Research Article: The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors

Posted 7/30/12 on PLOS, a very cool peer-reviewed, open access journal for the rest of us. A very nice US-based research article entitled "The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors" by Romano, et al.  This the life source for for HCV Drug Development and virology geeks alike. The authors look in-depth in the major resistance mutations at R155K, A156T, D168A and how they effect the binding of telaprevir, danoprevir, vaniprevir and MK-5172 to the HCV protease target. Also available as a PDF file at the PLOS site for an enthralling, page turning read (seriously!): http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002832

Gilead to combine GS-7977 and GS-5855 into a single pill...

Posted 7/27/12 on Bloomberg.com. Gilead doing exactly what they do best, and that is co-formulation. Now it's clear why they avoided a partnership with BMS in spite of a 100% SVR rate - not only do they have their own nuc and NS5A inhibitor, they want to make them one pill. Brilliant. Both the investment and drug development worlds will be watching this particular trial very closely I suspect.

Gilead’s Single Pill Hepatitis C Study Targets 2014 Approval

Bloomberg, By Michelle Fay Cortez and Ryan Flinn on July 27, 2012

Gilead Sciences Inc. (GILD) (GILD) said it plans to start a combination study of two drugs in a single pill to treat hepatitis C by the end of the year, putting it on track to request U.S. regulatory approval for the medicine in 2014.

Gilead, which spent $10.8 billion to acquire one of the medicines, GS-7977, plans to combine it with another, GS-5855, in a trial of 800 patients starting in the fourth-quarter, said Norbert Bischofberger, chief medical officer of the Foster City, California-based company, in a conference call yesterday. If the combination is effective, the company could apply for regulatory approval in the middle of 2014, Bischofberger said.

Gilead is among several drugmakers racing to develop new hepatitis C treatments that act more quickly with fewer side effects than the current standard of care. The goal is to provide doctors and patients with simpler, more effective treatments, Bischofberger said.

The company aims for a therapy that "will clearly be a one pill, once daily, maybe a 12 week course," for patients with all different types of hepatitis C, Bischofberger said. "That's our goal. We are very close."

Conventional therapy combines ribavirin with interferon, an injected immune-boosting protein that can cause flu-like side effects, for as long as 48 weeks.

Gilead is competing with Abbott Laboratories, Bristol-Myers Squibb Co., Johnson & Johnson, Merck & Co. and Vertex Pharmaceuticals Inc. (VRTX) (VRTX) to develop a new generation of hepatitis C treatments. Rising deaths among baby boomers from hepatitis C prompted U.S. health officials to declare in May that the entire age group is at risk and should be tested for the disease.

Idenix hepatitis C drug IDX719 gets FDA fast track designation...

Posted on 7-25-12 on businessweek.com. IDX719, Idenix's HCV NS5A inhibitor gets fast track designation from the FDA. 


July 25, 2012

CAMBRIDGE, Mass. (AP) — Shares of biotech drugmaker Idenix Pharmaceuticals Inc. rose Wednesday after the company said its experimental treatment for hepatitis C will be reviewed under the Food and Drug Administration's fast track program.



Drugs that receive fast track status at the FDA receive extra meetings and correspondence with regulators throughout the review process. The program is designed to speed up the approval of drugs that treat life-threatening diseases for which there are few other therapies.

Idenix has studied the safety and effectiveness of its drug, known as IDX719, in several small studies lasting up to seven days.

"We are pleased and encouraged by the receipt of fast track designation from the FDA for IDX719 as we believe this reflects the critical need for new treatment regimens to address HCV infection," said Idenix President and CEO Ron Renaud in a statement.

Shares of Idenix rose 24 cents, or 2.4 percent, to $10.31 in midday trading.

JID: Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prospective Study

JID article (can be DL'd here) looking at  the mortality rate of subjects who were HCV seropositive vs seronegative in a very large cohort. It suggests that any amount of replicating virus contributed to mortality from both hepatic and extrahepatic diseases, even if there was no liver damage present. My own takeaway here is HCV should be treated with the urgency granted to other viral diseases. The strategy of waiting two years for HCV- drugs that may/may not arrive to treat patients with replicating virus and no contraindications may not be the best way to go. Many thanks to Dr. Luber for the heads up on this study. 

Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic
Diseases: A Community-Based Long-Term Prospective Study

Mei-Hsuan Lee,1 Hwai-I. Yang,1,2,3 Sheng-Nan Lu,4 Chin-Lan Jen,1 San-Lin You,1 Li-Yu Wang,5 Chih-Hao Wang,6 Wei J. Chen,7 Chien-Jen Chen,1,7 and for the R.E.V.E.A.L.-HCV Study Groupa
1Genomics Research Center, Academia Sinica, Taipei; 2Molecular and Genomic Epidemiology Center, China Medical University Hospital, Taichung; 3Graduate Institute of Clinical Medical Science, China Medical University, Taichung; 4Department of Gastroenterology, Kaohsiung Chang-Gung
Memorial Hospital, Kaohsiung; 5MacKay Medical College, Taipei; 6Department of Cardiology, Cardinal Tien Hospital, Taipei; and 7Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan

Background. 
The study aimed to evaluate the risk of hepatitis C virus (HCV) infection on hepatic and extrahepatic
deaths. Methods. A cohort of 23 820 adults aged 30–65 years old were enrolled during 1991–1992. The seromarkers hepatitis B surface antigen (HBsAg), anti-HCV, and serum HCV RNA levels at study entry were tested. The vital status was ascertained through computerized linkage with national death certification profiles from 1991 to 2008.

