March 31, 2014

WHO to launch first-ever guidelines on hepatitis C treatment

07:30 - 08:30, Thursday, 10 April 2014

The International Liver Congress 2014, London ExceL, United Kingdom

The Global Hepatitis Programme is organizing a satellite session on the launch of the first-ever WHO guidelines for Hepatitis C treatment.

The satellite session will focus on evidence, recommendations and implications with a line-up of speakers from the Burnet Institute, Médecins Sans Frontières, the World Hepatitis Alliance and WHO.

The session will be held at the upcoming International Liver Congress 2014 in London on 10 April. The Congress will take place from 9-13 April 2014.

Download

Flyer of the event pdf, 50kb

Source

March 31, 2014 12:59 PM Eastern Daylight Time

MONTREAL--(BUSINESS WIRE)--New hepatitis C (HCV) treatment regimens have advanced rapidly in recent years, including the recent Health Canada approval of interferon-free therapy. To support patients to access these newest options, Pendopharm, a division of Pharmascience Inc., today announced that it has received a Priority Review designation from Health Canada for the first stand-alone ribavirin tablet for the Canadian market.

“New HCV treatment regimens, specifically in genotypes 2 and 3 where we can now eliminate interferon, have the potential to transform HCV treatment in Canada”

In Canada, ribavirin, a component of the current standard of care for the treatment of HCV, is only approved in a format that is co-packaged with pegylated interferon. As such, Pendopharm has sought Health Canada approval of the first stand-alone ribavirin to support the treatment of HCV. Health Canada has granted Pendopharm a Priority Review given the need for single-agent ribavirin in new and evolving HCV treatments.

Gilead Sciences Canada, Inc.’s Sovaldi® (sofosbuvir), the most recent HCV treatment to receive a Notice of Compliance from Health Canada, is the first treatment regimen that now allows some patients to eliminate interferon entirely. Sovaldi is a once-daily direct-acting antiviral agent for the treatment of genotypes 1 and 4 in combination with pegylated interferon and ribavirin, and in genotypes 2 and 3 in combination with ribavirin alone. Patients with genotypes 2 and 3 represent an estimated 30 per cent of HCV cases in Canada.

Responding to Patient Treatment Needs

Pendopharm and Gilead Sciences share a mandate to address medical areas of high unmet need and burden of illness, as well as to improve the quality of life of patients. “Pendopharm and Gilead Sciences are pleased to be part of the solution to bring the newest HCV interferon-free treatment regimens to physicians and patients,” commented Élise Vézina, Vice President and Division Head, Pendopharm, and Edward Gudaitis, General Manager, Gilead Sciences Canada, Inc. “Upon Health Canada approval of our ribavirin, we will work diligently with provinces to support timely access for patients,” added Ms. Vézina.

Hepatitis C is an emerging and costly public health issue, but many Canadians are not aware that HCV can be cured. It is estimated that more than 250,000 Canadians have chronic hepatitis C infection. Hepatitis C is the leading cause of liver cancer and liver transplantation in Canada. Combined with the indirect costs of HCV, the financial burden of the disease in Canada is estimated at $500 million annually.1

“New HCV treatment regimens, specifically in genotypes 2 and 3 where we can now eliminate interferon, have the potential to transform HCV treatment in Canada,” said Jordan Feld, MD, MPH, Staff Hepatologist, Toronto Western Hospital, Department of Medicine, Division of Gastroenterology. “Interferon has been the main stumbling block to treatment in the past. New regimens without interferon are a huge advance, giving us higher cure rates and shortened treatment duration with a lot fewer side effects. This gives us our best opportunity to successfully treat and cure Canadians with hepatitis C,” added Dr. Feld.

Company Information

Pendopharm is a division of Pharmascience Inc., a Canadian privately-owned company. Established in 1983, Pharmascience Inc. is the largest pharmaceutical company in Quebec, with a highly-skilled workforce of 1,300 people. It commercializes nearly 300 products, including branded prescription, OTC and BTC products as well as generic products in Canada and with its affiliates and distributors in Europe, Asia, Middle East, Africa and Oceania.

Strategically committed to growth, Pendopharm (www.pendopharm.com) is actively engaged in licensing, partnering, developing and marketing late-stage specialty prescription medicines as well as consumer brands.

Gilead Sciences, Inc. 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 Sciences has operations in North and South America, Europe and Asia Pacific. Gilead Sciences Canada, Inc. is the Canadian affiliate of Gilead Sciences, Inc. and was established in Mississauga, Ontario in 2005.

References:
1. Public Health Agency of Canada. The Evaluation of Hepatitis C http://www.phac-aspc.gc.ca/publicat/2008/er-re-hepc/er-re-hepc1-eng.php. October 17, 2013.

Contacts

Pendopharm
Élise Vézina, 514-340-9800 ext. 3482

Source

Gilead says has discounted hepatitis C drug for some health plans

By Deena Beasley
Sat Mar 29, 2014 12:13pm EDT

(Reuters) - Gilead Sciences Inc, under fire for pricing a new hepatitis C drug at $1,000 a pill, has discount agreements with a number of health insurers, a company executive said in an interview.

The medication, Sovaldi, has a list price of $84,000 for a 12-week course of therapy and is seen as a breakthrough in the treatment of the serious liver disease.

It has been shown to raise cure rates and cut treatment time with fewer side effects than older medicines, but critics maintain that a price of $1,000 each is too high for an easy-to-make pill needed by millions of Americans.

On March 20, Democratic lawmakers led by California Representative Henry Waxman asked Gilead to explain the price tag, and a meeting with the company is scheduled for next week.

Health insurers and state Medicaid programs for the poor are pushing for further discounts, fearing a multibillion-dollar pricetag from treating most hepatitis C sufferers with Sovaldi and similar new medicines likely to be approved in coming years.

Gilead shares have dropped 9 percent in the last week on concerns over the pushback on drug pricing. The news has also weighed on other biotechnology companies that are banking on their ability to command high prices for new treatments.

"It's the volume (of patients) payers are looking at here. It's not the price," said Gregg Alton, Gilead's executive vice president, corporate and medical affairs. "A lot of them are looking for a discount, but I think the real issue here is how many patients they now have in their plans that need hepatitis C treatment."

The Centers for Disease Control and Prevention estimates that about 3.2 million Americans are infected with hepatitis C, a liver-destroying virus transmitted through blood.

If each were treated with full-priced Sovaldi, the cost would be $269 billion. Gilead already provides a mandated discount off its list price to U.S. government health plans and insurers at about 23 percent.

Alton said the company has deals for "supplemental discounts" for government-funded agencies such the Veterans Administration and the Department of Defense, on top of the 23 percent. He would not provide details.

He said the VA, which accounts for about 10 to 15 percent of the hepatitis C population in the United States, has been "proactive" in recognizing the need to treat the disease, which can lead to liver failure and necessitate liver transplants.

He estimated that patients eligible for Medicaid, the government-funded health plan for the poor, account for another 10 to 15 percent of Americans with hepatitis C.

Alton singled out health maintenance organization Kaiser Permanente for taking action to secure Sovaldi, also at a discount, for its patients.

"We have an arrangement with Kaiser that works very well for both of us," the Gilead executive said. "They recognize that if they make the investment today, they get all the benefit."

He said that is because many Kaiser patients stay for many years with the organization known for quality, integrated care, even into retirement when they qualify for a managed Medicare plan. So Kaiser's upfront investment treating hepatitis C will pay off years later by averting future costs of liver disease. Kaiser officials were not immediately available for comment.

But many traditional insurers can't rely on the same kind of stability among their policyholders, who tend to switch health plans more frequently, meaning they cannot be sure of the same savings over time.

"One of the challenges we have with some insurers is that the benefits may not come to them," the Gilead executive said. "No matter how we price this product, the benefits and the savings are going to come later."

