Preventive Nutritional Support Helpful During Hepatitis C Therapy

By David Douglas

Reuters Health News

Nutritional support during antiviral treatment for hepatitis C helps limit weight loss and improves quality of life, Dutch researchers say.

"In our opinion, such nutritional support should be considered in all patients during antiviral treatment with pegylated-interferon alfa and ribavirin," Dr. Karel J. van Erpecum told Reuters Health by email.

Dr. van Erpecum of University Medical Center Utrecht and colleagues enrolled 53 patients in a randomized trial, assigning 27 to receive advice on nutrition, including a recommendation for frequent small meals, plus an energy- and protein-rich flavored drink to be taken daily before bedtime. The remaining patients received the advice and the supplements only if their weight dropped by at least 5% from baseline, according to a report online June 30th in the Journal of Hepatology.
At 24 weeks, both groups had lost weight, but the average loss was only 0.3 kg (0.3%) in the nutritional support group, vs 5.4 kg (6.9%) in the control group.

Similarly, Jamar Hand Grip Strength fell in both groups, but the decrease was minimal in the support group (from 40.7 to 39.7 kg), whereas it was significant in the control group (from 40.3 to 32.0 kg).
Digestive symptoms increased and quality of life scores deteriorated in both groups, but the impairments were significantly less in the intervention group. There was also a considerable reduction in energy, proteins and fat intake in the control group, while intake increased in the support group.

There was no significant difference in sustained virologic response between groups based on intention-to-treat analysis but there were significantly fewer patient-reported side effects in the preventive group.

Overall, the researchers conclude, "Preventive nutritional advice plus supplementation prevents weight loss and catabolic state during antiviral therapy for HCV, with improved digestive symptoms and quality of life."

What's not clear, Dr. van Erpecum added, are the potential benefits of nutritional supplementation during "triple therapy," which is currently advised for hepatitis C virus genotype 1 and includes the protease inhibitors boceprevir or telaprevir along with PEG-interferon and ribavirin. "These protease inhibitors are ingested together with meals, which could in theory decrease weight loss and catabolic state," he said.

SOURCE: http://bit.ly/P6ImkT
J Hepatol 2012.

Hepatitis C - Vertex lowers Incivek view; new drug data lifts shares

Tue Jul 31, 2012 4:02am IST

(Reuters) - Vertex Pharmaceuticals Inc (VRTX.O) reported further declines in sales of its hepatitis C drug Incivek and lowered its full year forecast for the medicine, but promising data on another drug for the virus lifted its shares more than 5 percent.
Vertex reported on Monday positive results from a very small, early stage trial of a hepatitis C medicine licensed from Alios BioPharma called ALS-2200 that appeared to allow investors to ignore falling Incivek sales. The experimental drug belongs to a class of medicines called nucleotide analogues, or nucs.

"It's all due to the data on their nuc," Brean Murray, Carret & Co analyst Brian Skorney said of the Vertex share jump.

He said the data looked comparable to early data from closely watched drugs being developed by Gilead Sciences Inc (GILD.O) and by Bristol-Myers Squibb Co (BMY.N).
"It puts them back in the hep C race," Skorney said. "It makes them a real player again."
If all goes well, Vertex said it could potentially begin pivotal Phase III testing of combinations including ALS-2200 by the end of 2013.

ISI Group analyst Mark Schoenebaum said the early ALS-2200 data surpassed expectations and agreed that it could be a serious potential rival for the drugs that Gilead and Bristol-Myers paid billions of dollars to acquire by buying other companies.

He added that Wall Street had not yet factored in the drug's potential in assessing the future value of Vertex.

"The Street has very little in the Vertex model for next generation hep C assets, so we think of this drug as all upside at this point," Schoenebaum said.
Second-quarter Incivek sales of $328 million fell short of Wall Street estimates of about $360 million and first-quarter sales of $356.9 million.

The company said it now expects full-year Incivek sales of $1.1 billion to $1.25 billion, down from its prior forecast of $1.5 billion to $1.7 billion.

Incivek, which was approved in May 2011, earlier this year eclipsed $1 billion in total sales, making it the fastest prescription drug to reach that mark in pharmaceutical history. But it must be taken with the difficult to tolerate injectable drug interferon and Incivek's life as a blockbuster is likely to end once all-oral treatment options become available over the next two years.

The continued decline in sales could indicate that patients are already beginning to wait for interferon-free regimens with fewer side effects being developed by several companies, including Vertex.
The company said it was still getting 70-75 percent of new hepatitis C prescriptions, but the number of patients beginning treatment has declined from initial demand. In addition to some patients delaying treatment, Vertex said many potential new patients were being recruited into clinical trials of new medicines being pursued by many companies.

"We believe ALS-2200 could become an important part of all-oral treatment regimens," Chief Executive Jeffrey Leiden told analysts on a conference call.

He said the company would move quickly to advance ALS-2200 into Phase II testing, and to develop all-oral regimens that include ALS-2200 in combination with its own medicines or those being developed by rival drugmakers.

Sales of the new cystic fibrosis drug Kalydeco were $46 million for the quarter, topping Wall Street estimates of about $41 million. Kalydeco, the first drug to treat the underlying cause of the life-shortening lung disease rather than just symptoms, won U.S. approval in late January and European approval just last week.

Kalydeco treats about 4 percent of cystic fibrosis patients with a specific gene mutation. It is currently testing Kalydeco in combination with another experimental drug with the hope of eventually addressing the larger cystic fibrosis population.
Vertex posted a net loss of $65 million, or 31 cents per share, after taking a $78 million charge as reserve against potential for excess Incivek inventory. That compared with a loss of $174 million, or 85 cents per share, a year ago.
Total revenue for the quarter of $418.3 million included $28 million in royalty payments from Johnson & Johnson (JNJ.N), which holds overseas rights to Incivek. That was short of analysts' revenue estimates of $471.2 million.

Vertex shares, which were already up about 50 percent this year, rose 5.3 percent to $52.60 in extended trading from their Nasdaq close at $49.96.

(Reporting by Bill Berkrot in New York; Editing by Bernard Orr, Leslie Gevirtz and Tim Dobbyn)

http://in.reuters.com/article/2012/07/30/us-vertex-results-idINBRE86T1HG20120730

Related-

ALS-2200-Vertex Announces Positive Results from Viral Kinetic Study in People with Hepatitis C

Vertex Announces Positive Results from Viral Kinetic Study of the Nucleotide Analogue ALS-2200 in People with Hepatitis C

- 4.54 log10 median reduction in HCV RNA observed in people with genotype 1 hepatitis C treated with a once-daily 200 mg dose of ALS-2200 for seven days; treatment was well-tolerated-
- Phase 2 studies of 12-week all-oral regimens planned for this year -

Continue reading....

