Vertex and Alios BioPharma Begin Clinical Studies of Nucleotide Drug Candidates ALS-2200 and ALS-2158 for the Treatment of Hepatitis C

December 9, 2011

-Studies to evaluate safety and effects on viral kinetics in people with chronic genotype-1 hepatitis C-

-Data expected in second quarter of 2012 could enable initiation of interferon-free, nucleotide-based combination studies in the second half of 2012-

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Alios BioPharma, Inc. today announced the initiation of two clinical studies for the nucleotide analogues ALS-2200 and ALS-2158, which are inhibitors of the hepatitis C NS5B polymerase. The studies will evaluate the safety and tolerability of ALS-2200 and ALS-2158 in healthy volunteers followed by a seven-day evaluation to observe the effects on viral kinetics in people with chronic genotype-1 hepatitis C. Data are expected in the second quarter of 2012, which could enable the initiation of studies to evaluate multiple all-oral, interferon-free combination regimens for chronic hepatitis C in the second half of 2012. Vertex has worldwide development and commercialization rights for ALS-2200 and ALS-2158, which were discovered by Alios BioPharma. Alios and Vertex are jointly conducting the Phase 1 studies announced today.

"These studies are an important step in our ongoing efforts to strengthen our leadership position in hepatitis C by developing all-oral regimens that could further improve the future treatment of this disease," said Peter Mueller, Ph.D., Executive Vice President, Global Research and Development, and Chief Scientific Officer for Vertex. "The studies of ALS-2200 and ALS-2158 announced today are designed to generate data that may provide the opportunity to rapidly advance into Phase 2 development where we could evaluate a number of nucleotide-based regimens beginning in the second half of next year, including regimens with INCIVEK or VX-222."

Study Design

The two Phase 1 studies announced today will be randomized, double-blind, placebo-controlled studies. The primary goals are to evaluate the safety and tolerability of single ascending doses of ALS-2200 and ALS-2158 in healthy volunteers and of multiple ascending doses in people with chronic genotype-1 hepatitis C. A secondary objective will be to evaluate the effects on viral kinetics of ALS-2200 and ALS-2158 during seven days of dosing in people with hepatitis C.

Dosing is now underway for the study of ALS-2200, and dosing is expected to begin next week for the study of ALS-2158. Vertex and Alios BioPharma expect to have complete data, including seven-day viral kinetic data, from each trial in the second quarter of 2012, which could enable the initiation of all-oral, interferon-free Phase 2 combination studies in the second half of 2012. These Phase 2 studies are expected to evaluate combination regimens of ALS-2200 or ALS-2158 with INCIVEK (telaprevir) or VX-222, potential dual nucleotide regimens and other interferon-free combination regimens that may also include ribavirin. INCIVEK is Vertex's FDA-approved protease inhibitor for chronic genotype-1 hepatitis C, and VX-222 is Vertex's investigational hepatitis C non-nucleoside polymerase inhibitor. The combination studies will be designed to generate sustained viral response (SVR or viral cure) data.

About ALS-2200 and ALS-2158

ALS-2200 and ALS-2158 are highly potent pan-genotypic nucleotide analogues that appear in in vitro and non-clinical studies to have a high barrier to drug resistance and the potential to be dosed orally once-daily. Both compounds are designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Each compound is structurally distinct and has its own unique mechanism of action, which supports the potential for developing these compounds together as a dual nucleotide regimen and as part of combination therapy regimens, including regimens with INCIVEK^TM (telaprevir) and VX-222. Data from in vitro studies showed that both ALS-2200 and ALS-2158 had a synergistic effect when combined together and with INCIVEK and VX-222. Additionally, in those in vitro studies, both compounds showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 and ALS-2158 through an exclusive worldwide licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK™ (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹ Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹

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

More than 170 million people worldwide are chronically infected with hepatitis C.⁶ In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.⁹ Hepatitis C is four times more prevalent in the United States compared to HIV.⁹ The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.¹⁰ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.^11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.⁹

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 1,900 employees around the world, and Science magazine named Vertex number one on its 2011 list of Top Employers in the life sciences.

