October 31, 2010

Hep C Update: Vertex, Merck and Gilead

By Adam Feuerstein
10/31/10 - 07:24 PM EDT

BOSTON (TheStreet) -- Updates on hepatitis C stocks from a weekend at the American Association for the Study of Liver Disease (AASLD) annual meeting:

Vertex Pharmaceuticals(VRTX_): Telaprevir was the superior hepatitis C drug coming into AASLD and no data or information released over the weekend, including from Merck(MRK_) and its competing drug boceprevir, changed that view.

If there's a debate left to have about telaprevir vs. boceprevir in hepatitis C, it's forecasting the market share each drug may garner once both are approved next year. Right now, the Street's consensus is overwhelmingly in favor of telaprevir (roughly 70-80%) to boceprevir's (20-30%). Analysts expect telaprevir sales in the range of $2.5 billion by the end of 2014.

Whether those estimate and market share splits change significantly or not could depend on feedback analysts and investors get from Hep C doctors attending AASLD after they get a chance to see full data presentations from the phase III studies of each drug Monday and Tuesday.

While we wait for those presentations, Vertex did issue a press release Saturday updating results from the two, previously announced phase III studies in treatment-naive hepatitis C patients.

As a reminder, in the phase III "Advance" study, 75% of patients treated with telaprevir plus the standard of care (long-acting interferon plus ribavirin) achieved a sustained viral response, which is essentially a cure. That compares to 44% of patients treated with standard of care alone. A second phase III study dubbed "Illuminate" confirmed that patients who respond well to telaprevir can be treated and cured in six months, half the time it normally takes to treat Hep C.

New data from the Advance study showed that 62% of African-Americans/Blacks were cured after treatment with telaprevir compared to 25% of African-American/Blacks treated with standard of care alone. This is significant because, historically, African American hepatitis C patients respond poorly to standard therapy.

Also from the Advance study, 62% of people with advance liver fibrosis or cirrhosis achieved a cure with telaprevir compared to 33% of similar patients treated with standard therapy.

Vertex also disclosed that 58% of telaprevir-treated patients in the Advance study and 65% of patients in the Illuminate study were able to cut total treatment time to 24 weeks from the 48 weeks of therapy normally needed to achieve a cure.

Merck: A press release Saturday updating results from two phase III studies of boceprevir contained a dizzying array of statistics but the overall profile of the drug -- not quite as good as telaprevir -- didn't change much.

Researchers are presenting the boceprevir data on Monday and Tuesday, which will hopefully shed light on why the analysis summarized in the Merck press release appears to exclude certain patients.
Boceprevir's overall cure rate for treatment-naive Hep C patients ranged from 63-66%, with the proportion of patients eligible for shortened therapy 44%. The cure rate was high (87% for African-American/Blacks and 97% for non-African Americans) for those patients that did receive shortened therapy due to an early and robust response to boceprevir.

Merck is also presenting data at AASLD from a study of boceprevir in patients who were not cured by previous treatments. When these "treatment resistant" patients were re-treated with boceprevir, cure rates ranged from 59% to 66% compared to 21% of patients re-treated with just standard of care.

Vertex has data on telaprevir in similar hard-to-treat patients that is superior to boceprevir, with cure rates of 65% overall that included patients much more resistant to therapy than those enrolled in Merck's boceprevir study. When similar treatment-resistant patients are compared across both studies, boceprevir's 66% cure rate falls short of telaprevir's 78% cure rate.

Vertex is not presenting its telaprevir data in treatment resistant patients at this year's AASLD meeting.

Gilead Sciences(GILD_): The HIV drug powerhouse should be a major player in developing new Hep C therapies because the viral diseases share similar traits. Yet Gilead has fumbled early Hep C drug development efforts, forcing the company to rethink strategy as competitors surged ahead.

In June, Gilead lured Duke University's Dr. John McHutchison, a leading Hep C researcher, to join the company and take over its R&D push into liver disease. On Saturday night, Gilead held a coming-out party for McHutchison, who gave investors a detailed look at the company's revamped Hep C drug development efforts.

Companies like Vertex are early winners for combining powerful, new oral drugs like telaprevir to the standard of care in Hep C -- injectable interferons and oral ribavirin. Gilead isn't trying to compete here; instead the company is taking a page from its HIV playbook, believing that the long-term future of Hep C treatment will be in developing combination of oral drugs --each acting against the Hep C virus in different ways -- that can eliminate the need for injectable interferon and perhaps even ribavirin, both of which can cause nasty side effects.

Just like Gilead sells a Atripla for HIV treatment -- a single, daily pill that combines three different medicines -- the company would like to one day develop a single, multi-drug pill for Hep C, said McHutchison.

At this year's AASLD, an early, 28-day study combining two oral drugs from Gilead's labs didn't yield promising results, but when those same drugs were combined with either ribavirin alone or in a quadruple combination wth ribavirin and interferon, the antiviral response was much more robust. In the quad combination, 93% of patients had undetectable viral levels after 28 days.
Saturday night, Gilead executives were honest about not knowing which, if any, of the oral drug combinations under development will eventually work. Gilead, however, will have seven experimental Hep C drugs that attack the virus in six different ways in human testing by next year.
That's an impressively deep and broad pipeline of Hep C drugs, which is reason for optimism even in the early days of testing.

Johnson & Johnson(JNJ_): In addition to partnering with Vertex on telaprevir, J&J is developing its own Hep C drugs, including TMC435. A phase IIb study being presented Monday shows that between 79% and 86% of patients treated with TMC435 and standard of care responded well enough to stop all therapy after 24 weeks.

This interim result for TMC435 looks better than the 58% and 65% of telaprevir-treated patients who were able to stop therapy after 24 weeks, except that J&J used a more liberal definition of response, which inflates its numbers.

Patient treated with higher doses of TMC435 also reported increases in certain liver enzymes levels, raising safety concerns about the drug.

Idenix Pharmaceuticals(IDIX_): IDX184 on its own doesn't appear to be the reason for the FDA clinical hold that temporarily shut down studies of IDX184 and IDX320 in September, according to safety data presented Sunday. No serious elevations in liver enzymes were observed in a study of IDX184 plus standard of care, which led the presenter to hypothesize that the problem is eitherwith IDX320 alone or the combination of the two drugs.

Pharmasset(VRUS_): The jury is still out on the optimal treatment duration for RG7128, which is partnered with Roche. Eighty-eight percent of patients responded to 12 weeks of treatment with a 1,000 mg, twice-daily dose of RG7128 plus standard of care compared to 49% of patients treated with standard of care alone, according to interim data presented Sunday.

Roche and Pharmasset are conducting another study of RG7128 looking at 24 weeks of dosing.

Merck: Vaniprevir posted impressive cure rates ranging from 61-84% after four weeks of dosing followed by standard of care, but the results are likely skewed by small numbers of patients. A larger study of vaniprevir in treatment-resistant patients is underway.


AASLD: Human Cells Grow on Animal Liver Scaffolds

By Kristina Fiore, Staff Writer, MedPage Today
Published: October 31, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
BOSTON -- Researchers reported here that they have pared down animal livers to their basic vascular structure and repopulated them with human liver progenitor and endothelial cells -- taking a small step toward ultimately creating completely bioartificial livers.

After a week in a bioreactor, human liver cells placed onto this liver "scaffolding" began to express signature proteins such as albumin, and the endothelial cells expressed von Willebrand factor -- clues that the cells were functioning normally, according to Pedro Baptista, PhD, PharmD, of Wake Forest University in Winston-Salem, N.C., and colleagues.

Baptista reported the group's findings during an oral session at the American Association for the Study of Liver Diseases meeting.

"We're looking into organ scaffolding because it offers a vascular system, and you can't really tissue engineer an organ without a vascular system," Baptista told MedPage Today.

"It's amazing because the cells recognize the chemistry of the matrix on their own and localize and attach in what we think are their native niches -- the endothelial cells attach to vascular structures and the hepatocytes attach in more parenchymal areas," he added.

Yet Baptista cautioned that the work is still very preliminary and his group is currently working on increasing the percentage of organ that gets repopulated with cells -- which currently stands at about 30%.

The purpose of creating bioartificial livers is to mitigate the organ donor shortage -- a persistent and growing problem in the U.S. During his talk, Baptista said the most recent statistics show that 109,000 people are awaiting organ transplants, 16,000 of whom are waiting for a donor liver.

Generating a liver scaffold has been done in the past -- and the technique can also be applied to other organs including the kidney and lungs -- but the organs had only been repopulated with animal cells.

To test the ability of growing human cells on these animal matrices, the researchers removed all existing cells from ferret livers with a detergent solution (Triton X-100 with a bit of ammonium hydroxide) to wash away cellular components such as membranes, nucleic acids, and cellular proteins.

That left behind an extracellular matrix that retains most of its microarchitecture, Baptista explained.

Next, the group seeded 70 million human liver progenitor cells and 30 million endothelial cells onto the matrix through the portal vein or vena cava, and left the organs in a bioreactor for a week.

During that time they found that the endothelial cells attached to the existing vascular channels, and the liver progenitor cells clustered throughout the bioscaffolding.

Baptista said that the "seeding is not quite there" at a 30% level, but his group is now looking at increasing the number of human cells initially infused -- perhaps to 300 or 400 million instead of 100 million.

The results still show, however, that the liver scaffold is biocompatible and can provide a sufficient substrate.

"It shows the cells are really able to recognize the native tissues and attach and engraft in those selected tissues," he said.

In fact, the liver cells were excreting higher levels of signature proteins including albumin and urea, and the endothelial cells expressed higher levels of von Willebrand factor and nitric oxide than comparator cells grown in Petri dishes, Baptista said.

He said a next step is to transplant the new organs back into animals to measure function and survival.