Vertex surges as rival hep C contender plays catch-up in clinic
Vertex investors barely noted yesterday evening that revenue from Incivek slipped in the second quarter. Their attention was on ALS-2200, a hepatitis C nucleotide analogue that has elbowed its way into the frenzied race for a near-term approval for an all-oral therapeutic regimen
"It puts them back in the hep C race," Skorney told the news service about the data. "It makes them a real player again."
"There was a median 4.54 log reduction in hepatitis C virus RNA in people with genotype 1 chronic hepatitis C who were new to treatment after seven days of dosing with 200 mg of ALS-2200 once daily," Vertex reported. Next Vertex says it will study ALS-2200 in a combo trial with Incivek. And if everything continues as hoped Vertex says it can launch a pivotal Phase III next year.
Late last week Gilead laid out an ambitious schedule for its combination hep C program, promising to race into a late-stage study later this year after gaining proof-of-concept human data for its NS5a inhibitor. The biotech mapped out a two-year clinical game plan that matches GS-5885 with 7977.

Continue reading.......

A Debate on Liver Fibrosis Progression in HIV/HCV-Coinfected Patients

A Debate on Liver Fibrosis Progression in HIV/HCV-Coinfected Patients

The rate of fibrosis progression is high early in the course of HCV infection, but whether it later declines is unclear.


In late 2011, Vogel and colleagues published a study showing that HIV-infected men with primary hepatitis C virus (HCV) infection had a higher rate of liver fibrosis progression than would be expected in early HCV infection — but that it declined upon resolution of primary HCV infection.1 Now, Fierer and colleagues have written a letter to the editor, questioning the use of transient elastography to measure fibrosis progression in that study.2

Fierer and colleagues argue that although transient elastography provides an accurate assessment of liver stiffness — and thus fibrosis — in the setting of chronic HCV infection, it might not do so during primary HCV infection, when acute inflammation is present. Inflammation can falsely elevate the liver-stiffness score, making the fibrosis stage appear to drop sharply as the acute inflammation associated with primary HCV infection subsides.

Fierer and colleagues assert that liver biopsy provides a more accurate assessment of fibrosis in the setting of primary HCV infection. In support of this assertion, they report the results of 29 liver biopsies (11 reported previously3) performed in HIV-infected men with primary HCV infection. They noted high histopathologic stages of fibrosis early in the course of primary HCV infection, which persisted through the first 1 to 2 years of infection. Contrary to what was reported by Vogel and colleagues, fibrosis stage correlated with increasing time from initial HCV infection.

Notably, both the Vogel and Fierer cohorts were very small with relatively short follow-up, which means that we still lack definitive data beyond the first 1 to 2 years of primary HCV infection. Nevertheless, these studies are important because they demonstrate that HIV-infected men who acquire HCV infection tend to have an elevated rate of fibrosis progression during the early stages of HCV infection. According to recently published data, this elevated rate is associated with increased risks for end-stage liver disease, hepatocellular carcinoma, and all-cause mortality.4 Whether early treatment of HCV infection with new antivirals will alter the course of incident HCV infection in HIV-coinfected individuals remains to be seen.
Sonia Nagy Chimienti, MD

Published in Journal Watch HIV/AIDS Clinical Care July 30, 2012

Citation(s):
1. Vogel M et al. Liver fibrosis progression after acute hepatitis C virus infection in HIV-positive individuals. Clin Infect Dis 2012 Feb 15; 54:556.
2. Fierer DS et al. Early-onset liver fibrosis due to primary hepatitis C virus infection is higher over time in HIV-infected men. Clin Infect Dis 2012 Jul 5; [e-pub ahead of print]. (http://dx.doi.org/10.1093/cid/cis538)

3. Fierer DS et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: A prospective cohort study. J Infect Dis 2008 Sep 1; 198:683.
4. Limketkai BN et al. Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV. JAMA 2012 Jul 25; 308:370.

Really? The Claim: Milk Thistle Combats Liver Disease


Really? The Claim: Milk Thistle Combats Liver Disease

By ANAHAD O'CONNOR

In the world of alternative medicine, milk thistle is the treatment of choice for liver disease, particularly chronic infection with hepatitis C.
But now more evidence has come in: In a careful, double-blinded study financed by the National Institutes of Health, researchers at the University of North Carolina found that milk thistle had no real effect on people with chronic hepatitis C.
The study, one of the most rigorous to date on this topic, followed 154 people with the disease for 24 weeks. Some were given a placebo while others received silymarin, the active ingredient in milk thistle, three times a day in either normal or high doses.....

Continue Reading...


Silymarin Is Ineffective for Chronic Hepatitis C Virus Infection

Published in Journal Watch Gastroenterology July 27, 2012

In the most rigorous trial to date, oral silymarin was not superior to placebo in decreasing disease activity.

Silymarin is a botanical extract of milk thistle commonly used by patients with liver disease. In vitro studies have demonstrated antiviral, anti-inflammatory properties of silymarin in hepatitis C virus (HCV) replicon systems. However, the few efficacy studies conducted in patients with chronic HCV infection have produced mixed results.

In a new multicenter, double-blind, placebo-controlled efficacy trial, investigators randomized 154 patients (median age, 54; 71% men) with chronic HCV infection who previously failed interferon-based therapy to receive 420 mg of silymarin, 700 mg of silymarin, or placebo three times daily for 24 weeks. The two oral doses of pure silymarin were determined by earlier dose finding studies and were three to five times higher than concentrations used in previous studies. The primary endpoint was a serum alanine aminotransferase (ALT) level of ≤45 U/L or a 50% reduction from baseline ALT to a level <65 U/L. Secondary endpoints included HCV RNA levels and quality-of-life indicators.
After 24 weeks of treatment, only two patients in each group achieved the primary endpoint. The mean decline in ALT levels at the end of treatment, the mean change in HCV RNA levels, and the quality-of-life indicators did not differ among the three groups.

Comment: This trial definitively demonstrates that silymarin, even at three to five times the typical dose, is ineffective in treating patients with chronic HCV infection. Unlike previous trials, this study used a pure, quantifiable formulation of silymarin and well-defined outcomes, its cohort was large and representative of the patient population, the treatment period was sufficiently long, and both medication and visit adherence rates were high. Clinicians should quote this study when addressing patients' questions regarding the use of milk thistle for treating HCV infection.

Atif Zaman, MD, MPH


Citation(s):
Fried MW et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: A randomized controlled trial. JAMA 2012 Jul 18; 308:274.

