EASL: HCV Drug Resistance

This is an excellant article written by Jules Levin of NATAP

from Jules: This is a controversial issue & was at this just completed EASL. Where a number of researchers said flatly 'we will be able to re-use HCV protease inhibitors after patients develop resistance if we wait 2 years for the mutations to disappear & this was pretty much said with regards to telaprevir following the oral presentation by Sullivan of Vertex reporting that mutations mostly disappear after 1.5 years following stopping telaprevir therapy'. This may end up being true but right now this is just a theory without any evidence, no data to support this supposition, it cannot be considered true until a study or real clinical evidence supports this. Until we have data on this question one cannot say flatly patients will be able to re-use a HCV protease after resistance and receive viral load reductions from the drug. Will such a study ever be done, I don't know. There are many other classes of HCV drugs in development so in the future patients ought to be able to switch to a regimen of 2-4 oral drugs with or without peg/rbv without a protease, so the question may be moot. Still I think we need to clarify this. One issue is that the Sullivan study did not use ultra-deep sequencing, which in this study below shows mutations missed by clonal sequencing are picked up by UDS. At baseline before therapy mutations pre-exist, so 2 years later you would expect these same pre-existing mutations to be present but HCV multi-drug therapy suppresses these mutations and SVR still has been achieved evidenced by the studies with telaprevir & boceprevir, but the question is will these mutations be further enriched after failing therapy, will mutations accumulate to a significant degree if a patient remains on failing therapy, will compensatory mutations accumulate, and will these situations persist & affect re-treatment with a PI, I don't know the answer to these questions and I don't think anyone does. Perhaps the prediction that this will not be a problem is correct but we don't know & we have not studied this adequately.

AASLD: Ultra-Deep Sequencing of the NS3 and NS5B Regions Detects Pre-Existing Resistant Variants to Direct Acting Antivirals (DAA) in HCV Genotype 1 Treatment-Naïve Infected Patients - (11/29/10)

"Minority variants resistant to PI or NNI were detected in 3 and 10 subjects respectively at frequencies that ranged from 0.6 to 14%. Concordance between UDPS and molecular clonal sequencing was 87% for MVs detected (by either method) at a level >10%; 68% for MVs detected at a level of 5% to 10%; and 26% for MVs detected at a level of 1% to 5%."

ULTRA-DEEP SEQUENCING OF THE NS3 AND NS5B REGIONS DETECTS PRE-EXISTING RESISTANT VARI- ANTS TO DIRECT ACTING ANTIVIRALS (DAA) IN HCV GENOTYPE 1 INFECTED PATIENTS NAïVE

AASLD ABSTRACT 2010 October

Severine Margeridon4, Sophie Le Pogam2, Tommy F. Liu4, Bozena Hanczaruk3, Todd E. Arnold3, Birgitte B. Simen3, Nancy Shulman1, Robert W. Shafer4, Isabel Najera2; 1Virology - Pharma Research Early Development, Roche Pharmaceuticals, Palo Alto, CA; 2Virol- ogy - Discovery, Roche Pharmaceuticals, Palo Alto, CA; 3454 Life- sciences, a Roche Company, Branford, CT; 4Infectious Diseases and Geographic Medicine, Stanford University Medical School, Stanford, CA

Background: Naturally occurring HCV drug-resistance minority variants (MVs) that are not detectable by standard consensus sequencing may have an impact on the effectiveness of HCV inhibitors. We used ultradeep pyrosequencing (UDPS) and molecular clonal sequencing to assess the prevalence of HCV drug-resistant minority variants to protease (PI), nucleoside ana- log (NA), and nonnucleoside polymerase inhibitors (NNI) in serum samples from DAA-naïve HCV infected subjects.

Methods: Samples were obtained from 39 DAA treatment naive HCV-infected subjects (27 genotype 1a and 12 genotype 1b). Molecular clonal sequencing and UDPS were performed span- ning those regions of the NS3 protease,and of the NS5B poly- merase including amino acid residues known to confer resistance to PIs, NAs and NNIs. The median viral load was 6.6 log10 IU/ml (range 5.1 - 7.6). UDPS was performed using the GS FLX Titanium platform (454 / Roche Life Sciences) at a median coverage per base of ~3,500. MVs for the UDPS were defined as mutations present in ≥0.5% of UDPS reads..whereas for the clonal sequencing analysis, MVs were defined as muta- tions present in ≥1 molecular clone.

Results: Plasmid control experiments identified a UDPS error rate of 0.1% - resulting from a combination of PCR and pyrosequencing error. No NA resistance mutation was detected by UDPS nor through molecular clonal sequencing. Minority variants resistant to PI or NNI were detected in 3 and 10 subjects respectively at frequencies that ranged from 0.6 to 14%. Concordance between UDPS and molecular clonal sequencing was 87% for MVs detected (by either method) at a level >10%; 68% for MVs detected at a level of 5% to 10%; and 26% for MVs detected at a level of 1% to 5%.

Conclusions: UDPS is a powerful technique for detecting minority variants within viral quasispecies. Optimization of a number of factors such as amplification error rate, input viral load, and the refining the sensitivity of the technique is ongoing. Comparison of results from molecular cloning and UDPS showed that no nucleoside analogs DRM as detected through either technique. Both techniques, however, detected the most prevalent NNI-DRMs with relative high concordance for MVs present at levels > 5%.

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IL28B-Genotype Testing Now and in the Era of Direct-Acting Antiviral Agents

Clinical Gastroenterology and Hepatology
Volume 9, Issue 4 , Pages 293-294, April 2011

Timothy R. Morgan, MD
Thomas R. O'Brien, MD, MPH

published online 24 December 2010.

Full Text

Peginterferon alpha and ribavirin treatment for 48 weeks leads to a sustained virological response (SVR) in 40%–50% of subjects infected with hepatitis C virus (HCV) genotype 1 or 4 (G1/4) while treatment for 24 weeks produces SVR in 70%–80% of patients infected with HCV genotype 2 or 3. The variability in response to treatment, especially between patients of different racial groups, suggested that human genetic variability might explain differences in treatment response and led to investigations of the role of host genetics in achieving an SVR.

Genome-wide association studies which examine the association between >500,000 single nucleotide polymorphisms (SNPs) and a disease of interest, have been exceptionally successful in finding SNPs associated with response to hepatitis C treatment. In 2009, 3 groups reported that SNPs located near the gene for interleukin-28B (IL28B) were strongly associated with the likelihood of achieving an SVR with peginterferon + ribavirin treatment.1, 2, 3 IL28B encodes a protein that is also known as interferon lambda-3 (IFN-λ3), a type III interferon. The receptors for interferon alpha, a type I interferon, differ from those for IFN-λ3, but both IFN-λ and IFN-α activate the same intracellular pathway (Jak/STAT), which results in expression of many interferon stimulated genes.4, 5, 6

SNPs rs12979860 and rs8099917, respectively located 3 and 8 kb upstream of IL28B, were the variants most strongly associated with treatment response in these studies. Among treatment naive G1-infected subjects of European ancestry who were enrolled in the IDEAL study, approximately 69% of those who carried 2 C alleles (C/C) at rs12979860 achieved an SVR compared with 33% of those with the C/T genotype and 27% with genotype T/T.7 Consistent findings were reported for rs8099917 among Japanese, Australian, and European populations.2, 3 These studies demonstrated that carriage of 2 IL28B favorable alleles strongly, but not fully, predicted SVR, while carriage of 1 or 2 unfavorable alleles did not completely predict failure to respond to treatment. It appears that rs12979860 is more predictive of SVR than rs8099917, especially among people of African ancestry in whom rs8099917 is less polymorphic than rs12979860.1

In the current issue of Clinical Gastroenterology and Hepatology, Stättermayer and colleagues performed IL28B genotype testing for rs12979860 and rs8099917 in 682 Austrian subjects (G1 = 372; G2/3 = 208; G4 = 102) who completed treatment with peginterferon and ribavirin and agreed to return for genetic testing.8 They found that subjects infected with G1/4 who carried 2 C alleles at rs12979860 (ie, the most favorable genotype) had a greater decline in HCV ribonucleic acid (RNA) 24 hours after the first injection of interferon than did G1/4-infected subjects who carried a T allele (either C/T or T/T). Similarly, subjects infected with G1/4 who carried rs12979860 C/C were more likely to achieve a rapid virological response (RVR; G1: 38% vs 12%) and SVR (G1: 79% vs 43%) as compared with carriers of the T allele. Among subjects infected with G2/3, rs12979860 C/C carriers had a higher likelihood of RVR (75% vs 53%), but the difference for SVR (81% vs 72%) did not reach statistical significance. IL28B rs12979860 genotype was the strongest pretreatment predictor of SVR, but when the initial response to peginterferon and ribavirin was considered, RVR rather than IL28B genotype was the strongest predictor of SVR in this population. The authors concluded that IL28B genotype influenced the rate of initial viral decline with peginterferon/ribavirin treatment and that IL28B genotype, in conjunction with RVR, might be useful parameters in predicting SVR in G1/4 subjects.

The findings of Stättermayer and coworkers confirm prior reports of IL28B genotype testing among subjects treated with peginterferon + ribavirin. Several investigators have reported that subjects with rs12979860 C/C have a greater initial decline in HCV RNA level and a higher likelihood of achieving RVR and SVR.1, 7, 9 Thompson reported that IL28B genotype is the most important pretreatment variable to predict SVR, but IL28B genotype loses importance as a predictor of SVR when RVR is included in a multivariate analysis.7 Stättermayer confirmed that rs12979860 is more informative than rs8099917 as a pretreatment predictor of SVR among those of European ancestry.1 In total, studies from Stättermayer and others show a strong association of IL28B genotype with virological response to peginterferon + ribavirin treatment, including the rate of early viral decline and the likelihood of achieving RVR and SVR.