Another group, from Massachusetts General Hospital in Boston, Mass., which presented its findings during a poster session at the AASLD meeting, used the same scaffolding technology and retransplanted the livers back into rats.

They found similar 30% function in the new organs, but the transplanted animals only survived for eight hours, Basak Uygun, PhD, told MedPage Today.

She said in an interview that her team used large doses of blood thinner to prevent the clotting that's typical when a scaffolded organ is reperfused, which may have had an effect on mortality.

But when the livers remained outside of the animals, they functioned well for 24 hours but were not followed-up longer, she added.

The next step is to reperfuse greater than 30% of the matrix with functioning cells, Uygun added.

Arun Sanyal, MD, of Virginia Commonwealth University Medical Center in Richmond, Va., and president of the AASLD, remarked that the findings of both groups "are in a very early stage, but they provide proof-of-concept that you can take these extracellular matrices and create functioning artificial livers."

"It's very interesting even though these are emerging technologies," Sanyal added.

Baptista said he can't forecast when these bioartificial organs would be available for use in the general population, though he predicted porcine livers would be good candidates for providing the extracellular matrices for human transplants.

In the meantime, he said the engineered livers could be used for drug discovery and development.

"I hope in the future," Baptista said, "there will be some type of bioengineered livers that will be suitable for transplant."

Baptista and Uygun said they had no disclosures.

The Wake Forest University work was supported by the Portuguese Foundation for Science and Technology.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Baptista PM, et al "The use of whole organ decellularization for the bioengineering of a human vascularized liver" AASLD 2010; Abstract 12.

Additional source: American Association for the Study of Liver Diseases meeting

Source reference:
Uygyn BE, et al "Engineering of a transplantable liver graft" AASLD 2010; Abstract 293.


AASLD: Successful HCV Tx Cuts Deaths Post-Transplant

By Michael Smith, North American Correspondent, MedPage Today
Published: October 31, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
BOSTON -- After a liver transplant, successful treatment for hepatitis C significantly reduces the risk of death, researchers reported here.

The finding, from a retrospective analysis of nearly 500 patients from 12 Italian liver transplant centers, suggests that antiviral treatment should be "strongly pursued," according to Maria Rendina, MD, of the University of Bari in Bari, Italy and colleagues.

Many physicians are reluctant to treat the recurrent disease aggressively because of a perceived lack of clinical effect and because of frequent adverse events, Rendina said at the annual meeting of the American Association for the Study of Liver Diseases.

But in this study population, she said, the lack of a sustained virologic response (SVR) -- defined as undetectable viral RNA 24 weeks after the end of treatment -- was "significantly and independently" associated with a threefold increased risk of death.

All told, Rendina's group studied outcomes for 464 consecutive liver transplant patients who were treated after their hepatitis C recurred. Over a median follow-up of six years, Rendina said, 35% of the patients achieved an SVR and most maintained the response throughout the study period.

But mortality was significantly lower among those with an SVR. In addition, she noted:

• Only 10% of those who were successfully treated died, including only one from liver-related causes.

• In contrast, 34% of those who did not achieve an SVR died, including 89 (or 28%) from liver-related causes.

• The difference was significant at P=0.001, but there was no significant difference in the rate of death from non-liver related causes.

Rendina said univariate analysis showed that older donor age, diabetes, having viral genotypes one or four, and lack of an SVR were all significant risk factors for death.

In a multivariate analysis, the lack of an SVR was associated with a significant hazard ratio for death of 3.3, she added.

Rendina noted that current treatments for hepatitis C (interferon, whether pegylated or standard, combined with ribavirin) are difficult to tolerate -- indeed, she reported 26% of the patients in the current analysis stopped treatment.

"New antivirals are urgently needed," she said.

The findings "extend the whole idea that if you have an SVR you actually improve mortality," according to Arun Sanyal, MD, of Virginia Commonwealth University Medical Center in Richmond, Va. Sanyal, president of AASLD, who was not part of the study.

Sanyal said data from the nontransplant population -- some presented at this meeting -- show that an SVR is associated with lower risk of death.

The Italian study, he said, shows that "post-transplant, if you knock the virus out then it really has a huge impact on liver-related death."

Taken together, the data "makes a really compelling case than an SVR really does represent a cure," Sanyal added.

The study may increase interest in treating more post-transplant patients, he commented, although the question of when to treat remains up in the air.

Rendina did not report any external support for the study. She said she had no financial disclosures.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Rendina M, et al "SVR to antiviral therapy is highly protective against liver -- related death in patients with HCV recurrence on the graft after liver transplantation (LT)" AASLD 2010; Abstract 4.


AASLD: HBV New Target for HIV Drug

By Michael Smith, North American Correspondent, MedPage Today
Published: October 31, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
BOSTON -- A drug widely used to treat HIV infection -- tenofovir (Viread) -- may become a "new friend" for physicians treating chronic hepatitis B, researchers reported here.

A multicenter European cohort study using the nucleotide analogue reverse transcriptase inhibitor (NRTI) tenofovir found that the drug appears to be safe and effective for treating hepatitis B, according to Pietro Lampertico, MD, of the University of Milan, and colleagues.

It was especially useful among hep B patients not previously exposed to an NRTI, Lampertico told the annual meeting of the American Association for the Study of Liver Diseases.

Lampertico was reporting interim results of a planned five-year analysis of 737 chronic hepatitis B patients treated with tenofovir at 17 European centers.

"We think it is very important to generate data about early clinical practice" because patients in clinical trials are often not representative of all patients with the disease, Lampertico told MedPage Today.

Tenofovir was approved in 2008 both in Europe and the U.S. for treating hepatitis B, but it has long been a mainstay of therapy for HIV. "It's an old friend for those in HIV, but it's a new friend for us," Lampertico said.

To see how well the drug performs in the real world of clinical practice, Lampertico and colleagues studied all patients -- except those with HIV coinfection -- who were put on the drug in each of the 17 centers. The main outcomes of the analysis were undetectable hepatitis B DNA and renal and tubular function.

The patients were stratified according to their previous exposure to NRTIs -- 71% were previously exposed and 29% were NTRI-naive, Lampertico reported.

Median follow-up was 16 months -- but in some cases it was as long as 52 months.

In the NRTI-naive patients, response rates rose over time, reaching 89% at 48 weeks, Lampertico reported. On the other hand, he said, the time to a response was significantly affected (at P<0.0001) by baseline viral load and some patients with extremely high viremia at the start of treatment did not achieve a response.

Indeed, at 48 weeks, 17 patients still had only a partial response, with a median residual viral load of 2.5 log10 international units per mL of serum.

In the previously treated patients, Lampertico said, those who had undetectable viremia on their previous regimen -- most on adefovir (Hepsera) -- continued to have undetectable viremia on tenofovir. Among those who had developed resistance on their previous regimen, 74% became undetectable on tenofovir.

The proportion of patients with impaired renal or tubular function was relatively small, Lampertico said, but those with previous exposure to adefovir were more likely to have low blood phosphorous levels and urinary phosphate absorption.

About 6% of patients had their tenofovir dose reduced because of reduced creatinine clearance, Lampertico said, but most of them were over 60, had previous exposure to adefovir, and had comorbid conditions with the potential to affect kidney function.

"There's a very good safety performance in naive patients," he said, "but in the experienced patients, we may see a few problems."

But he cautioned that the results -- while encouraging -- are provisional and may change as the study continues.

The analysis is "confirmatory and reassuring" that tenofovir works well in clinical practice, not just in trials, according to Arun Sanyal, MD, of Virginia Commonwealth University Medical Center in Richmond, Va. Sanyal, president of the AASLD, who was not part of the study.

"People are very interested in knowing what the gap is between outcomes in clinical trials and in real life," he told MedPage Today. "Clearly, it's a good antiviral agent."

But Sanyal added that the safety signal for tenofovir-exposed patients seen by Lampertico and colleagues needs more analysis. "We need more focused studies using state-of-the-art measures of renal injury," he said. That's an "important future direction," he concluded.

The study had no external support.

Lampertico reported financial links with Gilead, Roche, Bristol-Myers Squibb, and Novartis.

Sanyal reported financial links with Takeda, Salix, Ikaria, Exhalenz, Bayer Onyx, Norgine, Gore, Gilead, Intercept, Roche and Astellas.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Lampertico P, et al "Effectiveness and safety of tenofovir disoproxil fumarate in field practice: a multicenter European cohort study of 737 patients with chronic hepatitis B" AASLD 2010; Abstract 369.


New Diabetes Meds Diminish Markers of Fatty Liver

By Kristina Fiore, Staff Writer, MedPage Today
Published: October 31, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
BOSTON -- One of the newer classes of diabetes medications -- the glucagon-like peptide-1 (GLP-1) agonists -- appears to mitigate fatty liver disease in people with type 2 diabetes, according to two studies reported here.

Separate studies of treatment with daily liraglutide (Victoza) or weekly exenatide (Bydureon) -- both GLP-1 agonists -- found that the drugs lowered levels of alanine aminotransferase (ALT) compared with other diabetes medications and placebo.

Both studies were reported in poster presentations at the annual meeting of the American Association for the Study of Liver Diseases (AASLD).

Fatty liver disease and steatohepatitis are common complications of type 2 diabetes.

GLP-1 analogues have been shown to improve hepatic steatosis and markers of liver inflammation in murine models, since insulin resistance is thought to play a role in the pathophysiology of non-alcoholic fatty liver disease.

Other antidiabetic therapies -- including metformin and thiazolidinedione drugs, particularly pioglitazone (Actos) -- have shown promise in treating fatty liver disease, although thiazolidinediones are associated with weight gain.

The liraglutide investigators reported data from the LEAD-2 study, a 26-week phase III trial with a one-and-a-half year open-label extension.

