Hepatitis C And Clinical Trials

Good evening folks,

As most of you know, on Thursday Bristol-Myers Squibb announced they were discontinuing a mid-stage study of the experimental nucleotide polymerase inhibitor BMS-986094 for the treatment of hepatitis C.

On August 1, 2012 the company initially suspended the phase II trial due to a patient who experienced heart failure which now has resulted in death. There have been nine patients hospitalized and two remained hospitalized. As of yet, Bristol-Myers has not established a definitive relation between BMS-986094 and heart and kidney toxicity.

The press release is available here.

Update-
Friday - August 24, 2012, Janet Schaefer Vella, a nurse from Texas sued Bristol-Myers and Alamo Medical Research allegedly over heart problems after taking part in the hepatitis C BMS-986094 clinical trial in early July. A week into the trial she underwent a diagnostic test which indicated possible heart problems, now Ms. Vella is need of a heart transplant, read the complete article written by John MacCormack online here.

Recently IDX184 which is another experimental nucleotide polymerase inhibitor from Idenix Pharmaceuticals, was put on partial hold because of the potential for heart damage.

Update-
On Aug 27 Idenix placed IDX19368 on clinical hold, also a nucleotide polymerase inhibitor - (no patients have been exposed to IDX19368). The FDA informed Idenix of concerns related to serious heart issues seen in Bristol-Myers nucleotide polymerase inhibitor BMS-986094.

Excerpt

The FDA verbally informed Idenix that it placed IDX19368 on clinical hold due to concerns related to the serious cardiac-related adverse events reported for HCV patients treated with BMS-986094, a nucleotide polymerase inhibitor previously under development by Bristol-Myers Squibb Company.

To date, no patients have been exposed to IDX19368.

"Based on our discussions with the FDA, we understand the clinical hold is a precautionary decision made by the FDA in light of the adverse events seen with BMS-986094," said Ron Renaud, President and CEO.

"Both IDX184 and IDX19368 fall into the same broader class of NS5B inhibitors, and share the same active metabolite as BMS-986094. However, there are many attributes of our compounds, particularly the prodrug approach, that we believe favorably differentiate the toxicity profiles from that of BMS-986094. We recently learned that Bristol-Myers Squibb has agreed to share relevant information on BMS-986094 with us and hope this helps us to resolve this issue quickly."

The Loss Of A Patient

Great sadness has been expressed throughout the HCV community for the recent loss and hospitalized patients who participated in the BMS-986094 clinical trial. I offer my sincere condolences to the family and concern for all the patients involved.

Hepatitis C And Clinical Trials

When diagnosed with a serious chronic illness what ensues is a life met with uncertainty, riddled with mental and emotional challenges. Stressful medical decisions must be made as day-to-day life continues.

Battling this virus isn't for the weak, clinical trials use powerful medications, involving a bit of courage to administer, and a leap of blind faith to use.

This unfortunate death is a shocking reminder of the rare, but potential risk to all patients who volunteer to test new hepatitis C agents.
Entering into a clinical trial is like walking into a dimly lit room, small milestones bring a glimmer of light, but the room remains dark until the final results are in. 

We saw new and additional side effects with protease inhibitors telaprevir and boceprevir, we now have nucleotide polymerase inhibitors and obviously new serious concerns. Until we fully understand how or why this death happened, apprehension and concern remains for all the patients who took part in the BMS-986094 clinical trial.

The Doctor And Patient

Over the last 50 years the role between a doctor and patient has changed, now patients make the final decision regarding medical care or treatment. This has become an overwhelming process, especially for people living with a chronic and serious disease. In a 2010 study, at the University of Chicago, researchers found that two out of three patients would rather their doctor make those final decisions, although, only 14% of patients were assertive enough to speak up when they disagreed with the doctors recommendation.

Have you ever felt intimated by a doctor? Have you found yourself too polite or too scared to disagree with a new test or treatment advice?  Even when symptoms are present, explaining them becomes awkward, who wants to complain? For instance, how many times have you made an appointment because you're feeling pretty bad, although, when the doctor enters the room asking how you are, you quickly reply with - I'm fine thank you.

 Speak Up

For people participating in a clinical trial strong communication about any side effects is essential. Gone are those days of feeling intimated, bets are all off when you enter into a clinical trial. By speaking up early, the risk for serious side effects are lowered, plus an early assessment will help to ensure your safety.

If you are considering a clinical trial check out this guide from HCV Advocate first -
Guide to Understanding Clinical Trials and Medical Research in Hepatitis C

The Good News

With the help of  sites like HCV Advocate, and NATAP, patients are now treatment savvy, the day of the naive patient is slowly changing.

 Bristol-Myers and Idenix

With the enormous success of past and current hepatitis C clinical trials a false sense of security may have fallen upon the HCV community. Never did anyone anticipate a death, or toxicity issues as serious as those alleged with BMS-986094 or IDX184.