The human genome project promised to introduce an era of personalized medicine, in which genetic testing would be used to predict the likelihood of clinical outcomes, including response to drugs, in individual patients.10 In 2010 several clinical laboratories announced assays for IL28B rs12979860 genotype. Gastroenterologists now must decide whether to obtain IL28B genotype for their HCV-infected patients and, if so, how to incorporate these results into decisions regarding hepatitis C treatment. IL28B genotype joins a considerable list of pretreatment factors that have been shown to predict the probability of SVR, including HCV genotype, HCV RNA level, severity of liver fibrosis, and racial ancestry. Information on each of these factors can help inform the physician and patient of the likelihood of achieving an SVR, however, none alone is sufficient to guarantee or preclude the possibility of achieving an SVR. Although IL28B genotype alone is insufficient for deciding whether or not a patient is likely to respond to peginterferon and ribavirin, we believe that mathematical clinical prediction models based on IL28B genotype and clinical characteristics may prove useful for predicting SVR. Indeed, among interferon nonresponders who were re-treated with peginterferon + ribavirin in the HALT-C Trial, we have presented “proof of concept” that a model that includes IL28B plus some commonly measured clinical variables (HCV viral load, liver fibrosis score and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio) has good discrimination and predictive ability for the probability of SVR (O'Brien et al, Hepatology 2010;52:382A [abstract]). If validated, such a model could be used to calculate individually tailored probabilities of achieving an SVR for patients. Clinical prediction models may also be useful for on-treatment predictions of SVR.

The availability of IL28B genotype testing to help predict SVR coincides with another major advance in the treatment of chronic hepatitis C, the introduction of direct-acting antiviral agents (DAAs) that specifically target enzymes critical to HCV replication. At this writing, it appears likely that 2 HCV-specific protease inhibitors, boceprevir and telaprevir, will be approved by the Food and Drug Administration (FDA) in 2011. Data from clinical trials suggest that adding a protease inhibitor to the peginterferon + ribavirin regimen increases the overall SVR rate among treatment naive G1-infected patients to 65%–75% (Bacon et al, Hepatology 2010;52:216 [abstract]; Jacobson et al, Hepatology 2010;52:211 [abstract]). However, adding a viral protease inhibitor to current standard of care is not without additional risks. Patients taking these agents are subject to several potential adverse effects, including anemia and skin rash. Furthermore, patients who fail to achieve SVR on a regimen that includes a protease inhibitor will likely harbor resistant viruses that limit future use of protease inhibitors in that patient. Initial studies suggest that IL28B genotype may be predictive of response to treatment with protease inhibitors, too. Among Japanese patients who received telaprevir + peginterferon + ribavirin, Akuta and colleagues reported an SVR rate of 83% for subjects carrying rs12979860 C/C as compared with 32% among subjects who carried a T allele.11 If confirmed in other populations, these data suggest that carriers of the less favorable IL28B genotypes will be less likely to respond to triple therapy that includes protease inhibitors and raise the possibility that IL28B genotype-based models may be useful for predicting the likelihood of SVR in response to treatment with peginterferon + ribavirin + protease inhibitors.

Until now, the outcome of treatment for chronic hepatitis C could be broadly classified as either successful (SVR) or futile (nonresponse). The advent of the direct-acting antiviral agent (DAA) era promises to increase the number of patients for whom treatment is successful, but also introduce a third outcome—patients who not only fail treatment, but also harbor resistant viral strains that may compromise future treatment options. Thoughtful incorporation of IL28B genotyping into treatment decision-making may serve to increase the number of patients for whom treatment is successful while minimizing those in whom it is deleterious.

Acknowledgments

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

References

1.Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401

2.Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–1104

3.Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–1109

4.O'Brien TR. Interferon-alfa, interferon-lambda and hepatitis C. Nat Genet. 2009;41:1048–1050

5.Kotenko SV, Gallagher G, Baurin VV, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77

6.Sheppard P, Kindsvogel W, Xu W, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–68

7.Thompson AJ, Muir AJ, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139:120–129e18

8.Stättermayer A, Stauber R, Hofer H, et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naïve patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2011;9:344–350

9.McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology. 2010;138:2307–2314

10.Feero WG, Guttmacher AE, Collins FS. Genomic medicine--an updated primer. N Engl J Med. 2010;362:2001–2011

11.Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatol. 2010;52:421–429

Conflicts of interest The authors disclose the following: Timothy R. Morgan has received research support from Genentech, Vertex, Merck, and WAKO Diagnostics. Thomas R. O'Brien discloses no conflicts.

Funding This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.

PII: S1542-3565(10)01278-4
doi:10.1016/j.cgh.2010.12.014
© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Long-Term Consistent Use of HIV Therapy Protects the Liver

April 6, 2011

People with HIV who aren’t also infected with viral hepatitis are at significant risk of developing liver disease, but long-term consistent use of antiretroviral (ARV) therapy appears to be protective, according to a study published in the May 9 issue of Clinical Infectious Diseases.

Liver disease is now the No. 1 cause of death in people with HIV. While the vast majority of people with HIV who have liver disease are also infected with either hepatitis C virus (HCV) or hepatitis B virus (HBV), people with HIV who don’t have hepatitis are also at significantly increased risk for liver failure.

Two of the challenges of monitoring for liver disease in people who don’t otherwise have major risk factors are predicting who is most at risk and determining the best method to monitor for the disease. The gold standard for assessing a person’s liver condition is a liver biopsy, but that can be quite painful and it carries some health risks—plus, most providers would not perform a biopsy on someone who doesn’t have risks or signs of liver disease.

To help determine the risk of liver disease progression, and to validate the use of non-invasive methods for monitoring liver disease, Monia Mendeni, MD, from the University of Brescia School of Medicine, in Brescia, Italy, and her colleagues followed 1,112 HIV-positive people enrolled in the Italian Hepatotoxicity of Different Kinds of Antiretrovirals study.

To be eligible for the analysis, people needed to have enrolled in the study between 1996 and 2006. They also could not have either HBV or HCV, and they could not have been diagnosed with cirrhosis. The average length of follow-up in the study was six years. More than two thirds of the study participants were male, and the average age was 36. The majority of the participants did not have liver damage (fibrosis) at the beginning of the study.

Mendeni’s team used two methods for assessing the conditions of the participants’ livers. One is called an FIB-4 score, which is based on a calculation of a person’s age, alanine transaminase (ALT) levels and the ratio of aspartate transaminase (AST) levels to platelet count. A second method, called APRI, calculates only the AST to platelet ratio.

The team found that liver fibrosis progression was common, even in the absence of viral hepatitis. Using the FIB-4 scoring method, 259 (24 percent) of the participants progressed to a greater degree of liver fibrosis over the course of the study, with 89 of them being confirmed by liver biopsy to have fibrosis. Using the APRI scoring, 356 (31 percent) people had progression of liver fibrosis, which was confirmed by biopsy in 126 of them. Regardless of the scoring method, most people who initially showed progression reverted back to a healthier score without any sort of treatment intervention.

Mendeni and her colleagues found that the FIB-4 and the APRI scoring methods differed in their predictive value, particularly in people with the mildest fibrosis. Both methods, however, had a much higher degree of accuracy when predicting fibrosis in people with more advanced liver disease.

Overall, the team found that older age increased the likelihood of having liver fibrosis more than any other factor. Having a low CD4 count also increased the chance of having liver disease progression.

Of note, Mendeni’s team found—for the first time in any study—that longer-term use of ARV medication had a protective affect against liver disease progression. The effect was small, but present. The team also found that people who took Videx (didanosine), Zerit (stavudine) or Hivid (zalcitabine) were more likely to have fibrosis progression, confirming previous studies showing that these drugs may have a negative impact on the liver.

The authors acknowledge that FIB-4 and APRI are not gold-standard methods for assessing liver fibrosis, and thus may not have provided the most accurate measure of liver damage. They note, however, that performing proactive liver biopsies in people without significant risk factors is unethical. They also acknowledge that excessive alcohol use might also have influenced the study results, but point out that they tried to control for this by measuring gamma-GT levels.

“This study demonstrated that HIV-[positive people who aren’t also infected with HCV or HBV] display significant risk of [liver fibrosis] liv liver progression,” state the authors. “Although formal validations are necessary, in the meantime, FIB-4 and APRI should be used to identify those patients who are most at risk and who need further clinical work-up (such as liver biopsy) and more-proactive counseling to modify dangerous behaviors (such as alcohol abuse).”

“Lastly,” they conclude, “our results suggest the benefit of earlier [ARV] initiation for liver disease fibrosis in HIV-monoinfected patients, provided that the most dangerous drugs [e.g. Zerit, Videx and Hivid] are avoided.”

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EASL:Investigational compound PEG-interferon lambda achieved higher response rates with fewer flu-like and musculoskeletal symptoms and cytopenias than PEG-interferon alfa in Phase IIb study of 526 treatment-naive hepatitis C patients

Public release date: 2-Apr-2011

Contact: Cristi Barnett
cristi.barnett@bms.com
609-252-6028
TogoRun

(PRINCETON, N.J., April 2, 2011) – Bristol-Myers Squibb Company (NYSE: BMY) today announced results from the Phase IIb EMERGE clinical trial, in which treatment with the investigational compound PEG-Interferon lambda and ribavirin achieved higher rates of rapid virologic response (RVR) in genotypes 1, 2, 3, and 4, and complete early virologic response (cEVR) in genotypes 1 and 4 than the standard regimen of PEG-Interferon alfa and ribavirin in treatment-naïve patients chronically infected with hepatitis C (HCV). In this study, there were fewer flu-like and musculoskeletal symptoms and cytopenia, as well as fewer interferon and ribavirin dose reductions for anemia in the PEG-Interferon lambda arms up to 12 weeks. Rates of serious adverse events, depression and other common adverse events (incidence ≥10%) were similar across treatment arms up to week 12.