Results.
There were 19,636 HBsAg-seronegatives, including 18 541 anti-HCV seronegatives and 1095 anti-
HCV seropositives. Among anti-HCV seropositives, 69.4% had detectable serum HCV RNA levels. There were 2394 deaths that occurred during an average follow-up period of 16.2 years. Compared with anti-HCV seronegatives, anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66–2.15) for all causes of death; 12.48 (9.34–16.66) for hepatic diseases; 1.35 (1.15–1.57) for extrahepatic diseases; 1.50 (1.10–2.03) for circulatory diseases; 2.77 (1.49–5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38–12.08) for esophageal cancer; 4.19 (1.18–
14.94) for prostate cancer; and 8.22 (1.36–49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA.

Conclusions.
Monitoring HCV RNA in anti-HCV seropositives is essential for the prediction of mortality
associated with hepatitis C.

GUT: Vitamin B12 may improve SVR rates in HCV infected patients...

Study posted 7/18/12 via the journal GUT.  Researchers in Italy find a link between 5000 ug every 4 weeks of vitamin B12 and improved SVR... especially in the more difficult-to-treat genotype 1 patients with high baseline viral loads.  Researchers noted a 34% improvement in SVR in the arms containing B12 than in the arms that didn't. That's pretty cool in my book, but let's do a gut check all the same. OK, it's a small study, it's European (which means the patients have a higher probability of being Caucasian, lower BMI, CC alelle, genotype 1b, all that stuff that makes these patients more likely to respond to traditional pegylated interferon + ribavirin therapy than patient types over here in the States) but hey!! Vitamin B12 can be had on the cheap! Further prospective and larger clinical trials will have to be done to confirm or deny the seemingly extra added boost to SVR rates, especially with the new standard of care. Let's hope it's not another silymarin experience.

GUT
Vitamin B12 supplements may help treat hepatitis C

Safe and inexpensive option for boosting response rate to antiviral drugs

[Vitamin B12 supplementation improves the rate of sustained viral response in patients chronically infected with hepatitis C virus Online First doi 10.1136/gutjnl-2012-302344]

Adding vitamin B12 to standard hepatitis C virus (HCV) treatment significantly boosts the body’s ability to keep the virus at bay, indicates a pilot study published online in the journal Gut.

The effects were particularly strong in patients whose infection was proving difficult to treat effectively, the findings showed.

Between 60% and 80% of those infected with the viral liver infection HCV will go on to develop chronic hepatitis, and roughly a third of them will progress to cirrhosis and terminal liver disease.

Standard treatment of interferon (peg IFN) and ribavarin clears the virus in about 50% of patients infected with genotype 1 HCV and 80% of those infected with genotypes 2 or 3.   But this approach fails to clear the virus in around half of all those infected with HCV or the infection returns once treatment stops.  

While trials of new generation antiviral drugs show promise, they are expensive, and can make treatment more difficult. And questions still remain about how well they will work in practice, say the authors.

Experimental research dating back a decade suggests that vitamin B12 may have a role in suppressing HCV. The liver is the body’s primary storage centre for vitamin B12, but this capacity is impaired by diseases directly affecting the organ. The researchers therefore wanted to see if adding vitamin B12 to standard treatment would make a difference.

Ninety four patients with HCV infection were randomly allocated to receive standard treatment or standard treatment plus vitamin B12 (5000 ug every 4 weeks) for between 24 (genotypes 2 and 3) and 48 weeks (genotype 1).

The body’s ability to clear the virus was assessed after 4 weeks (rapid viral response), after 12 weeks (complete early viral response), at the end of treatment and at 24 weeks after stopping treatment (sustained viral response).

There was no difference between the two treatment approaches at 4 weeks, but there were significant differences in response at all the other time points, particularly 24 weeks after stopping treatment, which is the aim of HCV treatment and the closest it can be get to a cure.  

The effects were also significantly greater among those who carried the type 1 strain, which is particularly hard to treat, and those high levels of infection (high viral load) to begin with.

Overall, adding vitamin B12 to standard therapy strengthened the rate of sustained viral response by 34%, the findings showed.

The authors conclude that until clear eligibility criteria for treatment with the new generation antiviral drugs are established, standard treatment plus vitamin B12 is a safe and inexpensive alternative, particularly for those who carry a strain of the virus that is hard to treat.

They add: “This strategy would be especially useful in those countries where, owing to limited economic means, the new generation antiviral therapies cannot be given in routine practice.”

JAMA: Milk Thistle has no effect on serum ALT levels in HCV nonresponders...

Posted on 7/18/12 on the JAMA Network. Further evidence that Milk Thistle and Silymarin have no effect on serum ALT levels in patients with HCV. 

