How Eli Lilly Let a Billion-Dollar Molecule Slip Away, and Make a Fortune for Vertex

Ryan McBride 8/4/10

Careers can be made in the drug development business on a single drug like telaprevir, the hepatitis C treatment from Vertex Pharmaceuticals (NASDAQ:VRTX). If it gets approved, the drug has the potential to become a leading treatment for the chronic liver disease—and to make a multibillion-dollar fortune for Cambridge, MA-based Vertex—within the next few years.

So it’s a bit of shocker to people when they find out that the pharmaceutical powerhouse Eli Lilly (NYSE:LLY), which collaborated with Vertex to discover telaprevir, gave away almost its entire stake in the drug back in December 2002. Indianapolis-based Lilly began working with the smaller Vertex to discover drugs for hepatitis C virus in 1997, and telaprevir emerged as the two companies’ lead compound in the program in 2001.

Jump ahead to this spring. Vertex, which has West Coast operations in San Diego, reported in May that telaprevir passed a pivotal test, curing three out of four patients with the disease in a Phase III clinical trial, a major hurdle in its bid to gain FDA approval of the drug. The drug, known as a protease inhibitor, is considered by some a breakthrough because it has shown that it can cure patients at the twice the rate of existing therapies. Company executives say they hope to garner permission to begin sales of the drug in 2011.

While those results have helped Vertex build up a $7 billion market capitalization, hardly anybody remembers who could have been its early collaborator. Lilly played a key part in developing and funding early research of the drug, which analysts now project could become a $2 billion annual seller in the U.S. alone within two years of its potential launch. It’s a decision that Lilly has to regret, given that telaprevir’s potential has made Vertex the third most valuable biotech company based in Massachusetts, behind only Genzyme (NASDAQ:GENZ) and Biogen Idec (NASDAQ:BIIB).

“Telaprevir would not exist if Lilly hadn’t been involved in the collaboration,” says Roger Tung, a founding scientist of Vertex who supervised the group that worked with Lilly researchers on telaprevir. He is now founder and CEO of Lexington, MA-based Concert Pharmaceuticals. “Lilly was very involved, they did a lot of work, and they contributed substantially to the science.”

In hindsight, there’s a lot to be gleaned today from Lilly’s decision to end its work on telaprevir—and Vertex’s moxie to advance the drug into initial clinical trials several years ago on its own and without the backing of a major pharma player. Two former Vertex executives, who were once intimately involved in the firm’s collaboration with Lilly, biotech investor Rich Aldrich and Concert’s Tung, shared their perspectives on the deal that, fortunately for Vertex, fell apart.

At Vertex, the research budget relied heavily on contributions from its large pharma collaborators such as Lilly, GlaxoSmithKline (NYSE:GSK), and Sanofi-Aventis (NYSE:SNY). “We did a lot of deals while I was [at Vertex],” says Aldrich, the former chief business officer of Vertex who led its initial deal with Lilly. “The Lilly deal was an important one.”

During the collaboration, Lilly paid Vertex at least tens of millions of dollars in initial and annual fees and contributed its own scientists’ efforts to advance research of hepatitis C virus. The virus, which causes chronic damage to the liver, affects an estimated 170 million people worldwide and 3 million Americans. Existing drugs for the disease cause flu-like symptoms and patients must typically take them for nearly at year.

However, changes at both Lilly and Vertex led to the two firms’ “mutual decision” to part ways in late 2002. Officially, Lilly wanted out of its partnership with Vertex because of changes in its research priorities, and Vertex wanted to retain greater ownership of the drug than it would have if it kept Lilly as a partner, according to a Vertex regulatory filing.

Unofficially, there was more to the breakup than that. Around the time telaprevir started nearing its first human studies, Lilly tried to renegotiate the original deal it had struck with Aldrich that heavily favored Vertex, according to Tung. Lilly had agreed to pay for clinical development of the drug, tiered royalties to Vertex on potential North American sales of the treatment in the 20-percent range, as well as a portion of funding for Vertex’s planned specialty drug sales force, Aldrich says.

“I assume Lilly’s projections for producing that molecule and running the clinical program got very high as the drug advanced,” says Aldrich, who left Vertex in 2001, the year before the company and Lilly terminated their collaboration. “Add in the projected cost of a big launch in a new area, and the royalty and marketing support built into the deal with Vertex; at some point the projected return-on-investment must have turned negative.”

Tung, who remained at Vertex until 2005, says that unspecified personnel changes at Lilly also factored into the pharma giant’s decision to nix its partnership with Vertex. “Within Lilly, there were personnel issues that led toward this not being one of their more favored programs,” Tung says. “Some of the champions of the program within Lilly eventually got sidelined, so their political ability to push this forward was compromised.” Tung didn’t name who the telaprevir champions were at Lilly, or identify who put the kibosh on the program at Lilly later on.

Eli Lilly did not return a phone call seeking comment on its former partnership with Vertex this week.

In the ultimate pact to end the deal with Lilly, Vertex kept exclusive worldwide rights to telaprevir and Lilly was granted unspecified royalties on potential sales of the drug and others discovered in their collaboration. In the years that followed, Vertex went on to form separate deals to co-develop the drug with Janssen Pharmaceutica, a unit of New Jersey-based health products giant Johnson & Johnson (NYSE:JNJ), and the Japanese drugmaker Mitsubishi Tanabe, for markets outside the United States. Vertex retains exclusive rights to the drug in this country.

Vertex aims to confirm the results of its Phase III study in data from two other late-stage trials, the first of which will be revealed this month and the second in September. As of March 31, the company has spent more than $2.8 billion since its founding in 1989, much of it on the development of telaprevir. So expectations for the drug are quite high.

“Vertex has spent a lot of money to get to this point,” says Aldrich, who still works closely with Tung as co-founder and chairman of Concert. “If telaprevir had failed or just stumbled at any point along they way, they would have been in big trouble. At this point, it looks like the bet will pay off big for Vertex.”

Ryan McBride is Xconomy's correspondent. You can reach him at rmcbride@xconomy.com, or follow him on Twitter at http://twitter.com/Ryan_McBride.

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Sting of HIV Stigma Unabated

Shame over HIV infection remains great, according to a recent survey by the International Association of Physicians in AIDS Care. The group's president tells us how this stigma is perpetuating the disease.

By Neal Broverman

Among the presentations at July's XVIII International AIDS Conference in Vienna was one by the International Association of Physicians in AIDS Care. IAPAC, headed by president José Zuniga, reported on its AIDS Treatment for Life International Survey (ATLIS), which queried 2,035 HIV-positive people from 12 countries in the Americas, Europe, Asia, and Africa and examined how much shame and discrimination they experience because of their disease as well as the relationships they have with their doctors. Zuniga discussed the survey and its surprising results.

The Advocate: Tell us about ATLIS.

José Zuniga: We identified quite a significant amount of stigma, considering the fact that we’re now well into the 29th year of the HIV epidemic. What was surprising to us was that that stigma is persistent in developed-world settings as well. If we look at the data related to [the admission of] “I feel alone and isolated because I have HIV/AIDS,” the North American data — the only country we surveyed in North America is the United States — was at 42%, which was well above what we expected in Africa, where we had 24%. In addition, there was data indicating that 22% of Americans living with HIV indicated there was no one they could count on to help take care of them, which was quite significant. The other piece we were quite surprised about was that 16% of U.S. respondents cited discrimination due to their sexual orientation.

How was the survey conducted?

From January to March of this year we utilized a variety of media, including Internet and face-to-face interviews. [The methodology] depended on how we could get a nice variety of patients and ensure we reached certain demographics in each country.

So, it sounds like the results were a shock.

Absolutely. Given the fact that a great deal of work has been done around HIV awareness and attempts to address the determinants of stigma through a variety of means, that it persists still was quite troubling.

Something surprising was that a certain percentage of respondents in long-term relationships had not disclosed their HIV status to their spouse or partner. That certainly speaks to the need to advise people living with HIV/AIDS to, by all means, inform their spouses or partners about their serostatus so appropriate prevention methods can be utilized.

Did the respondents say why they were keeping their HIV status from their partners?

There was great fear of disclosure — not just with spouses and partners, but with family members too. That number [of people not disclosing their HIV status to their partners] is at 17% globally, which doesn’t seem that high, but if that continues to increase, we could see significant community and public health implications.

How were the results greeted in Vienna?

Quite surprising, when taken in combination with all the other data we presented. We found in general a significant gap in health care provider–patient communication around a number of issues — that could have a really detrimental effect on people with HIV. For example, we found physicians weren’t counseling their patients on the importance of smoking cessation. A large percentage of people living with HIV/AIDS smoke, larger than the general population. Smoking especially affects people with HIV/AIDS; they’re more at risk for lung cancer and cardiovascular disease. Yet they’re not being counseled on this very issue, and that’s a significant concern because we achieved success through HAART [highly active antiretroviral therapy] but then lose patients as a result of heart attacks and lung cancer.

The other area where we found significant gaps include around the issue of side effects. There are new treatment options that have fewer side effects for patients, but that dialogue is not happening. Which has a direct correlation to adherence; if you’re living with chronic diarrhea as a result of your drugs, you may not be as inclined to adhere to your therapy as much as you should, which could contribute to resistance.

Where do we go from here?