LEAD-2 patients received the GLP-1 agonist liraglutide (at a dose of 1.8, 1.2, or 0.6 mg/day), or glimepiride 4 mg/day or a placebo -- all in combination with metformin 1.5 or 2 g/day.

DEXA and computed tomography (CT) scans were used to measure body fat composition and hepatic steatosis, which was defined by a liver-to-spleen attenuation ratio less than one.

At baseline, 65.7% of the LEAD-2 patients had steatosis and 74% had metabolic syndrome, according to M.J. Armstrong, MD, of the University of Birmingham in England, and colleagues.

The LEAD-2 researchers found that patients with elevated ALT levels at baseline had a significant reduction from baseline with liraglutide (-8.53, P<0.0001).

This was a significant improvement over glimepiride -- 37% of patients on liraglutide had normalized ALT compared with 21% of those on glimepiride (P<0.05).

The effect of liraglutide on ALT appears to be independent of improvements in glycemic control, Armstrong and colleagues reported.

They also found that the liver-to-spleen attenuation ratio significantly increased with liraglutide, indicating reduced hepatic steatosis compared with both glimepiride and placebo (P<0.05).

The LEAD-2 investigators concluded that liraglutide reduces markers of liver inflammation and hepatic steatosis in patients with type 2 diabetes, but noted that the effects are dose-dependent -- results with 1.8 mg/day weren't as dramatic or significant as for the 1.2 mg or 0.6 mg daily doses.

In a second poster, Naga P. Chalasani, MD, of Indiana University in Indianapolis, and colleagues reported that weekly exenatide -- which was recently denied FDA approval -- also improved markers of fatty liver disease in diabetes patients.

Chalasani's group looked at pooled data from one 30-week and two 26-week trials totaling 541 patients with type 2 diabetes.

ALT was elevated at baseline in 60% of the study population.

The researchers saw a decrease in ALT among patients on exenatide, compared with a slight rise among those in the placebo group (-18.3% versus 2.1%).

Just over 13% of exenatide patients with elevated baseline levels achieved at least a 50% reduction in ALT, Chalasani and colleagues reported.

Levels of aspartate aminotransferase (AST) and alkaline phosphatase (ALP) also improved among the exenatide patents, the researchers noted.

Chalasani's group added that the reduction in ALT was mildly correlated to a reduction in weight.

They concluded that weekly exenatide improved markers of non-alcoholic fatty liver disease in patients with type 2 diabetes "likely because of its combined effects on ALT, weight, and other cardiometabolic risk factors."

Armstrong reported relationships with the Wellcome Trust.

The liraglutide study was supported by Novo Nordisk.

Chalasani reported relationships with Johnson & Johnson, Debiovision, Advanced Life Sciences, Eli Lilly, Teva, Atherogenics, Amylin, Salix, Abbott, Karobio, Genentech, Medpace, Phenomix, and Gilead.

The exenatide trial was sponsored by Amylin.

Primary source: American Association for the Study of Liver Diseases meeting

Source reference:
Chalasani NP, et al "Effect of once-weekly exenatide on ALT cardiometabolic risk factors in adults with type 2 diabetes" AASLD 2010; Abstract 661.

Additional source: American Association for the Study of Liver Diseases

Source reference:
Armstrong MJ, et al "Effects of two years of liraglutide treatment on fatty liver disease in patients with type 2 diabetes: Analysis of the LEAD-2 extension trial" AASLD 2010; Abstract 625.


AASLD: Drug Therapy Okay for Pregnant Women With Hep B

By Kristina Fiore, Staff Writer, MedPage Today
Published: October 31, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
BOSTON -- Pregnant women with active hepatitis B infection can be safely and effectively treated with telbivudine (Tyzeka), researchers said here.

A study involving more than 80 women found that just over half of the women given telbivudine achieved a complete virologic response right before delivery compared with none of the controls (P<0.001), according to Calvin Pan, MD, of Mount Sinai School of Medicine in Flushing, N.Y., and colleagues.

Additionally, a smaller proportion of babies born to women in the telbivudine group had surface antigens for hepatitis B virus compared with controls (4% versus 23%, P<0.001), the researchers reported at the annual meeting of the American Association for the Study of Liver Diseases (AASLD).

"I think this treatment is safe, and I support its use if the mother has active virus," Pan told MedPage Today.

There has been a controversy over whether pregnant women with hepatitis B should be treated, mainly due to concerns over the safety of the fetus.

Pan said this is the first randomized controlled trial to investigate drug safety and efficacy in pregnant women with active hepatitis B infection. Other case series have examined the question -- but no studies have been randomized and controlled.

To evaluate both virologic responses and safety parameters, Pan and colleagues assessed 88 pregnant women with active hepatitis B from their second or third trimester until four weeks postpartum.

A total of 53 women received 600 mg of telbivudine per day, while 35 women who refused drug treatment agreed to serve as controls.

All babies born to women in the study cohort also received 200 IU of hepatitis B immune globulin within 24 hours of birth to prevent the disease -- and were then vaccinated against the virus with the standard three-dose course at 0, 1, and 6 months.

The mean duration of treatment in the telbivudine group was 15 weeks and 100% were followed through the end of study, compared with 92% of the controls.

The researchers found that 53% of the telbivudine-treated women achieved complete virologic response prior to delivery, compared with none among the control group (P<0.001).

Four weeks after giving birth, 62% of the treated patients had a complete virologic response versus none of the controls (P<0.001).

As well, more women on treatment also had normalized alanine aminotransferase (ALT) levels compared with controls (77% versus 29%, P<0.001).

Both groups appeared to have decreased levels of hepatitis B "e" antigen -- but the drop was higher for those women treated with telbivudine (98% versus 60%, P<0.001).

Pan explained that pregnant women with active hepatitis B can have natural clearance of the virus without treatment, but noted that the decrease in the treatment arm "was still significantly higher."

In terms of fetal outcomes, more babies born to mothers who weren't on treatment had hepatitis B surface antigens compared with those on treatment (23% versus 4%, P<0.001).

Pan added that newborn outcomes were examined in greater detail in a second study, which found that at birth 6.32% of babies born to telbivudine-treated women had surface antigen to the hepatitis B virus -- compared with 30.43% in the control arm (P<0.001).

There were no discontinuations of telbivudine treatment due to adverse events -- nor were there any congenital deformities four weeks postpartum in either group.

Also, there were no differences in terms of postpartum hemorrhage, gestational age, infant height and weight, or Apgar scores.

Arun Sanyal, MD, of Virginia Commonwealth University in Richmond, Va., and president of AASLD, highlighted the findings during a press conference.

"Now we have more evidence," Sanyal said, "showing that it is possible with pharmacotherapy to reduce perinatal transmission and treat these women safely."

Pan said he had no disclosures.

Sanyal reported relationships with Takeda, Salix, Ikaria, Astellas, Exhalenz, Bayer Onyx, Norgine, Gore, Gilead, Intercept, and Roche.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Pan C, et al "A prospective open-label study to evaluate the efficacy, safety, and tolerability of telbivudine in HBeAg + chronic hepatitis B pregnant women" AASLD 2010; Abstract 364.


The association of cryoglobulinaemia with sustained virological response in patients with chronic hepatitis C

J Viral Hepat. 2010 Oct 25. doi: 10.1111/j.1365-2893.2010.01385.x. [Epub ahead of print]

Vigani AG, Macedo de Oliveira A, Tozzo R, Pavan MH, Gonçales ES, Fais V, Gonçales NS, Gonçales FL.

Departamento de Clínica Médica, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo, Brazil.


Summary.  Previous reports suggest cryoglobulinemia might influence the hepatitis C virus (HCV) infection clinical course and treatment response but this association has not been thoroughly evaluated. We aimed to assess the relationship between cryoglobulinemia and sustained viral response (SVR) in patients treated for HCV infection. We included patients with HCV infection treated from January 2003 through December 2006. Biochemical analyses, detection cryoglobulinemia, and liver biopsies were performed prior to treatment. Genotype 1 or 4 infections received Peg-interferon (IFN) alpha-2a or -2b for 48 weeks; genotypes 2 or 3 received IFN alpha for 24 weeks. All patients also received ribavirin. Of 329 enrolled patients, 242 (73%) were male and the median age was 43 years. Cryoglobulinemia was detected in 196 (59.6%) patients; liver biopsy was performed in 301. Multivariate analysis showed an association of cryoglobulinemia with severe active necroinflammation (A3) (adjusted odds ratio [AOR]= 9.48; 95% confidence interval [CI]: 1.50-59.92) and rheumatoid factor (RF) level (AOR= 1.01; 95% CI: 1.00-1.02). Variables associated with advanced fibrosis were age, aspartate aminotransferase and alkaline phosphatase levels, alcohol use, and presence of diabetes. Variables independently associated with SVR were cryoglobulinemia (AOR= 2.33, 95% CI: 1.26-4.32), absence of cirrhosis (AOR= 4.5, 95% CI: 1.4-14.80), and RF level (AOR= 1.008, 95% CI: 1.001-1.014). Our findings suggest cryoglobulinemia is associated with severe necroinflammatory activity in HCV-infected patients. We also provide the first evidence for an association between cryoglobulinemia and higher SVR rates, highlighting its potential role as a prognostic factor for treatment response.

© 2010 Blackwell Publishing Ltd.

PMID: 20969676 [PubMed - as supplied by publisher]


Livers grown in the laboratory could eventually solve organ transplant shortage

Made-to-measure organs for transplantation are a step closer to reality after scientists grew miniature human livers in the laboratory

By Richard Alleyne, Science Correspondent

Published: 1:00PM GMT 31 Oct 2010

The researchers created "working livers" the size of a walnut which functioned normally in laboratory conditions.