A few days ago Nature published an article reporting on the recent BMS trial. The excerpt below offers a quick look at a few HCV drugs.

For many years, the only available treatment for HCV was a combination of interferon-α and ribavirin. The interferon acted to boost the patient’s immune system, while ribavirin inhibited virus replication. A modified version of interferon-α, pegylated-interferon-α, which remains in patients’ bodies for longer, was introduced in 2001. But the treatment had severe side effects, including anaemia, severe depression and flu-like symptoms, and was not effective in all patients.

Last year, two new drugs, boceprevir and telaprevir were approved by the US Food and Drug Administration (FDA). Both of these drugs target HCV’s NS3-4A protease, which the virus needs to generate functional proteins. Both drugs, however, do have side-effects. Because they are taken in combination with interferon-α and ribavirin to prevent the emergence of resistance, the side effects of the original treatment regimen are still a problem.

Telaprevir was recently relabelled to take into account its potential for causing cardiac arrhythmias (FDA update) while boceprevir has been found to interact with HIV protease inhibitors, so co-administration is not recommended (FDA update).

Pharmaceutical companies are trying to find new drugs that are more effective and have fewer side effects. In addition to protease inhibitors, other potential drugs (including BMS-986094) act on the NS5B RNA polymerase enzyme, preventing amplification of viral RNA. 

Another class of drugs aim to stop viruses penetrating the host’s cells (see ‘New drug targets raise hopes for hepatitis C cure’).

Idenix Pharmaceuticals had a drug in trial that acted in a similar way as BMS-986094. That trial has now been put on partial hold by the FDA as a result of the BMS trial failure (see press release).  There may still be hope for other NS5B inhibitors in the pipeline, as not all of them share the same mechanism of action as BMS-986094. Gilead has an NS5B inhibitor in phase 3 trials, and Vertex is working on a similar drug.

The Pipeline

Additional information on new hepatitis C drugs can be found in a recent article written by Tracy Swan and Karyn Kaplan. The article was included in the "2012 Pipeline Report" by TAG.  The report includes the following topics: HCV drug resistance, DAA drug-drug interactions, nucleosides and nucleotide polymerase inhibitors, HCV protease inhibitors, and the next generation of drugs.

The report: Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch

NATAP has just added these updates-
New HCV Drugs: non nucleoside polymerase inhibitors 
HCV Update Selected Highlights: key new HCV drugs, timelines & recent news developments 

Another quick resource for information is: The Hepatitis C New Drug Pipeline

Fortunately for me, my trial experience ended with a cure.  May your own experience be carefully researched, just as successful, and extremely safe.

News Ticker-Hepatitis C And Vitamin D, New Hepatitis C Drugs And More

 

HCV News Ticker

 

 

 Vitamin D for Your Patients with Chronic Hepatitis C?

PII: S0168-8278(12)00602-2
DOI: http://dx.doi.org/10.1016/j.jhep.2012.07.026
Reference: JHEPAT 4348

To appear in: Journal of Hepatology

 

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Summary

Vitamin D is increasingly becoming recognized as an important physiological regulator with pleiotropic functions outside of its classical role in skeletal homeostasis. A growing body of clinical evidence highlights the prevalence and risks of vitamin D deficiency in patients suffering from chronic hepatitis C infection, and vitamin D supplementation has been proposed as an adjunct to current standards of care. This review considers the experimental evidence for the anti-inflammatory, anti-fibrotic and anti-viral effects of vitamin D, and discusses the therapeutic potential of vitamin D supplementation to protect against liver disease progression and improve responses to treatment.

Introduction
Advances in hepatitis C virus (HCV) pharmaceutical development are being made at a blistering pace; however, highly effective, non-toxic therapies remain a hope for the future. This leaves an immediate need for interventions that can minimize disease progression and/or improve sustained virological response (SVR) rates in the short term.

The aging of the HCV-positive population is creating an epidemic of end stage liver disease. Many patients cannot wait for second and third generation direct acting antiviral drugs to reach the clinic. As an interim measure, vitamin D supplements have been proposed as an adjunct to pegylated-interferon and ribavirin. This review integrates the known biological effects of the vitamin D system with recent clinical findings and discusses the therapeutic potential of vitamin D supplementation in HCV-positive patients. 

Download PDF here..........

New Therapies Against HCV:Expected Risks and challenges Associated with their use in the Liver Transplant Setting

Given the importance of viral clearance in the pre and post transplant setting such results have been thought to be somewhat unsatisfactory and the liver transplant community has been eagerly awaiting new anti- HCV therapies....

Despite some enthusiasm for the best of the second wave therapies, the third “wave” is likely to be the most significant and certainly most exciting. This wave aims to replace Interferon altogether. The regimes use DAAs in combination without Interferon but sometimes with Ribavirin eg: a HCV NS5A polymerase Inhibitor combined with second (or third generation) NS3/4 Protease Inhibitors or an NS5A inhibitor .....

Continue reading here....

