: First microRNA-targeted drug effective for hepatitis C



Uploaded Mar 27 - UMassMedicalSchool·

Miravirsen, the first microRNA-targeted drug to enter human clinical trials, successfully reduced hepatitis C (HCV) RNA levels in patients with chronic HCV infection in a phase 2a trial, according to results published March 27 in the New England Journal of Medicine. The development opens the door to a potential new treatment for the disease.

“This is particularly exciting for patients with chronic hepatitis infection,” said Gyongyi Szabo, MD, PhD, professor of medicine and a translational scientist studying chronic hepatitis C infection and liver function, who was not involved in the trial. “This may represent a new type of therapy that has the potential for future treatments in patients with the most difficult hepatitis C type to treat—genotype 1. Especially when one considers that current treatments have many side effects and limited efficacy.”

Globally, as many as 170 million people are estimated to suffer from HCV infection. Chronic HCV is a major cause of liver cirrhosis, liver failure, hepatocellular carcinoma and is the leading cause of liver transplants in the United States.

Inside the liver, the hepatitis C virus uses a liver-specific microRNA-122 (miR-122) molecule normally important for cholesterol metabolism to replicate. Miravirsen, developed by Santaris Pharma, works by sequestering and effectively inhibiting miR-122 so the virus can’t use it to propagate.

In the study, a total of 36 patients with chronic HCV genotype 1 received various doses of Miravirsen over a 29-day period. Two weeks after treatment, five patients receiving the two highest doses of the drug showed no observable signs of HCV RNA.

Essential for turning genes on and off, microRNA was discovered in 1993 by Victor R. Ambros, PhD, the Silverman Chair in Natural Sciences and professor of molecular medicine.

Additional Information-
Miravirsen- Hepatitis C drug goes after patients’ RNA
Results - New England Journal of Medicine

Increased risk of cognitive impairment in cirrhotic patients with bacterial infections

Related @ Healio

Bacterial infection increased cognitive impairment among cirrhotic patients

Patients with cirrhosis who developed bacterial infection were at significantly increased risk for cognitive impairment, according to recent results...
Read more...

Journal of Hepatology

Increased risk of cognitive impairment in cirrhotic patients with bacterial infections

Received 27 November 2012; received in revised form 2 March 2013; accepted 6 March 2013. published online 25 March 2013.

Accepted Manuscript
Abstract
PDF

Abstract
Background & aims

A causal relationship between infection, systemic inflammation and hepatic encephalopathy (HE) has been suggested in cirrhosis. No study, however, has specifically examined, in cirrhotic patients with infection, the complete pattern of clinical and subclinical cognitive alterations and its reversibility after the resolution. Our investigation was aimed at describing the characteristics of cognitive impairment in hospitalized cirrhotic patients, in comparison with patients without liver disease, with and without infection.

Methods
One-hundred and fifty cirrhotic patients were prospectively enrolled. Eighty-one patients without liver disease constituted the control group. Bacterial infections and sepsis were actively searched in all patients independently of their clinical evidence at entry. Neurological and psychometric assessment was performed at admission and in case of nosocomial infection. The patients were re-evaluated after the resolution of the infection and 3 months later.

Results
Cognitive impairment (overt or subclinical) was recorded in 42% of cirrhotics without infection, in 79% with infection without SIRS and in 90% with sepsis. The impairment was only subclinical in controls and occurred only in patients with sepsis (42%). Multivariate analysis selected infection as the only independent predictor of cognitive impairment (OR 9.5; 95% CI 3.5-26.2; p=0.00001) in cirrhosis. The subclinical alterations detected by psychometric tests were also strongly related to the infectious episode and reversible after its resolution.

Conclusions
Infections are associated with a worse cognitive impairment in cirrhotics compared to patients without liver disease. The search and treatment of infections is crucial to ameliorate both clinical and subclinical cognitive impairment of cirrhotic patients.

Miravirsen- Hepatitis C drug goes after patients’ RNA

Hepatitis C drug goes after patients’ RNA
    

Compound targets genetic material that virus uses for replicating
By Nathan Seppa
No matter what medications doctors throw at hepatitis C, it continues to defy treatment in some patients. But a new compound offers an approach quite apart from the rest: It assaults a kind of RNA that is implicated in allowing the virus to gain a foothold.
In most of a small group of patients who took the experimental drug, virus levels were knocked down, sometimes below the threshold of detection. The drug does this by targeting genetic material in the liver called microRNA-122. The hepatitis virus normally attaches to this RNA, gaining the stability it needs to propagate while hiding from immune system patrols.
The new drug, called miravirsen, binds to microRNA-122, sequesters it and indirectly thwarts viral replication, says study coauthor Harry Janssen, a hepatologist and physician at the University of Toronto. Janssen and colleagues report the findings March 27 in the New England Journal of Medicine.
Experimental Drug May Work Against Hepatitis C

Miravirsen greatly reduced virus in patients in small study

March 27, 2013
By Maureen Salamon HealthDay Reporter

WEDNESDAY, March 27 (HealthDay News) -- An experimental therapy for hepatitis C -- a "silent killer" linked to liver cancer and cirrhosis -- has shown promise in tamping down virus levels in early trials. Experts caution, however, that it's too soon to know if the injectable drug will someday gain a standing among emerging oral medications against the disease.

New research suggests that the drug, miravirsen, could potentially be part of a drug "cocktail" that manages the hepatitis C virus in much the same way as similar combinations have transformed HIV/AIDS from a death sentence into a chronic, manageable condition. Miravirsen suppresses molecules the hepatitis C virus needs to reproduce.

The drug decreased viral loads by about 500-fold at the highest doses used in a small, phase 2 study by an international group of researchers. Drug resistance, a common problem with other hepatitis C medications, did not develop among patients taking miravirsen. A phase 2 trial evaluates a drug's effectiveness while continuing to assess its safety.

"This is the first real clinical study of this approach and the results are encouraging," said Dr. Judy Lieberman, chairwoman of cellular and molecular medicine at Boston Children's Hospital. "What's exciting to me is that there doesn't seem to be any drug resistance developing. If there's a way to develop a drug cocktail that doesn't require a half a year of treatment ... that would be really exciting, but it's too early to tell."

Lieberman was not involved in the research but co-wrote an editorial accompanying the new study in the March 27 issue of the New England Journal of Medicine.