The EMERGE study findings were presented in a late-breaker oral session at the International Liver Congress (ILC), the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.

"There is a significant unmet medical need for more therapies that can benefit more hepatitis C patients. This is especially true for patients with HCV genotypes 1 and 4, who generally have lower response rates to treatment with PEG-Interferon alfa and ribavirin than patients with other genotypes," said Stefan Zeuzem, MD, chief of the department of medicine and professor of medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. "The EMERGE study results demonstrate that PEG-Interferon lambda may have the potential to help address this unmet need, and support further studies of this new type of investigational interferon."

PEG-Interferon lambda is the first investigational type III interferon. Interferon lambda mediates antiviral activity through a receptor that is distinct from that used by interferon alfa and is present on fewer cell types within the tissues of the body. This restricted distribution of the interferon lambda receptor offers the potential for more targeted delivery of interferon therapy.

Study Results

Viral Response: HCV Genotypes 1 and 4

In this study, HCV genotype 1 and 4 patients treated with PEG-Interferon lambda achieved statistically significant (p<0.05) higher rates of cEVR (primary study endpoint) versus PEG-Interferon alfa at all doses [lambda 240 µg: 56.3% (n=103), lambda 180 µg: 55.9% (n=102), lambda 120 µg: 55.0% (n=100) vs. alfa: 37.9% (n=103)]. These statistically significant (p<0.05) higher viral response rates were seen as early as four weeks of treatment, with greater rates of RVR at the two higher doses of PEG-Interferon lambda (lambda 240 µg: 16.5%, lambda 180 µg: 14.7%, lambda 120µg: 6.0% vs. alfa: 5.8%).

Viral Response: HCV Genotypes 2 and 3

In patients with HCV genotypes 2 and 3, treatment with all doses of PEG-Interferon lambda achieved cEVR rates similar to PEG-Interferon alfa [lambda 240 µg: 83.3% (n=30), lambda 180 µg: 96.6% (n=29), lambda 120 µg: 90% (n=30), and alfa: 86.2%, (n=29)]. Statistically significant (p<0.05) higher rates of RVR were achieved at the two higher doses of PEG-Interferon lambda (lambda 240 µg: 66.7%, lambda 180 µg: 75.9%, lambda 120 µg: 43.3% vs. alfa: 31%).

Safety

In this study, rates of adverse events commonly associated with interferon treatment were lower with PEG-Interferon lambda than with PEG-Interferon alfa. These adverse events included flu-like symptoms (lambda 240 µg: 9.7%; lambda 180 µg: 9.9%; lambda 120 µg: 12.5%; alfa: 42.9%), musculoskeletal symptoms (lambda 240 µg: 14.2%; lambda 180 µg: 14.5%; lambda 120 µg: 18.0%; alfa: 46.6%), neutropenia < 750/mm³ (lambda 240 µg: 0.0%; lambda 180 µg: 0.8%; lambda 120 µg: 0.0%; alfa: 15.2%), anemia with hemoglobin < 10 g/dL (lambda 240 µg: 12.9%; lambda 180 µg: 15.4%; lambda 120 µg: 20.5%; alfa: 43.9%.) and thrombocytopenia < 50K/mm³ (lambda 240 µg: 0.0%; lambda 180 µg: 0.0%; lambda 120 µg: 0.0%; alfa: 14.4%).

The proportion of patients that required interferon dose reductions were: lambda 240 µg: 12.7%; lambda 180 µg: 3.8%; lambda 120 µg: 0.8%; alfa: 18.8%, and the proportion of patients that withheld and/or reduced ribavirin were: lambda 240 µg: 11.2%; lambda 180 µg: 4.6%; lambda 120 µg: 10.2%; alfa: 20.3%. The proportion of patients who required ribavirin dose reductions for anemia were: lambda 240 µg: 0.7%; lambda 180 µg: 1.5%; lambda 120 µg: 2.3%; alfa: 12.8%.

Rates of serious adverse events, depression and other common adverse events (≥10%) were similar across treatment arms. Higher rates of elevated liver enzymes [AST or ALT >5x the upper limit of normal (ULN)] were seen in the highest-dose PEG-Interferon lambda treatment arm compared with PEG-Interferon alfa (lambda 240 µg: 17.4%; lambda 180 µg: 2.3%; lambda 120 µg: 0.8%; alfa: 7.6%), and direct bilirubin was also elevated (>1.2 mg/dL) in the highest-dose PEG-Interferon lambda treatment arm compared with PEG-Interferon alfa (lambda 240 µg: 7.6%; lambda 180 µg: 3.9%; lambda 120 µg: 0.8%; alfa: 0.8%); all resolved spontaneously without sequelae or following interferon dose modification and/or discontinuation.

About the EMERGE Phase IIb Study

The EMERGE study is a two-part, randomized, controlled, multicenter, phase II study of PEG-Interferon lambda in 526 treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4. Part one of EMERGE was a Phase IIa study, and results were previously presented at The American Association for the Study of Liver Diseases (AASLD) 2010 Liver Meeting. Part two of EMERGE is an ongoing, blinded Phase IIb study designed to evaluate the safety, efficacy, and pharmacokinetics of PEG-Interferon lambda vs. PEG-Interferon alfa, both in combination with ribavirin. The 526 patients were randomized into four dose groups: PEG-Interferon lambda 240 µg (n=134), PEG-Interferon lambda 180 µg (n=131), PEG-Interferon lambda 120 µg (n=128) and PEG-Interferon alfa 180 µg (n=133).

The study will continue for 48 weeks in genotype 1 and 4 patients and 24 weeks in genotype 2 and 3 patients. The primary endpoint of the study is the proportion of patients who achieve complete early virologic response (cEVR).

About PEG-Interferon lambda

PEG-Interferon lambda is the first investigational type III interferon in Phase IIb development for the treatment of hepatitis C. Native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than native human interferon alfa proteins. Lambda receptors are present on fewer cell types within the human body than alfa receptors. This restricted distribution of the interferon lambda receptor offers the potential for more targeted delivery of interferon therapy.

About Hepatitis C1

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with blood. An estimated 170 million people worldwide are infected with hepatitis C. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, 20 percent will progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a curable disease.

###

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com/ or follow us on Twitter at http://twitter.com/bmsnews.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the compound described in this release will move from exploratory development into full product development, that clinical trials of this compound will support a regulatory filing, or that the compound will receive regulatory approval or become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2010, in our Quarterly Reports on Form 10-Q, and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

Contacts:
Media: Cristi Barnett, 609-252-6028, cristi.barnett@bms.com
Investors: John Elicker, 609-252-4611, john.elicker@bms.com 

References
1 World Health Organization. Hepatitis C. Available at: http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index1.html. Accessed March 9, 2011.

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Breakthrough: Non-Interferon/Ribavirin Regimen Can Cure Hep C

April 4, 2011
by Tim Horn

In what is being heralded as a hepatitis C virus (HCV) treatment research breakthrough, a clinical trial evaluating two oral medications being developed by Bristol-Myers Squibb (BMS) suggests that at least some cases of chronic HCV infection can be cured without the use of either pegylated interferon or ribavirin (IFN/RBV).

The same study, reported Saturday, April 2, at the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, also appeared to cure 10 people living with HCV treated with a quadruple regimen, consisting of BMS’s BMS-650032 and BMS-790052 in combination with IFN/RBV.

Though a combination of IFN/RBV has long been the standard treatment for chronic HCV infection, both drugs are associated with side effects and neither drug works directly against the virus. The high rate of toxicities, compounded by their indirect mechanisms of action, help explain why current treatment isn’t highly effective in a proportion of people living with HCV, particularly those with hard-to-treat genotype 1 infection.

Direct-acting antivirals (DAAs), drugs that directly target HCV, have been in development for several years. Not only can they potentially maximize treatment responses and reduce the amount of time someone needs to be treated for HCV, but they also have been eyed as a way of treating hepatitis C without the need for either IFN or RBV.

Numerous studies at EASL suggest that DAAs, including protease inhibitors, NS5A inhibitors and polymerase inhibitors, can substantially increase rates of sustained virologic responses (SVRs)—maintaining an undetectable HCV viral load for six months after stopping treatment, or a viral cure—when used in combination with IFN/RBV. Not only did a clinical trial evaluating BMS’s protease inhibitor (BMS-790052) and NS5A inhibitor (650032) add to the encouraging news, but it also demonstrated that two DAAs used together, without IFN/RBV, can cure HCV in some patients.

The Phase II study looked at a cohort of 21 HCV genotype 1 null responders—patients who had very limited responses to previous treatment with IFN/RBV—of whom 19 had an unfavorable IL28B genotype, which predisposes HCV patients to treatment failure. The cohort was divided into two groups: Group A involved 11 patients treated with BMS-790052 plus BMS-650032 without IFN/RB for 24 weeks; Group B involved 10 patients treated with both BMS drugs plus IFN/RBV for 24 weeks.

Nine of the 10 patients treated with quadruple therapy had an SVR after 24 weeks (SVR24), reported Anna Lok, MD, of the University of Michigan Medical Center at Ann Arbor and her colleagues. The one patient who didn’t have an SVR24 was tested again 35 days later and found to have an undetectable HCV viral load, suggesting a possible cure rate of 100 percent in the small number of individuals who received four-drug treatment.

Of particular interest are the results among those treated with the DAAs without IFN/RBV. Four of the 11 patients had an SVR24—among the first individuals in a clinical trial to be successfully cured of HCV without today’s standard-of-care drugs.