They believe that in around five years they will be able to upscale the process and transfer the procedure from laboratory to hospital.

The development could eventually solve the transplant shortage and also remove the need for powerful drugs to prevent the body rejecting the organ.

"We are excited about the possibilities this research represents, but must stress that we're at an early stage and many technical hurdles must be overcome before it could benefit patients," said the project director, Associate Professor Shay Soker from the Wake Forest Institute for Regenerative Medicine in North Carolina.

"Not only must we learn how to grow billions of liver cells at one time in order to engineer livers large enough for patients, but we must determine whether these organs are safe to use in patients."

More than 600 liver transplants are carried out each year in Britain, but it is estimated that more than a fifth of patients die waiting.

Many livers have to be discarded because they are too old or too damaged to be of any use.

The technology opens up the prospect of growing other replacement organs, including kidneys or pancreases, for patients who are able to donate stem cells.

Artificially grown livers could be transplanted into patients or used to test the safety of experimental drugs.

Pedro Baptista, co-author, said: "Our hope is that once these organs are transplanted, they will maintain and gain function as they continue to develop."

The new technique works by effectively chemically stripping the old liver down too its basic "scaffold" or exoskeleton in a process of called "decellularisation".

Onto this frame of connective tissue and blood vessels, they then regrow the new liver using stem cells from the patient.

Stem cells from embryos could also be used.

Laboratory livers that were nourished by a special bioreactor for a week began growing and functioning like human organs, they said.

Liver disease is the fifth biggest killer in England and Wales, after heart disease, cancer, stroke and respiratory disease, and the only major cause of death that is still increasing year on year.

Some 16,087 people in Britain died from liver disease in 2008, a 4.5 per cent increase on the previous year, and the number of deaths is predicted to double in 20 years.

Sarah Matthews, for the British Liver Trust, said: "Technology such as this is much needed. Currently supply isn't meeting demand, and for every one person who receives a liver transplant, 10 people die.

"Expanding waistbands and heavy drinking habits are having an impact on the quality of donor organs available in the UK, therefore we desperately need developments in liver science. We are encouraged by these results but would also like to warn patients that this technology is a good few years off from becoming available," she said.

The research was presented at the annual meeting of the American Association for the Study of Liver Diseases in Boston.


Also See:
-- Creating Functional Hepatic Tissue in a Bioengineered Human Liver
-- Wake Forest scientists successfully grow 'miniature livers'

BMS posts data update on investigational compound PEG-IFN lambda for hepatitis C, Data presented at AASLD today

Pipeline Asset Update for PEG-Interferon Lambda

Pipeline Asset: PEG-Interferon lambda, a novel and potential first-in-class interferon in development for the treatment of hepatitis C virus (HCV) infection

Current Phase of Development: Phase II

Meeting or Publication: American Association for the Study of Liver Diseases (AASLD) 2010

Study Title: Pegylated Interferon Lambda (PEG-IFN-Lambda) Phase II Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naïve HCV Patients (Genotypes 1, 2, 3, or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype through Week 12

Abstract Number: 821

Date/Time of Presentation: Sunday, October 31, 2010 from 8:00 a.m. – 5:30 p.m. EDT

Media Embargo: Per AASLD press guidelines, these data are no longer under embargo.

Study Objective: To assess the safety and antiviral activity of four fixed doses of PEG-IFN-lambda in treatment-naïve patients with HCV genotypes 1, 2, 3, and 4

Study Conclusion: At PEG-IFN-lambda’s three highest dosing levels (120 mcg, 180 mcg, 240 mcg), virologic response at 4 and 12 weeks was similar to or greater than that observed and reported with standard interferons (PEG-IFN-alpha).

Adverse events were mild to moderate in severity and led to few treatment discontinuations.

Efficacy Results: The proportion of patients in each dosing arm that achieved undetectable viral load varied by patient genotype. In this study, undetectable viral load was defined as HCV RNA <25 IU/mL.

Proportion of patients with HCV genotypes 2 or 3 who achieved undetectable viral load:

Dose                                Week 4     Week 12

PEG-IFN-lambda 80 μg      60%          80%

PEG-IFN-lambda 120 μg    100%        100%

PEG-IFN-lambda 180 μg    80%          80%

PEG-IFN-lambda 240 μg   100%        100%

PEG-IFN-alfa-2a 180 μg    100%        100%

Proportion of patients with HCV genotypes 1 or 4 who achieved undetectable viral load:

Dose                               Week 4    Week 12

PEG-IFN-lambda 80 μg        14%          14%

PEG-IFN-lambda 120 μg      43%          71%

PEG-IFN-lambda 180 μg      67%          67%

PEG-IFN-lambda 240 μg      43%          43%

PEG-IFN-alfa-2a 180 μg      40%          40%

Adverse Events: The rate of treatment-related serious adverse events (SAEs) through Week 12 was:

-- All doses of PEG-IFN-lambda: 4% (2/45)
-- PEG-IFN-alfa-2a: 10% (1/10)

The rate of discontinuations due to treatment-related adverse events (AEs) through Week 12 was:

-- All doses of PEG-IFN-lambda: 4% (2/45)
-- PEG-IFN-alfa-2a: 10% (1/10)

Adverse Event   PEG-IFN-alfa-2a           All doses of PEG-IFN-
                                 (n=10)                                 lambda

Myalgia                       4 (40%)                              6 (13.3%)

Fatigue                       3 (30%)                            10 (22.2%)

Headache                    3 (30%)                            10 (22.2%)

Nausea                        3 (30%)                            10 (22.2%)

Injection site reaction  3 (30%)                              9 (20%)

Depression                   2 (20%)                              6 (13.3%)

Pruritus                       1 (10%)                              5 (11.1%)

Vomiting                     1 (10%)                              5 (11.1%)

Irritability                    1 (10%)                            11 (24.4%)

Insomnia                      0                                      11 (24.4%)

The majority of PEG-IFN-lambda adverse events were mild to moderate in severity. No apparent dose relationship was observed.

PEG-IFN-lambda Background: PEG-IFN-lambda is a novel and potential first-in-class interferon in development for the treatment of hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.

PEG-IFN-lambda is one of several molecules Bristol-Myers Squibb is studying for the potential treatment of hepatitis C. The portfolio of investigational compounds, which also includes several small molecule direct-acting antivirals, fits into the company’s overall R&D focus on diseases where there is major unmet medical need.

Study Background: The EMERGE study is a two-part, randomized, controlled, multicenter phase II, phase II study of PEG-IFN lambda in treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4.

These data are from the first part of the EMERGE study. In this ongoing, open-label Phase IIa study, 55 patients were randomized to receive PEG-IFN-lambda at one of four dose levels (80, 120, 180 or 240 mg) or PEG-IFN-alpha at 180 μg. Patients received PEG-IFN lambda and PEG-IFN alpha administered subcutaneously on a weekly basis, as well as ribavirin on a daily basis, dosed according to HCV genotype and body weight. Patients with HCV genotype 2 or 3 were studied for up to 24 weeks; patients with genotype 1 or 4 were studied for up to 48 weeks.

Inclusion Criteria:
-- 18 to 70 years of age
-- HCV genotype 1, 2, 3, or 4 with HCV RNA ≥100,000 IU/mL at screening
-- Naïve to prior IFN therapy
-- ALT, AST ≤5.0x ULN; INR ≤1.2; bilirubin ≤1.5 mg/dL; albumin ≤ULN
-- No evidence of decompensated liver disease or cirrhosis

Exclusion Criteria:
-- Mixed genotype HCV infection
-- History of decompensated liver disease
-- Co-infection with HIV or hepatitis B virus
-- Active substance abuse

ClinicalTrials.gov Identifier: NCT01001754

Request for More Information and Media Interviews: Invest
ors: John Elicker, 609-252-4611, john.elicker@bms.com

Media: Cristi Barnett, 609-252-6028, cristi.barnett@bms.com

Supporting information: The abstract can be viewed on the AASLD website.


Treatment of chronic hepatitis C with pegylated interferon and ribavirin in treatment-naive patients in 'true life': a plea in favor of independent postmarketing evaluations

Eur J Gastroenterol Hepatol. 2010 Nov;22(11):1297-302.

Pariente A, Lahmek P, Duprat C, Denis J, Faroux R, Renou C, Nalet B, Morin T, Cadranel JF; Investigator Group belonging to Association Nationale des Gastroentérologues des Hôpitaux Généraux (ANGH).
Unité d'hépatogastroentérologie, Centre Hospitalier, Pau Cedex, France. alex.pariente@free.fr


BACKGROUND: Results of treatments for chronic hepatitis C virus are only estimated and disclosed from pivotal trials.

AIM: To report the 'true life' results of pegylated interferon and ribavirin in treatment-naive patients.

METHODS: A prospective, multicenter observatory in 22 general hospitals.

RESULTS: Five-hundred and one patients were included, with 309 men (62%), aged 46 ± 11 years, weighting 70 ± 13 kg, infected with the following hepatitis C virus genotypes: 1 (50%), 2 (12%), 3 (28%), 4 (7.5%), 5 (0.6%). Liver biopsy, available in 436 patients showed stage F3 fibrosis in 24% and F4 in 13%. Two-hundred and seven patients had a comorbid condition. Treatment consisted of interferon alpha 2b in 340 patients and interferon alpha 2a in 161 patients. Dose reductions were necessary in 145 patients (29%). Treatment was prematurely interrupted in 145 patients (29%) owing to lack of efficacy (n =72) or side-effects (n =73). Sustained virological response (SVR) rates were 50% for all patients, and 37.1, 70.5, and 71% for patients with genotype 1, 2 and 3, respectively. At multivariate analysis, age, genotype, and fibrosis severity were the only independent factors of SVR.