Alton also sees the concerns over a deluge of patients demanding immediate treatment as unlikely to materialize.

"Most of the patients are not diagnosed, and many aren't seeking care currently," he said. "This is going to take some time."

ISI Group analyst Mark Schoenebaum noted on Friday data showing that new prescriptions of Sovaldi had dropped 5 percent in the past week. He estimated that Gilead's 2014 U.S. sales of Sovaldi, which was approved by the Food and Drug Administration late last year, will total as much as $9 billion even if it sees no new prescription growth.

(Reporting By Deena Beasley; Editing by Michele Gershberg, Tom Brown and David Gregorio)

Source

March 28, 2014

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Viral Hepatitis

Liesl M. Hagan1,*, Mark S. Sulkowski2 and Raymond F. Schinazi1

DOI: 10.1002/hep.27151

Copyright © 2014 American Association for the Study of Liver Diseases

Keywords: Olysio; Sovaldi; direct-acting antiviral agent; interferon-free

Abstract

Background: Treatment guidance for chronic hepatitis C (CHC) released by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) offer two options for interferon-ineligible/intolerant individuals with genotype 1 infection: sofosbuvir/ribavirin (SOF/RBV) for 24 weeks, or sofosbuvir/simeprevir (SOF/SMV) for 12 weeks. A 24-week course of SOF/RBV costs approximately US$169,000, with sustained virologic response (SVR) rates ranging from 52-84%; 12 weeks of SOF/SMV costs approximately $150,000, with SVR between 89% and 100%. Because SOF/SMV is currently used off-label, debate exists among physicians and payers about whether it should be prescribed and covered. This paper presents a cost-effectiveness analysis of these two treatment regimens accounting for costs of drugs, treatment-related medical care, re-treatment for individuals who do not achieve SVR, and natural history of continued HCV infection after failed re-treatment. The model uses a lifetime horizon and a societal perspective. Results: In the base case scenario, SOF/SMV dominated SOF/RBV in a modeled 50-year-old cohort of treatment-naïve and treatment-experienced subjects, excluding those who failed prior therapy with telaprevir or boceprevir. SOF/SMV yielded lower costs and more quality-adjusted life years (QALYs) for the average subject compared to SOF/RBV ($165,336 and 14.69 QALYs vs. $243,586 and 14.45 QALYs, respectively). In base case cost-analysis, the SOF/SMV treatment strategy saved $91,590 per SVR compared to SOF/RBV. Under all one-way sensitivity scenarios, SOF/SMV remained dominant and resulted in cost savings. Conclusions: These results suggest that a 12-week course of SOF/SMV is a more cost-effective treatment for genotype 1 CHC than 24 weeks of SOF/RBV among interferon-ineligible/intolerant individuals, supporting the AASLD/IDSA guidance and offering implications for both clinical and regulatory decision-making as well as pharmaceutical pricing. (Hepatology 2014;)

Source

March 27, 2014

-- If Approved, Once-Daily Tablet Would Simplify Therapy and Eliminate Need for Interferon and Ribavirin for Genotype 1 Hepatitis C Patients in Europe --

-- LDV/SOF Granted an Accelerated Assessment by the European Medicines Agency --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Mar. 27, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the company’s Marketing Authorisation Application (MAA) for a once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection, has been fully validated and is now under assessment by the European Medicines Agency (EMA). The data included in the application, which was submitted on February 27, 2014, support the use of LDV/SOF among adult patients with genotype 1 HCV infection for eight or 12 weeks, depending on prior treatment history and whether they have cirrhosis.

Genotype 1 is the most prevalent form of HCV in Europe, and accounts for 60 percent of infections worldwide. Current treatments for genotype 1 HCV include pegylated interferon and ribavirin (RBV), which may not be suitable for certain patients.

“Based on the results of the Phase 3 ION studies, LDV/SOF has the potential to transform HCV therapy for genotype 1 patients by eliminating the need for interferon injections and ribavirin and reducing the duration of treatment,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer. “If approved, LDV/SOF would be the first all-oral treatment option that has the potential to cure HCV in as little as eight weeks.”

The MAA for LDV/SOF is supported by three Phase 3 studies, ION-1, ION-2 and ION-3, in which nearly 2,000 genotype 1 HCV patients were randomized to receive the fixed-dose combination, with or without RBV, for treatment durations of eight, 12 or 24 weeks. Trial participants included patients who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens, and patients with compensated cirrhosis.

Review of the MAA will be conducted under the centralized licensing procedure, which, when finalized, provides one marketing authorization in all 28 member states of the European Union. The EMA has accepted Gilead’s request for accelerated assessment of LDV/SOF, a designation that is granted to new medicines of major public health interest.

LDV/SOF is an investigational product and its safety and efficacy has not yet been established. Although accelerated assessment of this investigational fixed-dose combination could shorten EMA’s review time by approximately two months, it does not guarantee a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) or final approval by the European Commission. If approved, LDV/SOF could be available for marketing in the EU by the end of 2014. Gilead has also submitted regulatory applications for LDV/SOF in the United States and Canada.

SOF as a single agent was granted marketing authorization in the European Union on January 16, 2014 under the tradename Sovaldi®, and is available in the United Kingdom, Ireland, Germany, France, Austria, Sweden and Finland. Sovaldi is also approved in the United States, Canada, New Zealand and Switzerland.

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 the European Commission and other regulatory agencies, including in the United States and Canada, may not approve the LDV/SOF fixed-dose combination in the currently anticipated timelines or at all, and any marketing approvals, if granted, may have significant limitations on its use. Further, additional clinical studies of LDV/SOF, including results from the 24-week arms of ION-1, may produce unfavorable results. As a result, Gilead may not be able to successfully commercialize LDV/SOF, 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 detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 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.

EU full prescribing information for Sovaldi is available at www.ema.europa.eu.

Sovaldi is a registered trademark of Gilead Sciences, Inc.

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.

For Gilead Sciences, Inc.
Patrick O’Brien, Investors
+1-650-522-1936
or
Cara Miller, Media (U.S.)
+1-650-522-1616
or
Arran Attridge, Media (Europe)
+44-208-587-2477

Source

Liver transplant chances tied to distance from center

By Andrew M. Seaman
NEW YORK  Fri Mar 28, 2014 12:00am IST

(Reuters Health) - People who live the farthest from liver transplant centers may be less likely to get on a waiting list, and ultimately to get a liver, than those who live closer, according to a new U.S. study.

The findings illustrate some of the potential unintended consequences of centralizing medical resources for specialized care, according to the study's authors.

"When designing these systems, it's important to keep this geography issue (as) an important feature," Dr. David Goldberg told Reuters Health. "Otherwise, it could get lost."

Goldberg is the study's lead author from the Hospital of the University of Pennsylvania in Philadelphia.

He and his colleagues note in the Journal of the American Medical Association that centralizing healthcare is a way to control costs, concentrate expertise and limit differences in the quality of care between regions.

While those approaches may be efficient, any benefit could be offset by patients having to travel long distances to access the care, they point out.

To see whether distance to centralized care is connected to outcomes for patients, the researchers analyzed data on liver patients within the Department of Veterans Affairs (VA).

The VA has five liver transplant centers nationwide, but veterans with additional insurance, such as Medicare, can use other transplant centers.

The researchers analyzed VA liver transplant records from 2003 to 2010. Overall, they had data on 50,637 veterans who were potentially eligible for transplants. Some 6 percent were put on waiting lists for a new liver - about half of those at VA transplant centers.

Of the patients receiving care at VA hospitals within 100 miles of a VA transplant center, about 7 percent were waitlisted at the VA centers and about 10 percent were waitlisted at any center.

That compared to about 3 percent having been waitlisted at VA centers and about 5 percent waitlisted at any center when veterans were being treated more than 100 miles from the closest VA transplant center.

Once on a waiting list, those veterans who were living farther away from a transplant center were less likely to get transplants, too.