Hepatitis C is one form of liver disease and affects about 170 million people worldwide, according to study background information. It's transmitted by shared needles or, less frequently, through sex.

Often symptomless, the infection is a major cause of liver cancer and cirrhosis, or scarring of the liver.

Led by Dr. Harry Janssen, a professor of medicine at the University of Toronto and Erasmus University Rotterdam in the Netherlands, researchers split 36 patients with hepatitis C into four groups.

Nine patients in each of the first three groups received a dose of either 3 milligrams (mg), 5 mg or 7 mg of miravirsen per kilogram of body weight for 29 days, while the last nine patients received a placebo. All were followed for 18 weeks. The so-called viral load of patients receiving the highest dose decreased by about 500-fold, Lieberman said, and the hepatitis C virus was below detectable levels in four of nine patients.

Meanwhile, the treatment caused no significant toxic effects in any patients, aside from mild injection-site reactions and a brief increase in liver enzyme levels. Calling the study "interesting," Dr. David Bernstein, chief of the division of hepatology at North Shore University Hospital in Manhasset, N.Y., said that as an injectable drug, miravirsen would be less desirable among patients than other new drugs for hepatitis C that can be taken orally.

"It's a novel concept, but it's only 36 patients and a phase 2 study," Bernstein said. "It's impressive that their viral loads came down, but most suffered a recurrence of the virus."

More information
The U.S. Centers for Disease Control and Prevention has more about hepatitis C.
Copyright © 2012 HealthDay. All rights reserved.

Original Article-New England Journal of Medicine
Treatment of HCV Infection by Targeting MicroRNA

Harry L.A. Janssen, M.D., Ph.D., Hendrik W. Reesink, M.D., Ph.D., Eric J. Lawitz, M.D., Stefan Zeuzem, M.D., Maribel Rodriguez-Torres, M.D., Keyur Patel, M.D., Adriaan J. van der Meer, M.D., Amy K. Patick, Ph.D., Alice Chen, B.A., Yi Zhou, Ph.D., Robert Persson, Ph.D., Barney D. King, M.D., Sakari Kauppinen, Ph.D., Arthur A. Levin, Ph.D., and Michael R. Hodges, M.D.
March 27, 2013DOI: 10.1056/NEJMoa1209026 

Background
The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid–modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function.
In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization.
Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram, 2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome.
The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.)



Research Published in the New England Journal of Medicine Demonstrates Marked and Long-Lasting Antiviral Activity Against HCV for Santaris Pharma A/S' Miravirsen, the First MicroRNA-Targeted Drug to Enter Clinical Trials

Final Phase 2a results show dose-dependent, prolonged antiviral activity in Hepatitis C patients --

HOERSHOLM, Denmark and SAN DIEGO, March 27, 2013 /PRNewswire via COMTEX/ --

Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced the publication of study results online in the New England Journal of Medicine (NEJM). The publication highlights the potential benefits of miravirsen, a host-targeted, pan-HCV genotype anti-viral agent and the first microRNA-targeted drug to enter clinical trials for the treatment of Hepatitis C virus (HCV). In the study, miravirsen, given as a four-week monotherapy treatment, provided robust dose-dependent antiviral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL). The effect was sustained well beyond the end of therapy.

Clinical data from the Phase 2a study demonstrated the following:

-- Miravirsen was safe, well tolerated and provided prolonged antiviral activity well after the last dose of miravirsen monotherapy (x5 weekly injections)
-- There were no signs of viral resistance
-- Adverse events were infrequent, mild and did not lead to study drug discontinuation
-- There were no dose limiting toxicities or discontinuations due to adverse events
-- Miravirsen was associated with dose-dependent reductions in HCV RNA that were sustained well beyond the end of the four-week dosing period
-- Four out of nine patients treated at the highest dose (7 mg/kg) with miravirsen became HCV RNA undetectable with just five weekly doses of miravirsen monotherapy

"We are excited because the data show that miravirsen offers long-lasting suppression of HCV RNA, a high barrier to viral resistance, a favorable tolerability and dosing profile, a low propensity for drug interactions and a very long duration of action. All of these properties suggest that miravirsen's unique mechanism-of-action may offer a potential cure for Hepatitis C patients, either in combination with other antiviral agents or as a monotherapy," said Harry Janssen, M.D., Head of the Liver Clinic at Toronto Western and Toronto General Hospital and lead author of the NEJM publication. "Due to its ability to target the host factor miR-122, miravirsen has the potential to change the way Hepatitis C is treated. This study is also the first to prove that blocking microRNA can be effective in treating Hepatitis C in humans without limiting side effects. This trial is a landmark study for new therapeutic modalities in many other diseases where microRNA's play a role, such as in cardiovascular disease, cancer and metabolic disorders."

Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the Hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the Hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the level of Hepatitis C virus is profoundly reduced.

"This is a seminal moment for the microRNA community as miravirsen is the first microRNA targeted drug to show efficacy in clinical trials, and we are honoured that such a prestigious journal as the New England Journal of Medicine has published this work," said Henrik Stage, Chief Executive Officer at Santaris Pharma A/S. "It's amazing to think that the journey from bench to bedside has occurred over such a short span of time. Recall that human microRNAs were only discovered in 2001, and miR-122's role in the HCV lifecycle determined in 2005. Based on the published results, microRNA targeted therapy has shown its potential to become a new important class of drugs, and the LNA platform has demonstrated its role as the chemistry of choice for RNA targeted therapies."
The randomized, double-blind, placebo-controlled, ascending multiple-dose Phase 2a study assessed the safety and tolerability of miravirsen in treatment-naive patients with chronic HCV genotype 1 infection. Patients were enrolled sequentially to one of three cohorts (9 active:3 placebo per cohort) at doses of 3, 5 and 7 mg/kg. Miravirsen was given as a total of 5 weekly subcutaneous injections over 29 days.

"These study results are the culmination of over 6 years of microRNA research at Santaris Pharma A/S," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "The results of this study highlight miravirsen's exceptional high barrier to resistance, long duration of action and good tolerability. Miravirsen would be especially suitable for treatment of hard-to-treat patients, for example those patients who have already failed treatment with pegylated-interferon and ribavirin combination or protease inhibitor triple therapy." Dr. Hodges continued, "Longer treatment durations of miravirsen are currently being tested in clinical trials in subjects who have failed initial therapy for HCV infection."