In the six patients who saw their HCV viral loads rebound during treatment with the DAAs, IFN/RBV was promptly added. Four of the patients then went on to achieve undetectable HCV viral loads. HCV resistance to both BMS-790052 and BMS-650032 was documented in all six patients who did not respond favorably to DAA therapy alone, though it is not clear what the implications of resistance are for those who potentially require retreatment with these or similar agents.

Many side effects were similar in both groups, including diarrhea, fatigue, headache, fever and difficulty sleeping. Most side effects, however, were mild to moderate in severity, and there were no discontinuations from the study due to adverse events. Moderate-to-severe drops in neutrophils, a type of white blood cell, was documented in six patients in the quadruple-therapy group, compared with no patients in the dual-DAA group.

Lok concluded that quadruple therapy can result in a high rate of cure in this difficult-to-treat population and that, based on the encouraging dual-DAA study results, that HCV infection can be cured without IFN or RBV.

Source

Also See:
EASL: Quadruple therapy shows 100 percent SVR for HCV patients previously unresponsive to treatment

In-vitro model systems to study Hepatitis C Virus

Published on: 2011-04-06

Hepatitis C virus (HCV) is a major cause of chronic liver diseases including steatosis, cirrhosis and hepatocellular carcinoma. Currently, there is no vaccine available for prevention of HCV infection due to high degree of strain variation.

The current treatment of care, Pegylated interferon alpha in combination with ribavirin is costly, has significant side effects and fails to cure about half of all infections. The development of in-vitro models such as HCV infection system, HCV sub-genomic replicon, HCV producing pseudoparticles (HCVpp) and infectious HCV virion provide an important tool to develop new antiviral drugs of different targets against HCV.

These models also play an important role to study virus lifecycle such as virus entry, endocytosis, replication and release and HCV induced pathogenesis. This review summarizes the most important in-vitro models currently used to study future HCV research as well as drug design.

Author: Usman AshfaqShaheen KhanZafar NawazSheikh Riazuddin

Credits/Source: Genetic Vaccines and Therapy 2011, 9:7

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Scientific Breakthrough: New Non-Invasive Oral HIV Rapid Test by OraWell Delivers Reliable Results in Just 10 Minutes

OraWell USA announces its revolutionary at-home oral HIV test, an AIDS test that now delivers accurate results in just 10 minutes!

Allentown, PA (PRWEB) April 6, 2011

OraWell USA proudly announces its revolutionary, first-of-its kind, at-home oral HIV test, which can deliver reliable results in as little as 10 minutes. Now, it’s easier than ever to have peace of mind and find out the results of an HIV test sooner, without the hassle or inconvenience of having to visit a doctor’s office or clinic. There is no blood draw required for the test, and best of all, the results are completely confidential.

According to the U.S. Centers for Disease Control and Prevention, more than one million people are living with HIV in the United States. More than one in five of those people living with HIV are unaware of their infection. Don’t live your life wondering if you are HIV-positive. Use the OraWell USA Oral HIV Rapid Test to find out the answer – the fast and easy way.

Reliable & Confidential HIV Test Results at Home

The OraWell Oral HIV Rapid Test 1&2 is a fully approved at-home test recommended by doctors and proven to deliver results with more than 99.98% accuracy. The test comes with supplies so patients can collect their own specimen of saliva as well as a panel to place the specimen onto for analysis. It’s as easy as collecting a sample of saliva and placing it on an easy-to-use specimen tray.

In about 10 minutes, patients using the test can learn the results, which are produced with a simple positive or negative response. There is no complicated scientific analysis of the results or confusing medical terminology to understand, so the OraWell Oral HIV Rapid Test is suitable for all users.

HIV and AIDS: Learn the Facts

It has been proven that acquired immunodeficiency syndrome (AIDS) is caused by viruses which are transmitted by sexual contact, blood transfusion, using contaminated blood products, and sharing contaminated needles. HIV-1 and 2 viruses, which may lead to AIDS, deplete T-helper cells in the body, leaving AIDS patients more susceptible to opportunistic infections and developing malignant tumors.

Patients with AIDS or those who are at risk of contracting the disease have a higher incidence of specific antibodies. The OraWell HIV-1&2 Antibody Saliva Rapid Screen Test was designed to detect these antibodies and identify any potential donors who are carrying these antibodies in their saliva.

OraWell At-Home HIV Test: How it Works

The OraWell HIV-1&2 Antibody Saliva Rapid Screen Test is a chromatographic immunoassay for the detection of antibodies to HIV-1&2 in human saliva. HIV-1&2 antibodies with binding protein are precoated onto membrane as capture reagents. During the testing, a specimen is allowed to react with the colloidal gold reagents which have been labeled with HIV- 1&2 specific antigens. If present in the saliva specimen, the antibodies will cause a pink-colored band to develop on the membrane in proportion to the amount of HIV-1&2 antibodies detected. A negative test result is indicated by an absence of this pink colored band in the test. As a procedural control, a pink-colored band will always appear in the control region of the test, regardless of the presence or absence of the antibodies.

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Progress Made on AIDS Vaccine

By Mercer R. Cook, CRIMSON STAFF WRITER
Published: Wednesday, April 06, 2011

A medical breakthrough in HIV prevention could eventually lead to the development of an AIDS vaccine, due to a recent discovery by researchers at the Harvard-affiliated Dana-Farber Cancer Institute.

Scientists took an antibody from an HIV-positive man who had not shown any symptoms of AIDS even after a decade of having HIV and administered it to rhesus monkeys. They then injected the monkeys with a form of the human HIV virus that was mutated so it could spread in monkeys.

Although the virus in the monkeys was a different strain than the original human virus, the antibody still effectively prevented the onset of AIDS symptoms. Monkeys who were administered the antibody remained completely symptom-free, while monkeys without the antibody suffered all of the normal effects of the virus.

This finding is significant because one of the fundamental challenges in the development of an HIV vaccine is accounting for the millions of different strains of the highly-mutable HIV virus. Due to the variance, an effective and practical vaccine must target commonalities between the strains.

“The big problem with so many millions of HIV virus out there is there needs to be a way to target the common theme,” said Harvard Medical School Professor Ruth M. Ruprecht, senior author of the study. “This is a step in the direction of identifying targets for vaccines.”

In this study, researchers were able to discover a similarity between multiple strains of the virus by discerning what part of the virus was targeted by the antibody.

Medical School instructor Nagadenahalli B. Siddappa, one of the lead authors of the study, also stressed the importance of the antibody’s apparently universal protective qualities, noting the difficulty scientists often face when attempting to develop a preventative vaccine for a continually evolving virus.

“[Scientists] always see different viruses,” he said. “This could be very useful.”

While researchers said they were excited about this finding and its potential significance, they also stressed that there is still a long way to go before any type of preventative vaccine is actually ready for use on humans. An active immunization, which could be widely administered to the public, must allow antibodies to be produced on their own by the body.

“The next step is to see if we can focus active immunization on the portion of the [virus] that is conserved,” Ruprecht said. “At the same time, we are trying to find other regions that are conserved” between strains.

Ruprecht also explained that this antibody is not thought to be a cure, though she left the possibility open.

“This is a different clinical situation,” she said. “This is not about the cure.”

—Staff writer Mercer R. Cook can be reached at mcook@college.harvard.edu.

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EASL: Telaprevir Add-On Effective After Initial HCV Therapy Fails

Daniel M. Keller, PhD

April 6, 2011 (Berlin, Germany) — Telaprevir added to standard pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) therapy for hepatitis C virus (HCV) infection was superior to retreatment with peg-IFN/RBV plus placebo in patients for whom standard therapy had failed in the past, researchers announced here at the European Association for the Study of the Liver (EASL) 46th Annual Meeting.

The safety and tolerability of adding telaprevir were similar to results seen in previous trials. Adverse events leading to permanent discontinuation of the drugs consisted mainly of anemia and rash, and were more prevalent in the telaprevir groups than in the control group.

Standard combination therapy with peg-IFN/RBV fails in approximately 60% of patients with HCV genotype 1, which is one of the more difficult genotypes to eradicate, noted Stefan Zeuzem, MD, chief of the Department of Medicine and professor of medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, who presented the study results.

The aim of the Re-Treatment of Patients With Telaprevir-Based Regimen to Optimize Outcomes (REALIZE) trial was to test the addition of telaprevir, a new small-molecule HCV protease inhibitor, to peg-IFN/RBV in 662 patients with HCV genotype 1 for whom peg-IFN/RBV had previously failed to produce sufficient and sustained viral suppression.

The primary objective of this pivotal phase 3 international, multicenter, double-blind, placebo-controlled trial was to compare the proportion of patients achieving a sustained virologic response (SVR) with telaprevir plus peg-IFN/RBV and the proportion achieving an SVR with placebo plus peg-IFN/RBV. All SVRs were below 25 IU HCV RNA (undetectable level).

Patients were divided into 3 categories: null responders did not show at least a 2 log10 drop in serum HCV RNA at week 12 of previous standard therapy; partial responders experienced at least a 2 log10 drop at week 12 of previous therapy but still had detectable HCV RNA in the blood at week 24; and relapsers achieved viral levels below the limit of detection at 42 weeks but then had a recurrence of detectable virus.

The groups were well matched at baseline. Approximately 70% were men, median age was approximately 50 years, 93% were white, HCV RNA was above 800,000 IU/mL in 86% to 89%, and almost 60% were in the advanced stages of disease with bridging fibrosis or cirrhosis (26%). About half were infected with genotype 1a and about half with genotype 1b. About 30% were previous nonresponders, 20% were partial responders, and 50% were previous relapsers.

Patients were randomly assigned to 1 of 3 treatment groups: 266 patients received telaprevir + peg-IFN/RBV for 12 weeks, then placebo + peg-IFN/RBV for 4 weeks (T12/PR48); 264 patients received a lead-in of placebo + peg-IFN/RBV for 4 weeks, then telaprevir + peg-IFN/RBV for 12 weeks (lead-in T12/PR48); and 132 patients received placebo + peg-IFN/RBV for 16 weeks (placebo/PR48).