And the likelihood of a liver patient dying over a five-year period rose with distance.

For example, a veteran living within 25 miles of a VA transplant center had about a 63 percent chance of being alive five years later, compared to about a 60 percent chance among people living more than 100 miles from a VA transplant center.

Organ transplant programs are highly specialized and organically require centralization, the authors acknowledge. Doctors would want patients available after a liver transplant for close monitoring and visits up to several times a week, Goldberg said.

It's possible that people living farther away from the VA transplant centers are less likely to even be evaluated for transplants because of the long distance, the researchers suggest. Alternatively, it could be that the transplant cannot move forward because patients and their families can't or won't relocate closer to the centers.

"While this issue of centralizing care may have many potential positives by concentrating expertise in one area, there are these unintended consequences that need to be considered," Goldberg said.

The study is not intended to be an indictment of the VA's transplant system, he added. In fact, the VA has approved the creation of two new transplant centers.

"I think that is one thing the VA should be credited for," Goldberg said.

SOURCE: bit.ly/1gtH8D4 JAMA, online March 25, 2014.

Source

March 26, 2014

The Promise of New HCV Therapies

HCV Next, January/February 2014

Your guide to the age after interferon

NewDrug

The future of treatment for hepatitis C virus infection is exciting. Many new drugs and combination therapies are moving rapidly through clinical trials and are becoming part of the conversation for FDA approval. The most recently approved tools at the disposal of clinicians are sofosbuvir and simeprevir, oral therapies that are associated with high cure rates.

The fast pace of development begs the question of whether an interferon-free future is near. Interferon has been the backbone of HCV treatment since it was approved by the FDA in 1991 for the treatment of HCV. In 1998, the addition of ribavirin to interferon was approved. Since the approval of pegylated interferon in 2001, the gold standard of treatment has been pegylated interferon with ribavirin with or without a protease inhibitor. However, the downsides associated with interferon, including adverse effects, need for careful monitoring and the fact that some patients are ineligible for treatment, and have left many desiring an interferon-free regimen.

Yet, interferon therapy is not quite a thing of the past. The approach figures into several recommended treatment options featured on HCVguidelines.org, the website recently launched by the American Association for the Study of Liver Diseases and Infectious Diseases Society of America, in collaboration with the International Antiviral Society-USA, which will serve as the clinical guidelines for HCV treatment in the United States (See Feature). However, a range of non-nucleoside polymerase inhibitors, nucleoside/nucleotide polymerase inhibitors, NS5A inhibitors, protease inhibitors and combinations thereof have demonstrated such overwhelmingly encouraging cure rates across genotypes in clinical trials that many believe the days of interferon are numbered.

The FDA has acted accordingly and provided accelerated 6-month approval status for several combination therapies. The speed with which new therapies are evolving has raised some eyebrows in the clinical community, but Donald M. Jensen, MD, said the development process is working exactly as it should.

“The duration of therapy is shorter with many of these drugs,” said Jensen, who is professor of medicine and director of the Center for Liver Diseases at University of Chicago Medical Center. Most combinations are being studied for 8 to 12 weeks of therapy and 12 weeks of follow-up.

“This has made the development of agents much quicker than with pegylated interferon and ribavirin-based therapies,” Jensen, a co-chair on the HCVguidelines.org panel, said. “The time factor has allowed for big breakthroughs and has opened the door for a number of combinations to be still in the game — not on the sideline.”

Andrew J. Muir, MD, MPH, associate professor of medicine and clinical director of hepatology at Duke University, put the issue in clinical terms: “The concern is not the pace of the FDA-approval process. The concern is that patients are dying of cirrhosis and liver cancer. We now have the tools to stop this disease and end pain and suffering.”

HCV Next spoke with several experts about the current drug pipeline. Their insights may help clinicians who treat this disease prepare for 2014 and beyond.

Continue reading full article here …..

The HCV Revolution Did Not Happen Overnight

ACS Medical Chemistry Letters

Ann D. Kwong *
InnovaTID, Inc., 125 Cambridge Park Drive, Cambridge,
Massachusetts 02140, United States

ACS Med. Chem. Lett., 2014, 5 (3), pp 214–220
DOI: 10.1021/ml500070q
Publication Date (Web): February 27, 2014
Copyright © 2014 American Chemical Society

*E-mail: ann.kwong@innovatid.org. Phone: 617-501-3453.

Abstract

The progress in HCV therapy in the last three years is similar to the progress that took HIV therapy 14 years. We are at the brink of approval for an all-oral drug combination that is dosed once daily as a single pill, has >95% efficacy, and is well tolerated. This article summarizes the path to this success and the challenges still ahead.

Looking back at the last 20 years in HCV drug discovery, I am struck by how fast the progress has been in recent years, and how slow it was in the early years. This viewpoint will attempt to identify some of the factors that contributed to both effects, in the hope that the knowledge will inform and accelerate future drug discovery.

HCV Revolution

The past decade was an exciting time in the world of hepatitis C virus (HCV) drug discovery. By 2011, over 50 companies worked on HCV, and in 2013, more than a dozen were conducting phase 2 and phase 3 clinical trials.(1) The past few years saw rapid progression toward “the Holy Grail” of HCV: an all-oral, highly tolerable therapy with a >95% cure rate for all chronic HCV infections. The FDA approved two first-generation HCV protease inhibitors in 2011, then a second-generation HCV protease inhibitor and a HCV polymerase nucleotide inhibitor in 2013. In addition, excellent phase 3 data has been reported for several all-oral drug combinations, which may launch in 2014 (Figure 1). Treatment success rates improved from 40% in 2001 to 79% in 2011 and 89% in 2013, with multiple phase 3 trials with oral combinations reporting efficacy rates above 95%. Remarkably, increased efficacy of the new regimens came without increased toxicity or less tolerability.

ml-2014-00070q_0001

Figure 1. Nonhead-to-head comparison of efficacy vs duration of HCV treatment regimens for different HCV genotypes as a function of the year of regulatory approval. The data reported are derived from multiple sources and different clinical trials and are shown side-by-side for pedagogical purposes and should not be construed to be definitive numbers. Efficacy (blue columns): the % sustained viral response (SVR), i.e., the % cure rate. A patient is said the be “cured” or have a “SVR” if their plasma HCV RNA levels become undetectable during treatment and remain undetectable for 24 weeks after the end of treatment. Duration (yellow columns): the total length of time a patient is on antiviral therapy, not just the length of time a patient is receiving a direct acting antiviral (DAA) drug. All the treatment durations shown in the graph were 12, 24, or 48 weeks. Geno, genotype; IFN, interferon; PR, pegylated interferon alfa 2a/b and ribavirin; RBV, ribavirin; DAA, direct acting antiviral.

Unmet Medical Need

HCV is a blood borne pathogen that chronically infects 170 million people. Thorough screening of blood supplies has significantly reduced new infections. Globally, the incidence of disease and the market for HCV drugs are inversely related. The Western Pacific, Southeast Asia, and Africa regions have the highest prevalence, with 126 million infections and no access to the new HCV drugs. However, the US and EU have 13 million chronic HCV infections, which are the target market for the new HCV drugs. Worldwide, treatment is complicated because HCV occurs in 6 major genotypes, which affect drug sensitivity and are unevenly distributed geographically and between income levels (Figure 2B).

ml-2014-00070q_0002

Figure 2. Breakdown of HCV-associated advanced liver disease in the US in 2008. (A) Time line of the development of HCV-associated liver disease. (B) Distribution of HCV genotypes by World Bank income regions. HCV has evolved into 6 major strains or genotypes that differ genetically from each other, which may result in a slightly different amino acid sequence in the region comprising and supporting the binding site of an antirviral drug. Therefore, drugs developed to inhibit genotype 1 HCV, the major genotype found in high-income and upper-middle income regions, might not inhibit genotypes found in the rest of the world such as genotypes 2–6. Panel B is taken from a poster entitled “Global distribution of HCV by prevalence and genotype” distributed by the Center for Disease Analysis (www.centerforda.com) at the 64th Annual Meeting of the American Association for the Study of Liver Diseases, Nov 1–5, 2013, Washington, DC (reproduced with permission from Homie Razavi). (C) 2008 US prevalence of HCV advanced advanced liver disease by age cohort. Upper graph: Each column breaks out the number of people with different types of advanced liver disease by age cohort (i.e., the blue box in the lower graph). The order of the types of advanced liver disease is the same for each age cohort. The number of patients (in thousands) with cirrhosis is shown in orange, decompensated cirrhosis is shown in green, liver cancer is shown in dark blue, liver transplant is shown in red, and liver cancer/transplant is shown in purple. Lower graph: Each column denotes the total number (in thousands) of people chronically infected with HCV in the US in 2008 as a function of age cohort. The upper portion of each column (dark blue) denotes the number of people with advanced liver disease.