Original Contribution | July 18, 2012

Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy

Michael W. Fried, MD; Victor J. Navarro, MD; Nezam Afdhal, MD; Steven H. Belle, PhD; Abdus S. Wahed, PhD; Roy L. Hawke, PharmD, PhD; Edward Doo, MD; Catherine M. Meyers, MD; K. Rajender Reddy, MD; for the Silymarin in NASH and C Hepatitis (SyNCH) Study Group
JAMA. 2012;308(3):274-282.

Context:  The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy.

Objective:  To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy.

Design, Setting, and Participants:  Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011.

Intervention:  Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks.

Main Outcome Measures:  The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures.

Results:  After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, −4.3 [95% CI, −17.3 to 8.7] U/L for placebo, −14.4 [95% CI, −41.6 to 12.7] U/L for 420-mg silymarin, −11.3 [95% CI, −27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, −0.05 to 0.18] log10 IU/mL for placebo, −0.03 [95% CI, −0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, −0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo.

Conclusion:  Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy.

Trial Registration  clinicaltrials.gov Identifier: NCT00680342

University of Florida researchers develop nanorobot to target Hepatitis C...

Posted 7/16/12 on the University of Florida website. Nanotechnology represents a fascinating, potentially less lethal and more efficacious way to treat disease states without the side-effects common with oral and injectable drugs. Using Nanotechnology, University of Florida researchers have designed a nanozyme that hyper-targets the Hepatitis C virus. Using a two pronged attack - a DNA oligonucleotide that recognizes the genetic material to be destroyed and instructs it's partnered enzyme to destroy the virus' mRNA. Should it become feasible, we may have a hyper-targeted therapy to treat Hepatitis C that would avoid the majority of adverse events and side effects we see with traditional medicinal oral and injectable therapies. 


UF researchers develop “nanorobot” that can be programmed to target different diseases

Monday, July 16, 2012.

GAINESVILLE, Fla. — University of Florida researchers have moved a step closer to treating diseases on a cellular level by creating a tiny particle that can be programmed to shut down the genetic production line that cranks out disease-related proteins.

In laboratory tests, these newly created “nanorobots” all but eradicated hepatitis C virus infection. The programmable nature of the particle makes it potentially useful against diseases such as cancer and other viral infections.

The research effort, led by Y. Charles Cao, a UF associate professor of chemistry, and Dr. Chen Liu, a professor of pathology and endowed chair in gastrointestinal and liver research in the UF College of Medicine, is described online this week in the Proceedings of the National Academy of Sciences.

“This is a novel technology that may have broad application because it can target essentially any gene we want,” Liu said. “This opens the door to new fields so we can test many other things. We’re excited about it.”

During the past five decades, nanoparticles — particles so small that tens of thousands of them can fit on the head of a pin — have emerged as a viable foundation for new ways to diagnose, monitor and treat disease. Nanoparticle-based technologies are already in use in medical settings, such as in genetic testing and for pinpointing genetic markers of disease. And several related therapies are at varying stages of clinical trial.

The Holy Grail of nanotherapy is an agent so exquisitely selective that it enters only diseased cells, targets only the specified disease process within those cells and leaves healthy cells unharmed.

To demonstrate how this can work, Cao and colleagues, with funding from the National Institutes of Health, the Office of Naval Research and the UF Research Opportunity Seed Fund, created and tested a particle that targets hepatitis C virus in the liver and prevents the virus from making copies of itself.

Hepatitis C infection causes liver inflammation, which can eventually lead to scarring and cirrhosis. The disease is transmitted via contact with infected blood, most commonly through injection drug use, needlestick injuries in medical settings, and birth to an infected mother. More than 3 million people in the United States are infected and about 17,000 new cases are diagnosed each year, according to the Centers for Disease Control and Prevention. Patients can go many years without symptoms, which can include nausea, fatigue and abdominal discomfort.

Current hepatitis C treatments involve the use of drugs that attack the replication machinery of the virus. But the therapies are only partially effective, on average helping less than 50 percent of patients, according to studiespublished in The New England Journal of Medicine and other journals. Side effects vary widely from one medication to another, and can include flu-like symptoms, anemia and anxiety.

Cao and colleagues, including graduate student Soon Hye Yang and postdoctoral associates Zhongliang Wang, Hongyan Liu and Tie Wang, wanted to improve on the concept of interfering with the viral genetic material in a way that boosted therapy effectiveness and reduced side effects.

The particle they created can be tailored to match the genetic material of the desired target of attack, and to sneak into cells unnoticed by the body’s innate defense mechanisms.

Recognition of genetic material from potentially harmful sources is the basis of important treatments for a number of diseases, including cancer, that are linked to the production of detrimental proteins. It also has potential for use in detecting and destroying viruses used as bioweapons.

The new virus-destroyer, called a nanozyme, has a backbone of tiny gold particles and a surface with two main biological components. The first biological portion is a type of protein called an enzyme that can destroy the genetic recipe-carrier, called mRNA, for making the disease-related protein in question. The other component is a large molecule called a DNA oligonucleotide that recognizes the genetic material of the target to be destroyed and instructs its neighbor, the enzyme, to carry out the deed. By itself, the enzyme does not selectively attack hepatitis C, but the combo does the trick.