U.S. issues warrant for Canadian linked to illegal Internet pharmaceutical scheme

U.S. issues warrant for Canadian linked to illegal Internet pharmaceutical scheme

By Stephen Maher, Postmedia News July 30, 2012

An American judge issued an arrest warrant Monday for a Canadian businessman over his role in an illegal Internet pharmacy operation.
Judge Irma Gonzalez, in the U.S. District Court for the Southern District of California, in San Diego, issued the warrant after Nathan Jacobson failed to show up for a sentencing hearing.
Jacobson, who grew up in Winnipeg and frequently hobnobs with senior Canadian politicians, was to be sentenced for conspiring to commit money-laundering.
Jacobson has offices and homes in Toronto and Israel. He pleaded guilty in May 7, 2008, to conspiracy to commit money laundering, according to U.S. attorney Phil Halpern in San Diego, but the plea has been sealed since then.
Jacobson and 17 others were charged in 2006 by a grand jury with 313 counts related to Affpower, an Internet pharmacy that dispensed drugs to Americans without legal prescriptions. Many of his co-accused have since been convicted, receiving long prison sentences.
Jacobson's role was clearing the payments — more than $46 million — through RX Payments Ltd., a credit-card clearing company registered in Malta but operating in Tel Aviv, Israel, according to court documents.
As part of his plea agreement, Jacobson agreed to forfeit $4.5 million.
Prosecutors hope that the judge will sentence him to prison time.


Continue Reading @ Montreal Gazette

The biggest blood supply risk: Tainted platelets-no longer HIV or hepatitis C

Published July 31, 2012

Hospitals and blood banks are adopting new measures to improve the safety of donated platelets—the tiny cells that make blood clot and heal injuries but that also present the No. 1 infection risk in the U.S. blood supply, the Wall Street Journal reported.
The biggest risk in the nation's blood supply is no longer HIV or hepatitis C, it's bacterial contamination of platelets, resulting in at least 20 deaths and hundreds of adverse reactions in recent years, health experts say.
A growing number of studies show that standard tests performed by blood banks before they ship platelets to hospitals miss the majority of contaminated platelets. Unlike other blood components such as red cells, which are refrigerated, platelets must be stored at room temperature to remain effective, but during storage periods that last up to five days bacteria can grow and multiply.
About 150 hospitals have adopted a new contamination test, made by Verax Biomedical Inc., that can be administered immediately before patients get a transfusion. Initially approved by the Food and Drug Administration in 2007, one barrier is cost: It adds about $25 to $30 to the average $540 cost of a unit of platelets.



New targets could enhance the body's defenses against West Nile and hepatitis C

  • Posted by HCV New Drugs
  • File Under

Two new targets have been discovered for antiviral therapies and vaccines strategies that could enhance the body's defenses against such infectious diseases as West Nile and hepatitis C. The targets are within the infection warning system inside living cells.

No vaccines exist for the viruses that cause West Nile or hepatitis C. New therapies are urgently needed to prevent and treat serious infections by these and related viruses. The University of Washington is engaged in a major, multipronged effort to design therapeutics that harness the warning signals the body produces when viruses attack. Such therapies would prod people's cells into launching a stronger counterattack to control infections by elusive viruses.

UW specialists in how the body fends off viral diseases are studying pattern recognition molecules, called RIG-I-like receptors, found inside living cells. When these receptors detect virus invasions, they call in the immune system to fight infection. Scientists in the laboratory of Dr. Michael Gale, Jr., UW professor of immunology, observed an interaction between these molecular dispatchers and a protein called 14-3-3 epsilon This protein acts a docking station where other proteins can gather. There they can more efficiently send out signals in response to threats.

The researchers noticed that the interaction between the alert trigger (RIG-I) and the docking station (14-3-3 epsilon) steps up when cells were infected with virus. The agitation prompts RIG-I to work with other proteins, such as TRIM25.

Those proteins are essential for RIG-I to warn the immune system to respond to a virus intruder. "Our work also demonstrated that RIG-I binding to 14-3-3 epsilon is important for RIG-I to move from within the cell where it detects viral RNA to a location on the cell's membrane where the cell's antiviral defenses can be activated," said Dr. Helene Liu, a postdoctoral fellow who led the study. The move is somewhat like running from the inner corridors of a building to a window to call for help.

"By understanding the molecular partners and location changes that RIG-I requires to convey its signal that virus is present in a cell, we can start to design therapeutics that can trigger this process to kick-off an antiviral immune response and fight virus infection," Liu said. The scientists reported these initial findings in the May 17 issue of Cell Host & Microbe.

The Gale laboratory reports additional observations on the RIG-I-like receptors in the August issue of Immunity, published online July 26. Postdoctoral fellows Dr. Mehul Suthar and Dr. Hilario Ramos found that, during West Nile virus infection, an RIG-I like receptor called LGP2 promotes the survival and activity of CD8+ T white blood cells, commonly called killer T cells.

These disease-fighters eliminate virus-infected cells from the body. "By increasing the ability and length of time CD8+T cells can work within the body when West Nile virus is present, the immune system is strengthened and has a better chance of eliminating the virus," Suthar commented. Ramos added, "Based on this work, we can consider new ways to boost vaccine effectiveness through design of adjuvants or immune-stimulants. These might be applied within a vaccine approach to regulate LGP2 to enhance immunity to infection." Gale directed the research effort for both projects. He heads the Center for Study of Innate Immunity to Hepatitis C Virus and the Center for Immune Mechanisms of Flavivirus Control, as well as two National Institutes of Health-funded multi-million dollar programs to develop new antiviral therapies and vaccine adjuvants.

"These two new discoveries," Gale said, "greatly advance our knowledge of how the body senses and responds to virus infection and provide us with new avenues to explore when designing antiviral therapies and new vaccines. "West Nile virus is an emerging virus that has spread across the United States, and hepatitis C virus infects over 170 million people globally.

Both viruses are devastating to the health of the individuals they infect. That is why the development of new clinical resources such as vaccines and antivirals for each is so critical." West Nile virus is spreading throughout North America through infected mosquitoes. It can cause paralysis and death in people. Hepatitis C virus is transmitted through contact with blood or blood products containing the virus. It causes swelling and inflammation of the liver.

Most hepatitis C infections are persistent because the virus evades the immune defenses that normally limit the course of disease. The virus generates a chronic liver inflammation which scars the organ's tissues. The scarring can lead to liver failure and increases the risk of liver cancer. While therapies are available to treat hepatitis C infections, these treatments have harsh side-effects and are not effective in all people. No antiviral therapies are available to treat people infected with West Nile virus.

Read more at: http://medicalxpress.com/news/2012-07-infection-cells-antiviral-vaccine-strategies.html#jCp

Hepatitis programs in Egypt improved disease burden

July 30, 2012
Progress has been made in the prevention of the spread of hepatitis C virus in health care situations in Egypt, but a comprehensive plan to prevent and control the disease is needed, according to results in the Morbidity and Mortality Weekly Report.

Egypt has a 10% prevalence of chronic hepatitis C among those aged 15 to 59 years, making it the largest burden of the virus worldwide, according to the report. Inadequate infection control during medical and dental procedures is the primary reason for this burden. In 2001, the Egyptian Ministry of Health and Population (MOHP) created a program to reduce this burden. A care and treatment program was launched in 2008.