First of all, we need to strengthen our efforts at education in broader society around HIV and its treatment and dispel some notions that continue to exist around individuals who become HIV-positive with respect to the discrimination we found — 16%, and that could obviously be higher, of U.S. respondents say they experience discrimination by their health care providers. We as a professional medical association need to spend more time educating health care providers about the importance of providing a safe place for people with HIV to benefit not just from highly active antiretroviral therapy but a place where they can have primary care services delivered in a nonjudgmental way.
 
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In Pivotal Phase III Studies, Merck’s Investigational Medicine Boceprevir Helped Majority of Patients with Chronic Hepatitis C Genotype 1 Infection Achieve Sustained Virologic Response, the Primary Endpoint of the Studies

August 04, 2010 08:09 AM Eastern Daylight Time

Merck Expects to Submit NDA by Year-End

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck today reported that two pivotal Phase III registration studies for boceprevir, its investigational oral hepatitis C protease inhibitor, have been completed and met the primary endpoints: in both studies in patients with chronic hepatitis C virus (HCV) genotype 1 infection, the addition of boceprevir to treatment with PEGINTRON® (peginterferon alfa-2b) and REBETOL® (ribavirin, USP) (Peg/riba) significantly increased the number of patients who achieved sustained virologic response (SVR; defined as undetectable virus levels 24 weeks after the end of treatment), compared to control groups that received Peg/riba plus placebo.

“The response-guided therapy approach used in these studies enabled those patients – both treatment-failure patients and treatment-naïve patients – who had undetectable virus at certain points of the study to achieve SVR with a shorter total treatment duration than current standard therapy”

.Boceprevir, in combination with Peg/riba, is being studied for the treatment of patients with chronic hepatitis C genotype I who have previously been treated (treatment-failure; HCV RESPOND-2) and in patients who are new to treatment (treatment-naïve; HCV SPRINT-2). Abstracts for boceprevir studies have already been submitted for presentation at a medical meeting later this year, and additional abstracts are being submitted this week. Merck plans to submit a New Drug Application (NDA) for boceprevir to the U.S. Food and Drug Administration on a rolling basis, and expects to complete regulatory submissions in the U. S. and E.U. in 2010.

“There is a clear need for new treatment strategies for chronic hepatitis C," said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. "We look forward to seeking regulatory approvals to bring boceprevir forward to help treat people living with chronic hepatitis C."

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir: 48 weeks of treatment for all patients (4-week lead-in with 1.5 mcg/kg/week of PEGINTRON and an investigational dose of 600-1,400 mg/day of REBETOL, followed by the addition of boceprevir 800 mg three times a day for 44 weeks), and response-guided therapy, in which patients with undetectable virus at week 8 and again at certain points later in the studies were able to stop all treatment at 36 weeks in HCV RESPOND-2 and at 28 weeks in HCV SPRINT-2. Patients who did not meet these criteria continued treatment with Peg/riba alone for a total treatment duration of 48 weeks. Control groups in the studies received Peg/riba at the doses described above plus placebo for 48 weeks.

The HCV RESPOND-2 study was conducted in 403 patients who failed prior therapy at U.S. and international sites, and patients were randomized into the three groups (48 weeks control; 48 weeks control plus boceprevir; control plus boceprevir using response-guided therapy) at a 1:1:1 ratio. In the boceprevir 48-week treatment group, 66 percent of patients achieved SVR, and in the boceprevir response-guided therapy group, 59 percent of patients achieved SVR, compared to 21 percent of patients in the control group (p<0.0001 for both, intent-to-treat analysis).

"These results are very exciting," said Bruce R. Bacon, M.D., professor of internal medicine, Saint Louis University School of Medicine, and co-principal investigator of the HCV RESPOND-2 study. “Patients who failed prior hepatitis C therapy are among the hardest to treat, and the use of boceprevir in this study helped significantly more of these patients achieve undetectable levels of the virus at 24 weeks after the end of therapy than treatment with Peg/riba alone."

In the HCV SPRINT-2 study, 1,097 treatment-naïve patients at U.S. and international sites were enrolled in two separate cohorts, one with 938 non-African-American/Black patients and the other with 159 African-American/Black patients. Patients were randomized into the three treatment groups (48 weeks control; 48 weeks control plus boceprevir; control plus boceprevir using response-guided therapy) at a ratio of 1:2:2. In the study overall, 66 percent of patients in the boceprevir 48-week treatment group achieved SVR, and 63 percent of patients in the response-guided therapy group achieved SVR, compared to 38 percent of patients in the control group (p<0.0001 for both, intent-to-treat analysis).

As specified by the HCV SPRINT-2 study protocol, results for the non-African-American/Black and African-American/Black patient cohorts were analyzed separately. Several previous studies have shown that African-American/Black patients have a lower response to HCV treatment than non-African-American/Black patients.1-3 Among the non-African-American/Black patients in the boceprevir 48-week treatment group, 69 percent achieved SVR, and in the response-guided therapy group, 67 percent of patients achieved SVR, compared to 40 percent in the control group (p<0.0001 for both, intent-to-treat analysis). Among the African-American/Black patients, 53 percent of patients in the 48-week treatment group and 42 percent of patients in the response-guided therapy group achieved SVR, compared to 23 percent in the control group (p=0.004 and p=0.044, respectively, intent-to-treat analysis).

“The response-guided therapy approach used in these studies enabled those patients – both treatment-failure patients and treatment-naïve patients – who had undetectable virus at certain points of the study to achieve SVR with a shorter total treatment duration than current standard therapy,” said Fred Poordad, M.D., chief of hepatology in the division of gastroenterology at Cedars-Sinai Medical Center, associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles (UCLA), and co-principal investigator of the HCV SPRINT-2 study.

In the HCV RESPOND-2 study, the five most common treatment-emergent adverse events reported for the boceprevir 48-week treatment group, boceprevir response-guided therapy group and control group, respectively, were: fatigue (57, 54, and 50 percent), headache (40, 43 and 49 percent), nausea (42, 44 and 38 percent), anemia (47, 43 and 20 percent) and dysgeusia (bad taste) (45, 43 and 11 percent). Treatment discontinuations due to anemia were 3 percent and 0 percent for the boceprevir groups, respectively, compared to 0 percent for the control group. Treatment discontinuations due to adverse events overall were 12 percent and 8 percent for the boceprevir groups, respectively, compared to 3 percent for the control group.

In the HCV SPRINT-2 study, the five most common treatment-emergent adverse events reported for the boceprevir 48-week treatment group, boceprevir response-guided therapy group and control group, respectively, were: fatigue (57, 53 and 60 percent), headache (46, 46 and 42 percent), nausea (43, 48 and 42 percent), anemia (49, 49 and 29 percent) and pyrexia (fever) (32, 33 and 33 percent). Treatment discontinuations due to anemia were 2 percent for each of the boceprevir groups compared to 1 percent for the control group. Treatment discontinuations due to adverse events overall were 16 percent and 12 percent for the boceprevir groups, respectively, compared to 16 percent for the control group.

About the studies

The HCV RESPOND-2 study was conducted in patients chronically infected with hepatitis C genotype 1 who failed prior therapy with peginterferon and ribavirin, including those who had experienced prior relapse or who were prior non-responders, and the HCV SPRINT-2 study was conducted in previously untreated (treatment-naïve) patients chronically infected with hepatitis C genotype 1. Approximately 25 percent of patients in each of the studies had less than a 1 log decrease in viral load after the 4-week Peg/riba lead-in period.

Sustained virologic response (SVR), the protocol-specified primary efficacy endpoint, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication (Roche TaqMan LLD=9.3 IU/mL). Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient’s 12-week post-treatment assessment was utilized.

In the HCV RESPOND-2 study, patients in the response-guided therapy arm who had undetectable virus at treatment week 8 and week 12 received a total of 36 weeks of therapy (lead-in with Peg/riba followed by the addition of boceprevir for 32 weeks); patients with detectable virus at week 8, but undetectable virus at week 12, stopped boceprevir treatment at week 36 and continued on Peg/riba alone for an additional 12 weeks, for a total treatment duration of 48 weeks. Patients in any arm of the study who had detectable virus at week 12 were considered treatment failures and discontinued treatment.

In the HCV SPRINT-2 study, patients in the response-guided therapy group of the study who had undetectable virus at treatment week 8 through week 24 received a total of 28 weeks of therapy (lead-in with Peg/riba followed by the addition of boceprevir for 24 weeks); patients with detectable virus at week 8, but undetectable virus at week 24, stopped boceprevir treatment at week 28 and continued on Peg/riba alone for a total treatment duration of 48 weeks. Patients in any arm of the study who had detectable virus at week 24 were considered treatment failures and discontinued treatment.

Merck's commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the hepatitis field by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to hepatitis care.

Conference call

Investors are invited to a live webcast of Merck's conference call today at 9:00 a.m. EDT by visiting Merck's Web site, www.merck.com/investors/events-and-presentations/home.html. Institutional investors and analysts can participate in the call by dialing (877) 381-5782 or (706) 758-9927. Journalists are invited to listen in on the call by dialing (800) 399-7917 or (706) 758-9928. A replay of the webcast will be available starting at 11 a.m. EDT today through 5 p.m. EDT on Aug. 11. To listen to the replay, dial (800) 642-1687 or (706) 645-9291. The conference ID No. is 92380347.

About PEGINTRON

PEGINTRON is indicated for use in combination with REBETOL (ribavirin) for the treatment of chronic hepatitis C in patients three years of age and older with compensated liver disease.

The following points should be considered when initiating therapy with PEGINTRON in combination with REBETOL: (1) These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. (2) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy data are available for treatment of longer than one year.