J Hepatol. 2012 Aug 10. [Epub ahead of print]

Myocardial injury in patients with chronic hepatitis C infection

Maruyama S, Koda M, Oyake N, Sato H, Fujii Y, Horie Y, Murawaki Y.
Source - Maruyama Medical Clinic, Hamada, Japan.

*myocardial [mi″o-kahr´de-al] -pertaining to the muscular tissue of the heart

Abstract

BACKGROUND & AIMS:

The existence of a direct pathogenic link between hepatitis C virus (HCV) infection and myocardial injury has not been confirmed. We investigated the association between myocardial conditions and HCV in patients with HCV-related chronic hepatitis using thallium-201 myocardial scintigraphy.

METHODS:

In 217 consecutive cases of chronic HCV infection without overt heart disease, we performed electrocardiography (ECG), echocardiography, serum tests on myocardial injury and thallium-201 myocardial scintigraphy. Myocardial injury was confirmed by severity score (SS), which was calculated as the sum of thallium-201 perfusion defect scores. SS was followed prior to and after interferon (IFN) therapy in 200 patients with chronic hepatitis C.

RESULTS:

An abnormal ECG was found in 9% of the patients with chronic hepatitis C. Abnormal severity score -SS was found in 87% of chronic hepatitis C patients. Independent factors related to higher pretreatment severity score-SS were histology activity index score, serum HCV RNA titer and indocyanine green disappearance rate.

After IFN therapy, SS was improved in patients with sustained virologic response. Among relapsers, the SS improved at the initial disappearance of HCV RNA, but SS worsened with reappearance of HCV RNA. The SS in non-viral responders did not change with IFN therapy.

CONCLUSIONS:

Myocardial perfusion defects were found in 87% of the patients with chronic hepatitis C and improved with viral eradication from IFN therapy.

Copyright © 2012. Published by Elsevier B.V.

 

New at NATAP

New HCV Drugs: non nucleoside polymerase inhibitors

 Written by Jules Levin, NATAP http://www.natap.org

Many observers have written off the class of HCV drugs non nucleoside polymerase inhibitors because resistance can develop quickly but does it really matter if this drug is used in combination with 2 other potent HCV drugs???

HCV protease is a potent class (3-4.5 or even 5 logs for a few proteases), as well HCV nucleotide is also a potent class (4.5 logs) and of course a big reason it's liked is because resistance is very hard to develop or won't at all. And of course NS5A is a potent class of drug (4-5 logs).

The non nucleoside polymerase inhibitors in development have shown a wide range of potency from 1.3 logs to 3.5 logs on average). Here is a review of this 'can't get no respect' class. What is interesting about this class is several of these drugs are fairly well along in development and are not far at all away from becoming avaliable. In phase 3 right now however.....Continue reading..

BMS052 HCV-NS5A Monotherapy in Phase 3 Now - (08/24/12)

TMC-435 HCV Protease in Phase 3 - (08/24/12)

BI1335 HCV Protease in Phase 3 Now - (08/24/12)

More Hep C Articles...

 

 

NH hospital workers urged to get tested following hepatitis C outbreak blamed on lab worker

MANCHESTER, N.H. — A New Hampshire hospital says it’s notifying about 500 employees and affiliated clinicians the state is recommending they be tested for hepatitis C after an outbreak of the disease linked to a lab worker there.

Exeter Hospital will be coordinating testing over the next two weeks.

The state public health department has held numerous testing clinics for patients of the hospital, where a former worker has been accused of stealing drugs and contaminating needles used on patients in the cardiac catheterization lab. Thirty-two former lab patients have been diagnosed with the same strain of hepatitis C as David Kwiatkowski (kwiht-KOW’-skee) since the investigation began in May.
Continue reading....

Healthy You

Elderly patients get inappropriate scripts

By Kirsty Oswald

23 August 2012 -PLoS ONE7: e43617

medwireNews: One in five prescriptions in primary care for the elderly is inappropriate, say the authors of a systematic review.

 

The review, which included data from 11 countries, including the UK, showed that both high- and low-risk medications were subject to inappropriate prescriptions.

 

"In spite of increasing attention to the quality of medication prescription among elderly persons presenting to the primary care setting, there are still high overall rates of inappropriate medication prescription [IMP]," say Dedan Opondo (University of Amsterdam, the Netherlands) and colleagues.

The systematic review included 19 English-language studies, which analysed rates of IMPs in patients aged over 65 years. They used the Beers criteria, which lists medications appropriate for elderly patients, and other tools to assess rates of IMP.

 

The authors found that the median rate of IMPs was 20.0%. However, it varied highly between studies, ranging from 2.9% to 38.5%.

 

The four most common IMPs were the pain reliever propoxyphene (4.5%), the antihypertensive doxazosin (4.0%), the antihistamine diphenhydramine (3.3%), and the antidepressant amitriptyline (3.2%).