Among patients receiving dialysis, the annual incidence of hepatitis C reduced from 28% to 6%, mostly in part to infection control programs implemented at MOHP facilities. In addition, there have been 23 hepatitis treatment facilities established in the country, which have provided care to almost 190,000 people with the disease.

During 2001, there were nearly 280 million injections given in Egypt, and an estimated 8% of these may have been unsafe. When the MOHP facilities were assessed, the following were found: there were few health care workers with knowledge of infection control; there were few infection control programs in the facilities; there was little understanding about standard precaution among health care workers; and there were inadequate procedures for equipment reprocessing, sterilization and waste management. Infectious control guidelines were developed in 2003, and after the implementation, improvements were observed.

The MOHP created the National Committee for the Control of Viral Hepatitis in 2006, which developed a National Control Strategy for Viral Hepatitis. This strategy called for effective surveillance, prevention measures to reduce the spread of both hepatitis B and hepatitis C and expansion of access to care and treatment. The program has cost the Egyptian government $80
million annually.

References:
CDC. MMWR. 2012;61:545-549.

Disclosures:
The researchers report no relevant financial disclosures.

http://www.healio.com/infectious-disease/gastrointestinal-infections/news/online/%7B0B91FED3-C91F-4BC8-8D57-A68130FAFA1B%7D/Hepatitis-programs-in-Egypt-improved-disease-burden

Sorafenib improved survival regardless of baseline characteristics in HCC patients

  • Posted by HCV New Drugs

Sorafenib improved survival regardless of baseline characteristics in HCC patients

Bruix J. J Hepatol. 2012;doi:10.1016/j.jhep.2012.06.014.

Patients with hepatocellular carcinomas had higher survival and disease control rates when treated with sorafenib compared with placebo, regardless of pretreatment disease characteristics, in a recent study.

Researchers performed subgroup analyses on 602 participants in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol trial. These patients randomly received 400 mg sorafenib (n=299) or placebo (n=303) twice daily, and analysis was conducted to determine whether patients’ baseline characteristics influenced drug efficacy and safety or survival rates.

Patients were split into subgroups based on disease etiology, tumor burden and stage, performance status and previous treatment, and then further divided into subsets. Survival rates were greater among treated patients compared with placebo patients, with HRs ranging from 0.50 to 0.85 (95% CI for all) across all subsets, compared with an HR of 0.69 (95% CI, 0.55-0.87) for the entire cohort. Median time to progression also was likely to be higher among treated patients (HR range 0.40-0.64 across all subsets), excluding those who tested positive for HBsAg antigen (HR=1.03) (95% CI for all). Among all subgroups, sorafenib improved disease control rates, including treated patients (34.4%-54.4%) compared with placebo patients (26.0%-43.1%).

The incidence rate of adverse events, which did not differ significantly, included diarrhea, hand-foot skin reaction and fatigue. Treatment-related events occurred in 71.9% to 84.9% in subgroups of sorafenib patients and 43.2% to 60.7% of those receiving placebo. Serious events occurred in 9.4% to 14.6% of treated patients and 5% to 25% of placebo patients.


“The efficacy and safety of sorafenib, relative to placebo, in patients with advanced HCC and well-preserved liver function do not appear to be affected by baseline health status, disease etiology, tumor burden, tumor stage or prior therapy,” the researchers concluded.

Disclosure: See the study for a full list of relevant disclosures.

NEW PERSPECTIVES IN HEPATOCELLULAR CARCINOMA

Seminars in Oncology
Volume 39, Issue 4 , Pages 367-368, August 2012
http://www.seminoncol.org/current

Introduction: Hepatocellular Carcinoma

  • Brian I. Carr, MD, FRCP, PhD (Guest Editor)
  • IRCCS S. de Bellis National Institute for Digestive Diseases, Castellana Grotte (BA), Italy; Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA
  • PDF (77 KB)
Article Outline
Copyright

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with 80% being in the developing world, in which the incidence is starting to decline, in part due to hepatitis B virus (HBV) vaccination. By contrast, HCC is increasing in the developed world, with hepatitis C virus (HCV) and obesity being contributing factors. Only a minority of patients present with tumors small enough to be amenable to potentially curative resection and the remaining patients have a typical survival of less than 12 months. Incidence-to-death ratios are thus almost 1. Although liver transplantation is potentially curative for two diseases simultaneously—namely, for HCC and for the underlying cirrhosis—it is not curative for most patients with advanced HCC and is not available to many patients with limited-stage disease due to poor availability of donor organs or, in the less developed world, due to its high cost. The reasons for the disappointing survival in patients with large HCCs are not entirely clear, unless they have concomitant portal vein invasion, which provides a route to vascular dissemination of the tumor. There are huge geographical variations in incidence and, for patients with cirrhosis, a male to female predominance. The reasons for the large gender disparity are far from clear. Geography may relate to the incidence of predisposing hepatitis and also to dietary contamination with mycotoxic and other hepatocarcinogens. Many of the predisposing causes are known, unlike with most other cancers, and include cirrhosis from any cause, hepatitis B and C chronic carrier status, aflatoxin B1 contamination of stored rice and grains in non-refrigerated conditions, and chronic alcoholism. These factors provide the potential for prevention strategies, including hepatitis virus vaccination or treatment, refrigeration of rural stored food grains, and psychological interventions for chronic alcohol abuse. The large number of years needed for a patient with a predisposing risk such as chronic hepatitis B or C or alcoholism to develop HCC makes it feasible to implement screening for early detection of those known to be at risk, similar to Pap smears for cancer of the cervix uteri.

All of the aforementioned data have been known for decades, with ultrasound screening,
percutaneous ethanol injection (PEI), surgical resection, liver transplant, or chemoembolization being the mainstay of the clinical practice. Why then the need for a special edition of Seminars in Oncology that is devoted to HCC? As summarized in the first article by this guest editor, the last 5 years have seen a great number of advances in a wide array of investigative areas, some of which did not even exist 10 years ago, including proteomics and genomic analyses of clinical samples in treatment decision-making, availability of targeted, non-cytotoxic (chemotherapy) kinase inhibitor therapies (sorafenib, regorafenib, brivanib, linifanib, erlotinib, bevacizumab, and temsirolimus, to name only a few) against specific steps in the cellular proliferation pathways, a vast array of potential new therapies directed against various aspects of cellular protein turnover and against metabolic pathways, newer internal radiation agents (yttrium 90, holmium 66, rhenium 88) and external radiation imaging techniques (IMRT) and particle types (protons), increasing availability of peripheral blood circulating tumor cells as substrates for genomics analysis, a whole array of potential new tumor markers, several of which are becoming part of clinical practice (L3 (fucosylated) form of alpha fetoprotein [AFP-L3], des-gamma-carboxyprothrombin [DCP], glypican-3) and newer diagnostic imaging modalities (contrast-enhanced ultrasound, flow magnetic resonance imaging).