In these 3 groups, drug doses were as follows: telaprevir 750 mg every 8 hours; peg-IFN 180 µg/week; and RBV 1000 to 1200 mg/day. The groups were followed-up and assessed for SVR at week 72. The primary statistical calculations were on previous relapsers and on previous nonresponders (a combination of previous partial responders and null responders).

Dr. Zeuzem reported that among previous relapsers, 83% to 88% achieved an SVR when treated with telaprevir plus peg-IFN/RBV. Less than 10% of them relapsed by week 72. In contrast, only 41% of previous nonresponders achieved an SVR with telaprevir, but this figure was still a 4-fold increase over the proportion with an SVR when retreated with peg-IFN/RBV and placebo. Overall, about 35% of patients in the 2 telaprevir groups failed to achieve an SVR; those failures occurred mainly among previous partial and previous null responders.

Addition of Telaprevir to Peg-IFN/RBV Enhances SVR Rates

Patient Group T12/PR48, % (n/N) Lead-in T12/PR48, % (n/N) Placebo/PR48, % (n/N)

Previous Relapsers
SVRa  83 (121/145)c  88 (124/141)c  24 (16/68)
Relapseb 7 (10/135)  7 (9/138)  65 (30/46)

Previous Nonresponders
SVRa  41 (50/121)c  41 (51/123)c  9 (6/64)
Relapseb  23 (16/69)  25 (18/72)  33 (3/9)

a SVR assessed 24 weeks after planned treatment completion
b Relapse: detectable virus at week 72 in patients with undetectable HCV RNA at end of assigned treatment
c  P < .001, comparison vs placebo/PR48

"The SVR rates tended to be higher in genotype 1b–infected patients, in particular in prior partial responders and prior null responders," Dr. Zeuzem reported. "The lead-in phase [group] showed numerically slightly higher [SVR] rates in the prior relapsers and the prior nonresponders, but there was an opposite trend for the prior partial responders."

When the data were analyzed by the degree of baseline fibrosis, all subgroups of patients responded better to telaprevir than to peg-IFN/RBV plus placebo. For example, among previous relapsers, 86%, 85%, and 84% achieved an SVR with telaprevir if they had no fibrosis, bridging fibrosis, or cirrhosis, respectively, compared with 32%, 13%, and 13%, respectively, with peg-IFN/RBV plus placebo. The addition of telaprevir added little or no benefit over peg-IFN/RBV alone for previous partial or null responders with cirrhosis.

Dr. Zeuzem noted that adverse events, which occurred at least 10% more frequently in the telaprevir groups than in the placebo group, were fatigue, pruritis, rash, anemia, nausea, diarrhea, and anorectal symptoms (described as pruritis, discomfort, or hemorrhoids).

The majority of adverse effects were grade 1 or 2, with some grade 3 rash in the pooled telaprevir groups. Rash was primarily eczematous, which resolved when therapy ended. Anemia was managed with RBV dose reduction when necessary, which occurred in 25% of the telaprevir-treated patients. Per protocol, erythropoiesis-stimulating agents were not permitted. In the telaprevir groups, 11% to 15% discontinued treatment because of adverse events; in the placebo group, 3% did.

Dr. Zeuzem concluded that "telaprevir/peg-interferon-ribavirin triple therapy was clearly superior to the standard peg-interferon/ribavirin treatment alone" in all 3 treatment-experienced populations."

He said a 4-week lead-in phase with peg-IFN/RBV did not reduce virologic failure or relapse rates and did not improve SVR rates. He noted that the safety of telaprevir was similar to that observed in previous studies. Adverse events, mainly anemia and rash, led to permanent discontinuation of study drugs more frequently in the telaprevir groups than in the control group.

Mark Thursz, MD, professor of hepatology at Imperial College, London, United Kingdom, and vice secretary of EASL, said: "I think these are very responsible conclusions . . . and I feel that the data that are coming out on this particularly difficult-to-treat group of patients — those who had previous treatment and failed — these are really exciting results. Overall, something like 60% of patients were successfully treated [and] reached an SVR in the REALIZE trial." He added that "partial responders [did] so-so; null responders, not so good. This is disappointing but not entirely surprising. They are particularly difficult groups to treat."

Dr. Thursz, who was not involved in the REALIZE trial, said that for patients for whom previous therapy has failed, "now we have treatment options to offer them, assuming that the commissioning authorities will pay for [the drugs] for those who don't pay for their own therapy."

In response to a question from the audience about the rashes and the possibility of Stevens–Johnson syndrome, Dr. Zeuzem said that of the several thousand people exposed to telaprevir, "to the very best of my knowledge, there is only 1 case of Stevens–Johnson syndrome described, but this case occurred after telaprevir was already discontinued, so a causal relationship cannot be justified from this single case. But I know that this single case has made many people very nervous."

Although anemia was more frequent in the telaprevir groups, "we have learned to manage anemia in this group of patients," Dr. Thursz said. "Most patients can tolerate more anemia than the pharmaceutical companies can."

Telaprevir is being developed by Vertex Pharmaceuticals. The US Food and Drug Administration has granted the drug priority review, which is expected on May 23.

Dr. Zeuzem reports relationships with Abbott, Achillion, Anadys, BMS, Gilead, iTherX, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, and Vertex. Dr. Thursz has disclosed no relevant financial relationships.

European Association for the Study of the Liver (EASL) 46th Annual Meeting: Opening session. Presented March 30, 2011.

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Roche Joins in Spanish Research Cooperation for Personalized Treatment of Hepatitis B and C

April 06, 2011 08:00 AM Eastern Daylight Time

PENZBERG, Germany--(BUSINESS WIRE)--Roche Diagnostics (SIX: RO, ROG; OTCQX: RHHBY) is cooperating with the Spanish Vall d’Hebron Institute of Research (VHIR), the Networking Biomedical Research Centre in Liver and Digestive Diseases (CIBEREHD), and the software producer Advanced Biological Laboratories Therapy Edge Spain (ABL) in a study designed to resolve the current limitations that prevent the individualization of anti-HBV and anti-HCV (hepatitis B and C) treatments. The project will utilize Roche’s 454 Sequencing Systems and bioinformatics analysis, together with other genetic and molecular analytical techniques. Ultimately, the research project aims to identify personalized treatment for each individual while minimizing the healthcare costs and side effects experienced by subjects.

Hepatitis C (HCV) infection affects 3% of the world population, representing a chronic disease for nearly 180 million people. Many infected individuals acquire the disease 15-25 years before identification of the virus and the use of diagnostic tests. The infection remains asymptomatic until advanced stages of the disease characterized by complications such as decompensated cirrhosis or hepatocellular carcinoma. While in the early stages resource use for controlling the disease is very limited, in the advanced stages resource consumption is enormous, and a significant percentage of individuals even require liver transplantation – with the resulting increase in direct and indirect costs, loss of quality of life and increased morbidity-mortality.

“The hepatitis C and B viruses exhibit great variability; a person infected with one of these viruses presents a complex population of variants comprising a structure known as ‘quasispecies’. The identification of these variants may be crucial for avoiding the selection of variants resistant to the new antiviral therapies,” explains Dr. Juan Ignacio Esteban-Mur, head of the line in hepatitis C, molecular biology, immune response and treatment of the liver diseases at VHIR. Dr. Esteban-Mur also is the coordinator of the viral hepatitis program of the CIBERHED, which comprises 8 Spanish research groups, specialized in this field.

The use of 454 Sequencing Systems makes it possible to gain a comprehensive profile of the complex viral populations that circulate in individuals, with the fundamental purpose of identifying the presence of viral quasispecies resistant to the existing antiviral treatments. The goal of the study is to apply this massively parallel sequencing approach to personalize the antiviral treatment strategies in individuals with chronic hepatitis C or B.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2010, Roche had over 80’000 employees worldwide and invested over 9 billion Swiss francs in R&D. The Group posted sales of 47.5 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: http://www.roche.com/.

For life science research only. Not for use in diagnostic procedures.

454, 454 LIFE SCIENCES, and 454 SEQUENCING, are trademarks of Roche.

Other brands or product names are trademarks of their respective holders.

Contacts
Roche Diagnostics
Dr. Burkhard Ziebolz
Phone: +49 8856 604830
Email: burkhard.ziebolz@roche.com

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Maintenance Therapy With Peginterferon Alfa-2b Does Not Prevent Hepatocellular Carcinoma in Cirrhotic Patients With Chronic Hepatitis C

Gastroenterology. 2011 Mar 16. [Epub ahead of print]

Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, Berg T, Poo JL, Mello CB, Guenther R, Niederau C, Terg R, Bedossa P, Boparai N, Griffel LH, Burroughs M, Brass CA, Albrecht JK; EPIC(3) Study Group.

BCLC Group; Liver Unit, Hospital Clinic of Barcelona, University of Barcelona; IDIBAPS, Centro de Investigación Biomédica en Red de Hepatología y Enfermedades Digestivas, Barcelona, Spain.

Abstract

BACKGROUND & AIMS: Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC(3)) program.

METHODS: Data was analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n = 311) or no treatment (controls, n = 315) for a maximum period of 5 years, or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event.

RESULTS: There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b, compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI], 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b, compared with controls (HR, 1.564; 95% CI, 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event, compared with controls ( P =.016). There were no new safety observations.

CONCLUSIONS: Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21419770 [PubMed - as supplied by publisher]

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Metabolic Syndrome Identified as Risk Factor for Liver Cancer

Roxanne Nelson

April 5, 2011 (Orlando, Florida) — Metabolic syndrome is a known risk factor for diabetes and heart disease, but researchers now report that it might also place individuals at higher risk for the development of liver cancer.