CONCLUSION: In true life, patients are older and more severe, and SVR is about 10% lower than in pivotal trials.

PMID: 20964260 [PubMed - in process]


Formal Patient Education Improves Patient Knowledge of Hepatitis C in Vulnerable Populations

Digestive Diseases and Sciences
DOI: 10.1007/s10620-010-1455-3

Miranda Surjadi, Cara Torruellas, Claudia Ayala, Hal F. Yee and Mandana Khalili



Hepatitis C (HCV) knowledge is limited in injection drug users (IDU). Vulnerable populations including IDUs are disproportionally affected by HCV. Effective HCV education can potentially reduce disparity in HCV prevalence and its outcome in this population.


This study aimed to assess the impact of formal HCV education and factors associated with improved HCV knowledge in the vulnerable population.


Over 18 months, 201 HCV-infected patients underwent a 2-h standardized education and completed demographic and pre- and post-education questionnaires.


Patient characteristics were: 69% male, mean age 49 ± 10, 49% White (26% AA, 10% Latino), 75% unemployed, 83% high school education and above, 64% were IDU, and 7% were HIV co-infected. On multivariate analysis, baseline knowledge scores were higher in patients with at least a high school education (coef 7.1, p = 0.045). Baseline knowledge scores were lower in African Americans (coef −12.3, p = 0.004) and older patients (coef −0.7, p = 0.03). Following HCV education, the overall test scores improved significantly by 14% (p = 0.0001) specifically in the areas of HCV transmission (p = 0.003), general knowledge (p = 0.02), and health care maintenance (p = 0.004). There was a high compliance with liver specialty clinic attendance following education.


Formal HCV education is effective in improving HCV knowledge. Although White race, younger age, and higher education were predictors of having more HCV knowledge prior to education, all patients independent of racial background had a significant improvement in their knowledge after education. Therefore, promoting effective HCV education among vulnerable populations may be an important factor in reducing the disparities in HCV disease.

Keywords Hepatitis C - Hepatitis C education - Vulnerable populations - Hepatitis C knowledge - Disparity of care


Accelerated hepatitis B vaccine schedule boosts completion rates in IDUs

Michael Carter
Published: 28 October 2010

The proportion of injecting drug users who receive all three doses of the hepatitis B vaccine can be increased using an accelerated vaccination schedule, US investigators report in the November 15th edition of the Journal of Infectious Diseases.

A small monetary incentive was provided to encourage individuals to attend so the three doses of the vaccine could be administered.

“Straightforward payment for receipt of immunizations may be not only ethically sound but also an economically sensible way to use public health resources”, comment the investigators.

Injecting drug users are one of the groups most affected by hepatitis B. The virus is highly infectious, especially in the acute phase, and long-term infection can lead to serious health problems including cirrhosis, liver failure and liver cancer.

A vaccine against hepatitis B is available. Vaccination programmes targeted at the groups most at risk of hepatitis B have helped reduce the incidence of the infection in the US. The vaccine is normally provided in three doses over a six-month period.

However, the proportion of drug users who have received the vaccine is low in comparison to other groups.

Therefore investigators from the Drugs, AIDS, STDs, and Hepatitis (DASH) project wished to see if accelerating the vaccination schedule helped improve vaccination rates.

Mindful that HIV and hepatitis C vaccines may be available in the future, they also wanted to see if providing enhanced information about the benefits of vaccination, and giving individuals a small cash incentive to be vaccinated helped to boost immunisation rates.

Patients were followed up at regular intervals for two years, and they were monitored to see if they developed levels of antibodies that were sufficient to protect them against hepatitis B.

The study population included 1260 drug users. All were negative for both HIV and hepatitis B.

They were randomised into one of four arms:

· Standard hepatitis B vaccination schedule (month 0, month 1, month 6) and standard health information about HIV.

· Standard hepatitis B vaccination schedule and enhanced health information focusing on the efficacy and benefits of immunisation against hepatitis B.

· Accelerated hepatitis B vaccination schedule (month 0, month 1, month 2) and standard health information.

· Accelerated vaccine and enhanced health information.

Overall, 75% of individuals received all three doses of the vaccine. This included 73% of those who received the vaccine over a six-month period, and 77% of individuals who were given the accelerated course of immunizations. The difference in immunisation adherence rates between the two schedules was not significant.

But the researchers then restricted their analysis to injecting drug users. This showed that accelerating the vaccination course did increase completion rates (75% vs. 66%, p = 0.04).

However, there was no evidence that providing enhanced health information helped to boost vaccination rates.

Other factors associated with completing the course of immunisations included age over 40 (p < 0.01), African American race (p = 0.03), having stable accommodation, and drinking alcohol (p = 0.02).

Use of speedball – an injected mixture of heroin and cocaine – was associated with poorer completion rates (p < 0.01), as was being homeless on the street (p = 0.02).

Information on response to the vaccine was available for 707 patients. After twelve months of follow-up 65% had developed the minimum antibody level to protect them against hepatitis B.

At six months, individuals who had received all three accelerated doses were significantly more likely than those awaiting their third dose in the standard vaccination regimen to have protective antibodies against hepatitis B (62% vs. 49%.

“The results of this study indicate that providing monetary incentives at each visit, free vaccinations, and a shorter vaccination schedule may encourage adherence, particularly among the highly at risk group of IDUs [injecting drug users]”, write the authors.

They conclude that their research “serves as a model for a future HIV or hepatitis B vaccine trials and provides information on the effectiveness of accelerated vaccination schedules for increasing immunization among drug users.”


Hwang L-Y et al. Accelerated hepatitis B vaccination schedule among drug users: a randomized controlled trial. J Infect Dis 202: 1500-09, 2010 (click here for study abstract).


ACIP delays vote on hepatitis B virus vaccine for diabetes

Posted on October 28, 2010

Issues that include cost-effectiveness and frailty among older adults with diabetes remain unresolved as the Advisory Committee on Immunization Practices continues to discuss hepatitis B virus vaccination.

Kathy Byrd, MD, of the Division of Viral Hepatitis and the National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention at CDC, discussed hepatitis B virus (HBV) vaccine coverage in high-risk adults, including high-risk heterosexuals, injection drug users and men who have sex with men.

“Some data show that HBV vaccination rates are 51% in high-risk adults and 41% in low-risk adults,” Byrd said. “We need to improve this coverage.”

She said the highest risk age is 18 to 20 years, regardless of risk behavior status, and individuals with more frequent access to health care systems have better vaccination uptake.

“However, coverage for high-risk groups, including health care workers, remains low,” Byrd said.

Mark Sawyer, MD, chair of the Advisory Committee on Immunization Practices Hepatitis Working Group, provided an overview of items for discussion within the 25-person group.

“The vote on HBV vaccination has been delayed because it is a complicated topic,” he said. “There are many areas of concern, including cost-effectiveness.”

Sawyer said other points of discussion include further defining risk factors for HBV and morbidity and mortality as stratified by age and health care setting.

“We are particularly interested in addressing infection control practices in diabetes care and management, and defining the characteristics of long-term care that are applicable,” he said.

Regarding vaccination, Sawyer said the group is discussing factors contributing to seroprotection and issues surrounding revaccination and duration of protection.

Infection control

Joseph Perz, MD, of the National Center for Emerging and Zoonotic Infectious Diseases at CDC, discussed infection control initiatives involving HBV.

“In the last 22 months, we have seen seven outbreaks of HBV in settings where patients are receiving assisted monitoring of blood glucose,” Perz said, adding that two of those outbreaks occurred across multiple assisted living facilities.

“Since 1990, there have been 26 outbreaks associated with assisted monitoring of blood glucose,” he said. “Despite efforts at control, outbreaks continue to mount. The shared use of blood-contaminated equipment increases transmission of blood borne pathogens.”

Perz said many assisted living facilities are not subject to national or uniform guidelines, and that the standard of care can suffer as a result. “Misuse of equipment has been seen in such facilities as acute care centers and ambulatory care centers,” he said. “Continued efforts are needed to stress adherence to control practices.”

Patients with diabetes

Trudy Murphy, MD, of the National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention at CDC, reviewed data on HBV in adults with diabetes and discussed policy considerations for HBV vaccination in adults with diabetes.

“We are seeing that about 18% of adults with diabetes had evidence of past or current HBV infection,” Murphy said. “Compare this with 5.2% among individuals without diabetes.”

She said after many months of review, the working group is considering a recommendation to vaccinate all adults with diabetes as soon as possible after diabetes diagnosis. Murphy noted, however, that some gray areas remain with regard to cost-effectiveness, seroprotection rates and duration of protection among older adults.

“It may be recommended to leave vaccination of frailer adults up to clinician judgment,” she said. “However, among most populations with diabetes, vaccination could decrease the burden of acute HBV, offer protection before the onset of complications, reduce reservoirs of HBV that contribute to chronic infection and decrease chronic liver disease, carcinoma and liver mortality.”


October 30, 2010

Three-Year Follow-Up Data Confirm Safety and Survival Benefit in Chinese Liver Failure Patients Treated With ELAD® Bioartificial Liver

Poster presentation scheduled at AASLD November 2nd

Vital Therapies, Inc.

/PRNewswire/ -- Vital Therapies, Inc., (VTI) today announced that a poster is being presented at the American Association for the Study of Liver Diseases (AASLD) meeting in Boston on Tuesday, November 2nd. It confirms that previously reported findings of improved transplant free survival (TFS) in Chinese subjects with acute-on-chronic liver failure (ACLF) treated with the ELAD® bioartificial liver support system are maintained for up to three years.