PEGINTRON is also indicated for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.

The following points should be considered when initiating therapy with PEGINTRON alone: Combination therapy with REBETOL is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, REBETOL. Combination therapy provides substantially better response rates than monotherapy.

Selected Safety Information on PEGINTRON......Continue Reading

UPDATE 3-Merck hepatitis drug works; anemia seen

Wed Aug 4, 2010 12:51pm EDT

* 66 pct cure rate seen with Merck's boceprevir
* Merck to seek boceprevir approval by year's end
* Side effects raise questions in one of two trials
* Merck shares slightly higher
* Shares of rival drugmaker Vertex up 3.5 pct (Adds analyst comments, details on Merck and Vertex drugs; changes byline)

By Ransdell Pierson and Bill Berkrot

NEW YORK, Aug 4 (Reuters) - Merck & Co (MRK.N) said its experimental hepatitis C treatment met the main effectiveness goals of two late-stage studies and it expects to seek approval for the high-profile medicine by the end of the year.

But a much higher percentage of patients taking the Merck drug, compared with those taking standard treatments, dropped out of one of the trials due to adverse events, including anemia.

The drug, boceprevir, was one of the most important experimental products gained by Merck through its acquisition of Schering-Plough Corp last year.

In the two trials, 66 percent of patients who took boceprevir plus standard drugs for a full 48 weeks were cured of the serious liver disease, a significantly higher cure rate than for standard treatment alone. But that compares with a 75 percent cure rate seen in a separate trial of a rival drug being developed by Vertex Pharmaceuticals Inc (VRTX.O).

Boceprevir and Vertex's telaprevir are considered possible blockbuster products because of their potential to cure far more patients and in as little as half the time of standard drugs that require almost a year of treatment and often cause flu-like symptoms that are tough to tolerate.

Vertex shares rose 3.5 percent to $36.47 as investors compared the Merck data with recently released data on the Vertex drug. Merck said it would provide more detailed clinical trial data at a meeting of the American Association for the Study of Liver Diseases that begins Oct. 29 in Boston.

Merck shares rose 19 cents, or 0.5 percent, to $35.01.

The new class of drugs, which are combined with standard treatments, work against the liver-damaging hepatitis C virus by blocking a protein called protease that the virus requires to replicate. The current standard treatments involve a combination of the injectable drug interferon and an anti-viral pill called ribavirin.

"Based on today's top line data, we are maintaining our view that, while telaprevir will likely take a majority of the initial hepatitis C protease inhibitor market, boceprevir will play a role in the category," J.P. Morgan analyst Chris Schott said in a research note.

Schott said investors will get a better picture of the respective strengths and shortcomings of the two drugs when full late-stage trial data on telaprevir and boceprevir are unveiled at the upcoming Boston meeting.

Merck said boceprevir, taken in combination with the company's Pegintron brand of interferon and ribavirin, significantly increased the number of patients who achieved a sustained virologic response, or SVR -- meaning no detectable virus levels 24 weeks after the end of treatment -- compared with those who received the standard drugs plus a placebo.

Achieving SVR, in layman's terms, is considered being cured of the disease.

One of the trials, called HCV RESPOND-2, involved 403 patients with genotype 1, the most common form of hepatitis C, who had failed prior therapy with interferon and ribavirin. The other trial, called HCV SPRINT-2, enrolled 1,097 patients with genotype 1 who had not previously been treated for the virus.

In both trials, a significant number of patients received 48 full weeks of treatment. But patients with undetectable virus at week 8 and again at certain points later in the studies were able to stop all treatment at 36 weeks in the smaller trial, and at 28 weeks in the larger study.

In the HCV RESPOND-2 study, 66 percent of those receiving boceprevir for 48 weeks were cured, while cures were seen in 59 percent of those receiving shorter treatment regimens of the medicine. That compared with a 21 percent cure rate for those receiving standard treatments.

In the HCV SPRINT-2 study of previously untreated patients, 66 percent of those receiving boceprevir for 48 weeks were cured, along with 63 percent of those on shorter regimens. Cures were seen in 38 percent of those receiving standard therapy.

Telaprevir's 75 percent cure rate in its own Phase III trial tested the drug in previously untreated patients.

Vertex is expected next month to unveil data from another late-stage trial of telaprevir in tougher-to-treat patients who had failed prior treatment with standard drugs.

Sanford Bernstein analyst Tim Anderson said available data from separate trials of boceprevir and telaprevir suggest the Merck drug is less effective.

Moreover, he said boceprevir seems more likely to cause anemia -- a side effect that could require patients to take intravenous anemia medicines that boost red blood cells. The question is whether the need for an additional anemia drug on top of the three-drug regimen will greatly discourage use of boceprevir, should it be approved.

Anderson forecast boceprevir would garner sales of $330 million in 2015, far below his forecast of $4.3 billion for the Vertex drug. (Reporting by Ransdell Pierson, Lewis Krauskopf and Bill Berkrot, editing by Maureen Bavdek, Dave Zimmerman and John Wallace)

Source

Hepatitis, Cholesterol Drugs Show Promise

August 4, 2010, 11:46 am
By ANDREW POLLACK

New drugs for hepatitis C and for super-high cholesterol succeeded in late-stage clinical trials and could be on their way to market, the drugs developers announced Wednesday morning.

Merck said that its antiviral drug boceprevir, when added to existing therapy, effectively cured about two-thirds of patients with hepatitis C. That was far better than the cure rate with the existing therapy alone.

Isis Pharmaceuticals and Genzyme said their drug for super-high cholesterol significantly lowered LDL, the so-called “bad cholesterol’’ in patients, who still had very high cholesterol levels despite taking the highest statin doses they could tolerate.

Still, investors had concerns with both drugs. For the cholesterol drug, called mipomersen, some patients had elevated liver enzymes, a sign the drug might damage the liver.

“Efficacy looks good but safety remains a key risk,’’ Geoffrey Meacham, an analyst at J.P. Morgan wrote in a note to clients Wednesday. Shares of Isis, a biotechnology company in Carlsbad, Calif. were down more than 3 percent at about 10 a.m.

Mipomersen, which is injected, is not likely to compete directly with statins like Pfizer’s Lipitor. It is intended initially for a relatively small number of patients with a genetic disorder that leads to extremely high levels of cholesterol.

But the two companies hope to gradually expand it to broader populations, if safety concerns do not stand in the way. Genzyme said it would file for the initial approval from the F.D.A. in the first half of 2011.

Merck is in a heated race with Vertex Pharmaceuticals to bring to market the first of a new class of hepatitis C drugs that are expected to make treatment far more effective and also possibly shorter in duration. The existing treatment — with alpha interferon and ribavirin – can take nearly a year, causes severe side effects and succeeds in eradicating the hepatitis C virus only about half the time.

“This is a compelling profile for boceprevir,’’ Peter S. Kim, president of Merck Research Laboratories, said on a conference call with analysts Wednesday. He said the company would complete its application to the F.D.A. for regulatory approval by the end of this year.

The early read by Wall Street was that Vertex’s drug would not be blown out of the water by boceprevir. Shares of Merck, a huge company, barely budged. Those of Vertex, whose future is heavily dependent on the success of its hepatitis C drug, were up about 5 percent.

Merck, which obtained boceprevir when it acquired Schering-Plough, announced the results of two clinical trials, which were somewhat complicated in their structure.

In a trial involving 1,097 patients who were undergoing treatment for the first time, 66 percent of those who got boceprevir plus standard therapy for 48 weeks had a so-called sustained virologic response, compared to 38 percent of those getting the standard therapy plus a placebo.

In Vertex’s phase 3 trial, the corresponding rates for its drug, telaprevir, were 75 percent and 44 percent.

A sustained virologic response means there was no detectable hepatitis C virus in the patient’s blood 24 weeks after the treatment ended. Many doctors say that is essentially a cure.

Merck’s other trial involved about 400 patients for whom prior treatment had been unsuccessful. For those who got boceprevir in a 48-week treatment regimen, 66 percent had a sustained virologic response, triple the 21 percent for those in the control arm.

Vertex has not yet reported phase 3 results for patients who have failed prior therapy.

Both Merck trials also looked at schemes in which treatment with boceprevir could be stopped at either 28 weeks or 36 weeks if patients had no detectable virus in their blood. The cure rates for those patients was nearly as good as for the full 48-week regimen. Merck did not say, however, how many patients were able to shorten the duration of treatment.

Merck said 15 percent of the patients in the trial testing initial therapy were blacks, a group that has a higher rate of hepatitis C than the rest of the nation’s population and also do less well on the existing therapy.

In the trial 53 percent of the blacks getting the 48-week treatment with boceprevir had a sustained virologic response compared to 23 percent for those in the control group.

The key safety issue for boceprevir appears to be anemia. That is already a side effect of ribarvirin, one of the two drugs now used to treat hepatitis. But the boceprevir seems to make it worse.

Merck executives said that anemia could be controlled using drugs like Procrit or Aranesp.

Both boceprevir and telaprevir inhibit the protease enzyme made by the virus. Both are taken orally three times a day. The patients in both Merck’s and Vertex’s trials had a strain of hepatitis C called genotype 1, which is the most common strain in the United States and Western Europe and is particularly hard to treat.

