Will Dropping Interferon Be the Magic Bullet for Reducing HCV Mortality?

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Will Dropping Interferon Be the Magic Bullet for Reducing HCV Mortality?

Mark S. Sulkowski MD - 10/22/2012 More from this author

Let’s start with the basic premise that most individuals with chronic hepatitis C would like to be cured of this potentially life-threatening infection. If this premise is true, why then has the large majority of HCV-infected patients in the United States not been treated with previous and current standard therapies?

Infected but Unaware
First, the majority of HCV-infected Americans is unaware that they are infected. The new CDC recommendations that all persons born between 1945 and 1965 undergo a one-time HCV antibody test are the first step to address this issue but much more work is needed to implement this strategy. Clearly, we need more programs on the national, state, and local levels to identify infected persons and link them to HCV care that includes education about the infection, counseling regarding alcohol cessation, and careful consideration of treatment options.

Adverse Events With Interferon
Second, treatments based on interferon alfa are associated with adverse effects—sometimes quite severe—in nearly all people who receive this agent. Given that most HCV-infected patients do not experience symptoms related to HCV infection itself, I find the fact that treatment will likely cause a decrease in quality of life to be a tough sell on an individual patient level, particularly for those found to have minimal liver disease. Individuals who decline to take interferon alfa are often termed “interferon unwilling”; of course, to some degree, most humans are at least partially “interferon unwilling,” but some will take the therapy based on the potential for HCV cure and prevention of the deadly complications of liver disease.

Currently, my hepatitis C practice is really focused on deciding who needs treatment now with current therapies and who can wait until we see the approval of interferon-free regimens. The decision-making process includes assessment of the patient’s current liver disease; in other words, can they wait a few years until new therapies arrive? The other factor is a judgment call: Can this individual human being tolerate current therapies? I admit that this is not an objective measure; instead, this gestalt is based on comorbid conditions, social factors (family, work, major life events), and of course the person’s willingness to take current therapy. This is really the art of medicine in the application of a powerful but toxic therapy.

On a population level, the problem with interferon alfa is even greater, as multiple studies have found that many HCV-infected patients are “interferon unable,” meaning that these individuals have medical and/or psychiatric conditions that make the delivery of interferon unwise. For example, in a recent analysis for the US Veterans Affairs system, approximately 65% of veterans with chronic HCV infection were deemed ineligible for interferon alfa–based therapy. Could these patients be treated with an intense, multidisciplinary team effort? Maybe, but the point is that we can’t address the public health problem of hepatitis C without “better” therapies. In this case, better means safe, simple and effective.

Potential Solutions
Better treatments will undoubtedly improve the quality of life of patients undergoing HCV treatment as well as that of the healthcare providers who have become accustomed to keeping the ship afloat by treating depression and anemia as well as offering strong words of encouragement. I, for one, am looking forward to the day when the decision to treat is not so complex and I can tell more patients that they are cured—more payoff, less work! Will it be that simple? Short answer: Nope. Yes, many patients will successfully undergo HCV treatment but others will present more challenges—starting with finding them and linking them to care. If we are going to bend downward the trajectory of HCV-related death in the United States, we’ll need to harness significant resources to develop programs to cure hepatitis C.

Your Thoughts?
So, tell me your thoughts. What are the major barriers to uptake of HCV treatment in your practice? How do you think interferon-free regimens with address these barriers?

Mark S. Sulkowski, MD, is Professor of Medicine, Medical Director, Viral Hepatitis Center, Divisions of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Dr. Sulkowski has disclosed that he has received funds for contracted research paid to Johns Hopkins University and consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Roche, and Vertex.

Topics: HCV

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Hepatitis C - Response to Interferon-α/Ribavirin Does Not Decrease on Retreatment

Response to Interferon-α/Ribavirin Does Not Decrease on Retreatment of Hepatitis C

Among study participants with the same end-of-study response status, HCV RNA declines at 4 weeks were similar between treatment-naive patients and treatment-experienced ones.

Participants in treatment studies of hepatitis C virus (HCV) infection are generally categorized as treatment naive or treatment experienced, based on previous receipt of an interferon-based regimen such as pegylated interferon-α plus ribavirin (P/R). Treatment-experienced individuals with P/R treatment failure can be further subdivided into relapsers, partial responders, and null responders, based on plasma HCV RNA concentrations during and after therapy.