A person can have a chronic HCV infection for decades with no obvious symptoms. Unfortunately, the longer a person is infected with HCV, the higher the chance of developing liver fibrosis, cirrhosis, failure, portal hypertension, and cancer. Typically, these symptoms occur over a period of 20–30 years (Figure 2A).

The good news is that, unlike infections with HIV and HBV, HCV can be cured. The bad news is that the majority of people infected do not know they have an HCV infection. In 2008, of the 2.68 million people in the US with chronic HCV infection, 59% were undiagnosed.(2) Figure 2C (bottom) shows the prevalence of advanced liver disease (dark blue box) in the diagnosed population as a function of age. These data reveal that baby boomers, born between 1945 and 1964, account for 75% of newly diagnosed chronic HCV patients and 84% of advanced liver disease patients. The upper graph in Figure 2B shows that the majority of advanced liver disease is decompensated cirrhosis, followed by cirrhosis. For perspective, although liver cancer represents a small fraction of advanced liver disease cases, it represents the fastest growing cancer death rate in the US. These data suggest that baby boomers are at high risk of progressing to advanced liver disease and support the CDC’s recommendation for targeted screening of this cohort.

Three Waves of HCV Drug Creation

Over the last 27 years, advances in three areas have enabled direct-acting antiviral drugs for HCV to move forward: (i) research and discovery, (ii) development, and (iii) approval and commercialization (Figure 3).

ml-2014-00070q_0003

Figure 3. HCV antiviral targets and a comparison of HCV and HIV drug creation timelines. (A) Schematic illustration of multiple steps in the HCV virus lifecycle that can be the target of an antiviral drug. IRES, internal ribosome entry site. (B) Comparison of HIV and HCV drug development time lines. POC, proof of concept; non-nuc, non-nucleotide; nuc, nucleotide; IFN, interferon alfa 2a/b; R or RBV, ribavirin; P, pegylated interferon alfa 2a/b; PR, pegylated interferon alfa 2a/b plus ribavirin.

First Wave (Research and Discovery) of HCV Drug Creation

The first wave from 1987–2002 set the foundation for the clinical development work that followed (Figure 2B). HCV replication can be inhibited at several different points in the lifecycle, by targeting either viral or host functions. As a consequence, more than 40 different treatment options are either in the market or in clinic trials; reviewed in refs 1 and 3. The crystal structures of the HCV NS3·4A protease and the NS5B RNA polymerase set a strong foundation for rational structure-based drug design, which in turn was critical for optimizing protease potency and allosteric binding. The development of the HCV replicon system in 1999(4) fueled an explosion in the scientific understanding of the HCV life cycle and enabled the development of high-throughput replicon cell-based assays. The replicon assay was used to identify a potent novel class of inhibitors that target the NS5A replication complex.(5)

Comparison of HCV and HIV Drug Development

In the past few years, rapid advances in the development of HCV drugs have looked like HIV drug development on speed, but is this a fair comparison? As shown in Figure 3, the first HIV drug was approved 3 years after the virus was identified as the etiological agent of AIDS. Since that time, the FDA approved 26 different direct-acting antiviral drugs or combinations targeting four different HIV drug targets (protease, reverse transcriptase, entry, and integrase).(1, 6) In contrast, it took 24 years after HCV was discovered for the first direct-acting antiviral drugs to be approved and 27 years for four combinations to be approved against two HCV targets (protease and polymerase).

Why Did It Take so Long for HCV DAAs to Be Developed?

Multiple factors that slowed the development of direct-acting HCV drugs included:4

• low perceived market value and a poor potential return on investment

• no tools to test the ability of compounds to inhibit HCV replication in vitro in cultured cells

• expensive licensing fees for reagents

• low pressure from patient lobbies

• a belief that all-oral treatment for HCV would never work because HCV was a liver disease, not a viral disease, and interferon would always be required.

• a poor understanding of the nature of HCV resistance to drugs led to the misconception that HCV could be successfully treated with monotherapy drugs like HSV or CMV drugs. In contrast, HCV is more like HIV and requires a multidrug combination to suppress resistant variants.

• a belief that all nucleoside/tide polymerase inhibitors are toxic, despite the fact that they are the backbone of HIV, HSV, CMV, and HBV antiviral therapy.

What Factors Increased the Speed of Research and Discovery for HCV Direct-Acting Antiviral Drugs?

The mantra of those who moved these drug combinations forward the fastest was “It’s the virus, stupid,” focusing on inhibiting HCV at multiple points in the virus lifecycle (Figure 3A) without going through a combination phase with PEGylated interferon and ribavirin. Finally, a critical, but less well-known, decision by regulatory authorities to permit drug companies to use the HCV replicon assay instead of an infectious virus assay or an animal model significantly increased the speed of development of all-oral combos.

Second Wave (Development) of HCV Drug Creation

The second wave lasted between 2003–2010 when HCV clinical virology and the clinical development path for HCV direct-acting antiviral drugs were set. The early development of the interferon-based drugs demonstrated that HCV could be cured and set the paradigm for treating a patient for a period of time after their HCV virus becomes undetectable and then monitoring for viral relapse after the end of treatment.

What Factors Increased the Speed of Developing HCV Direct-Acting Antiviral Drug Development?

With the dual goal of increasing the cure rate and reducing the duration of treatment, researchers designed novel clinical trials to explore the two parameters in the same study, rather than sequentially as had been traditional. In addition, clinical pharmacology modeling based on viral kinetics, population analyses, and pharmacokinetics was used to justify study design and to add subpopulations to the product label that were not explicitly tested. HIV research led to the use of HCV viral RNA levels as a primary end point in clinical trials, instead of following an indirect effect (ALT levels), and to the use of combinations of direct-acting antiviral drugs to combat resistance. This is exemplified by phase 3 data that revealed that three different combinations could cure patients with HCV: a protease inhibitor plus a NS5A inhibitor; a polymerase nucleotide inhibitor plus a NS5A inhibitor; and a protease inhibitor plus a polymerase allosteric inhibitor plus a NS5A inhibitor (Figure 1 and Table 1).

ml-2014-00070q_0004

Table a Three classes of HCV regimens (pegylated interferon + ribavirin (PR)), DAA + PR, and all oral DAA combos) are compared on the basis of efficacy, duration, dosing interval, dose size, price, mechanism of action (target), and compound structure. Only genotype 1 results and regimens with publically available compound structures were included. The price listed is a best-guess estimate based on publically available sources. SVR, sustained viral response; wks, weeks; DAA, direct acting antiviral; TID, 3 times a day dosing; BID, twice daily dosing; QD, once daily dosing; mg, milligram; NA, not available.

Another important factor that accelerated the development of HCV clinical study design and resistance studies was the founding of HCV DrAG, a collaboration between the major stake holders: academia, pharmaceutical companies, regulators, and community representatives.(7) HCV DrAG played a major role in facilitating the creation of new FDA and EMA guidances, which permit the combination of two or more unapproved drugs.