 

Additionally, the authors found that some high-risk medications, such as diazepam and nifedipine, had high rates of IMPs compared with other medications in their therapeutic classes.

Writing in PloS One, they say that their results show a need for interventions in primary care to improve the quality of prescriptions for the elderly: "Prescription of high-risk medication exposes the elderly to frequent and severe adverse drug events. Alternative low-risk medications should be prescribed when available."

 

medwireNews (www.medwire-news.md ) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

Full free text

 

Number of over-65s with cancer 'to triple by 2040'

Monday Aug 20 2012

One-in-four over-65s 'will have had cancer by 2040', according to the Daily Mail. The news is based on a study that estimated the number of people expected to be living with cancer in the UK by the year 2040
Continue reading...

HDL: Not So “Good” After All?

Berkeley Wellness Letter

 

After years of having it drilled into their heads, most people now know that LDL (low-density lipoprotein) is the “bad” cholesterol package that increases the risk of cardiovascular disease, and HDL (high-density lipoprotein) is the “good” type that helps reduce it by removing cholesterol from artery walls. So if your HDL number is high, you’ve probably patted yourself on the back; if it’s low, you may have tried to raise it by, for instance, exercising more, losing weight, drinking a daily glass of wine, or even taking medication, such as high-dose niacin.

 

But before you get too hung up on HDL, you should know that while the benefits of lowering elevated LDL are proven, the evidence for raising HDL by itself remains uncertain. That’s why standard cholesterol guidelines have focused almost exclusively on lowering LDL, which is the main purpose of statin drugs (they have little effect on HDL). And recently a study in the Lancet raised fundamental questions about the supposed benefits of raising HDL.

 

Genetic factors help determine HDL levels, sometimes very strongly. In the Lancet paper, an international team of researchers analyzed data from 20 studies involving people with genetic variants that raise HDL but do not affect LDL, triglycerides, or related blood lipids. They did a special kind of genetic analysis (called Mendelian randomization) that allowed them to determine whether high HDL, in and of itself, reduces coronary risk. Surprisingly, the evidence indicated that it does not.

 

An iffy link
Researchers and doctors have focused on HDL for good reason: observational studies have consistently found that people with high HDL levels are at decreased cardiovascular risk. But just because there’s an association between low HDL and heart disease, that doesn’t mean that low HDL causes it—or that raising HDL will help prevent it. Many factors in the blood can be higher or lower with certain diseases, but relatively few actually cause the diseases. Low HDL tends to go along with other metabolic abnormalities that could directly increase risk for coronary disease, such as high levels of smaller LDL particles and increased triglycerides (fats in the blood).

 

So the question remains, is low HDL an independent risk factor for cardiovascular disease or merely a marker for it?

 

What about drugs to raise HDL?

 

The Lancet study was not the first disappointing finding about the potential benefits of raising HDL. According to the accompanying commentary, the study confirms previous genetic analyses that “refute a causal role of HDL in coronary heart disease.”

 

Moreover, in recent years two high-profile HDL-boosting drugs were scrapped after they failed to produce the expected benefits in pre-approval studies; one actually increased cardiovascular risk. And as we reported last year, a major study called AIM-HIGH found that prescription niacin did not further reduce the risk of heart attacks or other cardiovascular events in high-risk people who had already lowered their LDL levels via high-dose statins—even though niacin raised HDL. (Niacin also lowers LDL and triglycerides, which may explain why it was shown to be beneficial in prior studies.) Other drugs are being developed to raise HDL substantially, but in ways different from the previous drugs.

 

The relationship between HDL and cardiovascular disease is complicated, largely because the biochemistry of HDL is so complex. Not only does HDL interact with other lipids in the blood, but all HDL is not alike. Some HDL may do a good job at keeping arteries healthy, while other HDL may not. HDL particle size and levels of various subparticles, as well as levels of inflammation and oxidative stress in the body, may determine if, and how much, HDL is cardioprotective.

 

Bottom line

There are many unanswered questions about HDL. It’s becoming increasingly clear that there’s more to it than that single number from a basic blood test. Still, low HDL is, at the very least, a marker for increased cardiovascular risk, and should be considered in the context of your other risk factors. It may, for instance, lead your doctor to order advanced blood tests for additional cholesterol-related components such as small LDL particles. A low HDL number may also lead your doctor to more aggressively lower your LDL by medication. If you have low HDL, you should still exercise, quit smoking, and lose excess weight. Such steps help protect the heart in many ways, regardless of their effect on HDL.
Issue: September 2012

BMS halts the development of BMS-986094 due to patient death

Bristol-Myers halts mid-stage study of promising hepatitis C drug

Published: Thursday, August 23, 2012, 7:25 PM Updated: Thursday, August 23, 2012, 7:36 PM

 By Bloomberg NewsThe Star-Ledger

Bristol-Myers Squibb is abandoning an experimental hepatitis C pill it acquired for $2.5 billion earlier this year after one patient died and others were hospitalized while taking the drug in a clinical trial.