According to data presented here at the American Association for Cancer Research 102nd Annual Meeting, metabolic syndrome is associated with an increased risk of developing hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

The authors found that 37.1% of patients with hepatocellular carcinoma and 29.7% with intrahepatic carcinoma had preexisting metabolic syndrome. Conversely, only 17.1% of individuals without cancer had metabolic syndrome.

"Given the high and increasing rates of obesity, the metabolic syndrome, and nonalcoholic fatty liver disease in the United States, this is a very important and timely study," said Lewis Roberts, PhD, who was approached by Medscape Medical News for independent comment. "It shows that the rates of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma are higher in individuals with the metabolic syndrome."

"It is important for physicians and other healthcare workers to be aware of these associations, as people with metabolic syndrome are not generally viewed as being at high risk for these cancers," explained Dr. Roberts, professor of medicine at the Mayo Clinic in Rochester, Minnesota.

Although the specific mechanism linking these 2 conditions is still undefined, Dr. Roberts pointed out that metabolic syndrome is associated with increased inflammation in the liver and other tissues. "Inflammation is an important cause of cell injury and genetic damage to cells; this is a potential link between the metabolic syndrome and both hepatocellular carcinoma and intrahepatic cholangiocarcinoma," he said.

There is an urgent need for more research in this area to further our understanding of the specific mechanisms that drive cancer development in individuals with metabolic syndrome and to determine whether there are low-risk methods that can be used to prevent cancer development, he added.

Incidence Rising in the United States

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are the 2 most common histologic types of primary liver cancer.

"In the United States, hepatocellular carcinoma is by far the most common, and accounts for about 70% of all primary liver cancers, whereas intrahepatic cholangiocarcinoma accounts for about 17%," said lead author Katherine McGlynn, PhD, a senior investigator at the National Cancer Institute.

Dr. McGlynn also noted that liver cancers are far more common among racial/ethnic minorities in the United States, especially hepatocellular carcinoma. Compared with white Americans, the incidence among all racial/ethnic minorities is at least 2-fold higher. The incidence of both types of cancer is rising; since the early 1970s, the incidence of hepatocellular carcinoma has jumped 212%, and the incidence of intrahepatic cholangiocarcinoma has risen by about 85%.

Metabolic syndrome, which is a collection of symptoms characterized by increased fasting glucose level, central adiposity, dyslipoproteinemia, and hypertension, has been previously linked to hepatocellular carcinoma, she explained, but the magnitude of the association has not been investigated at the population level in the United States.

"By the early years of the 21st century, unfortunately, over a third of the population is thought to have metabolic syndrome," she said. "Unfortunately, the prevalence is higher in some racial/ethnic minorities. Mexican Americans have a prevalence of about 45%."

Significantly More Common

Dr. McGlynn and colleagues used the Surveillance, Epidemiology, and End Results Program (SEER)–Medicare linked database to identify all people 65 years and older who were diagnosed with histologically confirmed hepatocellular carcinoma and intrahepatic cholangiocarcinoma between 1993 and 2005.

A total of 3,649 hepatocellular carcinoma cases and 743 intrahepatic cholangiocarcinoma cases were identified, as were 195,953 individuals without cancer who met the study inclusion criteria.

The team found that metabolic syndrome was significantly more common among people who developed liver cancer. After adjustment for demographic features and other risk factors, metabolic syndrome remained significantly associated with an increased risk for hepatocellular carcinoma (odds ratio [OR], 2.13; 95% confidence interval [CI], 1.96 to 2.31; P < .0001) and intrahepatic cholangiocarcinoma (OR, 1.56; 95% CI, 1.32 to 1.83; P < .0001).

Interventions Needed

As obesity rates continue to rise in the United States, so will the incidence of metabolic syndrome. Better interventions/methods are needed for initiating changes in diet and lifestyle, Dr. Roberts said.

Experts in the liver cancer field are very concerned that as efforts to limit the spread of hepatitis C and hepatitis B, currently the most common causes of liver cancer in the United States, are more and more successful, the metabolic syndrome and fatty liver disease will become the predominant causes of an increasing epidemic of liver and biliary cancers," he said.

"It is critical to initiate and support the necessary dietary and lifestyle interventions for preventing the development of metabolic syndrome, particularly in children and young adults," Dr. Roberts added.

American Association for Cancer Research (AACR) 102nd Annual Meeting: Abstract 945. Presented April 3, 2011.

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Factors that Affect Risk for Hepatocellular Carcinoma and Effects of Surveillance

Clinical Gastroenterology and Hepatology

Article in Press

Ju Dong Yang, William S. Harmsen, Seth W. Slettedahl, Roongruedee Chaiteerakij, Felicity T. Enders, Terry M. Therneau, Lucinda Orsini, W. Ray Kim, Lewis R. Roberts

Received 9 December 2010; received in revised form 25 February 2011; accepted 21 March 2011. published online 04 April 2011.
Accepted Manuscript

Abstract

Background & Aims
The incidence of hepatocellular carcinoma (HCC) in the United States is increasing. Surveillance might affect the stage at diagnosis and consequently the treatment options available for HCC. We evaluated risk factors for HCC, the proportion of cases detected via surveillance, tumor characteristics, treatment approaches, and overall patient survival in a referral center cohort.

Methods
The study included all patients diagnosed with HCC at the Mayo Clinic, Rochester, MN, from 2007 to 2009 (n=460). Clinical information was retrospectively abstracted from the medical record.

Results
Hepatitis C virus (HCV, 36%), alcohol use (29%), and nonalcoholic fatty liver disease (NAFLD, 13%) were the most common risk factors for HCC. HCV was present in 56% of patients younger than 60. NAFLD was present in 19% of patients older than 60. HCC was detected during surveillance in 31% of patients. Patients with worse liver function were more likely to be on surveillance. Transarterial chemoembolization, surgical resection, and liver transplantation were the most common treatment approaches for HCC. Patients diagnosed with HCC during surveillance had less-advanced disease, were more likely to be eligible for potentially curative treatments, and had increased survival times ( P <0.001).

Conclusion
At a major US referral center, the predominant HCC etiologies were HCV, alcohol use, and NAFLD. HCCs were detected during surveillance in the minority of patients. HCCs detected during surveillance were of less-advanced stage and patients were more likely to receive treatment that prolonged their survival.

Keywords: Etiology, surveillance, treatment, survival

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Merck, J&J’s New Hepatitis C Treatment Fetches $31,000 in France

By Naomi Kresge and Carol Matlack - Apr 4, 2011 4:15 PM ET
 
New hepatitis C drugs from Merck & Co. and Johnson & Johnson (JNJ) are being sold in France for 22,000 euros ($31,271) and more, a precedent some doctors say may limit access after the medicines are approved throughout Europe.
 
J&J and Vertex Pharmaceuticals Inc. (VRTX)’s telaprevir costs 22,000 euros under a French program for seriously ill patients for whom there is no other effective treatment on the market, according to patient association SOS Hepatites. Merck & Co. said its boceprevir costs 30,000 euros under the same program.

The price may drop once the drugs are approved for the broader market, Merck and J&J executives said. Still, the French model shows the new drugs may triple the cost of hepatitis C treatment, leaving England, Russia and eastern Europe likely to delay use or restrict which patients are allowed access, said Antonio Craxi, director of gastroenterology and internal medicine at the University of Palermo.

“It may be that we can’t use it at all until the price comes down,” Mark Thursz, professor of hepatology at Imperial College London, said in an interview at a conference in Berlin over the weekend. “It’s not the best economic environment to launch an expensive new drug.”

The U.K.’s National Institute for Health and Clinical Excellence may restrict the new drugs to patients who have tried existing treatments without success, Thursz said. The agency may also require genetic tests to determine whether patients are likely to respond to the medicines, he said at the meeting of the European Association for the Study of the Liver.

‘Triple the Cost’

Italy and Spain also may delay or restrict use, Craxi said. Italy spends about 350 million euros a year on existing hepatitis C treatments, he said. “If you triple the cost, that would be more than 1 billion euros,” he said.

Vertex fell 10 cents, or less than 1 percent, to $47.49 at 4 p.m. New York time in Nasdaq Stock Market composite trading. Merck rose 20 cents, or less than 1 percent, to $33.27 in New York Stock Exchange composite trading. J&J increased 66 cents, or 1.1 percent, to $60.15.

The new drugs are being reviewed by regulators at the European Medicines Agency. Both are scheduled for U.S. Food and Drug Administration hearings at the end of this month.

In France, telaprevir and boceprevir received special temporary authorization in December, under a program designed for seriously ill patients for whom there is no other effective treatment on the market, according to French pharmaceutical regulator AFSSAPS. This allowed the drugs to bypass the usual approval procedures, the regulator said.

500 Patients

About 500 patients are being treated in France now, said Michel Bonjour, spokesman for SOS Hepatites. The new drugs are prescribed together with the current standard therapy of interferon and generic ribavirin, and the total cost of a yearlong cycle of treatment may reach 45,000 euros to 70,000 euros per patient, Bonjour said in an interview. The cost is covered in full by France’s national health insurance program.

“It’s not a good indication of price elsewhere,” Patrick Bergstedt, senior vice president for vaccines and infectious diseases at Whitehouse Station, New Jersey-based Merck, said in an interview.

The very sick patients in the French program get 44 weeks of treatment with boceprevir, while a more typical course of therapy is 24 weeks to 32 weeks, he said. There’s a “high likelihood” the eventual commercial price for a course of treatment will be less than the 30,000 euros Merck charges under the French program, he said.

‘Cost Effective’

“It’s black and white that these drugs are cost- effective,” Bergstedt said. “The challenge will be how do you stratify treatment, and how do you use these drugs responsibly to ensure the patients with the greatest need are treated first.”