About Hepatitis CHepatitis C infection is a viral disease caused by the Hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates that approximately 3 percent of the world's population have been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver cancer[i]. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year[ii]. In Europe, there are about 4 million carriers[i]. The current standard of care treatment for genotype 1 is a protease inhibitor given with pegylated-interferon a and ribavirin. This triple combination is effective in about 70-80% of those treated[ii]. Patients that are not effectively treated have an increased risk for the progression of liver disease. By 2029, total annual medical costs in the United States for people with Hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion[iii].

About microRNAsMicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.

About Locked Nucleic Acid (LNA) Drug PlatformThe LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA-based drugs are a promising new class of therapeutics that are enabling scientists to develop drug candidates to work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.

About Santaris Pharma A/SSantaris Pharma A/S is a privately held clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the company's proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The company's research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies include a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The company has strategic partnerships with miRagen Therapeutics, Shire plc., Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the company holds exclusive worldwide rights to manufacture and sell products that comprise LNA as active ingredient for studies performed with a view to obtaining marketing approval. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit www.santaris.com for more information.

Santaris Pharma A/S® is a registered trademark of Santaris Pharma A/S. Santaris(TM) and LNA-antimiR(TM) are trademarks of Santaris Pharma A/S.

[i] World Health Organization - http://www.who.int/csr/disease/hepatitis/Hepc.pdf ii] Jacobson IM. Telaprevir for previously untreated chronic hepatitis C virus infection. NEJM 2011;364:2405-16[iii] Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx.
SOURCE Santaris Pharma A/S

Watch Dr. Joe Galati - Calculating the MELD Score and How it Works


Liver Transplant Houston: Calculating the MELD Score and How it Works

by Dr. Joe Galati
on 03/22/2013

For those patients awaiting a liver transplant, the MELD score, which is a number calculated by evaluating the bilirubin, creatinine, and INR, is what the allocation of donor livers is based on. The higher the MELD score, the more likely you will get a liver transplant. At the same time, the higher the MELD score, the greater chance of life threatening complications. The majority of deaths that occur on the liver transplant waiting list take place in those patients with the highest MELD scores.

This video outlines some of the features of the MELD score calculation, and the potential for “MELD Exception” points to be added to the calculated MELD score.

I look forward to receiving your feedback.


Virological Predictors of Response to Retreatment in Hepatitis C Genotype 2 Infected Patients


PLoS One. 2013;8(3):e58882. doi: 10.1371/journal.pone.0058882. Epub 2013 Mar 19.

Virological predictors of response to retreatment in hepatitis C genotype 2 infected patients.

Huang CF, Dai CY, Yeh ML, Huang JF, Huang CI, Hsieh MY, Lin ZY, Chen SC, Wang LY, Juo SH, Chuang WL, Lin YC, Yu ML.

Source
Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan ; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan ; Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Full Text - Public Library of Science

Abstract
BACKGROUNDAIMS:
The impact of virological factors and interleukin-28B (IL-28B) genetic variants on retreatment of hepatitis C virus genotype 2 (HCV-2) treatment-experienced patients remains unknown.

METHODS:
On-treatment virological responses and IL-28B rs8099917 genotype were determined in 46 HCV-2 treatment-experienced patients (42 previous relapsers; four previous non-responders) retreated with 24-week peginterferon/ribavirin.

RESULTS:
Forty (87.0%) patients carried the rs8099917 TT genotype and 6 patients (13.0%) carried the TG/GG genotype. The sustained virological response (SVR; seronegativity of HCV RNA throughout 24 weeks of the post-treatment follow-up period) rate was 71.7%. Compared with previous non-responders, previous relapsers had a significantly higher SVR rate (78.6% vs. 0%, P = 0.004) and a lower relapse rate (17.5% vs. 100%, P = 0.04). All the previous non-responders were with the rs8099917 TT genotype. As for those who relapsed, treatment responses, including the rates of rapid virological response (RVR, 80.6% vs. 66.7%, P = 0.59), early virological response (EVR, 97.2% vs. 83.3%, P = 0.27), end-of-treatment virological response (97.2% vs. 83.3%, P = 0.27) and SVR (80.6% vs. 66.7%, P = 0.59) and relapse rate (17.1% vs. 20.0%, P = 1) did not differ significantly between patients with the rs8099917 TT and those with the non-TT genotype. Multivariate analysis revealed that the most important factor predictive of an SVR in the retreatment of HCV-2 was previous relapse; the only factor predictive of an SVR for previous relapsers was the achievement of an EVR. Compared with the achievement of a RVR, the attainment of an EVR was more accurate in predicting an SVR (88% vs. 74%).

CONCLUSIONS:
Peginterferon/ribavirin is effective in the retreatment of HCV-2 relapsers, especially among those who achieved an EVR.

PMID: 23527043 [PubMed - in process]

Full Text - Public Library of Science

Preventable liver disease costs more than diabetes

Preventable liver disease costs more than diabetes

27 March, 2013
in Centenary

Sydney team hopes to reduce the burden with research-led intervention

27 March 2013

Liver diseases have an impact on the Australian economy 40 per cent greater than chronic kidney disease and Type 2 diabetes combined, according to a report released today.

The report estimates the annual burden of liver diseases in Australia at more than $50 billion. And yet almost all liver disease is preventable.

The Centenary Institute’s liver research unit is one of the biggest in Australia. It is also one of first in the world to try to come to grips with liver damage at its most fundamental molecular level.

Head of research into liver disease and damage at Centenary, Professor Geoff McCaughan, and his team are focusing their research on promoting liver health, and understanding how chronic liver damage can develop into liver cancer.

“New therapies against viral hepatitis together with public health measures in the fields of alcohol abuse and obesity would be a start in the fight to reduce the burden of liver disease,” says Prof McCaughan. “We are exploring ways to detect early liver cancer and to understand how liver cancers are resistant to therapies.”

Liver damage can be caused by viral infections such as Hepatitis B and C, as well as autoimmune diseases and lifestyle-related illnesses such as alcoholism, diabetes and obesity.

“We’re working on important projects exploring new therapeutic targets which could potentially lead to new therapies across a broad spectrum of chronic liver diseases,” says Prof McCaughan.

And by working with the Royal Prince Alfred Hospital (RPA), Centenary’s advances in research can be put into practice in the clinic in the minimum time possible.