Bristol-Myers suspended mid-stage studies of the drug, which was known only as BMS-986094, earlier this month after a patient developed heart failure.

The drug maker, which is based in New York but has a large presence in New Jersey, said yesterday it had decided to halt development of the drug, part of a class of medicines called nucleotide polymerase inhibitors. The company also said it was consulting with U.S. regulators to assess the treatment’s effects.

The original patient subsequently died and eight others suffered from heart and kidney toxicity, the company said in a statement released last night. Two of the patients remain hospitalized.

The hepatitis C treatment was thought by researchers and analysts to be a key therapy in a push by companies, including Gilead Sciences to replace the standard treatment, a regimen including a year of interferon injections that carry flu-like side-effects.

“The decision to halt development of the BMS-986094 has been guided by our overriding interest in protecting patients,’’ said Elliott Sigal, Bristol’s executive vice president and chief scientific officer. “In the interest of all patients, we will make relevant information available to inform the development of other investigational compounds to treat hepatitis C.’’

Bristol-Myers gained the drug with its acquisition of Inhibitex Inc. for $2.5 billion earlier this year.

The company was among a number of drugmakers racing to develop a new generation of medicines to treat an estimated 170 million patients with hepatitis C.

In a statement released after the close of the financial markets, Bristol Myers said it would continue investigating into the cause of the toxicity. The company will also continue to monitor patients who have received the medicine.

Star-Ledger staffwriter Susan Todd contributed to this report.

Source - http://www.nj.com/business/index.ssf/2012/08/bristol-myers_halts_mid-stage.html


Hepatitis C Drug Proves Dangerous
Nine patients are hospitalized and one is dead after taking an experimental drug for hepatitis C developed by Bristol-Myers Squibb Company (NYSE: BMY). On Thursday the company announced it had halted development of the drug, aimed at treating lever disease.

"The decision to halt development of BMS-986094 has been guided by our overriding interest in protecting patients," said Elliott Sigal, M.D., Ph.D., Executive Vice President and Chief Scientific Officer, Bristol-Myers Squibb.

Two of the original nine patients remain hospitalized and Bristol continues to monitor the health of over 100 patients who participating in the study. The company also notified nearly 150 others who were part of earlier test.
Continue reading....

Bristol Drops Hep C Drug After Patient Death
By Ed Silverman

You could see this coming. Last night, Bristol-Myers Squibb abandoned an experimental hepatitis C compound after one patient died of heart failure and nine others were hospitalized during a Phase II study. The move comes less than a month after the drugmaker suspended the trial due to safety issues among patients and that decision, not surprisingly, immediately raised questions about the future of the medication (back story).

The discontinuation is a huge disappointment for Bristol-Myers Squibb, which earlier this year agreed to pay $2.5 billion in cash for Inhibitex and its experimental compound, a nucelotide polymerase inhibitor that was renamed BMS-986094. The wisdom of that deal drew considerable skepticism, though, because the small drugmaker had completed only Phase I testing up to that point.

Continue reading at Pharmalot

BMS halts the development of BMS-986094 due to patient death

Bristol-Myers Squibb announced that it has discontinued the development of BMS-986094 for the treatment of hepatitis C

BMS-986094, formerly known as INX-189, is a nucleotide polymerase inhibitor that is currently being developed in the phase II clinical studies for the treatment of hepatitis C. The FDA has placed a clinical hold on the development of the compound which has also affected the development of Idenix's IDX184 and tanked Idenix shares.

The phase II trial was initially suspended on August 1, 2012 due to a heart failure case which now has resulted in death. As of now, nine patients have been hospitalized and two remained hospitalized. The company has yet to establish a definitive relation between the compound and kidney and heart toxicity. Hoever, for the interest of the patients, it has decided to halt the development of BMS-986094.

 

Hepatitis C Peg/Riba Therapy: With versus Without Fluvastatin-An Open-Label Randomized Controlled Study

From Journal of Viral Hepatitis

An Open-Label Randomized Controlled Study of Pegylated Interferon/Ribavirin Combination Therapy for Chronic Hepatitis C With versus Without Fluvastatin

C. Kondo; M. Atsukawa; A. Tsubota; N. Itokawa; T. Fukuda; Y. Matsushita; H. Kidokoro; T. Kobayashi; Y. Narahara; K. Nakatsuka; H. Kanazawa; C. Sakamoto

Posted: 08/23/2012; J Viral Hepat. 2012;19(9):615-622. © 2012 Blackwell Publishing

Discussion Only

Full text available at Medscape

In the present study, we, for the first time, show that fluvastatin significantly improved the SVR rate in a randomized controlled open-labeled study, and identified the patient characteristics that would have a likelihood of achieving SVR with addition of fluvastatin. So far, several studies have shown that concomitant addition of statins to the SOC treatment yielded a more favorable treatment outcome than SOC treatment alone.^[10–13]

However, some limitations still remained in these studies: a small number of study patients, a retrospective or pilot study, or a non-randomized controlled trial for the use of fluvastatin. Moreover, these studies have yet to clarify which patients would benefit from the additional effect of statins, or what are the factors that could contribute to the therapeutic benefit. This randomized controlled study designed to solve these limitations showed that fluvastatin, when added to PEG-IFN/ribavirin combination therapy, significantly improved SVR rates in patients with genotype 1b and high viral load chronic hepatitis C.