To date, no data have emerged to indicate resistance to interferon-α–based therapy, suggesting that the response rate to P/R should not be lower with retreatment than with initial therapy. To examine this issue, investigators at the FDA examined data for participants in eight earlier trials (2996 treatment-naive and 754 treatment-experienced patients with genotype-1 HCV infection who had completed P/R treatment and had week-4 viral load data available).

In both treatment-naive and treatment-experienced patients, the HCV RNA change from baseline at 4 weeks was strongly correlated with the likelihood of achieving a sustained viral response (i.e., an undetectable viral load 24 weeks after the end of treatment). When therapy response was compared between treatment-experienced patients (stratified according to previous treatment outcomes) and treatment-naive patients (stratified based on end-of-treatment outcomes), the 4-week decline in HCV RNA was similar between the corresponding groups.

Comment: Despite its retrospective nature, this study suggests that responsiveness to Interferon-α/Ribavirin  (P/R) does not decrease with retreatment. As the authors point out, this finding has implications for trials of interferon-based triple therapy — P/R plus one of the newer direct-acting antivirals emerging for HCV.

— Neil M. Ampel, MD

Published in Journal Watch Infectious Diseases September 19, 2012

Citation(s):

Liu J et al. Interferon responsiveness does not change in treatment-experienced hepatitis C subjects: Implications for drug development and clinical decisions. Clin Infect Dis 2012 Sep 1; 55:639.

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• Medline abstract (Free)

Flamel Technologies Medusa(R)-Formulated Interferon-Alpha Demonstrates Favorable Antiviral Activity and Safety in a Phase 2 Clinical Study

Flamel Technologies Medusa(R)-Formulated Interferon-Alpha Demonstrates Favorable Antiviral Activity and Safety in a Phase 2 Clinical Study

Completion of Enrollment Reached in Its On-Going Phase 2 Clinical Study

LYON, FRANCE, Jun 25, 2012 (MARKETWIRE via COMTEX) -- Flamel Technologies /quotes/zigman/60259/quotes/nls/flml FLML +1.22% today announced that its Medusa-formulated interferon-alpha ("IFN a-2b XL") was featured in a lecture and an oral presentation on June 25 at the 14th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD) held June 22-25, 2012 in Shanghai, China. The abstracts are entitled "Aggregate report on safety and efficacy of a new sustained release IFN (IFN XL) as compared to standard of care" and "Medusa formulated Interferon-alpha-2b Shows a Favorable Efficacy / Tolerability Profile vs. PEGylated IFN-alpha-2b in Hepatitis C Patients in the Phase 2 Study ANRS HC23 COAT-IFN." The abstracts presented by Professor Christian Trepo of Hopital de la Croix Rousse, Lyon, France, and Roger Kravtzoff, Preclinical and Clinical Director at Flamel Technologies, demonstrated a favorable antiviral activity and safety profile as compared with ViraferonPeg(TM) (marketed in the U.S. as PegIntron(TM)).

The abstracts presented the background, rationale and design of the on-going studies which are evaluating the therapeutic potential and safety of Flamel's Medusa-formulated IFN a-2b XL, a long acting, unmodified (in contrast to PEGylated interferons), fully active interferon injected once weekly in patients with chronic hepatitis C virus ("HCV") infection. The full presentation is available on Flamel's website at http://www.flamel.com/technology-platforms/medusa 

In addition, Flamel Technologies announced that it has reached its enrollment objective of 84 patients in its ongoing Phase 2 clinical study: ANRS HC23 COAT-IFN.

The principal investigator of the study, Professor Christian Trepo, remarked, "Preliminary results of this Phase 2 study are very consistent with those of Phase 1 and support the proof of concept of an improved tolerance without loss of efficacy of IFN XL. We believe this fulfills one of the most awaited needs for a future combination therapy."

Mike Anderson, Flamel's chief executive officer, stated, "Within the next five years, the number of HBV/HCV patients treated is expected to grow. In this context, the development of a new interferon formulation with good efficacy and better tolerance will be an important factor in hepatitis C treatment. Our formulation of Interferon-Alpha XL, a long acting formulation of Interferon-Alpha, is one of our more important development programs and is an example of the potential of the Medusa platform to improve the safety and efficacy of therapeutic proteins. In addition to seeing positive clinical data with our Medusa-formulated product candidate, we are grateful for the commitment of our clinical investigators to this important work and we look forward to their on-going participation in the trial."