The research group has received a $2.5-million grant from the US National Institutes of Health to test the genes of hundreds of Sydney-siders to work out why some heavy drinkers develop liver cirrhosis and some don’t.

They have also demonstrated the effectiveness of new Hepatitis C treatments which, when used in conjunction with existing therapy, boost the percentage of patients who clear the virus from 45 per cent to 70 per cent.

Prof McCaughan is the chair of the Australian Liver Association, which commissioned the report, and Director of the Australian Liver Transplant Unit at RPA. He believes the report is long overdue.

“It shows categorically that any advance in treating or preventing liver disease would not only benefit patients, but also the country’s bottom line.”

“Supporting the report’s recommendations, which include more complete collection of data, trials of hospital and community treatment programs, and screening for the more serious forms of liver disease, makes both human and economic sense,” says Prof McCaughan.

A copy of the report and further information at: www.gesa.org.au

For comment on the report contact Prof Geoff McCaughan on (02) 9565 6125 or 0418212805

And for more about the Centenary Institute’s liver program: www.centenary.org.au/p/ourresearch/liver

Sofosbuvir (GS-7977) Updates-Sofosbuvir combination shows promise in non-cirrhotic, treatment-naive HCV



Sofosbuvir combination shows promise in non-cirrhotic, treatment-naive HCV
Lawitz E. Lancet Infect Dis. 2013;doi:10.1016/S1473-3099(13)70033-1.

March 27, 2013
Data from a phase 2 trial suggest that adding 12 weeks of sofosbuvir to peginterferon alfa-2a and ribavirin may be beneficial in non-cirrhotic, treatment-naive patients with genotypes 1, 2 and 3 hepatitis C virus infection.

In the two-cohort trial, patients with HCV genotype 1, 2 or 3 from 22 centers in the United States were recruited from Aug. 16 to Dec. 13, 2010. The 122 patients with HCV genotype 1 were allocated to cohort A. These patients were randomly assigned to 200 mg sofosbuvir (Gilead Sciences), 400 mg sofosbuvir or placebo for 12 weeks, with peginterferon and ribavirin. Depending on viral response, the patients continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks. The 25 patients with genotypes 2 or 3 comprised cohort B. These patients all received 400 mg sofosbuvir plus peginterferon and ribavirin for 12 weeks.

In cohort A, 43 patients who received 200 mg sofosbuvir and 43 patients who received 400 mg sofosbuvir had undetectable HCV RNA at week 12 post-treatment, as did 26 patients in the placebo group. In cohort B, 23 patients had undetectable HCV RNA at week 12 post-treatment. The most common adverse events were fatigue, headache, nausea and chills, which are consistent with adverse events associated with peginterferon and ribavirin.

“Our data suggest further testing of the 400 mg once-daily dose of sofosbuvir in interferon-containing and interferon-free regimens for a total duration of 12 weeks across HCV genotypes, and that these regimens should be testing in a broader population of patients, including those with cirrhosis,” the researchers wrote. “In the ongoing phase 3 study, we are assessing sofosbuvir in combination with peginterferon and ribavirin for 12 weeks in treatment-naïve patients with HCV genotype 1.”

Disclosure: See the study for a list of financial disclosures.
Read more....

Mar 15
The Lancet
Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial
The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV.
View here

Mar 27
Gilead-Medivir Hepatitis C Drug Clears Virus in Patients
An experimental drug combination from Gilead Sciences Inc. (GILD), Medivir AB (MVIRB) and Johnson & Johnson (JNJ) eradicated the virus that causes hepatitis C in patients with the liver disease in a study.

The trial’s 80 patients, who had tried and failed other medications, took a two-drug mixture of Medivir’s simeprevir and Gilead’s sofosbuvir, according to research presented at the Conference on Retroviruses and Opportunistic Infections today in Atlanta. The patients took the combination for 12 or 24 weeks, with and without the antiviral ribavirin, researchers said.
Read more....

Mar 12
Simeprevir & sofosbuvir demonstrates good early cure rate with or without ribavirin
Simeprevir & sofosbuvir demonstrates good early cure rate with or without ribavirin

Liz Highleyman 
An all-oral combination of simeprevir plus sofosbuvir, with or without ribavirin, led to an early cure for most hard-to-treat prior null responders with genotype 1 hepatitis C studied in the phase 2a COSMOS trial, according to a presentation last week at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
Read more.......

Mar 4
Medivir:Simeprevir (TMC435) and Sofosbuvir (GS-7977) interim results from a phase IIa study
Medivir AB (sto:MVIR-B) today announced first interim results from the cohort 1 of a Phase IIa study of the investigational protease inhibitor simeprevir (TMC435) administered once daily with Gilead's investigational nucleotide inhibitor sofosbuvir (GS-7977) with and without ribavirin for 12 and 24 weeks in genotype 1 prior null-responder hepatitis C patients with mild to moderate fibrosis (METAVIR F0-2). Simeprevir is jointly developed by Medivir AB and Janssen R&D Ireland, an affiliate of the Janssen Pharmaceutical Companies.
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Press Release

Mar 26
Update on Phase 3 Study of Oral Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients
Gilead Announces Update on Phase 3 Study of Oral Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients
Read more.....

Mar 8
Interferon-free regimen cures 100% of hard-to-treat hepatitis C
By: PATRICE WENDLING Internal Medicine News Digital Network

ATLANTA – Adding ledipasvir to sofosbuvir and ribavirin produced sustained virological responses 12 weeks after therapy in 100% of treatment-naive and prior nonresponder patients with chronic hepatitis C genotype 1 in the ELECTRON trial.

"Certainly adding a second direct-acting antiviral agent, ledipasvir, increases the efficacy of sofosbuvir plus ribavirin," Dr. Edward Gane said at the Conference on Retroviruses and Opportunistic Infections.
 
Three-quarters of the roughly 170 million people infected with hepatitis C virus (HCV) worldwide have genotype 1, the most difficult strain to treat.
 
Current treatment includes triple therapy with a protease inhibitor plus peginterferon and ribavirin for 24-48 weeks, but PI-based therapy is limited by complex dosing regimens, the potential for resistance, and lower responses in prior nonresponders, explained Dr. Gane of Auckland Clinical Studies in New Zealand.
 
The investigators hypothesized that combining two direct-acting antivirals with a different mechanism would enhance response.
 