In the present study, the striking effect of fluvastatin with more than 80% SVR rate was observed in male patients, in patients who had a history of relapse, or in patients with more than two mutations in the ISDR. It has already been shown that various host and viral factors influence the therapeutic effect. As for host factors, patient age, gender, blood cell count, and IL28B SNPs have been reported to influence the therapeutic effect.^[14–18] As for HCV-related factors, the virus genotype, viral load, amino acid substitution in the core region,^[19] and number of ISDR mutations appear to influence the therapeutic effect.^[20–22]
.
Interestingly, the sub-analysis stratifying these factors showed that a high SVR rate was also observed in patients with these favorable factors among the fluvastatin compared to the non-fluvastatin group; i.e., male, core aa70 wild type, 2 or more ISDR mutations, low HCV-RNA level, and IL28B major genotype. Of note, the outcome of the fluvastatin combination therapy was also markedly favorable in patients who had a history of relapse after previous IFN therapy. These data suggest that the concomitant fluvastatin treatment may assure or consolidate a virological response when added to the SOC treatment.

When the treatment response was compared between the two groups, no significant differences were noted in the RVR, EVR, or ETR rate. Furthermore, there was no significant difference in early HCV dynamics during the first 12 week treatment period (24 h, 48 h, and 1, 2, 4, 8, and 12 weeks) between the groups (data not shown). Nevertheless, the concomitant use of fluvastatin significantly improved the SVR rate, suggesting that it might inhibit relapse after treatment completion in patients who were virological responders during treatment. Therefore it would be reasonable to speculate that the inhibition of viral relapse might be responsible, at least in part, for the significant improvement of the SVR rate with concomitant addition of fluvastatin.

Many studies have recently reported that the effect of antiviral therapy on chronic hepatitis C could be predicted at a high rate by focusing on IL28B SNPs.^[14–16] However, there has been no report in which IL28B SNPs were investigated in patients treated with PEG-IFN/ribavirin/fluvastatin therapy. SVR rates in patients with the major genotype were significantly increased in the fluvastatin group as compared with the non-fluvastatin group, while no significant difference was noted in patients with the minor genotypes between the groups. In addition, the major IL28B SNP genotype was also an independent predictor for SVR among patients treated with fluvastatin combination therapy.

Therefore, fluvastatin combination therapy, though highly effective in patients with the major genotype, does not appear to be effective for patients with such difficult-to-treat factors.

For genotype 1 chronic hepatitis C with a high viral load, PEG-IFN/ribavirin/protease inhibitor, such as telaprevir and boceprevir, combination therapy would become the standard of care quite soon. The addition of a protease inhibitor to PEG-IFN/ribavirin has been shown to result in SVR rates of around 80% in genotype 1 chronic hepatitis C with a high viral load. However, the noteworthy fact is that a marked number of cases developed anemia and severe rash during treatment, resulting in discontinuation of the therapy.

According to a recent report, the rate of treatment interruption due to the adverse reactions of PEG-IFN/ribavirin with telaprevir was 21%, compared to 11% in PEG-IFN/ribavirin without telaprevir.^[23] That is to say, concomitant addition of other agents to the standard treatment may cause the development of adverse effects due to the agents added or the risk of deterioration in already-known adverse effects. With regard to adverse events, on the other hand, no apparent severe adverse event was observed in any of the patients treated with fluvastatin in the present study. Thus, PEG-IFN/ribavirin with fluvastatin could be one therapeutic options that can be safely administered for chronic hepatitis C patients. Therefore, we would like to propose based on the present results, an algorithm in which future treatment for chronic hepatitis C patients with genotype 1b and high viral load would be selected.

In cases for which the novel therapy with a concomitant protease is not applicable due to adverse reactions, PEG-IFN/ribavirin with concomitant use of fluvastatin may be useful. Specifically, the fluvastatin combination therapy may be recommended for male patients and patients with the major IL28B SNPgenotype. By contrast, the therapeutic effect may not be improved by the concomitant addition of fluvastatin in intractable cases such as those with core amino acid 70 mutant type, with IL28B minor genotype, and female patients. For these patients, new combination therapies with protease,^[13,23–26] polymerase,^[27–29] or N5A inhibitors^[30] currently under development would be recommended.

Lastly, in vitro comparisons of the anti-HCV activity among various statins have been reported,^[8] and the superiority of fluvastatin has been demonstrated. On the other hand, there has been no comparison of the clinical effect among statins, and which statin should be added to IFN therapy to obtain favorable results in hepatitis C patients.