Source

Climbing to the next level: the German Virtual Liver Network

04 August 2010
HepatoSys/ German Virtual LIver Network

The aim of this unique research consortium is to grasp the whole organ and its functions in a computer model

In April 2010, an ambitious new project was launched in Germany: The German Virtual Liver Network. Funded by the Federal Ministry of Education and Research (BMBF), this major interdisciplinary research initiative is the only one of its kind in the world that focuses effort on a single organ across multiple scales of complexity. With an allocated budget over five years of approximately 43 million euros, it is also the only research network worldwide to be financed by a single national organization in systems biology. The Network’s goal is to create a computer model of the liver as a complete organ with all of its diverse and essential functions. Thus it should be possible to better understand the processes in the liver and to develop tailor-made medications.

A biochemical factory in the body

The liver is a unique organ: as the central metabolic organ of vertebrates, it synthesizes, converts and breaks down more than 10,000 substances daily, helping the body to digest food and detoxify itself. It aids digestion, controls iron uptake and synthesizes vital proteins such as coagulation factors. Furthermore, hepatic metabolism is a major factor that needs to be considered in drug development, as it is central to toxicity and drug efficacy. The exploration of the liver and its functions by the Network is therefore of the greatest relevance to medicine and the pharmaceutical industry.

Looking to the future with systems biology

In order to get an overall picture both of the liver as a whole and of the diverse and dynamic processes in the organ, the Network’s researchers are looking to systems biology for help. This branch of science, which deals with the exploration of biological processes at the systems level, seeks to create a holistic picture of dynamic life processes at all levels – from the genome to the proteome and up to the complete cell or even an entire organism. In order to achieve this goal, systems biology links quantitative methods from the field of molecular and cellular biology with techniques and tools from the areas of mathematics, computer sciences and systems sciences. “Systems biology can accelerate the transfer from academic research to use on patients and can cut costs in the development of medications. That’s why it is a key technology and a driving force of innovation for individualized medicine of the future,” emphasizes Federal Minister for Education and Research Annette Schavan in a BMBF's press release in July 2010.

From the cell to the whole organ

In recent years, the HepatoSys network dealt intensively with the systems biology of the liver cell. Building on these results, the project’s successor, the German Virtual Liver Network, now aims to understand the processes in cell aggregates up to the entire organ. For this ambitious project spanning the entire nation, 70 research groups from 41 institutions in science and industry have joined forces. Together these scientists aim to develop integrated computer models capable of generating experimentally testable predictions that are relevant to the physiology of the liver, as well as the function of the organism, and how this is disturbed in disease. This will contribute to an improved understanding of the liver as the body’s most important metabolic organ and how its function is affected in disease. By using validated simulations, these models will greatly benefit efforts to find new therapies, to predict how active substances distribute in the organ, where they attack, and how quickly they are broken down. Thus, medications can be developed in a more targeted, efficient and cost-effective manner and tailored to deliver the optimum dosage to the right patient at the right time.

A world leader

The German Virtual Liver Network is the first project worldwide to aim at building a truly multi-scale computer model of a complete organ– from the biomolecular and biochemical processes up to the anatomy of the whole organ – and including them in the simulation. “The challenge is immense, but we are looking forward to accepting it – not only to promote an understanding of the liver, but also to provide a strong impetus to the entire area of systems biological research. Our goal is to give evidence of a genuine impact on healthcare” says Adriano Henney, program director of the German Virtual Liver Network.

Source

Amarillo Biosciences (OTC-BB: AMAR) Revamps Interferon Technology

By Justin Kuepper on Wednesday, August 4th, 2010

Amarillo Biosciences, Inc. (AMAR), a biotech firm focused on using natural human interferon alpha administered in low doses, is targeting diseases similar to those targeted by companies like InterMune, Inc. (ITMN) and Amgen, Inc. (AMGN). Amar is seeking to install a paradigm shift in how interferon is used to treat disease.

Amarillo Biosciences, Inc. (OTC-BB: AMAR) is a biotechnology company focused on using natural human interferon alpha in low doses to target diseases including influenza, hepatitis C and chronic cough in COPD among others.

Amarillo Improves the Age-Old Interferon Therapy

First developed in the early 1980’s, interferon is a protein that is made and released by all nucleotide cells but particularly lymphocytes in response to the presence of pathogens – like viruses, bacteria, or tumor cells. The protein enables communication between cells in order to trigger the immune system to act and eliminate the threat. Currently, three major types of these proteins are being used to combat a number of diseases and disorders, including leukemia.

These same proteins have always existed in the nasal cavity, where it is released in small doses to stimulate the immune system when someone inhales a virus. While traditional interferon usage has focused on higher doses with significant side effects Amarillo Biosciences is focused on using low doses that are without side effects. Moreover, the company’s product is stable at room temperatures, less expensive, and easier to dose without a needle.

Several studies around the world have also confirmed the effectiveness of the treatment. CytoPharm, which licensed the drug in Taiwan and China, isconducting a US FDA and Taiwanese regulatory-approved Phase II trial on 165 hepatitis C patients. The full results aren’t expected until the end of 2010.

Hot and Growing End Markets of Utmost Importance

Amarillo Biosciences is initially focused on three markets, including influenza, hepatitis C and chronic cough (COPD), that represent a combined hundreds of millions of patients and hundreds of millions of dollars in revenues. It is this wide reach that could make the company’s drugs “blockbuster” status and make the company appealing to a variety of possible suitors.

For instance, the importance of effective flu treatments is difficult to overstate after the outbreak in 2008 and 2009. In the US alone, there are an estimated 25-50 million cases of the flu each year, which lead up to 150,000 hospitalizations and 30,000-40,000 deaths annually, according to data from Genentech, Inc. Extrapolated to the worldwide population, the flu is estimated to infect more than a billion people worldwide each year.

Hepatitis C is another condition that affects approximately 3.9 million people in the US and 300 million people worldwide, according to Clinaero, Inc. While the immune system can handle 15% of these cases, the remaining 85% of infected people need to be treated to fully rid of the disease, and many patients can end up having long-term liver infection – otherwise known as chronic hepatitis C – leading sometimes to Cancer.

Finally, chronic cough, or COPD, affects nearly 15 – 20 million US adults and is the fourth leading cause of death in the US. Meanwhile, the World Health Organization estimates that some 2.74 million people die of COPD every year worldwide, making it the 4th leading cause of death next to diseases like HIV/AIDS and coronary heart disease.

Dedication to Unlocking Shareholder Value

Amarillo Biosciences may be diligently working towards development of its revolutionary treatment, but it is also working diligently to maintain and unlock shareholder value. By developing a dietary supplement, MAXISAL(R), to address the market immediately and generate revenues, while negotiating to obtain a commercialization partner willing to pay upfront milestones, the company is hoping to avoid raising debt or equity that it doesn’t need.

Meanwhile, Amarillo’s low-dose oral interferon could represent a significant opportunity for shareholders down the road. With Phase II studies already underway, along with talks with potential partners, this stock could see some significant upside over the near-term.

Source

Vertex Beats Merck in Hep C Battle

By Adam Feuerstein 08/04/10 - 10:02 AM EDT

WHITEHOUSE STATION, NJ (TheStreet) -- Vertex Pharmaceuticals(VRTX) defeats Merck(MRK) in the first battle of the hepatitis C drug war.

Merck said Wednesday that between 63% and 66% of hepatitis C patients never treated before achieved a viral cure after receiving the company's experimental drug boceprevir plus the standard of care, according to top-line results from a phase III study known as SPRINT-2.

These boceprevir cure rates were significantly higher than the 38% of hepatitis C patients cured using standard of care alone. On these data, Merck said it will seek approval of boceprevir in the U.S. and Europe by the end of the year.

If approved, boceprevir may have a tough time competing against Vertex's hepatitis C drug telaprevir, which will also be filed for approval later this year. Results from a similar Vertex study in so-called "treatment-naïve" hepatitis C patients released in May showed that telaprevir plus the standard of care achieved a cure rate of 75%.

Moreover, patients can be cured of the hepatitis C virus using Vertex's telaprevir in as little as 24 weeks, while the shortest treatment duration with Merck's boceprevir is 28 weeks.

It's important to note that boceprevir and telaprevir have never been matched head to head in a single study, but that doesn't stop analysts and investors from comparing the efficacy and safety of the two drugs.

"The [boceprevir] data look ok from an efficacy and safety standpoint but we believe that they are inferior to what telaprevir has demonstrated thus far," wrote ISI Group biotech analyst Mark Schoenebaum in an email to clients soon after Wednesday's announcement.

In early trading, Vertex shares were up 5% to $37.04. Merck was essentially flat at $34.85.

Merck Wednesday also released data from a second phase III study known as RESPOND-2 which tested boceprevir in patients who previously failed to respond to treatment with standard of care.

In this study, cure rates for boceprevir patients (who also received standard of care therapy) ranged from 59% to 66%. By comparison, patients who were re-treated with standard of care achieved cure rates of 21%.

Source

UPDATE 2- Merck hepatitis drug works, side effects loom

Wed Aug 4, 2010 10:22am EDT

* Merck to seek boceprevir approval by year's end
* Side effects raise questions in one of two trials
* Shares of rival drugmaker Vertex rise 6 pct
* Merck shares unchanged (Adds details from study, bylines)

By Ransdell Pierson and Lewis Krauskopf

NEW YORK, Aug 4 (Reuters) - Merck & Co (MRK.N) said on Wednesday that two late-stage studies of its experimental hepatitis C treatment met their main effectiveness goals, and it expects to seek approval for the high-profile medicine by the end of the year.

But a much higher percentage of patients taking the Merck drug dropped out of one of the trials due to adverse events, including anemia, than those taking standard treatments -- which themselves are known for harsh side effects.