Short monotherapy proof-of-concept studies performed with inhibitors of HCV protease, NS5A, and HCV polymerase demonstrated that HCV replication could be inhibited in the absence of PEGylated interferon and ribavirin. Figure 3B lists some of the groundbreaking proof of concept studies. None of the development programs that were the first to demonstrate clinical proof of concept actually became approved drugs, illustrating the difficulty and risk inherent in creating drugs.

The first three HCV direct-acting antiviral drugs to be approved, telaprevir, boceprevir, and simeprevir, were protease inhibitors that had a low barrier to resistance, requiring them to be combined with PEGylated interferon and ribavirin to treat genotype 1 patients (Table 1). A nucleotide inhibitor of HCV polymerase, sofosbuvir followed, also in combination with PEGylated interferon and ribavirin for genotypes 1 and 4 patients. Sofosbuvir has a high barrier to resistance and was approved as an all-oral combination with ribavirin for patients with genotypes 2 and 3. The next two classes of compounds were polymerase non-nucleotide allosteric inhibitors (ABT-333) and NS5A replication inhibitors (daclatasvir, lepidipasvir, and ABT-267). In order to increase the barrier to resistance, the all-oral combinations shown in Figures 1 and 3 and Table 1 all include direct-acting antiviral agents with at least two different mechanisms of action. By focusing directly on developing an all-oral approach, bypassing developing a combination with PEGylated interferon and ribavirin, the time required to launch an all-oral combination was shortened.

Third Wave (Approval and Commercialization) of HCV Drug Creation

The third wave started in 2011. In this wave the FDA approved the first new antiviral regimen for chronic HCV in a dozen years. Two first generation direct-acting antiviral HCV protease inhibitors, telaprevir and boceprevir, were approved for used in combination with PEGylated interferon and ribavirin for patients with genotype 1 chronic HCV infection.(8) Patients and prescribers welcomed the greater efficacy and shorter treatment compared to PEGylated interferon and ribavirin (Figure 1 and Table 1).

It is well-known that the long path to drug approval has a high attrition rate. Only 10–20% of all compounds that enter the clinic are approved. Less well-known is the fact that 80% of approved drugs are not profitable.(9) What drives market success? Compared to boceprevir, telaprevir had similar potency, slightly better efficacy, slightly worse side effects, a simpler dosing regimen, lower pill burden, a higher price, and a newly built commercial operation. No one predicted what happened: telaprevir significantly outsold boceprevir with $2.11 billion for telaprevir vs $0.114 billion for boceprevir for the period between Q3 2011 to Q4 2012 and become the fastest drug in history to reach a billion dollars in sales. Why was telaprevir so successful? In my opinion, multiple reasons include, but are not limited to, higher efficacy, faster decline in HCV RNA in the first four weeks, lower pill burden, better dosing regimen, simpler treatment paradigm, experienced sales force and account managers, good patient copay support, and a great scientific story.

As is common with first generation drugs, there was significant room for improvement. Drawbacks of telaprevir and boceprevir included low efficacy rates in some patient populations, high pill burdens, significant serious side effects, and three times a day dosing (Table 1). The beginning of the endgame in the US and EU was revealed when Gilead announced phase 3 results, in which genotype 1 chronic HCV patients treated with 12-weeks of a once-daily fixed dose combination of an HCV polymerase nucleoside inhibitor (sofosbuvir) and NS5A inhibitor (ledipasvir) achieved a 96% cure rate.

Next Hurdle(s)

Now that potent and safe HCV direct-acting antiviral drugs are in hand, what are some of the outstanding issues?

Diagnosis and Treatment

In the US, most people with chronic HCV infection do not know they are infected. If these patients are not treated, many will develop advanced liver disease that will be costly and may be impossible to cure. An analysis of the HCV-associated nonpharmacological costs in the US between 2007 and 2009 showed that the rise in advanced liver disease more than doubled the overall growth in US healthcare costs (9.4% vs 4.3%).(2) However, if all of the currently undiagnosed people were to seek treatment, the current medical infrastructure will be overwhelmed. Now is the time to invest in diagnosis and treatment to avert a future avalanche of HCV-related advanced liver disease and associated costs.

Cost

The all-oral HCV therapy, highly efficacious and tolerable in the majority of patients, will become available in 2014. Like all new drugs, the new HCV treatment regimens are expensive. In the developed world, finding a price that works for all parties, patients, providers, payers, governments, and the pharmaceutical company, will be critical. The majority of people with chronic HCV infection do not live in the US, EU, and Japan, the primary market for current HCV drugs. We need a way to give patients in resource-poor countries access to effective HCV therapy despite their inability to pay high prices. I hope our industry will rise to the challenge to apply similar efforts to find a second Holy Grail: affordable access to curative HCV therapy for all, regardless of their country of residence or economic status.

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.

The authors declare no competing financial interest.

Acknowledgment

Many thanks to Amy Juodawlkis, Rosemary Camilleri, Alan Collis, and Daša Lipovšek for editorial assistance.

Abbreviations

AIDS acquired immunodeficiency syndrome
ALT alanine liver transaminase
CMV cytomegalovirus
EMA European Medicines Agency
EU European Union
FDA US Food and Drug Administration
HBV hepatitis B virus
HCV hepatitis C virus
HCV DrAG HCV drug development group
HIV human immunodeficiency virus
NS nonstructural
RNA ribonucleic acid

This article references 9 other publications.

References

1. Clayden, P., Collins, S., Daniels, C., Frick, M., Harrington, M., Horn, T., Jefferys, R., Kaplan, K., Lessem, E., and Swan, T., 2013 Pipeline Report. In HIV, Hepatitis C (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, Preventive Technologies, Research toward a Cure, and Immune-based and GeneTherapies in Development; Benzacar, A., Ed.; HIV i-Base and Treatment Action Group: New York, 2013; p 295. http://www.pipelinereport.org (accessed January 29, 2014).

2. Zalesak, M.; Francis, K.; Gedeon, A.; Gillis, J.; Hvidsten, K.; Kidder, P.; Li, H.; Martyn, D.; Orne, L.; Smith, A.; Kwong, A.Current and future disease progression of the chronic HCV population in the United States PloS One 2013, 8 ( 5) e63959 [CrossRef], [PubMed]

3. Hunt, D.; Pockros, P.What are the promising new therapies in the field of chronic hepatitis C after the first-generation direct-acting antivirals? Curr. Gastroenterol. Rep. 2013, 15 ( 1) 303 [CrossRef], [PubMed], [CAS]

4. Lohmann, V.; Korner, F.; Koch, J.; Herian, U.; Theilmann, L.; Bartenschlager, R.Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line Science 1999, 285 ( 5424) 110– 3[CrossRef], [PubMed], [CAS]

5. Gao, M.; Nettles, R. E.; Belema, M.; Snyder, L. B.; Nguyen, V. N.; Fridell, R. A.; Serrano-Wu, M. H.; Langley, D. R.; Sun, J. H.; O’Boyle, D. R., II; Lemm, J. A.; Wang, C.; Knipe, J. O.; Chien, C.; Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.; Hamann, L. G.Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect Nature 2010, 465 ( 7294) 96– 100[CrossRef], [PubMed], [CAS]

6. Flexner, C.HIV drug development: the next 25 years Nat. Rev. Drug Discovery 2007, 6 ( 12) 959– 66 [CrossRef], [PubMed], [CAS]

7. Forum for Collaborative HIV Research. HCV Drug DevelopmentAdvisory Group. http://www.hivforum.org/projects/hcv-drug-development-advisory-group.