In conclusion, fluvastatin-combined PEG-IFN/ribavirin therapy was safe and improved SVR rate in chronic hepatitis C patients with genotype 1b and high viral load.It was highly effective for male patients, patients with more than two mutations in the ISDR and patients who had a history of relapse after previous IFN treatment. Being male and major IL28B SNP genotype were independent predictors for SVR among patients on fluvastatin combination therapy.

Full text available at Medscape

Medivir Hepatitis C Drug-TMC435(simeprevir) important component in future interferon-free treatments

Medivir – Investor relation – Press Release

Excerpt-

CEO’s comment on the second quarter of 2012

“Good progress in all parts of the company” We continued to develop Medivir into a profitable Nordic pharmaceutical company, and made good progress in all parts of the company. Sales of original pharmaceuticals progressed as planned, and made continued stable progress in the second quarter. Parallel imports, through Cross Pharma, are operating on an expansive and fast-moving market where our experience and long-term commitment continued to create value.

TMC435 gained its generic name - simeprevir. Phase III trials on simeprevir continued as planned and new data presented in the period confirmed simeprevir’s good prospects of becoming an essential component in the optimal triple therapy for hepatitis C (HCV). Simeprevir’s competitive profile also engenders good hopes of an important role in future interferon-free therapies. Extensive phase II trials have demonstrated good safety and efficacy, not least in the hardest-to-treat patient groups where there is the greatest need for therapy.

The company’s proprietary projects progressed as planned. In May, phase I trials commenced on our in-house developed cathepsin K inhibitor MIV-711, for treating skeletal disorders. We also have strong hopes of being able to designate a nucleotide CD in our own early HCV projects before year-end. In June, we initiated a partnership with the Swedish University of Agricultural Sciences (SLU) in Uppsala on the development of new antibiotics against resistant bacteria, a project that is consistent with our strategy.

R&D

 

Simeprevir (TMC435) - Medivir’s protease inhibitor in clinical phase III for treating hepatitis C

Phase III trials on simeprevir progressed as planned during the period and we expect to be able to present initial data from these trials around the coming year-end. From extensive phase II trials, we know that simeprevir addresses needs in all patient groups effectively and safely, simultaneous with this compound being easy to administer, possible in a single day tablet dose. Good efficacy is especially important in the hardest-to treat and most severely affected patient groups. The strength of the results from treatment-naïve and treatment-experienced patients in phase IIb trials demonstrate that through its mechanism of action, simeprevir will be an important component in future interferon-free treatments.

Combination therapy is a prerequisite for realizing interferon and ribavirin-free treatments. In July, a phase II trial commenced designed to study combination treatment with simeprevir and daclatasvir from Bristol-Myers Squibb. This trial is another key step in collecting data for future combination therapies with simeprevir as a solid cornerstone. The combination trial in phase II on simeprevir and Gilead’s nucleotide inhibitor GS7977, which commenced at the beginning of the year, progressed well. We hope to be able to present the first partial results from this trial before year-end.

Hepatitis C projects in-house

 

Our own preclinical HCV projects progressed as planned in the second quarter. As previously, our goal is to be able to designate a CD in the nucleotide project before year-end.

Conference call for investors, analysts and the media
The Interim Report will be presented by the CEO, Maris Hartmanis, and members of Medivir’s management.

Time: 2 p.m. (CET) on Thursday, 23 August 2012

Participant telephone numbers: Sweden +46 (0)8 505 204 24
Europe +44 (0) 20 3003 2666
USA +1 866 966 5335

Continue reading............

The conference call will also be streamed via a link from the website www.medivir.com

Live Stream-
 http://livecast.wehay.com/stockontv/120823/medivir/

Occult HBV common in children born to HBsAg-positive mothers despite immunization

Occult HBV common in children born to HBsAg-positive mothers despite immunization

Shahmoradi S. J Hepatol. 2012;57:515-521.

August 23, 2012

Children born to mothers who tested positive for hepatitis B surface antigen were prone to occult HBV infection despite having been immunized shortly after birth in a recent retrospective study.

Researchers evaluated serum samples from 75 HbsAg (HBsAg)-negative children in the Amol region of northern Iran. All patients were born to HBsAg-positive mothers and had been immunized against HBV. The presence of HBV DNA was assessed according to real-time and sensitive standard polymerase chain reaction (PCR) to determine occult HBV infection (OBI).

Of the 75 children, 55 were anti-HBs-positive, nine were anti-HBc- and anti-HBs-positive, and 11 had no serologic HBV markers. OBI was diagnosed in 21 patients, with HBV DNA levels ranging from 77 to 9,240 copies/mL. All 21 patients with OBI were anti-HBs-positive, with five also testing positive for anti-HBC. No participants tested positive for anti-HBc alone. Investigators observed a strong association between HBV levels greater than 1,000 copies/mL and positive standard PCR results (P=.001).