Phase 2 Study Design 84 HCV patients have been treated in the on-going Phase 2 clinical study, randomized, three parallel-arm, comparative, open-label, multi-center study and were allocated to either IFN-a-2b XL, or PegIntron 1.5 ug/Kg, both in combination with weight based Ribavirin. Patients were each injected over a twelve-week period to compare the therapeutic potential and safety of IFN-a2b XL versus PegIntron in patients with chronic hepatitis C virus (HCV) infection (genotypes 1 and 4). This study was conducted on both naive and non-responder patients.

This Phase 2 clinical study is sponsored by Inserm-ANRS (French National Institute of Health and Medical Research -- French National Agency for Research on AIDS and Viral Hepatitis).
Summary of Results In the Phase 2 clinical study, the Medusa-formulated IFNa-2bXL at 27MIU has demonstrated a remarkably consistent safety profile across all available data. Improved tolerability of IFNa-2bXL was obtained in addition to good efficacy since the antiviral activity of IFNa-2bXL appears at least similar to that of reference Peg-IFNa-2b in a 3-month course of combined therapy.
Safety and Tolerability The available study data confirms the results obtained from previous clinical studies, indicating an improved tolerability of Medusa-formulated IFNa-2bXL at 27MIU compared to PegIntron. No serious adverse events were reported as definitely or probably attributable to Medusa-formulated IFN a-2b XL.

About IFN-alpha-2b XL IFN-alpha-2b XL is a new formulation of recombinant Interferon alpha-2b based on Flamel's proprietary Medusa hydrogel delivery system. Medusa is a versatile biodegradable carrier for the development of a wide range of novel and second-generation long-acting protein and peptide products. IFN-alpha-2b XL is designed to provide patients with a longer acting and more tolerable approach to interferon therapy compared with approved interferon regimens.
About Hepatitis C Hepatitis C virus is a blood-borne pathogen that causes inflammation of the liver. According to the U.S. Centers for Disease Control and Prevention (CDC), more than 75 percent of people infected with HCV will develop chronic infections, and 60 to 70 percent of these people will subsequently develop chronic hepatitis. HCV infection is the most common blood-borne viral infection in the United States. Approximately 4 million people in the United States are infected with HCV and the World Health Organization estimates that 170 million people worldwide -- 3 percent of the world's population -- are infected with HCV.

About Flamel Technologies Flamel Technologies SA /quotes/zigman/60259/quotes/nls/flml FLML +1.22% is a leading drug delivery company focused on the goal of developing safer, more efficacious formulations of drugs that address unmet medical needs. Its product development pipeline includes biological and chemical drugs formulated with the Medusa(R) and Micropump(R) proprietary platforms. Several Medusa-based products are at various clinical stages of development; Medusa's lead internal product candidate IFN-alpha XL (long-acting interferon alpha-2b) is being evaluated a Phase 2a trial in HCV patients. The Company has developed approved products and manufactures Micropump-based microparticles under FDA-audited GMP guidelines. Flamel Technologies has collaborations with a number of leading pharmaceutical and biotechnology companies, including GlaxoSmithKline (Coreg CR(R), carvedilol phosphate) and Merck Serono (long-acting interferon beta-1a). Flamel recently acquired Eclat Pharmaceuticals, a St. Louis, Missouri-based specialty pharmaceutical company focused on developing and commercializing niche brands and generic products. Additional information can be found at www.flamel.com

This document contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including certain plans, expectations, goals and projections regarding financial results, product developments and technology platforms. All statements that are not clearly historical in nature are forward-looking, and the words "anticipate," "assume," "believe," "expect," "estimate," "plan," "will," and similar expressions are generally intended to identify forward-looking statements. All forward-looking statements involve risks, uncertainties and contingencies, many of which are beyond our control that could cause actual results to differ materially from those contemplated in such forward-looking statements. These risks include risks that the acquisition of Eclat Pharmaceuticals will not be successful, the expected timing of the filing of our first New Drug Application (NDA) with the FDA may be delayed, the identified opportunities will not result in shorter-term, high value results, clinical trial results will not be positive or that our partners may decide not to move forward, management transition to a new chief executive officer may be disruptive or not succeed as planned, products in the development stage may not achieve scientific objectives or milestones or meet stringent regulatory requirements, products in development may not achieve market acceptance, competitive products and pricing may hinder our commercial opportunities we may not be successful in identifying and pursuing opportunities to develop our own product portfolio using Flamel's technology, and the risks associated with our reliance on outside parties and key strategic alliances. These and other risks are described more fully in Flamel's Annual Report on Form 20-F for the year ended December 31, 2011 that has been filed with the Securities and Exchange Commission (SEC). All forward-looking statements included in this release are based on information available at the time of the release. We undertake no obligation to update or alter our forward-looking statements as a result of new information, future events or otherwise.