The introduction of sorafenib into routine clinical practice has obliged us to re-evaluate some previously held views, due to some of the associated clinical trial findings. In particular, there are two. First, that survival was enhanced in treated patients compared to control patients, without meaningful tumor shrinkage. Thus decades of oncology thinking that tumor shrinkage was a key to a treatment's usefulness (and our discussions with our patients) needs to be re-appraised. Second, this agent, and many in its class, has the tumor vasculature as a prime target. Given that tumor size can remain unchanged and can be associated with enhanced survival, tumor stability (measured in part as time to tumor progression) becomes increasingly useful as a goal in its own right. We have spent decades in the clinic measuring tumor size and using this as a hallmark for the effectiveness of our therapy.

We now need to develop for clinical use semiquantitative techniques for measuring tumor blood flow and vascularity, and this is in process. Three other new general ideas have recently found support in recent experimental work. They are that patient subsets with likely different prognoses can be identified by molecular probing of tumor biopsy samples and that gene expression patterns of the underlying non-tumor liver may be important in predicting, and likely influencing, HCC growth. A consequence of these two ideas is the importance for clinical decision-making of tumor (and perhaps non-tumor) biopsy. We have entered a very exciting era in HCC clinical and basic research, with profound changes resulting in HCC clinical practice. This series of articles gives us a glimpse of the cornucopia that is unfolding in both diagnostics and therapy. The field of HCC studies promises to be different again in another 5 years, based upon what is unfolding now, especially as a consensus emerges as to which gene signature patterns are reliable and useful, together with the results of the many clinical trials that are just beginning or are being planned, using combinations of therapies that target differing pathways, or combinations of these agents with either chemotherapy or regional radiotherapy.

PII: S0093-7754(12)00119-4
doi:10.1053/j.seminoncol.2012.06.001

Four Michigan Facilities Linked to New Hampshire Hepatitis C Investigation

Four Michigan Facilities Linked to New Hampshire Hepatitis C Investigation

Contact: Angela Minicuci (517) 241-2112

FOR IMMEDIATE RELEASE: July 30, 2012

LANSING - The Michigan Department of Community Health (MDCH) has been investigating the employment history of a hepatitis C-positive healthcare worker who was arrested recently in New Hampshire for allegedly obtaining injectable narcotics and infecting patients with the hepatitis C virus.

Hepatitis C is a bloodborne viral infection, estimated to infect 1.6 percent of the U.S. population. It can cause inflammation of the liver that may lead to chronic health issues. Most infected individuals do not know they have the virus because hepatitis C can damage the liver for many years with few noticeable symptoms.

MDCH has confirmed that this individual previously worked in at least six Michigan facilities from 2003-2007 and is known to have been infected with hepatitis C since at least June 2010. The investigation has not uncovered evidence that the individual was infected with hepatitis C while employed at any Michigan facility. A negative hepatitis C test result at one hospital during his employment allows MDCH to exclude two hospitals from further examination as there was no risk posed by this individual to patients at these facilities.

MDCH recommends that all individuals with known risk factors for hepatitis C virus be tested. If you were a patient at one or more of the facilities listed below during the identified time periods and you received an injectable narcotic, you may have a risk factor of which you were previously unaware. You should consult the facility contact identified below and/or your primary care provider regarding hepatitis C testing. While the receipt of an injectable narcotic at these facilities during these time frames may represent a possible increased risk for hepatitis C for patients, it is clearly not the only risk. If you do not know if an injectable narcotic was administered to you, contact the facility to find out more information. While this testing is important, it need not be considered an emergency procedure.

"Hepatitis C is a chronic condition that can damage the liver for many years without noticeable symptoms," said Dean Sienko, Interim Chief Medical Executive of the MDCH. "Our goal of recommending testing is to ensure the appropriate use of the modern medicine now available to prevent deaths from hepatitis. In order to help potentially affected individuals, we are asking patients to get tested to protect their health."

Due to the length of time since potential exposure as well as the prevalence of the disease in the general population, a positive test result for patients of the facilities named below may not conclusively prove that hepatitis C was acquired from the individual currently under investigation at these facilities.

The Centers for Disease Control and Prevention (CDC) estimates that more than 2 million U.S. citizens born from 1945 through 1965 have been infected with the virus and is currently recommending testing for everyone born in that time frame. Hepatitis C can be detected with blood tests and treated with antiviral medications.

Identified Michigan hospitals, dates of interest, and facility contact information: 

Hospital Name
Dates of Interest
Facility Contact Information
Sinai Grace Hospital* June-October 2005 1-888-300-3627 or www.dmc.org/mdch
Harper Hospital** October 2005-September 2006 1-888-300-3627 or www.dmc.org/mdch
University of Michigan Hospital (Main Campus) September 11-December 8, 2006 1-877-233-4040
Oakwood Annapolis Hospital January 15-September 15, 2007 1-734-467-4111


*Patients who underwent procedures in interventional radiology that required intravenous narcotics *Patients who underwent procedures in the cardiac catheterization laboratory

Because this is an ongoing investigation, MDCH will continue to identify past employment history and work with all identified facilities in Michigan as well as the CDC. The MDCH will provide any updates to this information as it becomes available. For questions and information about hepatitis C, please visit the MDCH website at www.michigan.gov/hivstd or the CDC website at www.cdc.gov/hepatitis.

# # #

Related-UMHS one of six Michigan facilities linked to New Hampshire hepatitis C investigation

UMHS one of six Michigan facilities linked to New Hampshire hepatitis C investigation

July 30, 2012
ANN ARBOR, Mich.
The Michigan Department of Community Health has been investigating the employment history of a Hepatitis C-positive health care worker who was recently arrested in New Hampshire for allegedly obtaining injectable narcotics at hospitals there, and infecting patients with the Hepatitis C virus through used syringes.

An internal review requested by MDCH shows that the individual worked at the U-M Health System for three months of 2006; from Sept. 11 to Dec. 8. He was an interventional radiologic technologist, a position in the Department of Radiology’s interventional radiology procedures unit team for vascular interventional procedures. He did not have responsibility for administering medication to patients.
The investigation has not uncovered evidence that the individual was, in fact, infected with Hepatitis C while employed at UMHS or any other Michigan facility. There was no increase in the number of cases of Hepatitis C reported in the last quarter of 2006 after he worked at UMHS, as well as no increase in the number of cases for subsequent years.

As a precaution, patients who received injectable narcotics at the U-M Health System’s main medical campus in Ann Arbor from Sept. 11 – Dec. 8, 2006, may contact 877-233-4040, toll free. The call center for patient inquiries will open July 31 at 8 a.m. Patients who call will receive personalized help to determine whether they need testing for Hepatitis C. If testing is recommended, it will be offered free of charge.