About Alios BioPharma

Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including, hepatotropic and respiratory viruses and other chronic, acute and emerging viral diseases. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability. Alios is the recipient of the 2011 BayBio Pantheon Outstanding Partnering Award.

Special Note Regarding Forward-Looking Statements:

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including Dr. Mueller's statements in the second paragraph of this press release and statements regarding (i) the expectation that Vertex will receive data from two Phase 1 studies in the second quarter of 2012 that could enable initiation of interferon-free, nucleotide-based combination studies in the second half of 2012; (ii) the design, goals, objectives and expected timing of receiving data from the Phase 1 studies; (iii) the possible combination regimens that could be evaluated in Phase 2 studies and the potential design of such studies; and (iv) the potential for developing ALS-2200 and ALS-2158 together as a dual nucleotide regimen and as part of other combination therapy regimens. While the Company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, the possibilities that the outcomes from the Phase 1 studies may not be favorable, that the Company may not be able to successfully develop ALS-2200 or ALS-2158, and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. The Company disclaims any obligation to update the information contained in this press release as new information becomes available.

References:

¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.

² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

³ Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

⁴ Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

⁵ McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

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

⁸ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

⁹ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.

¹⁰ Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.

¹¹ Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

¹² Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.

(VRTX-GEN)

Vertex Pharmaceuticals Incorporated
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Media:
Zachry Barber, 617-444-6992
mediainfo@vrtx.com

Source: Vertex Pharmaceuticals Incorporated

Source

A sprint to increase response to HCV treatment: expectancies but caution

J Hepatol. 2011 Nov;55(5):1154-8. Epub 2011 Jul 1

Asselah T.

Source

Service d'Hépatologie, Hôpital Beaujon, Clichy, France. tarik.asselah@bjn.aphp.fr

Abstract

BACKGROUND:

Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.

METHODS:

We conducted a double-blind study in which previouslyuntreated adults with HCV genotype 1 infection were randomly assigned to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.

RESULTS:

A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (p < 0.001), and in 213 of the 311 patients (68%) in group 3 (p < 0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (p = 0.04), and in 29 of the 55 patients (53%) in group 3 (p = 0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.

CONCLUSIONS:

The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared to standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir.

BACKGROUND:

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

METHODS:

To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.

RESULTS:

A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, p < 0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10)IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41-46% of boceprevir-treated patients and 21% of controls.

CONCLUSIONS:

The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared to peginterferon-ribavirin alone.

Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Comment on

N Engl J Med. 2011 Mar 31;364(13):1195-206.

Source

Side-effects of pegylated interferon plus ribavirin therapy with or without protease inhibitor direct acting antiviral agents during treatment of chronic hepatitis C virus infection

Orv Hetil. 2011 Dec 11;152(50):1997-2009

[Article in Hungarian]

Hunyady B, Kovács B, Battyáni Z.

Source

Kaposi Mór Oktató Kórház Belgyógyászati Osztály Kaposvár Pécsi Tudományegyetem, Klinikai Központ I. Belgyógyászati Klinika Pécs Ifjúság u. 13. 7624.

Abstract

Hepatitis C virus (HCV) infection affects 2-3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-naïve patients infected with HCV genotype G1, and only 15-20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10-15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts - with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients. Orv. Hetil., 2011, 152, 1997-2009.

Source

Formulary management of the protease inhibitors boceprevir and telaprevir for chronic hepatitis C virus

J Manag Care Pharm. 2011 Nov;17(9):685-94

Tungol A, Rademacher K, Schafer JA.

Source

Prime Therapeutics LLC, 1305 Corporate Center Dr., Eagan, MN 55121. USA. jschafer@primetherapeutics.com.