Merck's drug, boceprevir, was one of the most important experimental products gained by Merck through its acquisition of Schering-Plough Corp last year.

It and a similar drug being developed by Vertex Pharmaceuticals Inc (VRTX.O), called telaprevir, have been considered possible blockbuster products because of their potential to cure more patients and in as little as half the time of standard drugs that require almost a year of treatment.

Vertex shares rose almost 6 percent to $37.23, as investors studied the general findings Merck provided. Merck said it would provide detailed clinical trial data at a medical meeting in November. Merck shares were unchanged.

The new class of drugs work against the liver-damaging hepatitis C virus by blocking a protein called protease that the virus requires to replicate. Current treatments, by contrast, involve a combination of the injectable drug interferon and an anti-viral pill called ribavirin.

Merck said boceprevir, taken in combination with the company's Pegintron brand of interferon and ribavirin, significantly increased the number of patients with sustained virologic response -- meaning no detectable virus levels 24 weeks after the end of treatment -- compared with patients receiving Pegintron, ribavirin and a placebo.

One of the trials, called HCV RESPOND-2, involved 403 patients with genotype 1, the most common form of hepatitis C, who had failed prior therapy with interferon and ribavirin. The other trial, called HCV SPRINT-2, enrolled 1,097 patients with genotype 1 who had not previously been treated for the virus.

In both trials, a significant number of patients received 48 full weeks of treatment. But patients with undetectable virus at week 8 and again at certain points later in the studies were able to stop all treatment at 36 weeks in the smaller trial, and at 28 weeks in the larger study. (Reporting by Ransdell Pierson and Lewis Krauskopf, editing by Maureen Bavdek, Dave Zimmerman)

Source

Feature: Hunting for a hepatitis vaccine

Understanding how the immune system responds to hepatitis C is crucial in developing a vaccine. An ongoing study by Andrew Lloyd and his team is hoping to shed light on this virus and its weaknesses.

Fiona Wylie (Australian Life Scientist)
04 August, 2010 10:35
 
This feature appeared in the May/June 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.
 
Professor Andrew Lloyd of the University of New South Wales is one of the central figures in the HITS study (Hepatitis C Incidence and Transmission Study) is a long-term prospective cohort study of eligible prison inmates in NSW. Lloyd’s cohort comprises high-risk, uninfected injecting drug users, who are followed at regular intervals longitudinally.

“Sadly we are identifying a significant number becoming infected,” he says. And this is despite significant education on preventative behaviours. “In terms of a hepatitis C vaccine, prisons are, for better or worse, a typical venue that might be targeted as a population in terms of vaccine preparation in the first instance, and ultimately for application of a effective vaccine.”

According to Lloyd, the ideal target population for a candidate hepatitis C vaccine must be well characterised, with well-understood risk behaviours, and a high documented incidence as well as a good follow-up likelihood, so that the effects of the vaccine on incidence are easier to interpret and more significant.

“These criteria are reasonably readily available in our prison population, but not so easy to find within the general population, particularly as injecting drug users, who are the main sufferers of hepatitis C in Australia, tend to be fairly socially chaotic (as a broad statement) outside the prison venue. We recently reported that, sadly, the prison population has an annual incidence of infection of about 30-40 per cent, which is very high.”

The success of hepatitis C vaccine development also requires some knowledge of the protective immunity strategies used by the body against the virus. “What we know already about hepatitis C infection is quite interesting,” says Lloyd.

“For a start, about one in every three people will successfully clear the virus after infection. This is good, because it means that there is something that the host immune response can do to get rid of the virus. The bad news is that most of those people apparently remain susceptible and so can get reinfected.

“Although, it also seems that re-exposure has a better outcome the second time around, meaning that your likelihood of clearing the virus on round two, three, four or five appears better than on the first round. So the evidence suggests that, yes, there probably is such a thing as protective immunity.”

Developing a hepatitis vaccine
 
The final part of Lloyd’s discussion at the ASM meeting will focus on recent work by the group regarding cellular immunity against hepatitis C infection. As part of the HITS study, Lloyd has been looking at high-risk cohort members who remain uninfected.

“These individuals have been using drugs, sharing needles and doing all the other high-risk behaviours for many years, but have no evidence whatsoever of the virus, by antibody testing and by PCR. And that is really a bit of a surprise,” he says.

“We know that the key element of the immune response that confers successful clearance is cellular immunity – that is, T cells reactive against the virus – and we have found that a significant minority of these high-risk, hard-core, long-standing injectors that were not infected actually have cellular immunity against hepatitis C infection.”

Analyses of T cells within this prison sub-group revealed a population of T cells with the right markers of defence against the virus and which are reactive against the virus when challenged in vitro, suggesting that these individuals have a degree of naturally occurring protective immunity.

“From the vaccine aspect, this means that for some individuals you don’t need to induce de novo primary immunity, but rather to simply boost pre-existing immunity, and the characteristics of that naturally occurring immunity might provide a facsimile of what you might try to generate with a vaccine.”

Current efforts are now focused on better characterising this immunity and in doing so, guiding the strategies for vaccine development and other prevention strategies in both the prison setting and the general community.

The HITS prison study being undertaken under the guidance of Lloyd, together with a more recently established community-based HITS cohort, is providing vital information for the global efforts to develop an effective hepatitis C vaccine.

As Lloyd explains: “It is such an important, time-consuming and challenging task to develop the right vaccine in the research lab, but in the hep C business, it is equally tough to find and manage the right populations to test candidate vaccines.”

Source

Hepatitis B linked to lymphoma in study

WASHINGTON
Tue Aug 3, 2010 6:37pm EDT

WASHINGTON (Reuters) - People infected with hepatitis B virus are around twice as likely to develop non-Hodgkin lymphoma, researchers reported on Tuesday.

Hepatitis B was already known to cause liver cancer and some scientists had suspected it might cause lymphoma, too. The study, published in Lancet Oncology, confirms this. Hepatitis C is also linked to lymphoma.

The blood cancer is not common and widespread vaccination against the viruses is unlikely to affect non-Hodgkin lymphoma rates much, the researchers noted. But it may be possible to treat the virus and help non-Hodgkin lymphoma patients, they said.

Dr. Eric Engels of the U.S. National Cancer Institute and Sun Ha Jee of Yonsei University in Seoul studied the records of more than 600,000 people in South Korea, where hepatitis B was extremely common before a vaccination campaign began in 1995.

Of these, 53,000 or about 9 percent had evidence of hepatitis B infection. After 14 years, rates of non-Hodgkin lymphoma were more common among the infected people -- 19.4 cases per 100,000 people compared to 12.3 per 100,000 who did not have hepatitis B.

Viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation, according to the U.S. Centers for Disease Control and Prevention. The various hepatitis viruses are not closely related -- the word hepatitis means inflammation of the liver.

An estimated 350 million people worldwide are infected with hepatitis B virus, which causes 340,000 cases of liver cancer a year and kills between 500,000 and 1.2 million people a year.

Researchers think both hepatitis B and C may cause lymphoma by overstimulating the immune system as it tries to fight off the liver infection.

(Reporting by Maggie Fox, editing by Alan Elsner)

Source

Cellular immune responses to HCV core increase and HCV RNA levels decrease during successful antiretroviral therapy

Gut doi:10.1136/gut.2009.205971

Paper

Janine Rohrbach 1, Nicola Robinson 2, Gillian Harcourt 2, Emma Hammond 3, Silvana Gaudieri 3,4, Meri Gorgievski 5, Amalio Telenti 6, Olivia Keiser 7, Huldrych F Günthard 8, Bernhard Hirschel 9, Matthias Hoffmann 10, Enos Bernasconi  11, Manuel Battegay 12, Hansjakob Furrer 1, Paul Klenerman 2, Andri Rauch 1,3, the Swiss HIV Cohort Study

1 Division of Infectious Diseases, University Hospital Berne and University of Berne, Switzerland
2 Nuffield Department of Clinical Medicine, Oxford University, UK
3 Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia
4 Centre for Forensic Sciences and School of Anatomy and Human Biology, University of Western Australia, Perth, Australia
5 Institute for Infectious Diseases, University of Berne, Switzerland
6 Institute of Microbiology, University Hospital Centre and University of Lausanne, Switzerland
7 Institute of Social and Preventive Medicine, University of Berne, Switzerland
8 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland
9 Department of Infectious Diseases, Geneva University Hospital, Switzerland
10 Division of Infectious Diseases, Kantonsspital St Gallen, Switzerland
11 Division of Infectious Diseases, Ospedale Regionale di Lugano, Switzerland
12 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland

Correspondence to
Andri Rauch, Klinik und Poliklinik für Infektiologie, University Hospital Berne and University of Berne, Inselspital PKT2B, 3010 Bern, Switzerland; andri.rauch@insel.ch

Revised 31 March 2010
Accepted 13 April 2010
Published Online First 26 July 2010

Abstract

Background Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected individuals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels.

Aims To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication.

Methods T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected individuals by ex vivo interferon-γ-ELISpot responses to HCV core peptides, that predominantly stimulate CD4+ T cells. HCV RNA levels were assessed by real-time PCR in 114 individuals.

Results The proportion of individuals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in individuals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log10 IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (−0.3 log10 IU/ml, p=0.02).

Conclusions Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected individuals.

Source

Rare Organ Transplant Gives Single Mom New Lease on Life

 A single mom from North Carolina recently received an extremely rare triple transplant. She received a new heart, lungs and a liver and is enjoying her new lease on life.