8. Jacobson, I. M.; Pawlotsky, J. M.; Afdhal, N. H.; Dusheiko, G. M.; Forns, X.; Jensen, D. M.; Poordad, F.; Schulz, J.A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C J. Viral Hepatitis 2012, 19 ( Suppl 2) 1– 26 [CrossRef], [PubMed], [CAS]

9. Dorato, M. A.; Buckley, L. A. Toxicology Testing in Drug Discovery and Development. In Current Protocols in Toxicology; Wiley: New York, 2007; Chapter 19, Unit 19.1.

Source

Rifaximin reduced hepatic encephalopathy events in cirrhosis

Provided by Clinical Advisor

March 25, 2014

liver_0513webexclusives_375215

Patients assigned rifaximin experienced significantly fewer hepatic encephalopathy events compared with patients assigned placebo.

Rifaximin decreased hepatic encephalopathy episodes in patients with cirrhosis, new study findings show.

“[Rifaximin] is approved to treat urea cycle defects that prevent the removal of ammonia from the body,” Bruce F. Scharschmidt, MD, of Hyperion Therapeutics in San Francisco, said in a press release. “Our trial was the first to investigate the efficacy of a direct ammonia lowering agent in patients with cirrhosis and hepatic encephalopathy.”

The phase 2 study included 178 patients with cirrhosis, of which 59 were previously assigned rifaximin (XIFAXAN, Salix Pharmaceuticals). Researchers aimed to determine the proportion of patients with hepatic encephalopathy assigned twice-daily 6mL rifaximin vs. placebo.  

Patients assigned rifaximin experienced significantly fewer hepatic encephalopathy events when compared with patients assigned placebo (21% vs. 36%; P=0.02). The total number of hepatic encephalopathy events were lower in those assigned the medication (n=35) when compared with those assigned placebo (n=57).

Further, there were 13 total hospitalizations in the rifaximin arm vs. 25 hospitalizations in the placebo arm. Ammonia levels in the blood were lower in patients assigned rifaximin versus placebo.

Among those not previously treated with the drug before enrollment, rifaximin decreased the number of patients with a hepatic encephalopathy event (10% vs. 32%; P<0.01), the time to a first event (HR=0.29; P<0.01) and the total number of events (7 vs. 31; P<0.01).

“Our findings provide evidence that elevated blood ammonia plays an important role in the development of hepatic encephalopathy,” Scharschmidt said. “Rifaximin reduced the risk for hepatic encephalopathy in patients with cirrhosis and further investigation of its therapeutic potential for patients with hepatic encephalopathy is warranted.”

“The study shows that [rifaximin] improves the outcome among cirrhotic patients with highly recurrent hepatic encephalopathy,” Juan Cordoba, MD, and Meritxell Ventura-Cots, MD, both of the Hospital Vall Hebron in Barcelona, Spain wrote in an accompanying editorial. “The new drug avoids the risk for sodium overload, was well tolerated and had a good safety profile.”

References

  1. Rockey DC et al. Hepatology. 2014;59(3):1073-1083.
  2. Cordoba J. Hepatology. 2014;59(3):764-766.

Disclosure: See study for full list of disclosures.

Source

Researchers take mathematical route to fighting viruses

PUBLIC RELEASE DATE: 24-Mar-2014

Contact: David Garner
david.garner@york.ac.uk
44-019-043-22153
University of York

Mathematicians at the University of York have joined forces with experimentalists at the University of Leeds to take an important step in discovering how viruses make new copies of themselves during an infection.

The researchers have constructed a mathematical model that provides important new insights about the molecular mechanisms behind virus assembly which helps to explain the efficiency of their operation.

The discovery opens up new possibilities for the development of anti-viral therapies and could help in the treatment of a range of diseases from HIV and Hepatitis B and C to the "winter vomiting bug" Norovirus and the Common Cold. The research is published in the Proceedings of the National Academy of Sciences (PNAS).

The researchers led by Professor Reidun Twarock, of the Departments of Mathematics and Biology at York, have established a theoretical basis for the speed and efficiency with which viruses assemble protective protein containers for their genetic information – in this case an RNA molecule - during an infection.

By incorporating multiple specific contacts between the genomic RNA and the proteins in the containers, and other details of real virus infections, the research team's mathematical model demonstrates how these contacts act collectively to reduce the complexity of virus formation, thus solving a longstanding puzzle about virus assembly – a form of Levinthal's Paradox. This also ensures efficient and selective packaging of the viral genome and has evolved because it provides significant selective advantages to viruses that operate this way.

Professor Twarock, a member of the York Centre for Complex Systems Analysis (YCCSA), said: "This truly interdisciplinary effort has provided surprising insights into a fundamental mechanism in virology. Existing experimental techniques for studying viral assembly are unable to identify the cooperative roles played by all the important components, highlighting the need and power of mathematical modelling. This model is a paradigm shift in the field of viral assembly. It sheds new light on virus assembly in a major class of viruses and their evolution, and opens up a novel strategy for antiviral therapy."

Professor Peter Stockley, of the Astbury Centre for Structural Molecular Biology at the University of Leeds, added: "These results provide a new perspective for our understanding of virus assembly, highlighting important features in the process that had previously been overlooked. We have already obtained proof of principle in a simple model virus that these functions can be targeted by drugs. The new opportunities for anti-viral intervention opened up by our paper also apply to viruses for which therapeutic options are currently limited. The new approach is enticing because it enables us to target co-operative aspects of viral assembly that are conserved across different viral strains, making it less likely that drug therapy would elicit resistance mutations. "

###

The research was funded by Engineering and Physical Sciences Research Council, the Biotechnology and Biological Sciences Research Council and the University of York.

Source

Liver tumors: 3-D MRI scans better predict survival after chemo

03/25/2014

In a series of studies involving 140 American men and women with liver tumors, researchers at Johns Hopkins have used specialized 3-D MRI scans to precisely measure living and dying tumor tissue to quickly show whether highly toxic chemotherapy – delivered directly through a tumor’s blood supply – is working.

The investigators say their findings, to be presented March 22-27 in San Diego at the annual meeting of the Society of Interventional Radiology, are the first “proof of principle” that this technology can show tumors in three dimensions and accurately measure tumor viability and death. Early data was also presented at the Radiological Society of North America annual meeting, December 1-6 in Chicago.

They also say their results – in patients with either primary liver cancers or metastatic tumors from cancers originating elsewhere in the body -- are evidence that using this technology before and after treatment is a faster and better tool for predicting patient survival after chemotherapy targeted directly at tumors, called chemoembolization.

Unlike standard methods to assess tumor response after chemoembolization, which are based on two-dimensional images and tumor size, the Johns Hopkins-developed 3-D technology also distinguishes between dead and live tissue, giving an accurate assessment of tumor cell death.

The new technology builds on standard 2-D methods and uses computer analytics to evaluate the amount of so-called contrast dye absorbed by tumor tissue. The dye is injected into patients before their MRI scan to enhance image production. Researchers say live tissue will absorb more dye than dead tissue, affecting image brightness, which can also be measured for size and intensity.

“Our high-precision, 3-D images of tumors provide better information to patients about whether chemoembolization has started to kill their tumors so that physicians can make more well-informed treatment recommendations,” says Johns Hopkins interventional radiologist Jean-Francois Geschwind, M.D., the senior investigator on the studies.

Geschwind, a professor in the Russell H. Morgan Department of Radiology at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, says that knowing the true extent of a tumor’s response to chemoembolization is particularly important for patients with moderate to advanced stages of the disease, whose liver tumors might initially be too large or too numerous to surgically remove.

In the first study, researchers compared the standard imaging method and the newly developed technology in 17 Baltimore men and women with advanced liver cancer. All were treated with surgery or liver transplantation after chemoembolization. The research team used existing MR analysis techniques, as well as the new 3-D method to compare the radiologists’ analyses with pathologic review of tumor samples after therapy and surgical removal. The error margin of the new 3-D image analysis, they say, was low (at up to 10 percent) when predicting the amount of dead tumor tissue found by pathologists whereas the standard, 2-D method deviated by as much as 40 percent from actual values.