SOURCE: Flamel Technologies
Copyright 2012 Marketwire, Inc., All rights reserved.

http://www.marketwatch.com/story/flamel-technologies-medusar-formulated-interferon-alpha-demonstrates-favorable-antiviral-activity-and-safety-in-a-phase-2-clinical-study-2012-06-25 

Timing, Duration of Biochemical Bugle Call Critical for Fighting Viruses

Timing, Duration of Biochemical Bugle Call Critical for Fighting Viruses

ScienceDaily (June 13, 2012) — Researchers have identified the primary player of the biochemical bugle call that musters the body's defenders against viral infection.Scientists at Washington University School of Medicine in St. Louis have shown that a key molecule, MDA5, is essential for producing enough interferon (the bugle call) to rally virus-fighting cells during certain viral infections. In mice, the lack of MDA5 forces the immune system to rely on less effective defenders, which may give the virus opportunities to establish or expand a chronic infection.

Like the cavalry charge in classic movies, timing is critical in fighting a viral infection. If a surge of interferon comes early enough, the immune system can limit or clear a virus. If the boost is too late, though, the defenses may already be overwhelmed.

"If an injection of interferon is given within a certain time frame in the infectious process, we found that it was possible to decrease viral spread and bolster antiviral CD8 T cell responses in our mouse model," says first author Yaming Wang, a predoctoral trainee in immunobiology. "Adding interferon may also boost the power of antiviral vaccines that are being designed to help the immune system recognize and attack chronic viral infections such as HIV."

The research appears June 14 in Cell Host and Microbe.

Viruses can cause both temporary and chronic infections. In chronic infections, the virus goes into periods of relative quiescence that limit its spread and diminish conflicts with the immune system. Those periods are often interrupted by flare-ups when the virus shifts gears and becomes more active again.

Interferon, which is made by the body in many forms, is named for its ability to interfere with viral replication. It is currently used with antiviral medications to treat patients with hepatitis C who are having flare-ups.

"Interferon puts cells into an antiviral state," says senior author Marco Colonna, MD, professor of medicine and of pathology and immunology. "This prevents viruses from infecting cells or reproducing in them."

Some forms of interferon also summon critical immune CD8 T cells to infection sites, where the T cells either fight the infection directly or store information about the virus to speed recognition if it returns.

Wang and his colleagues showed that MDA5 is the major source of interferon during a meningitis-type infection known as lymphocytic choriomeningitis virus.

Interferon production by a specialized immune cell, the plasmacytoid dendritic cell, dropped off rapidly within the first day of infection, but MDA5 continued to boost interferon production for three to four days.

Prolonging interferon production allows infection-fighting cells to stay in the battle longer, but also increases the risk that those same cells could cause autoimmune damage. The results suggest that timing and balance are critical, according to co-author Melissa Swiecki, PhD, a postdoctoral research associate.

"As we consider the implications of these results for expanding or refining our use of interferon in the clinic, timing and magnitude are going to be the key words. Can we find ways to get patients interferon when they need it and in just the right amount?" Swiecki says.

Colonna and his colleagues are planning follow-up studies in humans.

http://www.sciencedaily.com/releases/2012/06/120613133349.htm

How Interferon Works to Suppress Virus in Patients With HIV, Hepatitis

Old Drug Reveals New Tricks: How Interferon Works to Suppress Virus in Patients With HIV, Hepatitis

ScienceDaily (Feb. 29, 2012) — A drug once taken by people with HIV/AIDS but long ago shelved after newer, modern antiretroviral therapies became available has now shed light on how the human body uses its natural immunity to fight the virus -- work that could help uncover new targets for drugs.