Vertex, based in Cambridge, Massachusetts, referred questions to partner J&J, which will market telaprevir in Europe. J&J hasn’t decided on a final price, said Isabelle Lonjon-Domanec, global medical affairs leader for telaprevir at the New Brunswick, New Jersey-based company’s Tibotec Therapeutics unit.

Patients take telaprevir for 12 weeks together with standard treatment, then continue on the older standard drugs for a total of six months to a year of therapy.

Both new hepatitis C drugs are protease inhibitors crafted from the same technologies that led to discoveries in HIV research. Used in addition to existing therapies, they boost the chance of a cure from half of patients to between two-thirds and three-quarters of those treated, studies have shown.

U.S. Pricing

In the U.S., the new drugs may be priced at $35,000 to $40,000, estimates Howard Liang, a Boston-based analyst at Leerink Swann & Co.

“A cure saves a lot of money down the road,” Liang said in an interview. “It’s a shock to physicians, but I think it can be justified because it’s a cure.”

Hepatitis C, spread through contact with infected blood, is a virus that often lingers as a chronic condition, causing nausea and exhaustion as it destroys the liver over the course of years or decades. About 170 million people are infected, according to the World Health Organization.

Meanwhile, the next generation of drugs with even higher cure rates and fewer side effects is likely to reach the market within three years, Liang said.

Swedish drugmaker Medivir AB (MVIRB) has said it expects to begin selling a competitor pill to be used with interferon by 2013. Boehringer Ingelheim GmbH, Gilead Sciences Inc. (GILD) and Bristol- Myers Squibb Co. are among a dozen companies aiming for drug cocktails to replace the existing interferon combination.

Looming competition leaves Merck, Vertex and J&J without much time to recoup their investment, said Charles Gore, president of the Geneva-based patient advocacy group World Hepatitis Alliance.

“There is no easy answer to this,” Gore said in an interview. “We’ve got to have a way to give people access but incentivize the drug companies to research in this area.”

To contact the reporters on this story: Naomi Kresge in Berlin at nkresge@bloomberg.net; Carol Matlack in Paris at cmatlack@bloomberg.net

To contact the editors responsible for this story: Phil Serafino at pserafino@bloomberg.net;

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Cholesterol Regulator Plays Key Role in Development of Liver Scarring, Cirrhosis

Treated with a control substance, livers from normal and LXR-deficient mice appear identical and undamaged (top left and right). The bottom images show the greater degree of fibrosis (blue bands) in the livers of mice lacking LXRs (right) compared to normal mice (left) after liver injury. (Credit: UCLA)

ScienceDaily (Apr. 4, 2011) — UCLA researchers have demonstrated that a key regulator of cholesterol and fat metabolism in the liver also plays an important role in the development of liver fibrosis -- the build-up of collagen scar tissue that can develop into cirrhosis. Cirrhosis, in turn, is a major cause of premature death and is incurable without a liver transplant.

Published in the March issue of the journal Gastroenterology, the study shows that liver X receptors (LXRs), master regulators of cholesterol, fat and inflammatory gene expression, also control the fibrosis-making cells of the liver, known as hepatic stellate cells.

In the face of chronic liver injury -- due to excess fat, chronic viral hepatitis or alcohol abuse, for example -- stellate cells become activated and launch an inflammatory and fibrotic cascade that eventually results in the build-up of collagen scar tissue in the liver.

LXRs, when stimulated, "turn on" several hundred genes that hold instructions to create proteins for carrying out bodily processes in cells, from transporting and excreting cholesterol to synthesizing fat in the liver. They have also been shown to suppress inflammatory processes in several contexts.

"Our work sets the stage for looking at new ways to modulate cholesterol and/or fat metabolism in order to have therapeutic potential for the treatment of fibrosing liver diseases," said lead author Dr. Simon Beaven, an assistant professor of digestive diseases at the David Geffen School of Medicine at UCLA.

The research was done in the laboratory of senior author Dr. Peter Tontonoz, a professor of pathology and laboratory medicine at the Geffen School of Medicine and a Howard Hughes Medical Institute investigator.

Beaven noted that the recent rise in obesity has resulted in a surge in the prevalence of a condition known as fatty liver, which can be a precursor to fibrosis and chronic liver disease. Simple fatty liver, also known as non-alcoholic fatty liver disease, or NAFLD, is one of the most common reasons patients consult a liver doctor in the United States. Cirrhosis due to fatty liver is skyrocketing and within a decade may become the most common indication for liver transplantation.

Beaven said the need to find better treatments for liver disease is crucial.

"A 'holy grail' for liver researchers is to develop anti-fibrotic treatments that target activated stellate cells in order to slow or prevent the development of cirrhosis," Beaven said. "Our study offers the first detailed look at how LXRs specifically impact the activation of hepatic stellate cells and the subsequent development of liver fibrosis in animal models."

UCLA researchers have found that LXRs normally play a role in helping to reduce the collagen-producing actions of stellate cells when the cells are "activated" by liver damage. For the study, UCLA scientists first tested how activated stellate cells taken from mice would react when a chemical that induces LXR activity was added to the cell culture.

In stellate cells from normal mice, LXRs suppressed the inflammatory and fibrosis-promoting program. But in those taken from mice genetically lacking LXRs, that same program of genes significantly increased because the inhibitory effect of LXRs was no longer present.

"We showed that LXRs dampen stellate cell activation by repressing inflammatory and collagen-producing genes," Beaven said.

To further gauge the strength of the response, scientists took the medium from the cultures of LXR-deficient cells and added it to stellate cells from normal mice. These cells then showed a markedly exaggerated inflammatory and collagen-producing response, suggesting that LXR-deficient stellate cells are secreting signals to promote fibrosis.

The researchers noted that these experiments demonstrate that LXRs control a fibrotic response in stellate cells that can have a wide influence on neighboring cells.

The scientists also found that after replicating chronic liver injury, mice without LXRs had dramatically more liver fibrosis than normal mice.

"The genetic loss of LXRs rendered the mice susceptible to developing fibrotic liver disease," Beaven said.

But LXRs are also known to have important functions in the immune system. The researchers then wanted to know whether the effects they were seeing in animals were due to changes in stellate cell activity specifically or whether immune cells -- derived from bone marrow -- accounted for most of the effect. After extensive testing, the researchers found no differences

in the level of liver fibrosis among normal mice and animals lacking LXRs, suggesting that the contribution from the immune system was negligible.

"This finding, along with the cell culture studies, suggests that LXRs' influence on fibrosis most likely resides in altering stellate cell function in the liver," Beaven said. "This is a critical finding and opens an entire new field of study for stellate cell biologists."

Additional studies will further identify which genes in stellate cells are activated by LXRs and help researchers better understand the role of cholesterol metabolism in the fibrotic response.

This study was funded primarily by grants from the National Institutes of Health and the Howard Hughes Medical Institute. Collaborators from the University of Southern California were funded by core grants from the NIH and the Southern California Research Center for ALPD and Cirrhosis.

Other study authors included senior investigator Dr. Peter Tontonoz of the Howard Hughes Medical Institute; Kevin Wroblewski and Cynthia Hong from Tontonoz's lab; Jiaohong Wang and Hide Tsukamoto of the Southern California Research Center for ALPD and Cirrhosis, USC's Keck School of Medicine and the Department of Veterans Affairs Greater Los Angeles Healthcare System; and Steven Bensinger of the department of pathology at the David Geffen School of Medicine at UCLA.

Journal Reference:

1.Simon W. Beaven, Kevin Wroblewski, Jiaohong Wang, Cynthia Hong, Steven Bensinger, Hide Tsukamoto, Peter Tontonoz. Liver X Receptor Signaling Is a Determinant of Stellate Cell Activation and Susceptibility to Fibrotic Liver Disease. Gastroenterology, 2011; 140 (3): 1052 DOI: 10.1053/j.gastro.2010.11.053

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Peregrine's PS-Targeting Antibody Significantly Improves Anti-Tumor Effect of Sorafenib in Models of Advanced Liver Cancer

Apr 05, 2011 08:00 ET

AACR Data Presentation Supports Phase I/II Investigator-Sponsored Clinical Trial in Advanced Liver Cancer

TUSTIN, CA and ORLANDO, FL--(Marketwire - April 5, 2011) - Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced that its phosphatidylserine (PS)-targeting antibody significantly enhanced the anti-tumor effects of sorafenib (Nexavar®) in models of hepatocellular carcinoma (HCC), with 69% less tumor growth compared to sorafenib alone. This study, one of four poster presentations on Peregrine's PS-targeting antibodies at the Annual Meeting of the American Association of Cancer Research (AACR), was the basis for initiating a Phase I/II investigator-sponsored trial (IST) evaluating the company's lead antibody bavituximab with sorafenib in patients with advanced HCC. Bavituximab is currently in three randomized Phase II clinical trials in lung cancer and pancreatic cancer and several ISTs for additional oncology indications.

"Our studies show that sorafenib more than doubles the amount of the immunosuppressive molecule PS exposed on the blood vessels of HCC tumors," said Philip E. Thorpe, Ph.D., professor of pharmacology at UT Southwestern Medical Center, scientific adviser to Peregrine and inventor of the company's PS-targeting antibody technology. "These data suggest that the growth-blocking mechanisms of sorafenib combined with the vascular-targeting and immune-reactivation mechanisms of bavituximab may offer additive anti-tumor effects for patients with HCC."

As presented today at AACR, tumor growth was 69% less for the group receiving Peregrine's antibody in combination with sorafenib than for the group receiving sorafenib alone (mean tumor weight of 127 mg versus 409 mg, n=10, p < 0.01) after 59 days of treatment in an animal model study. Immunofluorescence analysis showed that treatment with Peregrine's antibody in combination with sorafenib decreased tumor blood vessel density from 14.2% to 4.5% (p < 0.01), versus 10.3% (p < 0.05) for Peregrine's antibody or 8.4% (p < 0.01) for sorafenib alone.