“They completely change their properties,” Cao said.

In laboratory tests, the treatment led to almost a 100 percent decrease in hepatitis C virus levels. In addition, it did not trigger the body’s defense mechanism, and that reduced the chance of side effects. Still, additional testing is needed to determine the safety of the approach.

Future therapies could potentially be in pill form.

“We can effectively stop hepatitis C infection if this technology can be further developed for clinical use,” said Liu, who is a member of The UF Shands Cancer Center.
The UF nanoparticle design takes inspiration from the Nobel prize-winning discovery of a process in the body in which one part of a two-component complex destroys the genetic instructions for manufacturing protein, and the other part serves to hold off the body’s immune system attacks. This complex controls many naturally occurring processes in the body, so drugs that imitate it have the potential to hijack the production of proteins needed for normal function. The UF-developed therapy tricks the body into accepting it as part of the normal processes, but does not interfere with those processes.

“They’ve developed a nanoparticle that mimics a complex biological machine — that’s quite a powerful thing,” said nanoparticle expert Dr. C. Shad Thaxton, an assistant professor of urology at the Feinberg School of Medicine at Northwestern University and co-founder of the biotechnology company AuraSense LLC, who was not involved in the UF study. “The promise of nanotechnology is extraordinary. It will have a real and significant impact on how we practice medicine.”

Credits

Guru Focus: Idenix Pharmaceuticals Lagging Behind In Breakthrough Hepatitis C Drug Development

Posted on 7/13/12 on www.gurufocus.com. The author is worried about Idenix's pan-genotype nuc, IDX184. I'm not as worried, but Idenix definitely needs other drugs beside it's own to pair IDX184 with - preferably those well into Phase IIb or Phase III studies.  Those are drugs that are most likely to make it to market first, barring any errant new safety signals that would gum up the works and put pinholes in the dreams of investors everywhere. A good example to follow is Medivr/Janssen's protease inhibitor TMC435. That partnership has done an outstanding job of partnering with every company with a drug that looks hopeful, expanding their status as the 'preferred partner' drug in every combination that looks effective and safe.  On the other hand, we've learned in HIV that a good, potent, well-tolerated nuc (preferably ones with a unique resistance profile) will always come in handy. A good drug never has to worry. Only the company developing it does. 

Idenix Pharmaceuticals Lagging Behind In Breakthrough Hepatitis C Drug Development
July 13, 2012

Idenix Pharmaceuticals (IDIX) is one of the biopharmaceutical companies focused on discovering, developing and commercializing drugs for the treatment of life-threatening human viral diseases such as Hepatitis C. Hepatitis C is a form of liver disease that is passed on from one person to another through contact of bodily fluids. The Hepatitis C virus can severely damage the liver as it is asymptomatic and therefore, the effects are slowly felt over a long period of time. Hepatitis C has the potential to kill if not detected early enough.

It is estimated that 75% to 85% of Hepatitis C infections become chronic, leading to serious liver disease such as cirrhosis and may even causing liver cancer. Researchers at the Centers for Disease Control and Prevention estimate that about 50% of the 3.2 million Americans who have chronic Hepatitis C do not know about it. This is frightening to say the least, given that Hepatitis C is now estimated to be killing more Americans than HIV, the virus that causes AIDS. The Hepatitis C virus has also been found to be more prevalent in the "baby boomer" generation born between 1945 and 1964. This was a time when casual sharing of needles and drug use was the norm. I was floored to discover that the current worldwide figure of persons considered to be living with chronic viral hepatitis stands at between 480 million and 540 million, with approximately 130 million to 170 million of them infected with the Hepatitis C virus.

IDX184 is a pan-genotypic oral nucleotide polymerase inhibitor and Idenix Pharmaceutical’s lead product for the treatment of Hepatitis C. It is Idenix’s belief that the Hepatitis C treatment paradigm will evolve rapidly within the next three to five years as various companies continue to develop direct-acting antivirals (DAAs) from different drug classes. The treatments would potentially reduce the duration of treatment from one year to six months or less, increase the sustained virologic response rates and improve drug tolerability. It would also be extremely convenient as patients would be able to take all the drugs orally. I believe this is significant as the side effects associated with the combination of Interferon and Ribaravin during treatment disqualify many Hepatitis C-infected candidates from undergoing the treatment. Therefore, a breakthrough in this area would be a huge stride for Idenix and has the potential to affect its share price positively. Idenix Pharmaceuticals has also co-developed a Hepatitis B drug candidate, telbivudine, with Norvatis Pharma AG (NVS). The product is commercially sold as Tyzeka®, and Idenix Pharmaceuticals earns royalties from the product sales.

Idenix Pharmaceuticals stock began trading on July 2004 with an initial public offering of 5.8 million shares at $14 per share. On 23 April, 2012 Idenix Pharmaceuticals gained 6.5% to even out at slightly below $9. Earlier in March 2012 the share price had traded at an average of $12. Idenix Pharmaceuticals released its fourth quarter and financial results for the year ending Dec. 31, 2011 in February. Its total revenue was $7 million compared to 10.2 million in the year ending Dec. 31, 2010. The company recorded a net loss of $52 million on Dec. 31, 2011 as compared to $61.6 million on Dec. 31, 2010. The share price seems to fluctuate a lot so if you’re looking to trade in stock it is probably advisable to consider day-trading or swing-trading as compared to making a long-term investment.