Due to the length of time since potential exposure, a positive Hepatitis C test result for patients who were treated during this employee’s tenure at UMHS will not conclusively prove that hepatitis C was acquired at UMHS.

The individual under investigation worked in at least five other Michigan health care facilities from 2003-2007 and has been infected with Hepatitis C since at least June 2010. Read the Michigan Department of Community Health press release for a complete list of Michigan health institutions for which this individual worked. A negative test result at one hospital during his employment allows MDCH to exclude two hospitals from further examination as there no risk posed by this individual to patients at these facilities.

Hepatitis C is a blood-borne viral infection, estimated to infect 1.6 percent of the U.S. population. Most infected individuals do not know they have the virus because Hepatitis C can damage the liver for many years with few noticeable symptoms. The Centers for Disease Control and Prevention (CDC) estimates that more than 2 million U.S. citizens born from 1945 through 1965 – the baby boomers – have been infected with the virus and is currently recommending testing for all of those born in that time frame. Hepatitis C can be detected with blood tests and can be treated with antiviral medications. The goal of testing is to leverage the appropriate use of effective treatments that are now available to prevent deaths from hepatitis.

MDCH will continue to work with hospitals in Michigan as well as the CDC. For questions and information about Hepatitis C, please visit the MDCH website at www.michigan.gov/hivstd or the CDC website at www.cdc.gov/hepatitis.

All media inquiries should be directed to MDCH at 517-373-3740.

For more information view the MDCH press release.

Related- Four Michigan Facilities Linked to New Hampshire Hepatitis C Investigation

Most Chronic Hepatitis C Patients Report Fatigue

NEW YORK (Reuters Health) Jul 27 - More than 50% of patients with chronic hepatitis C suffer from fatigue, which in many cases would improve with antiviral therapy, a new paper says.
The authors say their data "indicate that therapy of HCV can result in significant and sustained improvement in clinical symptoms, and that the measurement of fatigue using visual analog scales is successful in capturing these changes."

"Thus, patients with relatively nonsignificant biochemical or histologic disease, but who have troublesome symptoms such as fatigue, should be considered for antiviral therapy," Dr. Jay H. Hoofnagle from National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland and colleagues wrote online June 30th in the Journal of Hepatology.

On the other hand, they caution, "Improvements in fatigue scores were seen predominantly among patients who had moderate or severe levels of fatigue before treatment, and there was little or no improvement in patients who reported minimal fatigue initially. Such findings suggest that there is little room for improvement in fatigue among those with lower levels at baseline, or that the visual analog scale is not sensitive enough to detect minor improvements."

Their conclusions are drawn from the multicenter Virahep-C study, in which 401 patients with chronic hepatitis C, genotype 1 received peginterferon alfa-2a and ribavirin with extensive monitoring of HCV viral kinetics, immune function, genetics and interferon signaling pathways.
Treatment continued for up to 48 weeks. Just over half of the patients (207/401, 52%) reported fatigue at the time of screening. The prevalence and severity of fatigue were higher for women than for men, and fatigue was more common in patients with cirrhosis (66%) than in those with minimal (49%) or moderate fibrosis (53%).

In multivariate analysis at screening, younger age and lower alanine aminotransferase level were the only factors independently associated with more severe fatigue.

During treatment, the prevalence of fatigue increased from 52% to 78% at week four and ranged from 67% to 79% for the duration of treatment.

By 12 weeks after the end of therapy, the prevalence of fatigue had declined to 36% in responders and 42% in nonresponders, and the median fatigue visual analog scores had declined from 25 mm at baseline to 11 mm in responders and 17 mm in nonresponders.

Fatigue improved to a significantly greater extent among patients who achieved a sustained virologic response than among patients who never became HCV RNA negative (nonresponders).
However, the presence or severity of fatigue did not change significantly among patients who had virologic relapse or breakthrough.

Fatigue scores were associated with depression, but controlling for the presence of depression did not alter the significance of the improvements in fatigue severity after successful completion of therapy.
Dr. Hoofnagle did not respond to a request for comments.

SOURCE: http://bit.ly/QonE1t
J Hepatol 2012.

Liver Cancer Cells Stop Making Glucose As They Become Cancerous

  • Liver cells normally produce glucose to help maintain healthy blood-sugar levels, but they lose that ability when they become cancerous, this study shows.
  • This change might benefit tumor cells by helping them grow and proliferate.
  • The study tracks how this loss happens and suggests that reversing it might offer a new way to treat this often-deadly disease.

COLUMBUS, Ohio – As liver cancer develops, tumor cells lose the ability to produce and release glucose into the bloodstream, a key function of healthy liver cells for maintaining needed blood-sugar levels.
 
The findings come from a study by scientists at The Ohio State Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
 
The loss of this type of glucose production, a process called gluconeogenesis, is caused by the over-expression of a molecule called microRNA-23a. The change might aid cancer-cell growth and proliferation by helping to maintain high levels of glycolysis under conditions of drastically reduced mitochondrial respiration, also known as the Warburg effect.
 
The findings suggest that suppressing miR-23a might reverse this process and offer a new treatment for hepatocellular carcinoma (HCC), the most common form of liver cancer.
 
 
“This study identifies an important mechanism that severely blocks glucose production and its release from the liver as liver cells transform into cancer cells,” says principal investigator Dr. Samson Jacob, professor of molecular and cellular biochemistry and William and Joan Davis Professor in Cancer Research, Division of Hematology and Oncology at Ohio State and co-leader of the OSUCCC – James Experimental Therapeutics Program. “It is conceivable that delivery of an anti-miR23a to the tumor site could reverse this.”
 
For this study, Jacob and his colleagues used an animal model that develops diet-induced HCC, along with primary-tumor samples from patients and HCC cell lines. The mouse model mimics different stages of human hepatocarcinogenesis. Key findings include:

  • Levels of enzymes in the gluconeogenesis pathway were drastically reduced, along with transcription factors involved in the expression of the genes encoding those enzymes.
  • miR-23a expression was significantly up-regulated in the animal model and in primary human HCC.
  • miR-23a suppresses the enzyme glucose-6-phosphatase and the transcription factor PGC-1a, two important components of the gluconeogenesis pathway.
  • Interleukin-6 and Stat-3 signaling cause the upregulation of miR-23a.

“Based on our data,” Jacob says, “we conclude that gluconeogenesis is severely compromised in HCC by IL6-Stat3-mediated activation of miR-23a, which directly targets and suppresses glucose-6-phosphatase and PGC-1a, leading to decreased glucose production in HCC.”
 
Jacob notes that since glucose-6-phosphatase is also essential for liver cells to convert glycogen (the storage form of glucose) to glucose, suppression of this enzyme can block all pathways leading to glucose production by the liver.
 
Funding from the NIH/National Cancer Institute (grants CA086978) and NIH/National Institute of Diabetes and Digestive and Kidney Diseases (grant DK088076) supported this research.
 