At last year’s CROI meeting, Dr. Gane reported that treatment with the nucleotide NS5B inhibitor sofosbuvir (formerly known as GS-7977) and ribavirin alone led to early viral load suppression, but relapses within 4 weeks of stopping treatment resulted in 12-week posttreatment sustained virological response (SVR12) rates of 84% among treatment-naive patients and only 10% among previous interferon-based therapy null responders.
 
In the current arm of the trial, the NS5A inhibitor ledipasvir (formerly known as GS-5885) was added to sofosbuvir and weight-based ribavirin, all for 12 weeks, in 25 noncirrhotic treatment-naive and 9 null responders, defined by less than a 2-log reduction in HCV RNA after 12 weeks of peginterferon and ribavirin.
 
The majority of treatment-naive and null responders were genotype 1a (80% and 89%) and had high baseline HCV RNA loads (mean 5.9 log10 IU/mL and 6.9 log10 IU/mL). The more favorable IL28B genotype CC genotype was present in 36% of treatment-naive patients, but in no null responders. The patients median age was 48; 94% were white.
 
Early on–treatment viral suppression was very rapid, with all treatment-naive patients and all but one prior null responder having an undetectable viral load at week 4, Dr. Gane said. This patient’s load was on the threshold at week 4 and became undetectable by week 5, resulting in SVR12 rates of 100% in both groups.
 
No viral breakthroughs were observed, and all patients achieved an end-of-treatment response.
Unlike the earlier arm of the trial, however, both groups maintained undetectable HCV viral loads at 4 and 12 weeks after therapy, he said.
 
The triple combination was well tolerated and safe. Three serious adverse events occurred, but none were treatment related. One patient had to stop therapy at week 8 due to the event, but subsequently achieved SVR24. The most common adverse events were anemia (20%), depression (8%), and headache (4%), and all were in treatment-naive patients.
 
Grade 3 laboratory abnormalities occurred in 52% of the treatment-naive and 22% of null responders. No grade 4 abnormalities were seen, Dr. Gane said.
 
Ledipasvir and sofosbuvir have been combined into a single fixed-dose tablet and is being evaluated in phase III studies in patients with cirrhosis and to determine whether there is a need for ribavirin, he said. Additional studies are also underway to explore shorter durations of therapy.
ELECTRON was sponsored by Gilead Sciences. Dr. Gane reported ties with Gilead, Janssen-Cilag, Novartis, Pharmasset, Roche and Vertex.
 
Also view - 2013-Interferon Free Combinations
Additional updates @ NATAP‏

Gilead-Medivir Hepatitis C Drug Clears Virus in Patients


Gilead-Medivir Hepatitis C Drug Clears Virus in Patients

By Ryan Flinn & Shannon Pettypiece

An automated machine works on purification of a potential hepatitis C virus drug candidate at the Gilead Sciences Inc. lab in Foster City,

California. Photographer: David Paul Morris/Bloomberg

An experimental drug combination from Gilead Sciences Inc. (GILD), Medivir AB (MVIRB) and Johnson & Johnson (JNJ) eradicated the virus that causes hepatitis C in patients with the liver disease in a study.

The trial’s 80 patients, who had tried and failed other medications, took a two-drug mixture of Medivir’s simeprevir and Gilead’s sofosbuvir, according to research presented at the Conference on Retroviruses and Opportunistic Infections today in Atlanta. The patients took the combination for 12 or 24 weeks, with and without the antiviral ribavirin, researchers said.

“We went for the most difficult to cure, with the idea if we could show good efficacy there, it could be assumed the regimen could be efficacious in other patient populations,” Gaston Picchio, hepatitis disease area leader for J&J’s Janssen unit, said in a telephone interview. Medivir, based in Huddinge, Sweden, is working with J&J to develop simeprevir.

The interim results showed that among the 10 patients who had been off the treatment for 12 weeks, all of them still had their virus suppressed.

Gilead, Medivir and J&J are competing with Abbott Laboratories (ABT), Bristol-Myers Squibb Co. (BMY), Merck & Co. (MRK) and Vertex Pharmaceuticals Inc. (VRTX) to develop a new generation of oral hepatitis C treatments. The goal is to eliminate the standard therapy that requires ribavirin and an injection of interferon, an immune-boosting protein that can cause flu-like side effects for as long as 48 weeks.
Fewer Effects

Hepatitis C affects about 150 million people worldwide, according to the World Health Organization. The new drug regimens in testing are designed to be taken as pills, with shorter treatment durations and fewer side effects.

“Sofosbuvir continues to look like a backbone treatment,” said Brian Skorney, an analyst with Robert W. Baird & Co in a note to clients. “These results support our belief that sofosbuvir’s profile allows it to be combined with virtually any active HCV agent and eliminate the need for interferon and ribavirin.”

Gilead rose 1 percent to $43.87 at the close of trading in New York. The shares of the Foster City, California-based company had gained 87 percent in the past 12 months. Medivir climbed 3.8 percent to 90 kronor.

Gilead Therapy

While Gilead is unlikely to pursue a partnership with Medivir and J&J since the company is developing a combination of its own therapies, doctors may prescribe the pair reported in the study off-label, Brian Abrahams, an analyst with Wells Fargo Securities in New York, said in a note today.

“Of course, this would depend on pricing of the two components and payer acceptability, though with elimination of interferon and possibly ribavirin costs and side effects and substantial sustained virologic responses we believe the would likely be amenable,” Abrahams wrote.

Vertex is also testing an experimental drug, VX-135, with Medivir’s Simeprevir, and today’s clinical trial results could make that combination more likely, if no safety issues emerge, Abrahams said.

To contact the reporters on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net; Shannon Pettypiece in New York at spettypiece@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

http://globalregulatoryscience.com/2013/03/27/gilead-medivir-hepatitis-c-drug-clears-virus-in-patients/

Home Drugs Gilead-Medivir Hepatitis C Drug Clears Virus in Patients

Integrated Psych Care for High-Risk Hep C Patients May Increase Antiviral Treatment


By Rob Goodier

NEW YORK (Reuters Health) Mar 26 - Hepatitis C patients who have psychiatric disorders and problems with substance abuse may benefit from integrated care, a new study has found.

More patients in integrated care began antiviral treatment and achieved a sustained viral response in a trial of 365 patients at three Veterans Affairs medical centers, according to research presented March 20th at the annual meeting of the Society of Behavioral Medicine in San Francisco by Dr. Erick Groessl and a team at the University of California, San Diego and VA San Diego.