The poster is titled "3-year follow-up of acute-on-chronic liver failure (ACLF) subjects in randomized, controlled, multicenter trial of ELAD® bioartificial liver support system in 49 Chinese subjects reveals significant transplant-free survival (TFS) benefit." It is being presented by Dr. Michael Millis, Professor of Surgery, University of Chicago, and is coauthored by Drs. Zhongping Duan and Jing Zhang, Beijing You'an Hospital, and Shaojie Xin and Shaoli You, 302 Military Hospital, Beijing.

Previously, it was reported that 84-day follow-up of ACLF subjects enrolled at two liver treatment centers in China showed statistically significant improvements in TFS for ELAD treatment compared with standard of care (SOC). At least three years following enrollment, survivors were consented and underwent a cancer screen and physical exam in accord with a questionnaire.

Of 49 subjects enrolled, 84-day TFS was 21/32 (65.6%) in the ELAD group vs. 7/17 (41.1%) in controls. Three-year TFS was 14/32 (43.8%) in the ELAD group vs. 3/12 (25%) in controls. Of 84-day survivors, 2/21 (9.5%) ELAD and 2/7 (28.6%) controls died, 1/21 (4.8%) ELAD and 0/7 controls were transplanted and 4/21 (19.0%) ELAD and 2/7 (28.6%) controls were lost to follow-up. Survival analysis reveals a statistically significant improvement in TFS (p=0.045, log-rank analysis) for the ELAD treated subjects compared with SOC. Median survival of controls was 37 days, whereas median survival of ELAD treated subjects was at least 3 years. There was no evidence of tumor development in either group.

Dr. Millis commented, "This is the first time that a long term survival benefit has been demonstrated in subjects who recovered following treatment with ELAD. It is highly encouraging to note that those subjects that survive in the short term are able to go on to extended survival without any apparent increase in mortality or morbidity compared with subjects administered standard of care."

Dr. Duan, who served as a principal investigator for the study, commented, "China has about 95 million HBV carriers and chronic hepatitis B patients, and 38 million hepatitis C patients. It is estimated that 0.1%-0.5% of these patients will experience severe hepatitis due to acute hepatocellular necrosis or hypofunction, which results in hepatic insufficiency and hepatic failure. Mortality from this condition still remains around 50%-70% even with comprehensive internal medicine treatment, leading to as many as 400,000 deaths per year in China from acute liver failure. When approved for commercial sale in China, ELAD will be the first bioartificial liver support system proven to improve survival in this population."

In order to confirm these findings from China, VTI is conducting the SILVER (Stabilization In LiVER Failure) trial in the United States, Europe and Saudi Arabia which has achieved 50% of its targeted enrollment. Should this study yield positive findings, these results, along with data from other studies, will form the basis of regulatory filings for future marketing authorization.

About ELAD and the SILVER Trial

The SILVER protocol enrolls subjects with chronic liver disease who have been hospitalized as a result of an event, such as an infection or an episode of bleeding, which has caused deterioration of their liver function (acute-on-chronic liver failure, ACLF). The trial is designed to explore whether the use of ELAD in this setting can prevent continued deterioration of liver function, called progression, and thus improve survival. The trial design uses a well-established measure of liver function called the MELD score to define the status of liver function. Treatment with ELAD, along with standard of care, is compared with standard of care alone. The time to either death or deterioration of liver function by a pre-specified amount is measured. It is postulated that the use of ELAD may extend the time to progression and improve survival in this rapidly progressing patient population.

ELAD is a biologic liver support system using a proprietary line of allogeneic human liver cells refined by several leading cell experts. The cells are stable, immortal, can be grown in unlimited quantities and retain their hepatocyte (liver cell) characteristics. About one pound of cells is used for each treatment. The cells are grown in specially designed cartridges at VTI's cell culture facility and used to treat the patient for up to ten days.

About Vital Therapies, Inc.

Vital Therapies, Inc. (VTI) is based in San Diego, California, with a wholly owned subsidiary in Beijing, China. VTI is developing the first human liver cell-based Extracorporeal Liver Assist System (ELAD). ELAD could provide support for patients with severe liver failure by processing toxins and also synthesizing proteins and metabolites that are key products of normal human liver function. ELAD is in investigational clinical trials and VTI completed a pivotal trial and filed for market approval in China in September 2007. For additional information visit http://www.vitaltherapies.com/ or contact Terry Winters, PhD, CEO, Vital Therapies at +1 858 673 6840.

ELAD is a trademark of Vital Therapies, Inc.

SOURCE Vital Therapies, Inc.


Investigational Drug for Hepatitis C Boceprevir Achieved Significantly Higher Sustained Virologic Response Rates Compared to Control

Saturday, October 30, 2010 8:00 AM

Oct. 30, 2010 (Canada NewsWire Group) --

MONTREAL, Oct. 30 /CNW/ - Merck reported today that final results from two pivotal Phase III studies of boceprevir, its investigational oral hepatitis C protease inhibitor, demonstrated significantly higher sustained virologic response (SVR)1 rates in adult patients who previously failed treatment (treatment-failure; HCV RESPOND-2) and in adult patients who were new to treatment (treatment-naïve; HCV SPRINT-2) for chronic hepatitis C virus (HCV) genotype 1 compared to control, the primary objective of the studies. The results for the primary endpoints of these studies, which were first reported in a news release in August 20102, and a broad range of further data analyses from these studies are being presented in oral and poster presentations at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).3,4,5

"The most difficult aspect of managing hepatitis C is that treatment is an extremely long process that is often debilitating for many patients," said Dr. Stephen Shafran, MD, FRCPC, FACP, University of Alberta and an investigator in the SPRINT-2 trial. "These results are extremely exciting because boceprevir substantially increased success rates compared to standard therapy and many of the patients were able to be treated for 28 to 36 weeks."

An estimated 242,500 individuals are infected with HCV in Canada6 and in 2007, there were nearly 8,000 newly infected individuals.7 It is the leading cause of liver transplants in Canada.8

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir administered in combination with ribavirin plus peginterferon alfa-2b (Peg/riba) to assess whether the addition of boceprevir could improve SVR rates and potentially shorten overall treatment duration compared to the use of Peg/riba alone for 48 weeks, which is the current standard duration of therapy. In each study, patients were randomized to three groups:

Response-guided therapy (RGT), in which total treatment duration was based on certain early response criteria. Treatment-failure patients with undetectable virus (HCV-RNA) at week 8 were eligible to stop all treatment at 36 weeks. Treatment-naïve patients with undetectable virus (HCV-RNA) during weeks 8 through 24 were eligible to stop all treatment at 28 weeks.
48 weeks of treatment, in which patients received a 4-week Peg/riba lead-in followed by the addition of boceprevir for 44 weeks.
Control, in which patients received Peg/riba for 48 weeks.

In both studies, all patients were treated with a 4-week lead-in of peginterferon alfa-2b 1.5 mcg/kg/week and an investigational dose of 600-1,400 mg/day of ribavirin, followed by the addition of boceprevir (800 mg three times a day).

In primary results, addition of boceprevir significantly increased SVR rates compared to control

HCV RESPOND-2, which was conducted at U.S., Canadian and other international sites, included 403 adult patients who had failed prior therapy, including patients who relapsed or were non-responders to prior treatment with peginterferon and ribavirin. HCV SPRINT-2 was conducted in 1,097 treatment-naïve adult patients at U.S., Canadian and other international sites who were enrolled in two separate cohorts, one with 938 non-Black patients and the other with 159 Black patients.

As previously reported, the primary results of these two studies were as follows: In treatment-failure patients in HCV RESPOND-2, boceprevir increased SVR rates to 59 percent for the RGT arm (95/162) and 66 percent for the 48-week treatment arm (107/161) compared to 21 percent for control (17/80). In treatment-naïve patients in HCV SPRINT-2, boceprevir increased SVR rates to 63 percent for the RGT arm (233/368) and 66 percent for the 48-week treatment arm (242/366), compared to 38 percent for control (137/363). (All primary endpoints achieved statistical significance of p<0.0001 based on intent-to-treat analyses.)

Researchers present new analyses on boceprevir response-guided therapy

In secondary analyses presented for the first time at AASLD, researchers reported that nearly half of all patients in the boceprevir RGT arms met early response criteria and received a shorter total duration of therapy:

In the RGT arm of the treatment-failure study, 46 percent (74/162) of patients met the early response criteria and were eligible to stop all treatment at 36 weeks, which is 12 weeks shorter than current standard therapy. In these patients, the SVR rate was 86 percent (64/74).
In the RGT arm of the treatment-naïve study, 44 percent of patients (162/368) met the early response criteria and were eligible to stop all treatment at 28 weeks, which is 20 weeks shorter than current standard therapy. In these patients, the SVR rates were 97 percent (143/147) in non-Black treatment-naïve patients and 87 percent (13/15) in Black treatment-naïve patients.

For the corresponding patients in the boceprevir 48-week treatment arms of these studies, the SVR rates were 88 percent (74/84) in treatment-failure patients, 96 percent (137/142) in non-Black treatment-naïve patients and 95 percent (18/19) in Black treatment-naïve patients.

Patients in the boceprevir RGT arms of these studies who did not meet the early response criteria and were treated for up to 48 weeks also achieved substantially higher SVR rates compared to control. In these patients, the SVR rates were 40 percent (29/72) in treatment-failure patients, 74 percent (52/70) in non-Black treatment-naïve patients and 58 percent (7/12) in Black treatment-naïve patients.

"One of the hardest parts of treating patients with hepatitis C is seeing how physically and emotionally demanding the process is for them to go through," said Jo-Ann Ford, RN, MSN, Associate Director of Clinical Research, BC Hepatitis Program. "Boceprevir provides options to Health Care Professionals to adapt treatment based on individual patient response, avoiding unnecessary exposure to additional weeks of therapy."