Other Ohio State researchers involved in this study were Bo Wang, Shu-Hao Hsu, Wendy Frankel and Kalpana Ghoshal.
 
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only seven centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State’s cancer program as “exceptional,” the highest rating given by NCI survey teams. As the cancer program’s 210-bed adult patient-care component, The James is a “Top Hospital” as named by the Leapfrog Group and one of the top 20 cancer hospitals in the nation as ranked by

U.S.News & World Report.

###

Contact: Darrell E. Ward, Medical Center Public Affairs and Media Relations,

614-293-3737, or Darrell.Ward@osumc.edu
 

New genetic target found for diuretic therapy

  • Posted by HCV New Drugs
  • File Under

New genetic target found for diuretic therapy

CINCINNATI—Researchers at the University of Cincinnati (UC) have identified a new genetic target for diuretic therapy in patients with fluid overload—like those with congestive heart failure, liver cirrhosis or kidney failure.

These results, being presented in the July 30 advance online edition of the journal Proceedings of the National Academy of Sciences (PNAS), may lead to the first new diuretic therapy in 25 years and could help patients who experience diuretic resistance.
Manoocher Soleimani, MD, professor and chief in the division of nephrology and hypertension, says the role of diuretics is to increase urine output and help patients rid themselves of excess fluid when their kidneys are unable to do so.

"For the last several decades, physicians have been using diuretics either alone or in combination to help patients experiencing water retention," he says, adding that this can occur in patients with heart failure, kidney failure or other serious illnesses. "The most common diuretic used worldwide is hydrochlorothiazide, which works by inhibiting the kidneys' ability to retain water; these drugs can also be used to lower blood pressure. The reason they are so widely used is because they are mild and don't cause severe loss of fluid.

"However, they aren't effective with every patient."

In this study, researchers examined the specific segments of the kidneys, called tubules, and the salt-absorbing genes working there.

"The NaCl, or sodium-chloride, co-transporter (NCC), is targeted by hydrochlorothiazide and drugs in that class; it is located in the close proximity of the chloride-absorbing transporter pendrin, both of which absorb salt in the kidney," Soleimani says. "When pendrin is deleted from the body, there is no effect on salt excretion. We thought that pendrin was present to help NCC function in some way, and by using knockout animal models in this study, we found that these two genes cross-compensate for one another, and if NCC is not working, pendrin kicks in to do its job."

He says genetically engineered animal models without NCC had regular urine output and salt excretion; the same results occurred in models without pendrin. However, models lacking both genes lost large amounts of salt, were 40 percent smaller in size and produced an excessive volume of urine.
"In addition to experiencing major volume depletion, mice lacking both genes developed kidney failure," Soleimani says. "We were able to show that all of these problems resulted from salt wasting; when we put these models back on high-salt diets, the problems including electrolyte abnormalities and volume depletion were all corrected after just one week."

Soleimani says these findings could lead to a targeted diuretic therapy that inhibits pendrin, further helping patients with severe fluid overload who may not respond well to hydrochlorothiazide.
"By giving a pendrin inhibitor in conjunction with thiazide, a mild diuretic, it could greatly relieve fluid retention, providing another treatment option and improving patient outcomes," he says.

###
This study was funded by a Merit Review Award from the U.S. Veterans Administration, the National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases, the Center on Genetics of Transport and Epithelial Biology, the U.S. Renal Care Organization and UC.

http://www.eurekalert.org/pub_releases/2012-07/uoca-ngt072512.php

Gilead preps late-stage sprint on blockbuster hepatitis C studies

Jul 30, 2012 06:05AM

It looks as if Gilead can't be shamed into a late-stage hepatitis C collaboration with Bristol-Myers Squibb after all.

Despite taking heat for its refusal to commit to BMS ($BMY), Gilead ($GILD) has now mapped out a plan to get its own in-house combo into a late-stage study later this year. And it believes it has the goods to jump ahead, nailing down the pivotal data needed for a 2014 regulatory filing after a high-speed, forced march into the clinic.

A few weeks ago BMS CEO Lamberto Andreotti blasted Gilead for refusing to push ahead on a Phase III study combining Gilead's GS-7977--purchased for a princely sum when the company bought out Pharmasset for $11 billion--with BMS's daclatasvir after the oral treatment offered stellar results in a mid-stage study. Daclatasvir is an NS5a inhibitor and the combo produced high cure rates at 12 weeks for the genotype 2/3 as well as genotype 1 hep C groups. Not surprisingly, BMS, which acquired daclatasvir in the $2.5 billion Inhibitex buyout, wanted to jump into a late-stage study with a combo that promised to swiftly move ahead as a new market leader. And experts in the field were left chomping at the bit.

Dr. Scott Friedman, chief of liver diseases at the Mount Sinai School of Medicine, chided Gilead, telling Bloomberg last April that the main focus should be on patients, not stockholders.
Gilead, though, struggled to remain free, with R&D chief Norbert Bischofberger saying there was no need to jump "wildly" ahead. And in his presentation to investors last week, Bischofberger mapped out a two-year clinical game plan that matches GS-5885--its own NS5a inhibitor--with 7977. A Phase I, fixed-dose combination study was launched just days ago, he said in the quarterly call. And if investigators get the right read on bioavailability, they plan to start the Phase III in a matter of months.

"This Phase III study is planned as a forearm randomized trial in 800 patients, evaluating the fixed dose combination with or without Ribavirin for either 12 or 24 weeks in treatment-naïve genotype 1 infected patients," said Bischofberger. "The study will contain an interim futility analysis after the first 200 patients or 50 per arm have been enrolled, an independent data, safety monitoring board will evaluate the SVR4 rates of the 12-week treatment arms. If the predefined response rates are met, then the remaining 600 patients will be subsequently enrolled."

Success in the first late-stage study would pave the way to a second confirmatory study, launched next year. Regulatory filings could be filed in 2014. And that could pave the way to a monumental blockbuster approval, as the hepatitis C patient population now waits for a new treatment that won't require interferon injections.

Four late-stage studies of 7977 with Ribavirin are underway now and Bischofberger says regulatory filings for that could come as early as the middle of next year.
- here's the story from Bloomberg on the combo study


ALS-2200-Vertex Announces Positive Results from Viral Kinetic Study in People with Hepatitis C

Vertex Announces Positive Results from Viral Kinetic Study of the Nucleotide Analogue ALS-2200 in People with Hepatitis C

- 4.54 log10 median reduction in HCV RNA observed in people with genotype 1 hepatitis C treated with a once-daily 200 mg dose of ALS-2200 for seven days; treatment was well-tolerated-

- Phase 2 studies of 12-week all-oral regimens planned for this year -

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and its collaborator Alios BioPharma, Inc. today announced positive results from a viral kinetic study of the nucleotide analogue ALS-2200 for the treatment of hepatitis C. There was a median 4.54 log10 reduction in hepatitis C virus (HCV) RNA in people with genotype 1 chronic hepatitis C who were new to treatment (n=8) after seven days of dosing with 200 mg of ALS-2200 once daily. ALS-2200 was well-tolerated in this study, and no patients discontinued due to adverse events. Based on these data, Vertex plans to begin Phase 2 studies this year of 12-week all-oral regimens including ALS-2200 in people with genotype 1 hepatitis C, pending discussions with regulatory agencies.
  