Shereyse Joyner from Ahoskie, NC, is believed to be only the twelfth patient in the U.S. since 1988 to receive the triple organ transplant.
2:06 (mm:ss)

Transcript of Video
 
Source

Celsion's Phase III ThermoDox® HEAT Study Recommended as Priority Clinical Trial for HCC

Celsion Corporation announced today that the consensus recommendations of the National Cancer Institute (NCI) Clinical Trials Planning Meeting (CTPM) for Hepatocellular Carcinoma have been released and published in the August 2010 issue of Journal of Clinical Oncology, the official publication of American Society of Clinical Oncology (ASCO). In addition to evaluating the current standard of care, the NCI panel also recommended Celsion's Phase III ThermoDox ® HEAT Study as a Priority Clinical Trial for HCC.

"We are pleased this prominent panel of experts at the NCI Clinical Trials Planning Meeting have recognized the importance of our Phase III HEAT Study," stated Michael H. Tardugno, President and Chief Executive Officer of Celsion. "Upon completion of the trial and eventual marketing approval, ThermoDox plus RFA will provide an additional therapeutic option for patients afflicted with HCC, a dreadful disease with high unmet medical need." Dr. Nicholas Borys, Chief Medical Officer of Celsion Corporation commented, "This JCO article also reinforces the global importance of new therapies for HCC, and highlights the prominence of the ThermoDox program, which is now over 2/3rds enrolled in 75 global sites and 11 countries."

Celsion's global Phase III ThermoDox study for primary liver cancer plans to enroll 600 patients and is being conducted under a FDA Special Protocol Assessment (SPA). The study is designed to evaluate the efficacy of ThermoDox in combination with radiofrequency ablation (RFA) when compared to patients who receive RFA alone as the control. The primary endpoint for the study is progression-free survival. Additional information on the Phase III ThermoDox clinical study may be found at http://www.clinicaltrials.gov/.

About ThermoDox®

ThermoDox® is a proprietary heat-activated liposomal encapsulation of doxorubicin, an approved and frequently used oncology drug for the treatment of a wide range of cancers including breast cancer. ThermoDox® is administered intravenously and in combination with hyperthermia has the potential to provide local tumor control and improve quality of life. Localized mild hyperthermia (39.5-42 degrees Celsius) releases the entrapped doxorubicin from the liposome. This delivery technology enables high concentrations of doxorubicin to be deposited preferentially in a targeted tumor.

ThermoDox has already demonstrated remarkable evidence of clinical activity in Phase I studies for primary liver cancer and recurrent chest wall breast cancer. For the primary liver cancer indication, Celsion has been granted FDA Orphan Drug designation. For recurrent chest wall breast cancer, ThermoDox® is being evaluated in a pivotal Phase I/II open-label, dose-escalating trial that is designed to measure durable local complete response at the tumor site.

ThermoDox® is a registered trademark of Celsion Corporation


About ThermoDox Global Phase III HEAT Study

Celsion's global ThermoDox Phase III study for HCC, the most common form of primary liver cancer, is being conducted under a Special Protocol Assessment with the U.S. Food and Drug Administration (FDA). The 600 patient study, is designed to evaluate the efficacy of ThermoDox in combination with RFA when compared to patients who receive RFA alone as the control. The primary endpoint is progression free survival with a secondary confirmatory endpoint of overall survival. A pre-planned, un-blinded interim efficacy analysis will be performed by an independent Data Management Committee when 50% of the progression-free survival endpoint events are realized in the study population. Based on an historical review of RFA cases, Celsion expects the study could be completed by the middle of 2011, and pending positive data, a New Drug Application would be submitted to the FDA before the end of 2011. Additional information on the ThermoDox Phase III clinical study may be found at http://www.clinicaltrials.gov/.

About Primary Liver Cancer

Primary liver cancer is one of the most deadly forms of cancer and ranks as the fifth most common solid tumor cancer. The incidence of primary liver cancer is approximately 20,000 cases per year in the United States and is rapidly growing worldwide at approximately 1,000,000 cases per year, due to the high prevalence of Hepatitis B and C in developing countries. Among the standard treatment options for liver cancer is surgical resection of the tumor; however 70% to 80% of patients are ineligible for surgery. Radio frequency ablation (RFA) has increasingly become the standard of care for non-resectable liver tumors, but the treatment becomes less effective for larger tumors.

About Celsion

Celsion is dedicated to the development and commercialization of innovative oncology drugs including tumor-targeting treatments using focused heat energy in combination with heat-activated drug delivery systems. Celsion has licensed ThermoDox(R) to Yakult-Honsha for the Japanese market and has a partnership agreement with Phillips Medical to jointly develop its heat activated liposomal technology in combination with high intensity focused ultrasound to treat difficult cancers. Celsion has research, license, or commercialization agreements with leading institutions such as the National Institutes of Health, Duke University Medical Center, University of Hong Kong, Cleveland Clinic, and the North Shore Long Island Jewish Health System.

For more information on Celsion, visit our website: http://www.celsion.com/

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials by others; possible acquisitions of other technologies, assets or businesses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Company's periodic reports filed with the Securities and Exchange Commission.

Source

Histologic outcomes in hepatitis C-infected patients with varying degrees of virologic response to interferon-based treatments

Pockros PJ, Hamzeh FM, Martin P, Lentz E, Zhou X, Govindarajan S, Lok AS.
Scripps Clinic, La Jolla, CA.

Abstract

Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon-based therapies can experience treatment-related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1-6) with baseline and follow-up liver biopsies from eight phase 2 to phase 4 interferon-based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of >/=1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels HEPATOLOGY 2010;).

Source

Diagnosis of occult hepatitis C without the need for a liver biopsy

Journal of Medical Virology
Volume 82 Issue 9, Pages 1554 - 1559
Published Online: 15 Jul 2010
Copyright © 2010 Wiley-Liss, Inc., A Wiley Company

Inmaculada Castillo 1, Javier Bartolomé 1, Juan Antonio Quiroga 1, Guillermina Barril 1 2, Vicente Carreño 1 *

1 Foundation for the Study of Viral Hepatitis, Madrid, Spain
2 Department of Nephrology, Hospital Universitario de la Princesa, Madrid, Spain
email: Vicente Carreño (fehvhpa@fehv.org)

* Correspondence to Vicente Carreño, Fundación para el Estudio de las Hepatitis Virales, Guzmán el Bueno 72, 28015 Madrid, Spain.

Funded by:
-Fundación Investigaciones Biomédicas, Madrid, Spain
-Fundación Caja Navarrra, Pamplona, Spain

Keywords
occult HCV • PBMCs • HCV-RNA • anti-core HCV

Abstract

The diagnosis of occult hepatitis C virus (HCV) infection is based on the presence of HCV-RNA in the liver. This study aimed to evaluate the use of combining non-invasive assays to diagnose occult HCV. A total of 122 patients with occult HCV (HCV-RNA in the liver without detectable anti-HCV and serum HCV-RNA) and 45 patients with cryptogenic chronic hepatitis (without HCV-RNA in the liver and negative for anti-HCV and serum HCV-RNA) were included. HCV-RNA was tested in peripheral blood mononuclear cells (PBMCs) and in 2 ml of ultracentrifuged serum. Anti-core HCV was examined by a non-commercial enzyme-linked immunosorbent assay. All controls were negative for the three HCV markers studied. Among patients with occult HCV, 36% were anti-core HCV positive, 57% had serum HCV-RNA after ultracentrifugation, and 61% had HCV-RNA in PBMCs. Combining the results of the assays, 91% of the patients were positive for at least one marker. Intrahepatic HCV-RNA load was significantly higher in patients who were positive simultaneously for the three HCV markers than in patients who were negative for all markers (P = 0.006) and than in those with one or two HCV markers (P = 0.039). Replication of HCV in liver was detected more frequently in patients with three (93%, P = 0.002), two (82%, P = 0.001), and one HCV marker (73%, P = 0.011) than in those without markers (27%). In conclusion, testing for all these markers allows diagnosis of occult HCV without the need for a liver biopsy and these assays may help to elucidate the clinical significance of occult HCV infection. J. Med. Virol. 82:1554-1559, 2010. © 2010 Wiley-Liss, Inc.

Accepted: 17 May 2010

Digital Object Identifier (DOI)
10.1002/jmv.21866 About DOI

Source

An early viral response to standard interferon-alpha identifies resistance to combination therapy with peginterferon and ribavirin in patients infected by HCV genotype 1

Journal of Medical Virology
Volume 82 Issue 9, Pages 1537 - 1544
Published Online: 15 Jul 2010
Copyright © 2010 Wiley-Liss, Inc., A Wiley Company

Hidenori Toyoda *, Takashi Kumada, Seiki Kiriyama, Makoto Tanikawa, Yasuhiro Hisanaga, Akira Kanamori, Toshifumi Tada, Makiko Takagi, Takeshi Hiramatsu, Takanori Hosokawa, Takahiro Arakawa, Masashi Fujimori

Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
email: Hidenori Toyoda (hmtoyoda@spice.och.ne.jp)

*Correspondence to Hidenori Toyoda, Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu 503-8502, Japan.