Another competitor, Gilead Sciences (GILD) made astronomical progress in April 2012, when a mid-stage clinical trial revealed that a combination of the GS-7977 drug and the antiviral Ribaravin cleared the virus in approximately 88% of the patients. The GS-7977 drug was administered together with Ribaravin, completely eliminating the need for the injectable interferon. Gilead Sciences is the world’s largest HIV drug maker, so this news comes as no surprise.

Gilead’s shares have evened out at an average of $51 after they jumped from about $47 to an average of $53. These developments have clearly placed Gilead Sciences ahead of the pack, and I would not hesitate to recommend trading its shares.

Vertex Pharmaceuticals (VRTX) is also in the process of carrying out a study to evaluate the effectiveness of a Hepatitis C treatment on patients who are not on antiretroviral therapy for HIV versus those who are on a Atripla- or Reyataz-based treatment for HIV. Vertex Pharmaceuticals is carrying out the study in collaboration with Janssen, one of Johnson & Johnson (JNJ)'s pharmaceutical companies. The study is intended to evaluate the safety and tolerability of the Incivek drug combination therapy in patients infected with both the Hepatitis C virus and HIV. The drug is marketed in the U.S. and Canada and is also available in the Far East and Japan.

Vertex Pharmaceuticals stock is trading at an average of $37. January 2012 was a terrible month for Vertex with their share price dipping to $34 after an analyst at Leerink Swann reduced the sales forecast for Incivek from $2.3 billion to $1.5 billion this year, citing recent developments of interferon-free regimens and the possibility of more aggressive developments. There is a great need for Hepatitis C treatment and more so amongst those infected with HIV. If Vertex Pharmaceuticals manages to develop a drug that can be safely used to treat those co-infected with Hepatitis C and HIV then it is safe to say that it will be worth your while to invest in Vertex Pharmaceuticals.

Victrelis, a product of Merck & Co. (MRK), was approved for the U.S. market by the Food and Drug Administration just last year for the treatment of Hepatitis C. It is surprising therefore when I learned from my research that the drug’s effectiveness is lowered when used in combination with some antiretroviral therapy drugs. It’s not all bad news though. Merck recently agreed to pay Endocyte (ECYT) up to $1 billion to develop and commercially market Vintafolide, an experimental cancer drug. Merck will own all the global rights meaning that a surge in sales will push its share price upwards. Merck is currently trading at an average of $28 and its future outlook does not look very promising at the moment.

Abbot Laboratories (ABT)'s main line of business is in the discovery, development, manufacture and sale of a wide range of health care products. Abbot Laboratories released data earlier in April 2012 from a mid-stage clinical trial that indicated combining ABT-450 boosted by an antiviral, Ritonavir, along with Ribaravin and a polymerase inhibitor achieved a 95% cure rate. Deutsche Bank consequently boosted Abbot Laboratories rating to “Buy” in March 2012 with a price target of $70. The share price is currently trading at slightly under $60. I’d say this is pretty close to what analysts at Deutsche Bank projected. Abbot Laboratories is in the process of separating into two healthcare companies by the end of the year, so it is advisable to carry out day trading and keep a close eye on the share price.

Levels of Hepatitis C Virus Higher Among African-Americans and Males

Posted on 7/10/12 on www.amren.com. A collaborative study between the National Institutes of Health Clinical Center and UCSF to be published in the July issue of "Hepatology" showed that among IVDUs males and African Americans were more likely to have HCV and/or HIV than any other demographic. This has implications for treatment in that African Americans are less likely to respond to current therapy than any other demographic. 

Levels of Hepatitis C Virus Higher Among African-Americans and Males

Medical Xpress, July 10, 2012

Epidemiologists have determined that levels of hepatitis C virus (HCV) found among injection drug users (IDUs) were higher in individuals who are male or African American even after differences in other factors were considered. The study, which was funded by the National Cancer Institute and performed with collaborators from the National Institutes of Health Clinical Center and the University of California—San Francisco, was the first to simultaneously examine the association of demographic, viral and human genetic factors on HCV RNA levels. Results of the study published in the July issue of Hepatology, a journal of the American Association for the Study of Liver Diseases (AASLD), also showed higher levels of HCV among IDUs who were co-infected with human immunodeficiency virus (HIV).

A 2010 report from the Centers for Disease Control and Prevention (CDC) estimates that up to 3.9 million Americans have chronic HCV—a leading cause of liver cancer, end-stage liver disease and liver transplantation. According to the CDC 17,000 new cases and 2,800 acute cases of HCV were reported in 2010. Previous epidemiologic studies suggest one-third of those 18 to 30 year-old IDUs and up to 90% of older IDUs are infected with HCV.