Tolerability profile in treatment-failure patients

The five most common treatment-related adverse events in the HCV RESPOND-2 study reported for the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (54, 57, and 50 percent), headache (41, 39 and 48 percent), nausea (44, 39 and 38 percent), chills (35, 30 and 30 percent) and influenza-like illness (23, 23 and 25 percent). Anemia was reported in 43, 46 and 20 percent of patients in the study arms, respectively. Serious adverse events were reported in 10, 14 and 5 percent of patients in the study arms, respectively.

Treatment discontinuations due to adverse events over the total course of all treatment were 8 percent and 12 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 3 percent for control. Treatment discontinuations due to anemia were 0 percent and 3 percent for the boceprevir arms, respectively, compared to 0 percent for control. Erythropoietin (EPO) for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 41 and 46 percent of patients in the boceprevir RGT and 48-week treatment arms, respectively, compared to 21 percent for control.

Tolerability profile in treatment-naïve patients

The five most common treatment-related adverse events in the HCV SPRINT-2 study reported for the boceprevir RGT arm, boceprevir 48-week treatment arm and control, respectively, were: fatigue (52, 57 and 59 percent), headache (45, 43 and 42 percent), nausea (46, 42 and 40 percent), anemia (49, 49 and 29 percent) and dysgeusia (bad taste) (37, 43 and 18 percent). Serious adverse events were reported in 11, 12 and 9 percent of patients in the study arms, respectively.

Treatment discontinuations due to adverse events over the total course of all treatment were 12 percent and 16 percent for the boceprevir RGT and 48-week treatment arms, respectively, compared to 16 percent for control. Treatment discontinuations due to anemia were 2 percent for each of the boceprevir treatment arms compared to 1 percent for control. EPO for management of anemia was allowed at the discretion of the investigator per the study protocol, and was used by 43 percent of patients in each of the boceprevir treatment arms compared to 24 percent for control.

The HCV RESPOND-2 and HCV SPRINT-2 studies each employed futility or "stopping" rules, whereby patients in any treatment arm who had detectable virus at week 12 in the HCV RESPOND-2 study or at week 24 in the HCV SPRINT-2 study were considered treatment failures and discontinued all treatment. These stopping rules allowed for patients in the studies who did not respond to treatment to have their therapy stopped early, thereby avoiding unnecessary treatment.

Merck's global commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the field of viral hepatitis 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 viral hepatitis care.

About boceprevir

Boceprevir is not approved in Canada.

About ribavirin plus peginterferon alfa-2b:

Ribavirin plus peginterferon alfa-2b, known as PEGETRON® in Canada, is indicated for the treatment of adult patients (≥ 18 years of age) with chronic hepatitis C who have compensated liver disease and are positive for HCV-RNA, including patients who have not received previous treatment or who failed prior treatment with interferon alpha (pegylated or non-pegylated) and ribavirin combination therapy.1

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit http://www.merck.com/.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2009 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (http://www.sec.gov/).

1 ® Registered trademark of Schering-Plough Ltd. Used under license.
1 SVR, the protocol specified primary efficacy endpoint of the studies, 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. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment was utilized.

2 Merck news release: 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. Available at: http://www.merck.com/newsroom/news-release-archive/home.html. Aug. 4, 2010.

3 B.R. Bacon et al. HCV RESPOND-2 Final Results: High Sustained Virologic Response Among Genotype 1 Previous Non-Responders and Relapsers to Peginterferon/Ribavirin when Re-Treated with Boceprevir Plus PEGINTRON (Peginterferon alfa-2b)/Ribavirin. Abstract 216.

4 F. Poordad et al. Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1: SPRINT-2 Final Results. Abstract LB-4.

5 J. Bronowicki et al. Response-Guided Therapy (RGT) with Boceprevir (BOC) + Peginterferon alfa-2b/Ribavirin (P/R) for Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype (G) 1 Was Similar to a 48-Wk Fixed-Duration Regimen with BOC + P/R in SPRINT-2. Abstract LB-15.

6 Health Canada. http://www.phac-aspc.gc.ca/hepc/faq-eng.php . Accessed Oct. 28. 2010.

7 Health Canada. http://www.phac-aspc.gc.ca/hepc/faq-eng.php . Accessed Oct. 28. 2010.

8 Canadian Liver Foundation. http://www.liver.ca/Liver_Disease/ . Accessed Oct. 28. 2010.

Media Contacts:
Mona Aubin Merck
514 428-3768

Julia Alter Edelman

(Source: CNW )
(Source: Quotemedia)


Creating Functional Hepatic Tissue in a Bioengineered Human Liver

Presented: Sunday, 31 October 2010, 11:45 am Eastern Time
By American Association for the Study of Liver Diseases (AASLD)
Published: Saturday, Oct. 30, 2010 - 6:00 am

BOSTON, Oct. 30 -- /PRNewswire/ -- Researchers at Wake Forest University Baptist Medical Center's Institute for Regenerative Medicine demonstrated the generation of a bioengineered human liver organoid using a liver bioscaffold made from an intact liver extracellular matrix, and filled (seeded) with primary human liver progenitor and endothelial cells.

The ability to generate a liver scaffold and preserve its vascular network had been demonstrated previously. These studies showed the possibility of seeding these bioscaffolds with liver cells from animals, but the possibility of generating functional human hepatic tissue was still in question.

The current study demonstrated that human liver cells can be seeded through the portal vein of the liver bioscaffold, and can be maintained in a specialized bioreactor with constant culture medium perfusion up to one week. Progressive human liver tissue formation was documented, as well as liver-associated functions. Widespread cell proliferation inside the bioengineered liver tissue with low cell apoptosis was also observed.

According to Pedro Baptista, PharmD, PhD, "These studies provide the basis to begin transplantation of bioengineered livers in small animal models. We believe that this functional hepatic tissue, once transplanted, will maintain and further gain function as it progressively grows and develops in vivo. Also, the exclusive use of human cells opens new horizons for drug testing and toxicology studies. This will more closely mimic drug metabolism in the human liver, which animal models can, at times, be extremely difficult to predict."

"This technology may provide a new approach for liver bioengineering, enabling the use of organ scaffolds with human cells to produce functional human liver tissue," said Dr. Baptista.

The researcher hails this as a new approach to whole organ liver bioengineering that might prove to be critical for drug discovery and treatment of liver disease. "This laboratory-generated hepatic tissue offers great potential as a drug discovery and toxicology testing platform. Moreover, we believe that further translation into larger animal species opens the door for the generation of transplantable bioengineered human livers that can help patients with end-stage chronic liver disease who are waiting for a donor."

Abstract title:

The Use of Whole Organ Decellularization for the Bioengineering of a Human Vascularized Liver

About the AASLD

AASLD is the leading medical organization for advancing the science and practice of hepatology. Founded by physicians in 1950, AASLD's vision is to prevent and cure liver diseases. This year's Liver Meeting®, held in Boston, Massachusetts, October 29-November 2, will bring together more than 7,500 researchers from 55 countries.

A pressroom will be available from October 30 at the annual meeting. For copies of abstracts and press releases, or to arrange for pre-conference research interviews contact Gregory Bologna at 703-299-9766. To pre-register, call Ann Haran at 703-299-9766.

Press releases and all abstracts are available online at http://www.aasld.org/.

Media Contact: Gregory Bologna
Press Room: October 30 – November 2, 2010
Hynes Convention Center, Room 208
Telephone: 617-954-3106

Researchers: Pedro Baptista, PharmD, PhD; Shay Soker, PhD
Email: pbaptist@wfubmc.edu; ssoker@wfubmc.edu
Phone: 336-713-1325

This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.xpresspress.com/.

SOURCE American Association for the Study of Liver Diseases (AASLD)

Also See: Wake Forest scientists successfully grow 'miniature livers'

New Data From Phase 3 Studies Showed Superior SVR (Viral Cure) Rates Achieved with Telaprevir-Based Combination Therapy in People with Hepatitis C, Regardless of Race or Stage of Liver Disease

Industry updates: Oct 30, 2010

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced new data from its Phase 3 studies of people with genotype 1 chronic hepatitis C who have not been treated previously. In these studies, the majority of people achieved superior sustained viral response (SVR or viral cure) rates with a telaprevir-based combination regimen, compared to current therapies, regardless of race/ethnicity or stage of liver fibrosis (factors known to limit response to current hepatitis C treatments). Patients in the ADVANCE and ILLUMINATE studies were given telaprevir with pegylated-interferon and ribavirin for the first 12 weeks of the studies, followed by treatment with pegylated-interferon and ribavirin alone for a total of either 24 weeks or 48 weeks based on their response to treatment at weeks 4 and 12. Final data from the Phase 3 ADVANCE and ILLUMINATE studies are being presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), which takes place in Boston October 29 to November 2.

“In our Phase 3 program, starting people with 12 weeks of telaprevir-based combination therapy resulted in significant improvements in viral cure rates, regardless of race, extent of liver damage or experience with prior treatment,” said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. “The results of the ADVANCE and ILLUMINATE studies represent a major milestone in the development of telaprevir and offer hope for doctors and the millions of people living with hepatitis C who need new and more effective medicines.”

Vertex Pharmaceuticals Incorporated is developing telaprevir in collaboration with Tibotec and Mitsubishi Tanabe Pharma.


Overall in ADVANCE, 75% of people treated with a telaprevir-based combination regimen for 12 weeks, followed by an additional 12 or 36 weeks of pegylated-interferon and ribavirin alone, achieved SVR, compared to 44% of people treated with 48 weeks of pegylated-interferon and ribavirin alone. New data from this study showed that 62% of African Americans/Blacks achieved SVR with telaprevir compared to 25% of African Americans/Blacks who were treated with pegylated-interferon and ribavirin alone. Additionally, 62% of people with advanced liver fibrosis or cirrhosis (scarring of the liver) achieved SVR with telaprevir compared to 33% who were treated with pegylated-interferon and ribavirin alone.