Patients with hepatitis C dosed with ALS-2200 in this study had a dose-dependent, consistent and rapid decline in HCV RNA. After three days of dosing, a median 3.85 log10 decline was observed among patients in the 200 mg dose group. In this dose group, a median 4.54 log10 decline was observed after seven days of dosing, which was maintained for up to two days after the completion of dosing. Four of eight patients in this dose group achieved HCV RNA levels below the limit of quantification (<LOQ = < 25 IU/mL). There were no serious adverse events observed in people dosed with ALS-2200 in the study. Data from this study have been submitted to a medical meeting for presentation in the second half of this year.
  
Based on these data, Vertex expects to conduct a study to evaluate ALS-2200 in combination with INCIVEK® (telaprevir), the company’s approved protease inhibitor for people with genotype 1 hepatitis C, and a study of ALS-2200 in combination with ribavirin. These studies will evaluate 12 total weeks of treatment with a primary endpoint of SVR12 (sustained viral response: undetectable hepatitis C virus 12 weeks after the end of treatment) in people with genotype 1 hepatitis C.
“We’re encouraged by the substantial, rapid and consistent viral decline and initial safety results from this study, which make ALS-2200 a very promising part of Vertex’s hepatitis C pipeline,” said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. “ALS-2200, with its high level of antiviral activity, gives us flexibility to explore several combinations of all-oral treatment regimens for hepatitis C. We’re moving quickly to begin the first Phase 2 trials this year.”
  
Additional results from the study of ALS-2200 in people with hepatitis C are included in the following table:
Dose Group
Median Baseline
HCV RNA
(Log10 IU/mL)
(Min, Max)
Median Change From
Baseline After 3 Days
of Treatment
(Log10 IU/mL)
(Min, Max)
Median Change From
Baseline After 7 Days
of Treatment
(Log10 IU/mL)
(Min, Max)
Placebo
(n=8)
6.30
(5.70, 6.90)
0.13
(-0.34, 1.22)
0.11
(-0.28, 0.66)
15 mg
(n=8)
6.11
(5.46, 7.00)
-0.49
(-0.20, -0.99)
-0.97
(-0.17, -1.59)
50 mg
(n=8)
6.19
(5.73, 7.21)
-1.83
(-1.41, -2.20)
-3.02
(-2.21, -3.57)
100 mg
(n=8)*
6.49
(5.67, 7.00)
-2.60
(-1.81, -3.78)
-3.95
(-3.39, -4.51)
200 mg
(n=8)**
6.18
(5.66, 6.72)
-3.85
(-2.87, -4.17)
-4.54
(-3.81, -5.08)

*One patient had an HCV RNA level below the limit of detection (Roche COBAS Taqman HCV test, Version 2) during the study.
        
**Four patients had HCV RNA levels below the limit of quantification (<LOQ = < 25 IU/mL) during the study.
“The rapid advancement of ALS-2200 through this first viral kinetic study underscores the strength of our collaboration with Vertex and our shared commitment to develop new medicines for hepatitis C,” said Lawrence M. Blatt, Ph.D., Founder, President and Chief Executive Officer of Alios BioPharma. “We look forward to continued collaboration with Vertex and to the start of multiple Phase 2 studies of ALS-2200 later this year.”
  
ALS-2200 Phase 1 Trial Design
This double-blind, placebo-controlled, Phase 1 trial was designed to evaluate the safety and tolerability of single ascending doses of ALS-2200 in healthy volunteers and of multiple ascending doses in people with genotype 1 chronic hepatitis C. A secondary objective was to evaluate the effects on viral kinetics of ALS-2200 during seven days of dosing in people with hepatitis C. The first part of the trial enrolled healthy volunteers to evaluate pharmacokinetics of single ascending doses of ALS-2200. The second part of the study enrolled people with hepatitis C to evaluate the antiviral activity of multiple ascending doses of ALS-2200. Of the patients with hepatitis C in the ALS-2200 treatment groups, two were genotype 1a, 29 were genotype 1b and one patient’s genotype 1 subtype was not able to be determined.
  
About ALS-2200 and ALS-2158
Vertex and Alios are also conducting a Phase 1 seven-day viral kinetic study of a second nucleotide analogue, ALS-2158. Data from this study are expected in the next few months.
  
ALS-2200 and ALS-2158 are nucleotide analogues that appear to have a high barrier to drug resistance based on in vitro studies. Both compounds are designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Each compound is structurally distinct (adenosine and uridine) and has a different mechanism of action. In vitro studies ofboth compounds showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.
  
Vertex gained worldwide rights to ALS-2200 and ALS-2158 through an exclusive worldwide licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.
  
About INCIVEK
INCIVEK® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication.
  
INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).
  
Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic®.

IMPORTANT SAFETY INFORMATION
Indication
INCIVEK® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.
  
Important Safety Information
INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.
  
INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.
INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.
  
Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.
  
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.2 However, approximately 60 percent of people do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9,10 Hepatitis C is four times more prevalent in the United States compared to HIV.10 The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting 82 percent of people with the disease.11 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.12,13 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10

About Vertex
Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and Science magazine named Vertex number one on its 2011 list of Top Employers in the life sciences.
Vertex's press releases are available at www.vrtx.com.
  
About Alios BioPharma
Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including HCV, RSV, Influenza and other chronic, acute and emerging viral diseases. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability.

Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Kauffman’s statements in the fourth paragraph of this press release, Dr. Blatt’s statements in the sixth paragraph of this press release and statements regarding (i) Vertex’s plan to begin Phase 2 studies in 2012 of 12-week all-oral regimens including ALS-2200 in people with genotype 1 hepatitis C, pending discussions with regulatory agencies; (ii) Vertex’s expectations regarding the design of these planned Phase 2 studies and (iii) the timing of receipt of data from an ongoing study of ALS-2158. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the initiation of Phase 2 studies of ALS-2200 may be delayed or prevented, outcomes from any future studies of ALS-2200 may not be favorable and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
   
(VRTX-GEN)
References:
1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010. Accessed July 26, 2012.
2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.
3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
9 Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.
10 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx Updated January 11, 2010. Accessed July 26, 2012.
11 Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.
12 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
13 S.D. Holmberg, K.N. Ly., et.al. The Growing Burden of Mortality Associated with Viral Hepatitis in the United States, 1999-2007. AASLD 2011 Annual Meeting.
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