In a series of additional studies, Geschwind and his team used the standard and new imaging techniques to analyze the MRI scans of more than 300 liver tumors in some 123 other men and women, also from the Baltimore region. All patients were treated at The Johns Hopkins Hospital between 2003 and 2012, and each received pre- and post-chemoembolization MRI scans to assess the effects of therapy on the tumors.

Using the new 3-D method method, Geschwind’s team found that patients who responded well to therapy lived 19 months longer (an average of 42 months) than patients who did not respond well (average 23 month survival). Standard methods showed slightly less difference in survival (average 18 months longer) between patients who responded to therapy and those who did not respond.

Geschwind says the 3-D technology’s improved accuracy removes a lot of the guesswork that now goes into evaluating treatment outcomes. The new assessment takes seconds to perform, he adds, so radiologists can provide faster, almost instantaneous treatment advice.

Geschwind and his team plan further software refinements to the new approach before training more physicians to use it. He also has plans to study how it can affect treatment decisions, and whether these therapy choices help people live longer.

The software used in the MRI scans was developed at Johns Hopkins and at Philips Research North America, in Briarcliff Manor, N.Y. Philips, whose parent company is based in the Netherlands, manufactures some of the MRI devices used in the study.

Liver cancer kills nearly 20,000 Americans each year, and is much more prevalent outside the United States, where it is among the top-three causes of cancer death in the world. Experts cite the rising numbers of hepatitis C infections, which cause chronic liver inflammation and are a leading risk factor for liver cancer.

Funding support for this study was provided by the French Society of Radiology and Philips Research North America. Additional funding support was provided by the National Cancer Institute, and the National Center for Research Resources, both members of the National Institutes of Health (R01 CA160771, P30 CA006973, and UL1 RR 025005), and the Rolf W. Günther Foundation for Radiology and Radiological Sciences.

In addition to Geschwind, Johns Hopkins scientists involved in the study were Julius Chapiro, M.D., Rafael Duran, M.D., Laura Wood, M.D., Ph.D., Vania Tacher, M.D., Toby Charles Cornish, M.D., Ph.D., Nikhil Bhagat, M.D., Constantine Frangakis, Ph.D., Hooman Yarmohammadi, M.D., Michael Chao, M.Sc., Rongxin Chen, M.D., Ph.D., Zhijun Wang, M.D., Ph.D., and Vivek Charu, M.D., Ph.D. Additional research assistance was provided by MingDe Lin, Ph.D., a Philips biomedical engineer based at Johns Hopkins who has been collaborating with Geschwind for the past seven years on the new technology.

Abstracts described in this news release include:

SIR abstracts:

1830145 Quantitative 3-D Volumetric Assessment of Tumor Response after Intra-arterial Therapy of Colorectal Cancer Metastases to the Liver - a new surrogate marker for survival;
Scientific Session TACE IV, Wednesday 3/26 - 1:39 PM - 1:48 PM, Room 16 A

1859360 Uveal Melanoma Metastatic to the Liver: the Role of Quantitative and Functional MR Imaging in the Assessment of Early Tumor Response after TACE;
Scientific Session TACE I, Sunday 3/23 - 2:42 PM - Room 16 A

1831150 Radio-pathological correlation of 3-D-quantitative contrast-enhanced and functional MRI in HCC patients after TACE- do we see what we treat?
Scientific Session TACE II, Monday 3/24 - 9:03-9:12 AM - Room 16 A

RSNA abstract:

SSSC16-07 Volumetric Tumor assessment Predicts Survival in Patients Treated with Transarterial Chemoembolization for Hepatocellular Carcinoma

For additional information, go to:
http://www.sirmeeting.org/
http://www.hopkinsmedicine.org/vascular/staff/physicians/geschwind.html
http://www.hopkinsmedicine.org/vascular/procedures/chemoembolization/

Source

HIV and Hepatitis C vaccines now closer to reality

Published on March 26, 2014 at 5:01 AM

Plans for a new type of DNA vaccine to protect against the deadly HIV and Hepatitis C viruses have taken an important step forward, with University of Adelaide researchers applying for a patent based on groundbreaking new research.

Professor Eric Gowans from the University's Discipline of Surgery, based at the Basil Hetzel Institute at the Queen Elizabeth Hospital, has submitted a patent application for what he describes as a relatively simple but effective technique to stimulate the body's immune system response, thereby helping to deliver the vaccine.

While pre-clinical research into this vaccination technique is still underway, he's now searching for a commercial partner to help take it to the next stage.

Professor Gowans' work has focused on utilizing the so-called "accessory" or "messenger" cells in the immune system, called dendritic cells, to activate an immune response. These are a type of white blood cell that play a key role during infection and vaccination.

"There's been a lot of work done in the past to target the dendritic cells, but this has never been effective until now," Professor Gowans says. "What we've done is incredibly simple, but often the simple things are the best approach. We're not targeting the dendritic cells directly - instead, we've found an indirect way of getting them to do what we want."

Professor Gowans and his team have achieved this by including a protein that causes a small amount of cell death at the point of vaccination.

"The dead cells are important because they set off danger signals to the body's immune response. This results in inflammation, and the dendritic cells become activated. Those cells then create an environment in which the vaccination can be successful," Professor Gowans says.

Using a micro-needle device provided by United States company FluGen Inc., the researchers can puncture the skin to a depth of 1.5mm, delivering the vaccination directly into the skin. "We chose the skin instead of the muscle tissue, which is more common for DNA vaccines, because the skin has a high concentration of dendritic cells," Professor Gowans says.

Because the technique has the potential to translate to other, more common viruses in addition to the devastating HIV and Hepatitis C, the project attracted seed funding from The Hospital Research Foundation, and additional funding from the National Health and Medical Research Council (NHMRC).

The research is still in the pre-clinical phase, with a patient study due next year. "This technique has worked much better than I anticipated," Professor Gowans says. "We're now ready for a commercial partner to help us take this to the next phase, and we're in discussions with some potential partners at the moment."

Professor Gowans will present some of his work at the forthcoming 5th Australasian Vaccines & Immunotherapeutics Development Meeting (AVID2014), 7-9 May in Melbourne, Australia. Last month he was an invited speaker at the 23rd Australian Conference on Microscopy and Microanalysis (ACMM23) in Adelaide. A paper about this work has already been published recently in Immunology & Cell Biology.

SOURCE University of Adelaide

Source

New genetic targets IDed for HCV treatment

Provided by Clinical Advisor

March 20, 2014

DNA changes on the IFNL3 gene have been associated with better treatment responses and natural ability to clear infection among patients with hepatitis C infection.

genetics_0513blog_380766

Two single-letter DNA changes on the IFNL3 gene on chromosome 19 have been associated with better treatment responses and natural ability to clear infection among patients with hepatitis C infection, and may offer novel targets for therapy, according to researchers.

“[The IFNL3 gene], has received considerable attention in the field of HCV, as many independent genome-wide association studies have identified a strong association between polymorphisms near IFNL3 and clearance of HCV,” Ram Savan, PhD, assistant professor of immunology at the University of Washington in Seattle and colleagues reported in Nature Immunology. “However, the mechanism underlying this association has remained elusive.”

Previous study findings have shown that patients of Asian descent with HCV respond better to treatment when compared with those of African descent. So researchers pooled data from entire human genomes in hopes of identifying gene clusters associated with a response to therapy for HCV.

Two single-letter genetic variations on the IFNL3 gene located near an area that encodes for interleukin-28B, a cytokine known to play a role in the body's immune defense against viruses, may play a role in the body's ability to control HCV infection.

Individuals who carry the T (for thymidine) variant have an unfavorable outcome in fighting HCV, while those who carry the G (for guanosine) variant have a favorable outcome, the researchers found.