Keywords
chronic hepatitis C • standard interferon • peginterferon and ribavirin • non-response • resistance to interferon

Abstract

As combination therapy with peginterferon (PEG-IFN) and ribavirin has a high morbidity, identifying individuals with hepatitis C virus (HCV) who will not respond to the treatment would be beneficial. The early responses of serum HCV RNA levels to standard interferon (IFN) and PEG-IFN were examined to determine if it was possible to identify resistance to combination therapy. One hundred thirty-one patients infected with HCV genotype 1b were enrolled. Patients were given 6 MU of standard IFN alpha-2b at least 2 weeks before initiating combination therapy. Serum HCV RNA levels were measured before, 24 hr after the administration of standard IFN, and 24 hr after the administration of PEG-IFN (at the start of the combination therapy). The association between reductions in HCV RNA levels at 24 hr after the administration of standard IFN and PEG-IFN and the outcome of combination therapy were analyzed. Reductions in HCV RNA levels were poorer in patients who did not respond than in those with a sustained virologic responses or relapses (P < 0.0001), both 24 hr after the administration of standard IFN and 24 hr after the administration of PEG-IFN. Reductions in HCV RNA levels 24 hr after the administration of standard IFN were an independent factor associated with non-response by multivariate analysis. An early reduction in viral load to a single administration of standard IFN is a useful predictor of non-response in patients with HCV genotype 1, allowing for pretreatment identification of patients who will not benefit from combination therapy. J. Med. Virol. 82:1537-1544, 2010. © 2010 Wiley-Liss, Inc.

Accepted: 20 April 2010

Digital Object Identifier (DOI)
10.1002/jmv.21858 About DOI

Source

Serum aminotransferase levels instead of etiology affects the accuracy of transient elastography in chronic viral hepatitis patients

Journal of Gastroenterology and Hepatology

Published Online: 28 Jun 2010
Journal compilation © 2010 Blackwell Publishing Asia Pty Ltd and Journal of Gastroenterology and Hepatology Foundation

Hye Jin Cho, 1 Yeon Seok Seo, 1 Kwang Gyun Lee, 1 Jong Jin Hyun, 1 Hyonggin An, 2 Bora Keum, 1 Ji Hoon Kim, 1 Hyung Joon Yim, 1 Yoon Tae Jeen, 1 Hong Sik Lee, 1 Hoon Jai Chun, 1 Soon Ho Um, 1 Chang Duck Kim, 1 Ho Sang Ryu 1

Department of Internal Medicine 1 and Department of Biostatistics, 2 Korea University College of Medicine, Seoul, Korea

Correspondence to Yeon Seok Seo
Department of Internal Medicine, Korea University College of Medicine, 126-1, 5-Ga, Anam-Dong, Seongbuk-Gu, Seoul, Korea (136-705)
Tel: 82-2-920-6608 / FAX: 82-2-953-1943
e-mail: drseo@korea.ac.kr

This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Gastroenterology and Hepatology, but has yet to undergo copy-editing and proof correction. Please cite this article as an "Accepted Article"; doi: 10.1111/j.1440-1746.2010.06419.x

KEYWORDS
FibroScan • liver stiffness • alanine aminotransferase • necroinflammation

ABSTRACT

Background: It is still uncertain whether the accuracy of transient elastography (TE) in predicting the fibrosis stage is similar in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study was performed to evaluate whether the underlying cause of chronic viral hepatitis affects the predictive accuracy of TE. Methods: Patients with CHB or CHC who were admitted for a liver biopsy were enrolled. Patients underwent TE and laboratory tests on the same day as the liver biopsy. The predictive accuracy was analyzed by comparing the areas under the receiver-operating characteristic curves (AUCs). Results: Two-hundred seven patients were enrolled, comprising 121 CHB patients and 86 CHC patients). The patients were aged 44 ± 14 years, and 121 (58.5%) of them were men. AUCs for predicting significant fibrosis were significantly lower in CHB patients than in CHC patients (P = 0.043). The serum alanine aminotransferase (ALT) level was associated with overestimation and underestimation of the fibrosis stage, while the cause of chronic hepatitis was not. AUCs for predicting significant fibrosis were significantly lower in patients with ALT levels >70 IU/L (AUC, 0.830; 95% CI, 0.742-0.898) than in patients with ALT levels ≤70 IU/L (0.944; 0.882-0.979; P= 0.015). Conclusions: Although the predictive accuracy of TE in predicting significant fibrosis differed significantly with the cause of chronic hepatitis, this difference was due to the degree of serum ALT levels rather than to the cause of hepatitis itself. Avoiding performing TE in patients with elevated ALT levels is recommended to guarantee the predictive accuracy of TE.

Received date: 06-Apr-2010
Accepted date: 07-Jun-2010

DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1440-1746.2010.06419.x About DOI
 
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Vaccine Shows Some Promise Against Advanced Cancers

But only a minority of patients benefited and more work may need to be done, experts say

Monday, August 2, 2010
 
MONDAY, Aug. 2 (HealthDay News) -- Scientists have genetically tweaked a virus to fashion a therapeutic vaccine that appears to attack a variety of advanced cancers.
 
The vaccine has provoked the required tumor-fighting immune response in early human trials, but only in a minority of patients tested.

And one expert urged caution. "They were able to generate an immune response [with the vaccine]. That's a good thing but we need a little more information," said Dr. Adam Cohen, assistant professor in medical oncology at Fox Chase Cancer Center in Philadelphia. He was not involved in the study.

"This is the first study in cancer patients with this type of vaccine, with a relatively small number of patients treated so far," Cohen noted. "So while the immune response data are promising, further study in a larger number of patients will be required to assess the clinical benefit of the vaccine."

One vaccine to treat prostate cancer, Provenge, was recently approved by the U.S. Food and Drug Administration. However, Cohen noted that many other cancer vaccines have shown early promise and not panned out.

The theory behind therapeutic cancer vaccines is that people with cancer tend to have defects in their immune system that compromise their ability to respond to malignancy, explained study lead author Dr. Michael Morse, associate professor of medicine at Duke University Medical Center.

"A vaccine has to work by activating immune cells that are capable of killing tumors and those immune cells have to survive long enough [to] get to the tumor and destroy it," he explained.

For this vaccine, the authors used the Venezuelan equine encephalitis virus, an "alphavirus" that affects the nervous systems of equines, including horses and donkeys.

Alphaviruses provide an attractive vector for vaccines because they naturally seek out dendritic cells, which stimulate the body's immune system.

In their work, the authors removed the innards of the virus and substituted instead a gene for the carcinoembryonic antigen (CEA). This immune system biomarker is overproduced in many different types of cancer.

The vaccine was then administered multiple times over a period of three months to 28 patients with advanced, recurrent forms of lung, colon, breast, appendix or pancreatic cancer. The participants had already failed several rounds of standard chemotherapy.

Five patients displayed a response to the therapy: Two who had already been in remission stayed in remission; two patients saw their cancers stabilize; and a liver lesion in one patient with pancreatic cancer was no longer evident.

The responses tended to occur in patients with smaller tumors and in those receiving higher doses of the vaccine.

The alphavirus-based vaccine also managed to evade the immune system's regulatory T cells, which could have shut down the body's immune response, the researchers said.

Although T cell levels were elevated in some patients, the vaccine was able to get around them.

Co-authors included employees from Alphavax, which develops new vaccine technology. The study was partially supported by the U.S. National Cancer Institute.

SOURCES: Michael Morse, M.D., associate professor, medicine, Duke University Medical Center; Adam Cohen, M.D., assistant professor, medical oncology, Fox Chase Cancer Center, Philadelphia; Aug. 2, 2010, Journal of Clinical Investigation, online

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Boomers May Be Last Boom of Hepatitis C

U.S. Centers for Disease Control and Prevention • U.S. News

August 2, 2010

A new study of U.S. blood donors shows a "strikingly lower prevalence" of hepatitis C virus (HCV) compared with 1992-93, according to lead researcher Dr. Edward Murphy of the University of California-San Francisco.

HCV is a blood-borne infection that is primarily contracted from dirty syringes, but a small number of cases are sexually transmitted or passed from mother to infant during childbirth. The body can clear hepatitis C, though infections become chronic 75 percent to 85 percent of the time. CDC estimates that 1 percent to 5 percent of people with chronic HCV eventually die of cirrhosis or liver cancer.

In the early 1990s, about a half a percent of blood donors were positive for HCV antibodies, indicating either a chronic infection or past infection that cleared. From 2006 to 2007, the study analyzed samples from nearly 960,000 blood donors at six U.S. blood banks, finding less than a tenth of a percent were positive for HCV antibodies.

Murphy said the decrease probably reflects an overall decline of hepatitis C, especially among younger Americans. The baby boom generation, which had higher rates of injection drug use than subsequent generations, has more carriers of the infection and is at higher risk for HCV-related liver disease.

Two other factors for higher risk of hepatitis C among blood donors were found. Among women, the odds of having HCV antibodies increased with the number of children they had given birth to -- from 1 infection in 3,300 among women who had never given birth to 1 in 1,000 among women with five or more children.

Obese adults were less likely than their normal-weight peers to have HCV antibodies. And among those with antibodies, obese persons were less likely to have the genetic material that signals the ongoing presence of HCV.

The study, "Hepatitis C Virus Prevalence and Clearance Among U.S. Blood Donors, 2006-2007: Associations with Birth Cohort, Multiple Pregnancies, and Body Mass Index," was published in the Journal of Infectious Diseases (2010;202:576-584).
 