Response-guided therapy was used in ADVANCE, whereby patients whose virus was undetectable at weeks 4 and 12 of treatment with telaprevir-based therapy were eligible to reduce their treatment time by half – from 48 weeks to 24 weeks. ILLUMINATE was designed to confirm both the use of response-guided therapy and to evaluate whether there was any benefit in extending therapy from 24 weeks to 48 weeks in people who met these criteria. In ADVANCE and ILLUMINATE, 58% and 65% of people, respectively, met these criteria for 24-week total treatment. In ILLUMINATE there was no benefit in extending therapy to 48 weeks.

In ILLUMINATE, 72% of people overall achieved SVR with telaprevir-based therapy. New data from this study showed that 60% of African Americans/Blacks and 63% of people with advanced liver fibrosis or cirrhosis achieved SVR with telaprevir-based therapy in the overall study analysis. Of African Americans/Blacks whose virus was undetectable at weeks 4 and 12, 88% of people achieved SVR in both the 24-week and 48-week randomized treatment arms. There was no control arm of pegylated-interferon and ribavirin alone in ILLUMINATE.

The safety and tolerability profile of telaprevir was consistent in both trials, with low discontinuation rates of all drugs during the telaprevir treatment phase due to adverse events.

“Less than half of people with the most common form of hepatitis C - genotype 1- achieve a viral cure with currently approved medicines, and factors such as race and extent of liver fibrosis can further limit cure rates to less than a third,” said Ira Jacobson, M.D., Chief of the Division of Gastroenterology and Hepatology, at New York-Presbyterian Hospital/Weill Cornell Medical Center, and the Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College. “After treatment with telaprevir-based combination therapy in the ADVANCE study, 75% of people overall achieved a viral cure. Importantly, 62% of African Americans/Blacks and people with extensive liver disease achieved a viral cure – nearly twice as many as those who received pegylated-interferon and ribavirin alone.”

“Many patients today are not motivated to begin hepatitis C therapy given the year-long treatment time and low cure rates with approved therapies,” said Kenneth Sherman, M.D., Ph.D., Professor of Medicine at the University of Cincinnati College of Medicine, Director of the Division of Digestive Diseases for UC Health. “Data from the ILLUMINATE study are extremely promising and showed that high viral cure rates and shorter treatment duration may be possible for the majority of people who have not been treated previously.”

Additional Data at AASLD

Results from the EXTEND study are also being presented at the meeting. EXTEND is a long-term follow-up study of patients who received telaprevir-based regimens in the PROVE Phase 2 clinical trials and was designed to evaluate whether people maintain their SVR (viral cure) over time and to observe changes in hepatitis C viral resistance variants in those telaprevir-treated patients who had not achieved SVR. The results showed that after an average of two years of follow-up, SVR rates with telaprevir were durable in 99% (122/123) of patients with SVR who took part in the trials. Among patients who did not achieve SVR and who had resistant variants at the start of the EXTEND study, 89% (50/56) no longer had detectable variants.

Safety & Tolerability Results from ADVANCE and ILLUMINATE

The safety and tolerability results of telaprevir-based combination regimens were consistent in the ADVANCE and ILLUMINATE studies. Treatment discontinuation rates of all drugs due to adverse events during the telaprevir treatment phase in the ADVANCE study were low in the telaprevir arms (7% to 8%) and the control arm (4%). The most common adverse events (>25% of people) reported in both studies, regardless of treatment arm, were rash, fatigue, pruritis, headache, nausea, anemia, insomnia, diarrhea, influenza-like symptoms and pyrexia. The majority of these adverse events were mild to moderate.

To optimize each patient’s opportunity to achieve viral cure in the Phase 3 studies, sequential discontinuation of the drugs was recommended if discontinuation of treatment was necessary due to adverse events. Investigators were not required to discontinue the use of all three drugs at once, and, for example, patients may have continued on pegylated-interferon and ribavirin after discontinuing telaprevir only.

In ADVANCE, discontinuation of telaprevir or placebo only due to adverse events during the telaprevir treatment phase occurred in 11% of people in the 12-week telaprevir arm, 7% of people in the 8-week telaprevir arm and 1% of people in the control arm. In ILLUMINATE, 12% of people overall discontinued telaprevir only due to adverse events during the telaprevir treatment phase.

Discontinuation of all drugs due to either rash or anemia was low in both studies (1% to 3%). Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. Ninety-two percent and 95% of rash was mild to moderate in ADVANCE and ILLUMINATE, respectively. Rash was managed with the use of topical corticosteroids and antihistamines, and anemia was primarily managed by reducing the dose of ribavirin. The use of erythropoiesis-stimulating agents (ESAs) were not allowed in any of the Phase 3 clinical studies.

Planned NDA Submission and Additional Phase 3 Analysis

Three Phase 3 studies, ADVANCE, ILLUMINATE and REALIZE will form the basis of the clinical portion of the telaprevir New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA), which is expected to be complete in the fourth quarter of 2010. REALIZE evaluated telaprevir in three groups of people with genotype 1 hepatitis C who did not achieve a viral cure with previous treatment: (1) those who relapsed, (2) those who achieved a partial response and (3) those who had a null response to prior treatment (<2 log10 reduction in HCV RNA at week 12). Topline results from REALIZE were reported in a press release on September 7, 2010.

At a 2010 medical meeting,Vertex’s collaborator Tibotec reported results on the correlation of poor interferon response (<1 log10 reduction in HCV RNA at week 4) with the standard definition for null response (< 2 log10 reduction in HCV RNA at week 12).12,13 In these results, 38% (9/24) of patients who had a less than 1 log10 response at week 4 subsequently had a greater than 2 log10 reduction in HCV RNA at week 12. This analysis suggested that some patients would be misclassified as null responders using the definition of a less than 1 log10 reduction in HCV RNA at week 4.

An additional sub-analysis in the REALIZE study showed that among the combined partial responder and relapser patients in the telaprevir delayed start (lead-in) arm of the REALIZE study, 18% (31/171) had a less than 1 log10 reduction in HCV RNA at week 4 and of these patients, 58% (18/31) achieved SVR compared to 31% (46/147) of patients prospectively-defined as prior null responders (<2 log10 at week 12) in the combined telaprevir-based treatment arms. Each prior response category contained a different proportion of patients that experienced a less than 1 log10 reduction in HCV RNA at week 4 of the delayed start (lead-in) arm, but SVR rates among these subgroups also varied by prior response category. These data suggest that prior treatment response is a better predictor of SVR than a 1 log10 reduction at week 4 and that prospectively defined null responders and those patients with a less than 1 log10 reduction in HCV RNA at week 4 of a lead-in represent different patient populations.

About the Telaprevir Development Program

To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 hepatitis C who had not been treated for their disease previously (ADVANCE and ILLUMINATE) as well as people who had been treated before but did not achieve a viral cure (REALIZE). A fact sheet on the Phase 3 telaprevir development program is available at http://www.vrtx.com/aasld2010.html

Phase 3 ADVANCE Trial

The pivotal Phase 3 ADVANCE study evaluated telaprevir-based response-guided regimens in 1,095 treatment-naïve patients. The primary endpoint of ADVANCE was SVR, defined as the proportion of people who had undetectable HCV RNA both at the end of treatment and 24 weeks after the end of treatment. The secondary endpoint was to evaluate the safety of telaprevir when dosed in combination with pegylated-interferon and ribavirin. As part of a response-guided design, people in the telaprevir-based treatment arms who had undetectable HCV RNA at weeks 4 and 12 of treatment were eligible to receive a total of 24 weeks therapy. Patients who did not meet the response-guided criterion but were undetectable at week 24, received 48 weeks of total therapy.

Phase 3 ILLUMINATE Trial

The ILLUMINATE trial was a supplemental Phase 3 study designed to evaluate whether there was any benefit in extending therapy from 24 to 48 weeks in people whose hepatitis C was undetectable at weeks 4 and 12 of therapy. The primary endpoint of the study was the proportion of people who achieved SVR in the randomized treatment groups, evaluated by a non-inferiority analysis.

Phase 3 REALIZE Trial

REALIZE was the second pivotal Phase 3 trial and was designed to evaluate telaprevir-based regimens in people who had received pegylated-interferon-based therapy but did not achieve a cure. REALIZE is the only Phase 3 clinical trial to date of an investigational direct-acting antiviral to include all major subgroups of difficult-to-treat patients including null responders, who were defined as people who had a less than a 2 log10 reduction in viral load by week 12 of a prior course of therapy.

Vertex retains commercial rights to telaprevir in North America. Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.

About Hepatitis C

Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the liver and blood of people with the disease.2 According to a 2010 report from the Institute of Medicine, up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.3 Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved treatment regimen, do not achieve SVR, 4,5,6 or viral cure.1

Hepatitis C is spread through direct contact with the blood of infected people.2 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.2 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.2 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8,9,10,11 In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.8 The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.11 By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.11

Additional resources for media, including a hepatitis C backgrounder and glossary of common terms, are available at: http://investors.vrtx.com/press.cfm

About Vertex

Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.

Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.

Lexiva is a registered trademark of the GlaxoSmithKline group of companies.

PEGASYS® and COPEGUS® are a registered trademarks of Hoffman-La Roche.


1 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

2 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010.

3 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010.

4 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

5 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

6 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

8 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected
persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

9 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

10 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

11 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc.

12 Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010.

13 United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.

Special Note Regarding Forward-looking Statements

This press release contains forward-looking statements, including statements regarding (i) the data from ILLUMINATE being extremely promising and (ii) the expectation that the Company’s NDA for telaprevir will be completed in the fourth quarter of 2010. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in submitting the NDA for telaprevir and/or obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; and that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based combination therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex’s website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.