Among the infected patients, 13 had one or more genetic mutations in regions involved with functional and/or immune epitope activity, and 10 had G145R mutations. The G145R mutation was associated with greater HBV DNA levels, with 60% of patients with the mutation indicating viral loads more than 1,900 copies/mL (P=.012).

“Our study is the first report on the prevalence of OBI among a selected high-risk group of children born to HBsAg-positive mothers, particularly from a region with low-to-intermediate prevalence of HBV,” the researchers wrote. “It is suggested that HBsAg negativity is not sufficient to completely exclude HBV DNA carriers. OBI seems to be relatively frequent in immunized children born to HBsAg-positive mothers. Further studies on the clinical significance of OBI, alternative immunization regimens (eg, administration of boosters) or more effective HBV vaccines (a third generation or HBV DNA vaccines) are required.”

http://www.healio.com/gastroenterology/news

Victrelis(boceprevir) - Factors That Predict Response of Patients With Hepatitis C

Published on Aug 22, 2012 by AmerGastroAssn

Dr. Fred Poordad discusses his manuscript, "Factors That Predict Response of Patients With Hepatitis C Virus Infection to Boceprevir."

Researchers identify gene that disrupts inflammatory process implicated in liver cancer

Targeting inflammation to prevent, treat cancers

Drs. Anatolij Horuzsko (from left) and Juan Wu look at the molecules that control inflammatory responses to gain a better understanding of how chronic inflammation is linked to cancer.

Augusta, GA—Researchers at the Georgia Health Sciences University Cancer Center have identified a gene that disrupts the inflammatory process implicated in liver cancer.

Laboratory mice bred without the gene lacked a pro-inflammatory protein called TREM-1 and protected them from developing liver cancer after exposure to carcinogens.

The study, published in Cancer Research, a journal for the American Association for Cancer Research, could lead to drug therapies to target TREM-1, said Dr. Anatolij Horuzsko, an immunologist at the GHSU Cancer Center and principal investigator on the study.

"We have long suspected that chronic inflammation is a very powerful tool in the initiation of cancer, and also in the progression or metastasis of cancer," said Horuzsko. "We [looked] at the molecules that control inflammatory responses to gain a better understanding of how this process works. One important triggering receptor for inflammation is TREM-1."

TREM-1's role in promoting inflammation is useful in cases such as battling viral or bacterial infections and in maintaining normal tissue function. But as Horuzsko's team discovered, in abnormal conditions—such as liver damage due to alcohol abuse or other irritants—production of TREM-1 goes haywire. A chronic, low-level state of inflammation is produced as TREM-1 leads to the development of other inflammatory agents, which causes more damage, increases cell production and creates mutated cells. These mutated cells then reproduce—planting the seeds that can lead to cancer.

During the 14-month study, Horuzsko and his team used mouse studies to gather data on the effect of TREM-1 in the liver cells and identify potential sources for therapies. Because a mouse's life span is about three years, the length of the study mimicked a similar 20- to 30-year cancer progression of liver cancer in humans.

Two sets of mice—one with the TREM-1 gene removed—were exposed to the cancer-causing agent diethylnitrosamine, or DEN, which is present in tobacco smoke, chemicals and other products. Within just 48 hours of DEN injection, the control mice were already showing signs of liver cell injury and death and high levels of TREM-1 expression in the liver's Kupffer cells. These specialized liver cells normally destroy bacteria and worn-out red blood cells. Eight months later, these mice also showed massive liver tumors.

But the mice with the gene removed remained healthy, showing very few changes—and very small, if any, tumors after eight months. The only difference between the two groups was the appearance of TREM-1 in the Kupffer cells.

Horuzko's team hopes the findings—and their potential in TREM-1-related cancer treatment—will be applicable to other cancers as well. "TREM-1 could be a target for any inflammation-associated cancer," said Horuzsko. "In the future, we could use a drug to target TREM-1 in the body. We are already working in this direction."

Horuzsko's team also identified another potential target for drug therapy during the study—a product of liver cell injury and death called HMGB1. HMGB1 is a previously unknown activating ligand, or agent, that stimulates Kupffer cells to produce the TREM-1 protein and start the inflammatory process.

"Advanced drug therapies for cancer are a growing field of research, and immune therapies are an important part of our mission," said Dr. Samir N. Khleif, Director of the GHSU Cancer Center. "Studies like Dr. Horuzsko's are leading the way to identify targeted therapies that will become our future standards of care. As we open the door to new scientific discoveries, this enables us to provide better care to patients and families with cancer. "

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The GHSU Cancer Center is the region's only dedicated clinical cancer and cancer research center, offering Phase 1 clinical trials. The center is also working to become Georgia's second National Cancer Institute-designated cancer center.

The Cancer and Inflammation Program at the National Cancer Institute also provided work on this study, which was funded by National Institutes of Health grants.

http://www.eurekalert.org/pub_releases/2012-08/ghsu-tit082212.php