A copy of the AACR poster is available at Peregrine's website at http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html.

About the Phase I/II HCC Investigator-Sponsored Trial

In an ongoing open-label Phase I/II trial, patients with advanced HCC are receiving bavituximab weekly and sorafenib (400 mg) twice daily, until disease progression or toxicity. Phase I of the trial is dose escalation (0.3, 1 or 3 mg/kg) to determine the maximum tolerated dose (MTD) and Phase II is expansion of the study at the MTD. Approximately 50 patients are being enrolled in this trial, which is being conducted at UT Southwestern Medical Center.

Primary objectives are to determine the MTD of bavituximab in patients with advanced HCC treated with sorafenib and the radiographic median time to progression. Secondary objectives include response rate, progression free-survival, overall survival, safety and tolerability. Further information about this trial is available at PeregrineTrials.com, UT Southwestern Medical Center Clinical Trials, and ClinicalTrials.gov.

About Peregrine's Investigator-Sponsored Trials (IST) Program

Peregrine's IST program offers oncologists the opportunity to conduct clinical trials using bavituximab in solid tumor indications.

About Bavituximab

Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor.

About Hepatocellular Carcinoma (HCC)

According to the National Cancer Institute, primary liver and bile duct cancers are the sixth most common cause of cancer death in men, and ninth most common in women. Approximately 24,000 new cases of these two cancers are expected to be diagnosed this year in the United States, with approximately 19,000 deaths attributable to these forms of cancer. The most common risk factor for liver cancer is chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. Currently approved treatment options for HCC are surgery, radiation, chemotherapy, targeted therapeutics, tumor ablation, and tumor embolization.

Xiaoyun Cheng and Philip E. Thorpe, UT Southwestern Medical Center, Dallas, TX. Phosphatidylserine-targeting antibody combined with sorafenib has strong anti-tumor activity against human hepatocellular carcinomas in mice. In Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research (AACR); 2011 Apr 2-6; Orlando, FL. Abstract 2643.

About Peregrine Pharmaceuticals

Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com/.

Nexavar® (sorafenib) is a registered trademark of Onyx Pharmaceuticals/Bayer Healthcare.

Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that results from investigator-sponsored trials will not be consistent with results experienced in earlier clinical trials and preclinical studies, the risk that investigators may experience delays in patient enrollment, risk that results may not support registration filings with the U.S. Food and Drug Administration, and the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs. Factors that could cause actual results to differ materially or otherwise adversely impact the company's ability to obtain regulatory approval for its product candidates include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company's SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2010 and the quarterly report on Form 10-Q for the quarter ended January 31, 2011. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.

Peregrine Contact:
Amy Figueroa
Peregrine Pharmaceuticals
(800) 987-8256
info@peregrineinc.com

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EASL: Jennerex and Transgene Announce the Presentation of Positive Clinical Data of JX-594 in Patients With Liver Tumors

SAN FRANCISCO and ILLKIRCH, France, April 5, 2011 /PRNewswire/ -- Jennerex, Inc., a private clinical-stage biotherapeutics company focused on the development and commercialization of first-in-class targeted oncolytic products for cancer, and Transgene (NYSE Euronext Paris: FR0005175080), a bio-pharmaceutical company specialized in the development of immunotherapeutic products, today announced that new data from Phase 1 and 2 clinical studies of JX-594 were presented in an oral presentation at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) over the weekend at the Internationales Congress Centrum in Berlin, Germany.

The data from abstract #LB-283, entitled "JX-594, A Targeted Multi-Mechanistic Oncolytic Poxvirus, is Well-Tolerated and Exhibits Anti-Tumor Activity in Patients with Primary Liver Cancer and Liver Metastases," were presented by Caroline Breitbach, Ph.D., director of translational research.

"We are pleased to present these data on JX-594 at the EASL meeting, as they provide further evidence that both primary liver cancer and metastases to the liver can be treated safely with JX-594, with transient flu-like symptoms being the most common adverse events. Anti-cancer activity continues to be clearly demonstrated in a broad spectrum of common solid tumor types," said David H. Kirn, M.D., president and chief executive officer of Jennerex.

"We look forward to reporting additional clinical results in patients with advanced liver cancer from two ongoing studies—a randomized Phase 2 trial of JX-594 evaluating survival across two dose groups, and a Phase 2 clinical trial evaluating JX-594 in combination with sorafenib," added Philippe Archinard, chairman and chief executive officer of Transgene.

Clinical Results

This presentation highlighted data from 35 patients with either primary liver cancer, known as hepatocellular carcinoma (HCC), or cancer metastases to the liver (including colorectal cancer, melanoma and renal cancer). All patients were given intratumoral (IT) injections (up to eight treatments) over the course of JX-594 therapy. Twenty-three patients (66%) exhibited significant tumor necrosis and responses by modified Choi criteria (decreased tumor density). Choi responses have also been documented in non-injected tumors, consistent with prior data on JX-594. Seven patients (20% of evaluable) also exhibited objective response by Response Evaluation Criteria in Solid Tumor (RECIST) criteria, including two complete responses upon long-term follow-up. Twenty patients (57%) had stable disease as defined by RECIST criteria.

About JX-594

JX-594 is a proprietary, engineered oncolytic virus that is designed to selectively target and destroy cancer cells. JX-594 is designed to attack cancer through three diverse mechanisms of action: the lysis of cancer cells through viral replication, the ablation of the blood supply to tumors through vascular targeting and destruction, and the stimulation of the body's immune response against cancer cells (ie active immunotherapy). Phase 1 and Phase 2 clinical trials in multiple cancer types to date have shown that JX-594, delivered either directly into tumors or systemically, induces tumor shrinkage and/or necrosis and is well-tolerated by patients. Objective tumor response has been demonstrated in a variety of cancers including liver, colon, kidney, lung and melanoma.

Transgene holds an exclusive license to develop and commercialize JX-594 in Europe and neighboring countries. Green Cross Corporation, a leading company in the development, manufacturing, and commercialization of viral vaccines and other biological products, holds an exclusive license to develop and commercialize JX-594 in South Korea, and Lee's Pharmaceutical Ltd. holds an exclusive license to develop and commercialize JX-594 in China.

About Liver Cancer and Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related deaths world-wide with about 660,000 patients dying from the disease annually. Most HCC cases develop on the background of chronic liver cirrhosis; in regions with the highest incidence of HCC, East Asian and African countries, the majority of cases are related to hepatitis B; in developed Western countries and Japan the disease is commonly related to hepatitis C, heavy alcohol consumption and non-alcoholic fatty liver due to metabolic syndromes such as diabetes and obesity. There is accumulating evidence that the incidence of HCC is increasing in Western countries. Despite recent advances, the treatment of advanced HCC remains a significant unmet medical need with a median expected survival under current therapies of less than one year.

About Jennerex

Jennerex, Inc. is a clinical-stage biotherapeutics company focused on the development and commercialization of first-in-class, breakthrough targeted oncolytic products for cancer. The Company's lead product JX-594 is currently in two Phase 2 clinical trials in patients with primary liver cancer—an international, randomized, Phase 2 clinical trial, and a Phase 2 study of JX-594 in combination with sorafenib. Published studies designed to establish optimal dose levels and the safety profile of JX-594 have shown its ability to selectively target and cause destruction of a variety of common cancer types. JX-594 and other product candidates under development are designed to attack cancer tumors through three diverse mechanisms of action: the lysis of cancer cells through viral replication, the ablation of the blood supply to tumors through vascular targeting and destruction and the stimulation of the body's immune response against the cancer. Jennerex is headquartered in San Francisco and has related research and development operations in Ottawa, Canada and Pusan, South Korea. For more information about Jennerex, please visit www.jennerex.com.

About Transgene:

Transgene, a member of the Institut Merieux Group, is a publicly traded French biopharmaceutical company dedicated to the development of therapeutic vaccines and immunotherapeutic products in oncology and infectious diseases, and has five compounds in clinical development: TG4010 and JX594 (TG6006) having completed initial phase II trials, TG4001 in phase IIb trial, TG4040 in phase II trial and TG4023 in phase I trial. Transgene has concluded strategic agreements for the development of two of its immunotherapy products, an option agreement with Novartis for the development of TG4010 to treat various cancers, and an in-licensing agreement with US-based Jennerex Biotherapeutics, Inc., to develop and market JX594 (TG6006), an oncolytic product.

Transgene has bio-manufacturing capacities for viral-based products. Additional information about Transgene is available on the internet at http://www.transgene.fr/

Cautionary note for Transgene regarding forward-looking statements

This press release contains forward-looking statements referring to the joint clinical testing and development and commercial potential of JX-594. Clinical testing and successful product development and commercialization depend on a variety of factors, including the timing and success of future patient enrolment, the risk of unanticipated adverse patient reactions, regulatory approval and the level of demand for the product by the medical community. Results from future studies with more data may show less favorable outcomes than prior studies, and there is no certainty that product candidates will ever demonstrate adequate therapeutic efficacy or achieve regulatory approval or commercial success. In addition, forward-looking statements regarding product development, testing and marketing costs are by the nature subject to uncertainties as a result of unforeseen difficulties and expenses which may arise, and future product development costs may exceed current expectations. For further information on the risks and uncertainties involved in the testing and development of Transgene's product candidates, see Transgene's Document de Reference on file with the French Autorite des marches financiers on its website at http://www.amf-france.org/ and Transgene's website at http://www.transgene.fr/.

SOURCE Jennerex, Inc.

RELATED LINKS
http://www.jennerex.com/
http://www.transgene.fr/

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