"This is just the kind of smart study that addresses the heightened focus in healthcare on identifying interventions that will really work in the real world," said Dr. Kathy Goggin, a psychologist at the University of Missouri-Kansas City who was not involved in the study.

In email to Reuters Health, she added, "Reducing patient burden while improving outcomes is good for everyone and will likely lead to significant cost savings."

The research team screened 1167 patients at the three HCV clinics. Of these, 65% were eligible for antiviral treatment and had psychiatric and/or substance use risk factors. Ultimately, 365 patients were randomized to either integrated care or usual care.

In this high-risk cohort, 51% were homeless at some point five years before treatment, 50.4% were risk-positive for post-traumatic stress disorder, and the mean Beck Depression Index score was 15.34, which indicates mild depression.

Patients who were randomized to receive integrated care were 1.6 times more likely to initiate antiviral therapy at all three treatment centers, at 32.4% compared to 19.7% (p=0.006).

More than twice as many patients achieved a sustained viral response in the integrated-care group, at 24 patients compared to 11 (13.2% vs 6.0%; p=0.016). "It is very important to remember that this is the SVR rate among all people randomized for the study," Dr. Groessl told Reuters Health. "That rate is a function of percent treated and the SVR rate among those treated." For example, he said, 59 patients in the integrated care group were treated, and their SVR rate was roughly 40%. In the usual care group, 36 patients were treated, and their SVR rate was roughly 30%.

There were also fewer deaths in the integrated-care group, at six, compared to 11 in the usual-care group (3.3% vs 6.0%; p=0.022).

"This model has been studied at three VA sites, so we plan to study the implementation of the program at additional VA sites and non-VA sites in the near future," Dr. Groessl said.

Possible barriers to the future adoption of this model of care may be inherent organizational differences at different health care centers and also the potential need for new funding for clinical staff. "We will address both of these factors in our planned implementation study," Dr. Groessl said.

http://www.medscape.com/viewarticle/781460

Vitamins A, D deficiencies common among patients evaluated for liver transplantation

Vitamins A, D deficiencies common among patients evaluated for liver transplantation

  • March 27, 2013
Most liver transplant candidates are vitamin A- and vitamin D-deficient, with bilirubin levels, BMI and Child-Turcotte-Pugh class predictive of vitamin A deficiency, according to a recent study.Researchers performed a retrospective chart review of 63 patients who underwent liver transplantation at a single medical facility between January 2008 and September 2011. Demographic information was collected and levels of vitamins A, E and 25-OH-D were assessed, along with BMI, MELD score and Child-Turcotte-Pugh (CTP) class.

Full Story »

Triple Therapy: Once-Daily Ribavirin Promising for Hepatitis C

Medscape Medical News > Conference News

Once-Daily Ribavirin Promising for Hepatitis C

Megan Brooks
Mar 26, 2013

For patients with hepatitis C virus receiving triple therapy, once-daily ribavirin dosing does not increase gastrointestinal adverse effects, and most patients prefer it over twice-daily dosing.

This finding comes from a study presented at the International Conference on Viral Hepatitis (ICVH) 2013 in New York City, which was sponsored by the International Association of Providers of AIDS Care and the Icahn School of Medicine at Mount Sinai.

Ribavirin is approved for twice-daily or divided dosing, but many of the new antivirals in the pipeline for hepatitis C will be taken once daily. "For convenience, we were interested in looking at once-daily ribavirin dosing," said presenter Kian Bichoupan, who is a graduate student at the Icahn School of Medicine at Mount Sinai in New York City.

"The half-life of ribavirin is 2 weeks," he explained, "so there is no reason to suspect there is any difference between taking it once a day or twice a day. Any opportunity that we have to make it easier for patients to take ribavirin would be attractive."

Bichoupan and colleagues conducted a study to assess adverse effects associated with twice-daily and once-daily weight-based ribavirin.

They used a structured interview and reviewed patient medical records to examine ribavirin dosing, changes in dosing over time, dosing preferences, and gastrointestinal (GI) adverse effects such as nausea, diarrhea, and vomiting. "We chose GI side effects because they are known to be more related to ribavirin," Bichoupan explained.

The study cohort consisted of 58 patients receiving telaprevir-based triple therapy and 16 receiving boceprevir-based triple therapy. Mean age was 59 years and time on treatment was about 25 weeks.
Patients can potentially take once-daily ribavirin and have fewer side effects and better adherence.

Adverse events were fairly common; 46% of patients required epoetin alfa for anemia, 9% received transfusions, and 14% visited the emergency department — mostly for anemia-related issues.

However, there was no statistical difference between once-daily and twice-daily ribavirin dosing in the frequency or percentage of patients with GI adverse effects, the investigators report.

GI symptoms were no worse in the once-daily group than they were in the twice-daily group, and most patients preferred taking ribavirin only once a day.

In patients who switched from twice-daily dosing to a lower once-daily dose, the prevalence of nausea, vomiting, and diarrhea was lower, which was "interesting," Bichoupan said.

In addition, this trial confirms what other trials have shown — "that ribavirin dose reductions do not have an impact on sustained virologic response," he noted.

"These results are promising. Patients can potentially take once-daily ribavirin and have fewer side effects and potentially better adherence," Bichoupan said. This is a small observational study, he acknowledged, and a randomized controlled trial is needed to confirm the findings.


Mark Nelson, MD, from Chelsea and Westminster Hospital, London, the United Kingdom, who is also ICVH 2013 conference cochair, told Medscape Medical News that "with the advent of new once-daily therapies, both with and without interferon, and the potential necessity of ribavirin as part of the regimen, the potential for using ribavirin once daily without increase in toxicity should lead to improvements in adherence and the potential, therefore, of even better results than currently seen in clinical practice."

This study was funded by Kadmon Pharmaceuticals. Mr. Bichoupan has disclosed no relevant financial relationships. Coauthor Valérie Martel-Laferrière, MD, from the Icahn School of Medicine at Mount Sinai, was funded by the 2011 AMMI Canada/Pfizer Post Residency Fellowship and the 2012 Grant of the CHUM Foundation. Coauthor Douglas Dieterich, MD, also from the Icahn School of Medicine, reports relationships with Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharpe & Dohme, ViiV Healthcare, and AbbVie.

International Conference on Viral Hepatitis (ICVH) 2013: Abstract 30. Presented March 25, 2013.