“With such a high incidence and prevalence of hepatitis C virus infection among IDUs, it is important to understand the characteristics of the infection in this group,” explains lead author Dr. Thomas O’Brien of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute in Rockville, MD. “The HCV RNA level is an important predictor of response to treatment in patients with chronic hepatitis C. Our study is the first to examine simultaneously the viral, demographic, and genetic factors that impact HCV levels in ethnically diverse IDUs.”

Participants were originally recruited for the Urban Health Study—a multi-ethnic group of IDUs in San Francisco. Researchers used interview data and biological samples from participants to analyze demographic, viral and host characteristics of cancer-causing viruses. A total of 1701 participants had detectable HCV RNA and were included in the present study. The median age at enrollment was 46 years and median age of first illicit drug injection was 18 years. Close to 75% of participants were men and 56% were African American, 34% European (non-Hispanic) and 7% Latino (non-African American).

Adjusted analysis revealed that age, gender, racial ancestry, HIV-1 infection, and IL28B rs12979860 genotype were all independently associated with the HCV RNA level. “We know that the level of HCV is an important predictor of treatment response and that these levels seem to be influenced by a number of demographic, clinical, viral and human genetic factors,” concludes Dr. O’Brien.

Biolex Therapeutics files for $38M bankruptcy

Posted 7-6-2012 on Bizjournals.com. Biolex Therapeutics has filed for bankruptcy, which effectively terminates the development of it's controlled release alpha interferon-2b and presumably it's relationship with OctoPlus as a result. Boo.  

Biolex Therapeutics files for $38M bankruptcy

Triangle Business Journal by Chris Bagley, Staff Writer
Date: Friday, July 6, 2012, 8:07am EDT

Chris Bagley
Staff Writer- Triangle Business Journal

Biolex Therapeutics Inc. has filed for bankruptcy liquidation, marking an inauspicious end to $190 million that investors had poured into the Pittsboro-based company since its founding in 1997.

The company's Chapter 7 filing on July 3 cited $38 million in liabilities, including nearly $5 million owed to Intersouth Partners of Durham. Other large creditors include Clarus Lifesciences, a venture capital firm with offices in the San Francisco and Boston areas, which is owed $8.4 million, and an investment arm of the pharmaceutical giant Johnson & Johnson, which has a $3.8 million claim, according to Biolex's filing.

Clarus, Intersouth and the J&J fund are also listed as the company's largest, second-largest and third-largest shareholders, with 27 percent, 13 percent and 11 percent stakes, respectively.

Biolex's filing showed just $803,000 in assets.

Biolex recently had faced an increasingly daunting task of raising money to develop its Locteron drug for hepatitis C. The company had touted the drug as likely to have milder side effects and more convenient dosing than existing hepatitis C treatments.

Biolex shrank from 70 employees at its peak to about 13 in February. CFO Dale Sander told Triangle Business Journal that month that the company was considering a sale as one of several alternatives to continue Locteron's development.

Like other varieties of hepatitis, hep C can cause fatigue and loss of appetite ­or no symptoms at all and can ultimately lead to cirrhosis. The lettered varieties of hepatitis are all brought about by different viruses, and the drugs for treating them also vary.

Chris Bagley covers the legal-services industry, transportation and utilities. Follow him on Twitter @cbagley.

HALT-C trial analysis shows reduced HCV viremia has clinical benefit...

Posted ahead of print of the American Journal of Gastroenterology on www.nature.com. A new analysis of the mammoth HALT-C trial revealed some very cool news for patients patients who achieved a significant viral load reduction while on Peg-Inf + RBV but relapsed after end of treatment (dubbed "responder relapsers). Those patients who showed improved HAI (Ishak Hepatic Activity Index) demonstrated reduced hepatic inflammation and thus less fibrosis progression and clinical complications followed out a median of 6 years than those not in that group. Bottom line, patients who were 'responder relapers' didn't go through therapy all for naught and experienced a benefit in lower fibrosis progression and it's associated complications. Hopefully this benefit will extend as well to those same patients that responded to new triple therapy but relapsed after end of treatment.


The American Journal of Gastroenterology , (12 June 2012) | doi:10.1038/ajg.2012.137


Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

Chihiro Morishima, Mitchell L Shiffman, Jules L Dienstag, Karen L Lindsay, Gyongyi Szabo, Gregory T Everson, Anna S Lok, Adrian M Di Bisceglie, Marc G Ghany, Deepa Naishadham, Timothy R Morgan, Elizabeth C Wright and for the HALT-C Trial Group15

Abstract
OBJECTIVES:

During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.

METHODS:

Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.

RESULTS:

Among 657 patients who received full-dose peginterferon/ribavirin “lead-in” therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3–4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.

CONCLUSIONS:

Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

Incivek (telaprevir) product labeling revised...

Posted at FDA.gov on 6/26. The FDA revised the product labeling for Incivek. The changes were a combination of DDI, warnings, clinical trial data revisions and corrections. See below for full list of changes. 

Incivek (telaprevir) product labeling revised

The Incivek (telaprevir) product labeling was recently revised to include the following changes:

1. Update the clinical comment for neuroleptic drug pimozide in Section 4 Contraindications to state: "Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias"

2. Update Section 5 Warnings and Precautions subsection 5.4 Anemia to state: "Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during INCIVEK combination treatment and as clinically appropriate."