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The Independent Effects of Fatigue and UDCA Therapy on Mortality in Primary Biliary Cirrhosis: Results of a 9 Year Follow-Up

David E Jones a, Ahmad Al-Rifai a, James Frith a, Imran Patanwala a, Julia L Newton b

Received 14 January 2010; received in revised form 7 May 2010; accepted 8 May 2010. published online 02 August 2010.
Accepted Manuscript

Abstract

Background & Aims
Long-term outcome in Primary Biliary Cirrhosis (PBC) remains unclear. Whilst response to Ursodeoxycholic Acid (UDCA) is associated with good outcome, this effect is not universal. Early data from our group have suggested that one factor associated with a poorer outcome in PBC is fatigue. The aim of this study was to explore the inter-relationship between UDCA use, response, and fatigue in determining outcome over 9 years in a unique, comprehensive patient cohort.

Methods
Longitudinal prospective study of a geographically-defined complete cohort of PBC patients in North- East England and matched community controls.

Results
Survival to death or transplant was significantly lower in PBC patients than in the case-control population (88/136 (65%) v 114/136 84% (p <0.001 by log-rank test), with better survival in UDCA responders (defined using the Paris criteria) than in patients not treated with UDCA at study outset. Compared to the whole control group survival was reduced in PBC patients fatigued at study outset but not in those without fatigue (p <0.0001); an effect independent of the beneficial effect of UDCA response and of conventional parameters of liver disease severity. UDCA responders without fatigue at the study outset had a 9 year survival which was identical to controls. Patients without fatigue at the study outset who developed fatigue during follow-up had significantly worse survival than patients who remained without fatigue throughout (p <0.05). Fatigued controls had worse survival than non-fatigued controls (p = 0.05).

Conclusions
Survival in a comprehensive cohort of PBC patients is substantially reduced compared with case-matched community controls. Development of fatigue and non-treatment with UDCA were specifically (and independently) associated with increased risk of death in PBC.

Keywords: Fatigue, outcomes research, quality of life, liver cirrhosis, biliary

No full text is available. To read the body of this article, please view the PDF online.

a Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK

b Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, UK

PII: S0168-8278(10)00679-3
doi:10.1016/j.jhep.2010.05.026
© 2010 Published by Elsevier Inc

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Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension?

Dominique Thabut a b, Vijay Shah a

Received 21 April 2010; received in revised form 7 July 2010; accepted 12 July 2010. published online 02 August 2010.
Accepted Manuscript

Abstract

Portal hypertension accounts for the majority of morbidity and mortality that is encountered in patients with cirrhosis. Portal hypertension is initiated in large part through increases in intrahepatic vascular resistance. Fibrosis, regenerative nodule formation, and intrahepatic vasoconstriction are classical mechanisms that account for increased intrahepatic vascular resistance in cirrhosis. Recent data suggests that intrahepatic angiogenesis and sinusoidal remodeling could also be involved in sinusoidal resistance, fibrosis, and portal hypertension. While angiogenesis is defined as the formation of new vessels deriving from existing ones, sinusoidal remodeling in its pathological form associated with cirrhosis is characterized by increased mural coverage of vessels by contractile HSC. Most attention on the mechanisms of these processes has focused on the liver sinusoidal endothelial cell (SEC), the hepatic stellate cell (HSC), and the paracrine signaling pathways between these two cell types. Interventions that target these vascular structural changes have beneficial effects on portal hypertension and fibrosis in some animal studies which has stimulated interest for pursuing parallel studies in humans with portal hypertension.

Keywords: Portal hypertension, cirrhosis, angiogenesis, vascular remodeling, receptor tyrosine kinase

No full text is available. To read the body of this article, please view the PDF online.

a Gastroenterology Research Unit, Advanced Liver Disease Study Group, Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN, USA.

b Université Pierre et Marie Curie, AP-HP, Service d’Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, FRANCE.

PII: S0168-8278(10)00632-X
doi:10.1016/j.jhep.2010.07.004
© 2010 Published by Elsevier Inc.

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Hepatitis C Virus NS2 Protein Triggers Endoplasmic Reticulum Stress and Suppresses its Own Viral Replication

Annette von dem Bussche a, Raiki Machida a, Ke Li a, Gideon Loevinsohn a b, Amrin Khander a b, Jianguo Wanga b, Takaji Wakita b, Jack R. Wands a, Jisu Li a

Received 28 December 2009; received in revised form 22 April 2010; accepted 6 May 2010. published online 02 August 2010.
Accepted Manuscript

Abstract

Background & Aims
We previously reported that the NS2 protein of hepatitis C virus (HCV) inhibits the expression of reporter genes driven by a variety of cellular and viral promoters. The aim of the study was to determine whether the broad transcriptional repression is caused by endoplasmic reticulum (ER) stress.

Methods
Phosphorylation of the translation initiation factor eIF2α and HCV replication were detected by Western and Northern blot, respectively. De novo protein synthesis was measured by metabolic labeling. Activation of ER stress responsive genes was determined by promoter reporter assay, as well as mRNA and protein measurement by real time PCR and Western blot.

Results
Transient or inducible NS2 protein expression increased eIF2α phosphorylation and reduced de novo protein synthesis. It up-regulated promoter activities and transcript levels of ER stress inducible genes including GRP78, ATF6, and GADD153, as well as GRP78 protein level. The same effect was observed when NS2 was synthesized as part of the core-E1-E2-p7-NS2 polypeptide. NS2 protein also inhibited reporter gene expression from the HCV internal ribosome entry site and consequently reduced HCV replication. The full-length HCV replicon activated GRP78, ATF6, and GADD153 promoters more efficiently than the subgenomic replicon lacking the coding sequence for both the structural proteins and NS2. Abrogation of HCV infection/replication, by an inhibitor of the NS3 protease, relieved ER stress.

Conclusions
HCV infection can induce ER stress, with NS2 protein being a major mediator. The stress can be relieved by a feedback mechanism.

Abbreviations: HCV, hepatitis C virus, NS2, no-structural protein 2, ER, endoplasmic reticulum, eIF2α, eukaryotic translation initiation factor 2, GRP78, glucose regulated protein 78, ATF6, activating transcription factor 6, GADD153, growth arrest and DNA damage induced gene-153, CMV, cytomegalovirus, SV40, simian virus 40, TNFα, tumor necrosis factor alpha, NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells, HBV, hepatitis B virus, FL, full-length, SG, subgenomic, SEAP, secreted alkaline phosphatase, ECL, enhanced chemiluminescence, PERK, PKR-like ER kinase, IRE1, inositol-requiring enzyme 1, IRES, internal ribosomal entry site, DGD, glycine decarboxylase, p.t., post transfection

Keywords: HCV infection, ER stress, viral pathogenesis, NS2 protein

No full text is available. To read the body of this article, please view the PDF online.

a Liver Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA

b Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo 162-8640, Japan

PII: S0168-8278(10)00622-7
doi:10.1016/j.jhep.2010.05.022
© 2010 Published by Elsevier Inc.

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U.S. dietary supplements often contaminated: report

By Maggie Fox, Health and Science Editor
WASHINGTON
Tue Aug 3, 2010 6:14am EDT

(Reuters) - Many popular dietary supplements contain ingredients that may cause cancer, heart problems, liver or kidney damage, but U.S. stores sell them anyway and Americans spend millions on them, according to Consumer Reports.

The consumer magazine published a report on Tuesday highlighting the U.S. Food and Drug Administration's lack of power to regulate such supplements, and said the agency rarely uses what little power it does have.

The report from the influential group urged Congress to speed up small moves toward giving the agency more clout, especially in regulating supplements.

Despite the "natural" labels carried by many of the supplements, many are contaminated.

Yet Americans flock to take them, according to the magazine, citing the Nutrition Business Journal as saying the market was worth $26.7 billion in 2009.

"Of the more than 54,000 dietary supplement products in the Natural Medicines Comprehensive Database, only about a third have some level of safety and effectiveness that is supported by scientific evidence," the report reads.

In addition, the FDA has not inspected any supplement factories in China, even though the agency set up field offices there starting in 2008, Consumer Reports said.

The organization pointed to 12 supplement ingredients in particular that it said could be dangerous: aconite, bitter orange, chaparral, colloidal silver, coltsfoot, comfrey, country mallow, germanium, greater celandine, kava, lobelia, and yohimbe.

Potential dangers include liver and kidney damage, heart rhythm disorders and unhealthy blood pressure levels, it said.

INDUSTRY FRIENDLY LAWS

The group is critical of the 1994 Dietary Supplement Health and Education Act or DSHEA, which it describes as industry friendly and which prevents the FDA from regulating supplements in the same way as it regulates prescription medications.

The Federal Trade Commission regulates the marketing of herbal supplements, whose makers are not allowed to claim they treat medical conditions.

The FDA has banned only one supplement ingredient -- ephedrine alkaloids -- although it has persuaded many companies to pull their products off the market.

"Supplements are marketed with very seductive and sometimes overblown sales pitches for increasing your performance in the bedroom, slimming down, or boosting your athletic prowess," said Nancy Metcalf, senior program editor for the magazine.

"And consumers are easily lulled into believing that supplements can do no harm because they're 'natural'," Metcalf said in a statement.

"However, some natural ingredients can be hazardous, and on top of that the FDA has repeatedly found hazardous ingredients, including synthetic prescription drugs, in supplements."

In May, the Government Accountability Office found that sellers of ginseng, Echinacea and other herbal and dietary supplements often tell consumers the pills can cure cancer or replace prescription medications.

Experts at the Institute of Medicine said earlier this year the FDA needs to use the same strict standards to regulate supplements as it uses for drugs, and the GAO said the FDA should ask Congress for more power to regulate supplements.

(Editing by Todd Eastham)

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