In an article published online this month by the journal PNAS, a group of U.S. and Swiss researchers led by scientists at the University of California, San Francisco (UCSF) presented the first clinical assessment of how this drug fights infections in people. The drug, called interferon, is a biotechnology product based on a protein the body naturally produces to fight infections.

While purified interferon was given to people with HIV/AIDS in the early days of the epidemic because it alleviated many of the symptoms of the disease, its mode of action was always something of a black box.

"Nobody knew how it worked," said Satish K. Pillai, PhD, lead investigator and assistant professor of Medicine at UCSF and the San Francisco VA Medical Center.

Experiments in the laboratory in recent years have shown how interferon may work to suppress HIV in vitro, but there was no clinical evidence until now showing how the drug attacks HIV in treated patients. The problem is that so few people actually take interferon for HIV any more. However, interferon is still used in combination with other drugs to treat hepatitis C, which gave the team the possibility to assess its effect on HIV.

Interferon is commonly used to treat people with hepatitis C virus, and Pillai and his colleagues were able to identify 20 people enrolled in the Swiss HIV Cohort Study, which began in 1988, who have both HIV and hepatitis C. All 20 were taking interferon to treat their hepatitis C, but none were receiving antiretroviral drugs to treat HIV. This allowed researchers to examine how interferon works to suppress the virus.

How Interferon Works

The new work sheds further light on somewhat mysterious components of the immune system known as restriction factors, which are chemicals the human body produces to keep viruses like HIV in check and prevent them from infecting other cells.

These are just two fronts in the overall battle between HIV and the immune system -- a battle in which the immune system seeks to destroy the virus while the virus constantly counters by undermining the immune system.

Unlike other parts of the immune system, where whole cells gobble up invading pathogens or attack other cells, the action of these restriction factors is more subtle and localized within the infected cell itself -- one of the reasons scientists didn't appreciate what they do until just a few years ago.

One of them, called APOBEC3, fights viruses by stealthily jumping onto new virus particles as they form. Therein, the APOBEC3 protein fouls up HIV's genetic material by mutating it. When the virus tries to infect another cell, it no longer has the potency to replicate.

Another factor, called tetherin, takes an even more direct approach. It attaches to virus particles as they emerge from infected cells in the body and literally tethers them in place, preventing them from moving elsewhere in the body where they could infect new cells.

HIV has its own countermeasures to thwart these defenses. It produces a protein known as Vpu that neutralizes tetherin. Another HIV protein, called Vif, subverts APOBEC.

In the new study, Pillai and his colleagues showed that interferon combats HIV by mediating the action of both of these restriction factors. They collected samples from the 20 patients and measured the levels of APOBEC3 and tetherin before, during and after they took the drug interferon. The levels increased in response to interferon when the drug was in the bloodstream, and patients with the highest restriction factor levels showed the most precipitous drop in HIV viral load during interferon treatment.

While this insight does not immediately suggest new drugs or new ways of treating people with HIV, Pillai said scientists armed with this knowledge may one day figure out how to enhance this defense mechanism and specifically enhance the expression of restriction factors like tetherin and APOBEC3 in HIV-1-infected individuals.

If these factors can be induced to higher levels, their attack on the virus may become more potent -- perhaps even overriding HIV's countermeasures and helping flush the virus from infected cells.

The article, "Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo," was written by Satish K. Pillai, Mohamed Abdel-Mohsen, John Guatelli, Mark Skasko, Alexander Monto, Katsuya Fujimoto, Steven Yukl, Warner C. Greene, Helen Kovari, Andri Rauch, Jacques Fellay, Manuel Battegay, Bernard Hirschel, Andrea Witteck, Enos Bernasconi, Bruno Ledergerber, Huldrych F. Günthard, Joseph K. Wong, and the Swiss HIV Cohort Study.

In addition to UCSF, the authors of this study are affiliated with the San Francisco VA Medical Center, the Veterans Affairs San Diego Healthcare System at the University of California at San Diego, the Gladstone Institute of Virology and Immunology, and the Swiss university hospitals of Zurich, Berne, Lausanne, Basel, Geneva, St. Gallen and Lugano.

This work was funded by the National Institutes of Health and through the American Recovery and Reinvestment Act (ARRA). Additional support was provided by Swiss HIV Cohort Study Project 594; the Veterans Affairs Merit Review; and several Swiss National Science Foundation Grants. The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation and the Swiss HIV Cohort Study Research Foundation.