3. Update Section 5 Warnings and Precautions subsection 5.6 Laboratory Tests to state the following: Use of a sensitive real-time RT-PCR assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification equal to or less than 25 IU per mL and a limit of HCV-RNA detection of approximately 10-15 IU per mL.

4. Update Section 7 Drug Interactions to remove desipramine from Table 5: Established and Other Potentially Significant Interactions. Also added to Section 7 was a statement that no dose adjustment is needed for Incivek when given with either raltegravir or buprenorphine. The corresponding results from the drug-drug interaction trial with raltegravir and buprenorphine are included in Section 12 Pharmacokinetics.

5. Update Section 14 Clinical Studies to include revisions to the definition of sustained virologic response (SVR) and to correct the SVR rates for African American and Cirrhotic subpopulations as follows:

SVR was defined as HCV RNA less than 25 IU per mL at last observation within the SVR visit window (i.e., weeks 32-78 for patients assigned to 24 weeks of treatment and weeks 56-78 for patients assigned to 48 weeks of treatment).

Trial 108 (ADVANCE)

Twenty-six subjects were Black/African Americans. The overall SVR among Black/African American subjects was 62% (16/26). Among these subjects, 35% (9/26) were assigned to 24 weeks of treatment and of those 89% (8/9)achieved SVR.

Twenty-one subjects had cirrhosis at baseline and the overall SVR in these subjects was 71% (15/21). Among subjects with cirrhosis, 43% (9/21)were assigned to 24 weeks of treatment and of those 78% (7/9)achieved SVR.
Trial 111 (ILLUMINATE)

Sixty-one (11%) of subjects had cirrhosis at baseline. Among subjects with cirrhosis, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 61% (11/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group.
Blacks/African Americans comprised 14% (73/540) of trial subjects. Thirty-four (47%) Black/African American subjects achieved an eRVR and were randomized to T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 88% (15/17), compared to 92% (244/266) for Caucasians among randomized subjects.
Trial C216

Twenty-six percent (139/530) of INCIVEK-treated subjects had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 84% (48/57) compared to 7% (1/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders.
Four percent (19/530) of treatment experienced subjects who received INCIVEK combination treatment were Black/African Americans; the SVR rate for these subjects was 63% (12/19) compared to 66% (328/498) for Caucasians.

The complete revised label can be viewed on the FDA web site at Drugs@FDA.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

PLoS ONE: Discovery of Novel Biomarker Candidates for Liver Fibrosis in Hepatitis C Patients: A Preliminary Study

Posted 7/5/12 on PLoS ONE.org. UK researchers utilized methodology within the discipline of Proteomics to identify plasma-based proteins that could possibly be used clinically to discriminate between the intermediate stages of fibrosis. Twenty biomarkers were validated in comparison to the commonly used markers in FibroTest, ELF, Hepascore and FIBROSpect by Western blotting. These markers will be further validated using a large clinical cohort. Any advance in this area that would possibly be used to avoid liver biopsy would greatly benefit patients. 


Discovery of Novel Biomarker Candidates for Liver Fibrosis in Hepatitis C Patients: A Preliminary Study

Bevin Gangadharan1*, Manisha Bapat1#, Jan Rossa1#, Robin Antrobus1, David Chittenden1, Bettina Kampa1, Eleanor Barnes2,3, Paul Klenerman2, Raymond A. Dwek1, Nicole Zitzmann1
1 Oxford Antiviral Drug Discovery Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom, 2 Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, 3 Oxford NIHR Biomedical Research Centre, The John Radcliffe Hospital, Headington, Oxford, United Kingdom

Abstract

Background
Liver biopsy is the reference standard for assessing liver fibrosis and no reliable non-invasive diagnostic approach is available to discriminate between the intermediate stages of fibrosis. Therefore suitable serological biomarkers of liver fibrosis are urgently needed. We used proteomics to identify novel fibrosis biomarkers in hepatitis C patients with different degrees of liver fibrosis.

Methodology/Principal Findings
Proteins in plasma samples from healthy control individuals and patients with hepatitis C virus (HCV) induced cirrhosis were analysed using a proteomics technique: two dimensional gel electrophoresis (2-DE). This technique separated the proteins in plasma samples of control and cirrhotic patients and by visualizing the separated proteins we were able to identify proteins which were increasing or decreasing in hepatic cirrhosis. Identified markers were validated across all Ishak fibrosis stages and compared to the markers used in FibroTest, Enhanced Liver Fibrosis (ELF) test, Hepascore and FIBROSpect by Western blotting. Forty four candidate biomarkers for hepatic fibrosis were identified of which 20 were novel biomarkers of liver fibrosis. Western blot validation of all candidate markers using plasma samples from patients across all Ishak fibrosis scores showed that the markers which changed with increasing fibrosis most consistently included lipid transfer inhibitor protein, complement C3d, corticosteroid-binding globulin, apolipoprotein J and apolipoprotein L1. These five novel fibrosis markers which are secreted in blood showed a promising consistent change with increasing fibrosis stage when compared to the markers used for the FibroTest, ELF test, Hepascore and FIBROSpect. These markers will be further validated using a large clinical cohort.