Update on Phase 3 Study of Oral Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients‏

Gilead Announces Update on Phase 3 Study of Oral Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients

Date(s): 26-Mar-2013 8:30 AM

For a complete listing of our news releases, please click here

-- Enrollment in ION-1 Study Continues Following Planned DSMB Review --
 
FOSTER CITY, Calif.--(BUSINESS WIRE)--Mar. 26, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today provided an update on ION-1, a Phase 3 clinical trial evaluating a once-daily fixed-dose combination of the nucleotide sofosbuvir and the NS5A inhibitor ledipasvir with and without ribavirin (RBV) for 12 or 24 weeks among treatment-naïve genotype 1 patients with hepatitis C virus (HCV) infection (n=800). A planned review by the study's Data and Safety Monitoring Board (DSMB) of safety data from 200 patients in all four arms and of SVR4 rates (sustained virologic response four weeks after completion of therapy) from 100 patients in the two 12-week duration arms concluded that the trial should continue without modification. This recommendation is based upon the observed SVR4 rates exceeding the predefined threshold of 60 percent and the absence of significant safety issues. Enrollment of the remaining 600 patients in ION-1 is now underway.
Sofosbuvir/ledipasvir is also being evaluated in a second Phase 3 study, ION-2, initiated in January 2013, which is now fully enrolled. ION-2 is evaluating sofosbuvir/ledipasvir with RBV for 12 weeks, and with and without RBV for 24 weeks, among 400 treatment-experienced genotype 1 HCV patients. Participants in this study failed to respond to past therapy containing pegylated interferon (peg-IFN) or peg-IFN plus a protease inhibitor.
Sofosbuvir, ledipasvir and the sofosbuvir/ledipasvir fixed-dose combination are investigational products and their safety and efficacy have not yet 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 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 possibility of unfavorable longer-term results from the ION-1 study, the possibility that the proportion of patients who maintain a sustained virologic response with longer follow up will not be as favorable as the SVR4 rates observed in the study, and the possibility of unfavorable results from ION-2 and other ongoing and subsequent clinical trials involving sofosbuvir and the fixed-dose combination of sofosbuvir/ledipasvir. In addition, Gilead may make a strategic decision to discontinue development of sofosbuvir, ledipasvir and/or the fixed-dose combination regimen if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. As a result, these compounds may never be successfully commercialized. 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 detail in Gilead's Annual Report on Form 10-K for the year ended December 31, 2012, 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)‏

Hepatitis C- Interferon free regimens for the “difficult-to-treat”: Are we there?

Related-Interferon-free regimen cures 100% of hard-to-treat hepatitis C

Journal of Hepatology
Volume 58, Issue 4 , Pages 643-645, April 2013

Maria-Carlota Londoño, Sabela Lens, Xavier Forns PII: S0168-8278(13)00021-4
DOI: http://dx.doi.org/10.1016/j.jhep.2013.01.007

Interferon free regimens for the “difficult-to-treat”: Are we there?

Developments in the treatment of chronic hepatitis C over the last 2years have been remarkable. For the first time ever, we are now certain that this chronic infection can be cured without the need of interferon and ribavirin. Gane and colleagues provided the proof of concept that oral antiviral therapy with two direct-acting antivirals (DAAs) without interferon can suppress viral replication [1]. In their study, they showed that the combination of an NS5B nucleoside polymerase inhibitor (RG7128) and an NS3 protease inhibitor (danoprevir) had potent antiviral activity even in null responders; some patients achieved undetectable HCV-RNA only 14days after treatment initiation. Unfortunately, the combination of DAAs in this study was limited to 2weeks and was followed immediately by treatment with peginterferon and ribavirin, thus preventing the assessment of sustained virological response to an interferon-free regimen [1]. The combination of the protease inhibitor asunaprevir with the NS5A inhibitor daclatasvir is the first oral interferon-free regimen proved to be effective [2], [3]. In the study by Lok et al. [3], 11 previous null responders received both drugs for 24weeks and a total of 4 patients (2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) achieved a sustained virologic response (SVR). In the study by Chayama et al. [2], 11 genotype 1b null responders underwent the same interferon-free regimen and the 9 individuals who completed 24weeks of therapy achieved SVR.

In this issue of the Journal of Hepatology, Suzuki et al. [4] evaluated the efficacy of dual therapy with asunaprevir and daclatasvir in 43 subjects infected with genotype 1b considered poor candidates for current treatment for hepatitis C (21 null responders and 22 ineligible or intolerant to interferon-based therapy). SVR at 12 and 24weeks was 90% for null responders and 64% for ineligible/intolerant to interferon-based therapies. Treatment was well tolerated and virological failures were only observed in the cohort of ineligible/intolerant patients (3 breakthroughs and 4 relapses). In the accompanying manuscript, Karino et al. [5] characterized the escape viral mutations in patients experiencing virological failures. The authors found that NS3 and NS5 resistance-associated variants (RAVs) were detected together at the time of virological failures.

One of the strengths of the study of Suzuki et al. [4] is that it deals with difficult-to-treat patients: well-documented null responders and patients who are intolerant or ineligible to interferon. Although the latter group was rather heterogeneous (individuals older than 70years, with depression or other co-morbidities), this profile of patients represents a significant proportion of our current candidates to antiviral therapy. Obviously, the combination of peginterferon, ribavirin and a first generation protease inhibitor (boceprevir or telaprevir) is not an option for patients with absolute contraindications to interferon and it is also a poor choice for individuals with co-morbidities or those who are old. In Japan and China, hepatitis C virus expanded decades before that of the United States and Europe [6]. Therefore, candidates to antiviral therapy in Asia are often older than corresponding patients in Western countries. Older age is not an absolute contraindication for an interferon-based therapy. A French group showed good efficacy in a small group of patients older than 65years treated with pegylated interferon and rivabirin [7]. Nevertheless, other studies have demonstrated a trend towards lower SVR rates, as well as higher rates of dose reductions and discontinuations of therapy in this population as compared to younger individuals [6], [8]. Currently, there are no data on the safety and efficacy of triple therapy in old patients. In the CUPIC French cohort, cirrhotic patients up to 83years old have been included: though the number of severe adverse events using triple therapy seems clearly higher than those reported with peginterferon and ribavirin alone [9], a specific analysis in older patients has not been performed.