Their data showed that HCV could induce liver cells to target the activities of the IFNL3 gene with two microRNAs. MicroRNAs are silencers: They stop the messengers who transmit information to produce a protein from a gene, in this case the production of the antiviral interferon lambda-3.

These two particular microRNAs are generally turned off in liver cells, until HCV coerces them to act on its behalf. Normally, these so called myomiRs are associated with myosin-encoding genes in skeletal and heart muscle.

"This is a previously unknown strategy by which HCV evades the immune system and suggests that these microRNAs could be therapeutic targets for restoring the host antiviral response," the researchers wrote.

Adding support to this suggestion is the researchers' observation that the bad-acting microRNAs in question could not land on and repress interferon lambda-3, if the host carried the favorable "G" variant. In those cases, the host is able to escape adverse regulation by HCV, the researchers observed.

“Our data reveal a previously unknown mechanism by which HCV attenuates the antiviral response and indicate new potential therapeutic targets for HCV treatment,” the researchers concluded.

References

  1. McFarland AP et al. Nature Immun. 2014;15:72-81.

Disclosure: See study for full list of disclosures.

Source

March 24, 2014

Idenix

March 24, 2014

CAMBRIDGE, Mass., March 24, 2014 (GLOBE NEWSWIRE) -- Idenix Pharmaceuticals, Inc. (Nasdaq:IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced three poster presentations featuring clinical and preclinical data for the Company's nucleotide prodrug, IDX21437, and for samatasvir, Idenix's once-daily pan-genotypic NS5A inhibitor, at The International Liver Congress™ 2014, the 49th annual meeting of the European Association for the Study of the Liver (EASL), taking place in London, April 9-13, 2014. Full abstracts can now be viewed at the EASL Congress website.

The following abstracts will be presented in poster sessions during The International Liver Congress™ 2014 on Saturday, April 12, 2014, 9:00 am – 6:00 pm BST:

  • Poster No. 1244: Gupta et al. "Favorable Preclinical Profile of IDX21437, a Novel Uridine Nucleotide Prodrug, for Use in a Direct-Acting Antiviral (DAA) Regimen for HCV."
  • Poster No. 1221: Zhou et al. "Pharmacokinetic (PK) Drug-Drug Interaction between Samatasvir (IDX719), a Pan-Genotypic NS5A Inhibitor, and Simeprevir in Healthy Volunteers and HCV-Infected Subjects."
  • Poster No. 1222: Lawitz et al. "A Phase II Study of Samatasvir (IDX719) in Combination with Simeprevir and Ribavirin in Treatment-Naïve HCV-Infected Subjects with Genotypes 1b and 4 (HELIX-1 Study)."

ABOUT IDX21437

IDX21437, a next-generation uridine nucleotide prodrug inhibitor, has completed the single-dose portion of a phase I/II clinical trial and is currently being evaluated in the seven-day proof-of-concept portion of the trial, with results expected in the first half of 2014. Extensive preclinical testing for IDX21437 has demonstrated favorable antiviral activity across genotypes 1-6 and a safety profile which supported advancement into clinical trials. Based on this progress, the Company's goal is to initiate an Idenix-sponsored combination clinical trial of IDX21437 and samatasvir in mid-2014.

ABOUT SAMATASVIR

Samatasvir is an NS5A inhibitor with low picomolar, pan-genotypic antiviral activity in vitro. To date, samatasvir has been safe and well-tolerated after single and multiple doses of up to 150 mg in healthy volunteers up to 14 days duration, and in HCV-infected patients up to 12 weeks duration. There have been no treatment-related serious adverse events reported in the program. Samatasvir has demonstrated potent pan-genotypic antiviral activity in HCV-infected patients with mean maximal viral load reductions up to approximately 4.0 log10 IU/mL across HCV genotypes 1-4 in a proof-of-concept, three-day monotherapy study.

Under a non-exclusive collaboration with Janssen Pharmaceuticals, Inc., Idenix is evaluating all-oral, direct-acting antiviral HCV combination regimens including samatasvir, simeprevir (TMC435), a once-daily protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, and TMC647055/r, a once-daily non-nucleoside polymerase inhibitor boosted with low-dose ritonavir being developed by Janssen. In this program, Idenix is conducting two ongoing phase II 12-week clinical trials, HELIX-1 and HELIX-2.

ABOUT HEPATITIS C

Hepatitis C virus is a common blood-borne pathogen infecting three to four million people worldwide annually. The World Health Organization (WHO) estimates that more than 150 million people worldwide are chronically infected with HCV, representing a nearly 5-fold greater prevalence than human immunodeficiency virus.

ABOUT IDENIX

Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical Company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.

FORWARD-LOOKING STATEMENTS

This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the Company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "intends," "will," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the Company's potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of IDX21437, samatasvir or any other drug candidate; the successful development of novel combinations of direct-acting antivirals for the treatment of HCV; and the likelihood and success of any future clinical trials involving samatasvir, IDX21437or our other drug candidates. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the Company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; and the Company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in the Company's annual report on Form 10-K for the year ended December 31, 2013 as filed with the Securities and Exchange Commission (SEC) and in any subsequent periodic or current report that the Company files with the SEC.

All forward-looking statements reflect the Company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the Company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the Company's estimates change.

Idenix Pharmaceuticals Contact:
Teri Dahlman (617) 995-9807

Source

Mar 24, 2014

NORTH CHICAGO, Ill., March 24, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) will present new data from its phase III hepatitis C development program at the 2014 International Liver Congress™ (ILC) in London, April 9-13. Detailed results from the SAPPHIRE-I, SAPPHIRE-II, PEARL-III, and TURQUOISE-II studies will be presented at the ILC on April 10-12. 

In presentations at the ILC, investigators will share detailed data results of four studies from AbbVie's phase III clinical trial program, the largest phase III program of an investigational, all-oral, interferon-free regimen for the treatment of chronic hepatitis C virus (HCV) infection in genotype 1 (GT1) adult patients.

Following is a list of AbbVie's phase III clinical trial program data being presented at the ILC:

  • SAPPHIRE-II: Phase III Placebo-Controlled Study of an Investigational Interferon-Free, 12-Week Regimen in 394 Treatment-Experienced Adults with HCV GT1
    Oral Presentation: General Session 1 and Opening
    April 10, 14:00-14:15 BST; ICC Auditorium
  • SAPPHIRE-I: Phase III Placebo-Controlled Study of an Investigational Interferon-Free, 12-Week Regimen in 631 Treatment-Naive Adults with HCV GT1
    Oral Presentation: General Session 2 and Awards 1
    April 11, 10:15-10:30 BST; ICC Auditorium
  • PEARL-III: Sustained Virologic Response 12 Weeks Post-treatment (SVR12) with an Investigational 12-Week Regimen in 419 Treatment-Naive HCV GT1b-Infected Adults
    Late Breaker Poster: Poster P1299
    April 12, 9:00-18:00 BST; Poster Exhibition
  • TURQUOISE-II: SVR12 Rates in 380 HCV GT1-Infected Adults with Compensated Cirrhosis Treated with an Investigational Regimen
    Oral Presentation: Late Breakers
    April 12, 15:30-15:45 BST; ICC Auditorium

AbbVie will present additional data in presentations throughout the Congress. The full ILC 2014 scientific program can be found at www.ilc-congress.eu/.

About AbbVie's Investigational HCV Regimen
The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) with or without ribavirin (RBV) (weight-based), dosed twice daily. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing sustained virologic response (SVR) rates across different patient populations.

Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.

AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral regimen with and without RBV with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.

Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ³6.

See approved product labels for more information.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. 

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission.

AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

SOURCE AbbVie

For further information: Media: Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com; Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com; Investor Relations: Elizabeth Shea, +1 (847) 935-2211, elizabeth.shea@abbvie.com

Source