Conclusions/Significance
This study identifies 20 novel fibrosis biomarker candidates. The proteins identified may help to assess hepatic fibrosis and eliminate the need for invasive liver biopsies.

Citation: Gangadharan B, Bapat M, Rossa J, Antrobus R, Chittenden D, et al. (2012) Discovery of Novel Biomarker Candidates for Liver Fibrosis in Hepatitis C Patients: A Preliminary Study. PLoS ONE 7(6): e39603. doi:10.1371/journal.pone.0039603

Editor: Ravi Jhaveri, Duke University School of Medicine, United States of America

Received: November 30, 2011; Accepted: May 22, 2012; Published: June 26, 2012

Copyright: © 2012 Gangadharan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the Oxford Glycobiology Endowment and a ‘Blue Skies’ research grant from United Therapeutics Corp. NZ is a Senior Research Fellow of Linacre College, Oxford. PK was supported by the Wellcome Trust, The James Martin School for the 21st Century and the NIHR Biomedical Research Centre Programme (Oxford). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Professor Raymond Dwek is a Director and Member of the Scientific Board of United Therapeutics Corp., which supported this work in part through a “Blue Skies” research grant. A patent covering the biomarkers in this study has been filed. The patent number is 61178334. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

* E-mail: Bevin.Gangadharan@bioch.ox.ac.uk

# These authors contributed equally to this work.

Medivir and BMS partner for TMC435 and daclatasvir Phase II trial ...

Medivir press release dated on 6-29-12. Medivir/Janssen will partner with Bristol Myers Squibb for a 180 patient open-label phase II combination trial combining the protease inhibitor TMC435 with BMS's NS5A inhibitor daclatasvir both with and without ribavirin. The patient population will consist of genotype 1a and 1b treatment naive and null responder subjects. Of note in genotype 1a subjects, ribavirin will be included in both the 12 and 24 week arms. Given the  recent change in inclusion criteria in the COMMAND-3 trial, this isn't surprising. Genotype 1b subjects will be randomized to arms either with or without ribavirin. Subjects in the high-need category with F3/F4 fibrosis scores will make up approximately 35% of the population of the trial. 

Medivir announces an interferon-free phase II combination trial with TMC435 and daclatasvir to commence shortly

29-Jun-12

· The phase II interferon-free combination study with TMC435 and daclatasvir will evaluate treatment-naïve or previous null responder patients with HCV genotype 1a and 1b

· The study will include approx. 180 patients and will evaluate a combination of TMC435 and daclatasvir, with or without Ribavirin, in four different cohorts for 12 or 24 weeks of treatment

Stockholm, Sweden - Medivir AB (OMX:MVIR), the research-based pharmaceutical company focused on the development of high-value treatments for infectious diseases, announces that a phase II combination study with the investigational compound TMC435 and Bristol-Myers Squibb’s investigational compound daclatasvir will start in July. This study is part of the clinical collaboration agreement between Janssen R&D Ireland and Bristol-Myers Squibb Company (NYSE:BMY) announced on 2 December 2011 and on 18 April 2012.

TMC435 and daclatasvir (BMS-790052)
TMC435, a once daily potent NS3/4A protease inhibitor (PI) in phase III clinical development for the treatment of chronic genotype-1 hepatitis C virus (HCV) infection, will be investigated in an interferon free phase II trial in combination with Bristol-Myers Squibb´s investigational NS5A replication complex inhibitor, daclatasvir (BMS-790052), also in phase III development.

The purpose of this study is to assess the efficacy and safety of TMC435 and daclatasvir in combination with or without Ribavirin in chronic genotype-1 hepatitis C infected patients who are treatment-naive or null responders to previous Peginterferon alfa/Ribavirin therapy.

Study design
In this open label phase II study the potential to achieve sustained viral response (SVR), 12 (SVR12) and 24 (SVR24) weeks post treatment in treatment-naïve and null responder patients infected with HCV genotype 1a and 1b will be evaluated. Patients with advanced liver disease (F3/F4) will be allowed up to approx. 35% of the total treated population.

Cohort one and two will include patients with genotype 1b where TMC435 and daclatasvir will be dosed with or without Ribavirin for 12 weeks with a 36 weeks follow-up or for 24 weeks with a 24 weeks follow-up.

Cohort three and four will include patients with genotype 1a where TMC435, daclatasvir and Ribavirin will be dosed for 12 or 24 weeks with a 24 weeks post treatment follow-up.

For additional information from these recently updated studies, please see www.clinicaltrials.gov

For more information about Medivir, please contact:

Medivir Rein Piir, EVP Corporate Affairs & IR Mobile: +46 708 537 292
M:Communications medivir@mcomgroup.com
Europe: Mary-Jane Elliott, Amber Bielecka, Hollie Vile +44(0)20 7920 2330

About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The World Health Organization estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is TMC435, a novel protease inhibitor in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Pharmaceuticals.

In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialisation of TMC435 in the Nordic markets, once approved.

Medivir’s first product, the unique cold sore product Xerese®/Xerclear®, is launched in collaboration with GlaxoSmithKline to be sold OTC under the brand name ZoviDou in Europe, Japan and Russia.