Similarly, triple therapy is not an ideal alternative for most previous null responders, since SVR rates in this subpopulation rank only between 30% and 40% [10], [11]. Moreover, subgroup analyses from the REALIZE study [10] suggest that in cirrhotic null responders SVR is below 15%. In order to accomplish the definition of “difficult-to-treat” patients, it would have been interesting if the study by Suzuki et al. had included patients with advanced liver disease (biopsy-proven cirrhosis was an exclusion criterion).

Response rates obtained in this study using daclatasvir and asunaprevir can be considered excellent. It is surprising though, that the only virological failures reported were in the group of intolerant/ineligible patients [5]. Although the small number of patients precludes any definitive interpretation, there are several potential explanations. Firstly, it is important to notice that 10 out of the 21 null responders (sentinel cohort) received a significantly higher dose of asunaprevir, which was not the case in any of the 22 intolerant/ineligible individuals. Second, patients experiencing virological failure had below-median daclatasvir and asunarpevir levels, but this was also the case for other individuals who achieved sustained viral clearance. A lack of compliance did not seem to play a major role in the lower efficacy in this group (though cannot be completely excluded). A more interesting hypothesis is the potential effect of pre-existing resistance-associated variants (RAVs). In a complementary manuscript, Karino et al. [5] performed a careful characterization of virological escape mutants in patients included in the first study. Interestingly, most patients experiencing viral breakthrough or relapse had daclatasvir RAVs at baseline, being NS5A-Y93H the predominant polymorphism in all 3 patients with virological breakthrough and in 2 of the 4 relapsers. The global prevalence of this variant is around 4% [5], [12] and may be higher in genotype 1b-infected patients (∼10%). Indeed, NS5A-Y93H was found at baseline in five other patients who achieved SVR in this study.

In every patient with virological failure, resistant variants to both agents emerged together at the time of failure (NS3-D168A/V and NS5A-L31M/V-Y93H). At baseline, a combination of these NS3 and NS5A variants was not detected by clonal sequencing; however, their presence at low levels cannot be excluded due to the limited number of clones analyzed. Currently, assessment of minor NS3 plus NS5A RAVs from the same RNA sequence is not possible by ultra-deep sequencing technologies, since the size of the analyzed fragments is still a limitation (a fragment of ∼4000 base pairs encompassing NS3, NS4 and NS5A is far too large for the current technology).
A final point analyzed in the accompanying manuscript by Karino et al. was the persistence of RAVs after treatment interruption [5]. This is a very relevant topic, since it may impact future treatment options in patients who develop drug resistance. As reported with other protease inhibitors, asunaprevir-resistant NS3-D168 substitutions generally decayed during the follow-up period, which implies a lack of replicative fitness compared to the wild type virus in the absence of selective pressure (drug). This was also reproduced in the replicon system, where double NS3 RAVs (D168V plus Q80L or S122G) had a replicative ability similar to the D168V variant alone. Obviously, a more thorough sequence analysis using ultra-deep pyrosequencing would be necessary to fully establish the dynamic decay of these RAVs, after treatment interruption and to make sure that these variants do not remain enriched for longer periods relative to baseline. In fact, a small study including 5 patients who were first treated with simeprevir monotherapy (5days), and then retreated more than 1year later with pegylated interferon, ribavirin and simepervir, analyzed the potential clinical implications of the presence of RAVs. In this study [13], 3 patients achieved SVR and 2 did not. Deep sequencing indicated low-level persistence of simeprevir RAVs in the 2 patients who did not achieve SVR. We do not know if the presence of these resistant strains at low levels explained the lack of response to re-treatment. What is really interesting in the study by Karino et al. [5] is that in some individuals, NS5A variants associated with daclatavir resistance persisted for at least 48weeks after treatment interruption. As already mentioned, longer follow-up studies are important to establish the clinical impact of these more fitted resistant strains in case these patients will be retreated with NS5A inhibitors.

Overall, the ideal combination of DAAs is still unknown, but some of the inherent characteristics of the antiviral agents may help predict which combination will be more effective (Table 1). The inclusion of a nucleo(s)tide NS5B polymerase inhibitor in a combination seems reasonable [14]. These drugs offer a high barrier to resistance (RAVs have a very poor fitness), are pangenotypic and have proved to be very effective in several phase 2 trials. The simple combination of sofosbuvir and ribavirin for 12weeks appears to be extremely successful in naïve genotype 1, 2 or 3 patients (though this combination using such a short regimen is insufficient to cure previous null responders) [15]. Combinations including more than 2 DAAs targeting different viral proteins also seem a good approach. Recently, a study including both naïve and null responder genotype 1 patients assessed the efficacy of ABT450/r (ritonavir-boosted NS3 inhibitor), ABT267 (NS5A inhibitor), ABT 333 (NS5B non nucleoside inhibitor) and ribavirin. This combination achieved SVR12 rates close to 100% in naives and around 90% in null responders [16]. Unfortunately, patients with advanced liver disease have not yet been included in these studies. The only data regarding cirrhotic patients treated with oral regimens comes from the SOUND-C2 study, where an NS3 protease inhibitor (faldaprevir), a non-nucleoside NS5B inhibitor (BI207127) and ribavirin were combined in genotype 1 naïve patients: reported SVR12 rates in cirrhotics were around 60% [17].

Table 1. Characteristics of direct antiviral agents approved for hepatitis C treatment or entering phase 3 studies.

Genotypes in parenthesis indicate documented activity in vitro.

Within the next few years, we will certainly witness more progress. When choosing a combination of antiviral agents, we will need to take into consideration a certain number of variables: potency, genetic barrier to resistance, range of activity (pangenotypic or not), potential drug–drug interactions. Importantly, safety and simplicity of the regimen will also be very relevant. Up to now, most of the oral compounds appear to be safe and well tolerated by most patients, but until large phase 3 studies are finished, safety needs to be closely monitored. Most of our current knowledge on interferon-free regimes is based on phase 2 trials including small numbers of patients. Added to which, we still have very little information on the safety and efficacy of these regimens in difficult-to-treat subjects, particularly in null responders with advanced fibrosis or cirrhosis, or in special populations such as transplant patients with hepatitis C recurrence. Over the next 2–3years, we will start to see data on large cohorts (phase 3 studies) and in small series of really difficult-to-treat individuals and in special populations. By then, it will be easier to answer the question: “are we there?”.

 
Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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