Abstract

Background: Hepatitis C virus (HCV) is the most common chronic bloodborne illness in the United States. The incidence of acute hepatitis C in the United States peaked near 50,000 cases in the late 1980s but has stabilized since 2003 to less than 5,000 cases annually. The combination of pegylated interferon (peginterferon) and ribavirin has been the standard recommended treatment for HCV. Protease inhibitors telaprevir and boceprevir were approved by the FDA in May 2011 for the treatment of hepatitis C genotype 1 in combination with peginterferon and ribavirin. Objective: To review the phase 3 trials for telaprevir and boceprevir and provide managed care considerations. Methods: A MEDLINE review was performed for articles published and available through September 15, 2011, using keywords "boceprevir" or "telaprevir" with an emphasis on phase 3 trials. The literature search was limited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans. Additional information was obtained from the FDA website. Results: Three phase 3 trials are available for telaprevir, which provided data that were the basis for FDA approval. Boceprevir demonstrated efficacy and safety in 2 pivotal phase 3 trials. Both agents demonstrated statistically significantly higher rates of virologic response compared with the standard of care involving peginterferons and ribavirin. Telaprevir and boceprevir also demonstrated efficacy in the treatment of patients who had previously failed dual therapy for hepatitis C. Safety concerns for both agents include anemia, drug interactions, skin rashes, and gastrointestinal adverse events. Conclusions: Decision makers have many factors to consider in developing a strategy around hepatitis C. Increased drug costs, patient management, adherence, comparative safety and efficacy, and appropriate utilization management controls are important issues. Payers may consider developing clinical programs to encourage adherence and appropriate use and leverage an appropriate channel to ensure cost-effective therapy.

Source

Clinical relevance of detectable but not quantifiable hepatitis C virus RNA during boceprevir or telaprevir treatment

Hepatology. 2011 Nov 16. doi: 10.1002/hep.24791. [Epub ahead of print]

Harrington PR, Zeng W, Naeger LK.

Source

Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993. Patrick.Harrington@fda.hhs.gov.

Abstract

Boceprevir- and telaprevir-based treatments for chronic hepatitis C virus (HCV) infection use specific response-guided therapy (RGT) guidelines. Eligibility for shortened treatment duration is based on achieving Undetectable HCV RNA early during treatment. It is unclear whether a detected HCV RNA level that is below the assay lower limit of quantitation (Detectable/BLOQ) is comparable to an Undetectable HCV RNA level, particularly regarding RGT decision making. We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive understanding of the frequency and clinical relevance of Detectable/BLOQ HCV RNA measurements. In Phase 3 trials P05216 (boceprevir), C216 (telaprevir) and 108 (telaprevir), Detectable/BLOQ levels were reported for approximately 10-20% of all on-treatment HCV RNA measurements. In P05216 and C216, subjects with Detectable/BLOQ HCV RNA, on average, had a reduced sustained virologic response (SVR) rate compared to subjects with Undetectable HCV RNA at the same on-treatment timepoint. At key RGT timepoints (Week 8 for boceprevir, Week 4 for telaprevir), subjects with Detectable/BLOQ HCV RNA had an approximately 20% lower SVR rate compared to subjects with Undetectable HCV RNA, and this difference widened for later on-treatment timepoints. A similar trend was observed for Study 108, but the differences in SVR rates were more modest, which may be explained by a higher frequency of reported Detectable/BLOQ results. Analyses of Phase 2 boceprevir and telaprevir trials indicated subjects with Detectable/BLOQ HCV RNA at RGT timepoints benefited from extended treatment duration. CONCLUSIONS: During boceprevir- and telaprevir-based treatment, subjects with Detectable/BLOQ HCV RNA had a reduced virologic response compared to subjects with Undetectable HCV RNA. Eligibility for shortened treatment duration should be based on patients achieving Undetectable HCV RNA at RGT decision timepoints. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

Source

HCV Infection May Predict Coronary Artery Disease

By: HEIDI SPLETE, Internal Medicine News Digital Network

NATIONAL HARBOR, MD. – Coronary artery disease was significantly more prevalent in patients with hepatitis C virus infection, compared with control subjects, based on a retrospective review. The findings were presented at the annual meeting of the American College of Gastroenterology.

"An association of coronary artery disease [CAD] with hepatitis C has been suggested, but definitive data are still lacking," said Dr. Sanjaya Satapathy, who conducted the study while at Long Island Jewish Medical Center in New Hyde Park, N.Y.

To estimate the prevalence of CAD in hepatitis C patients, Dr. Satapathy and his colleagues reviewed data from 934 individuals with hepatitis C infection who were seen at a single center between May 2002 and December 2008. Of these patients, 63 had undergone coronary angiography. The investigators compared their data with data from 63 matched controls without hepatitis C.

Overall severity of CAD according to the combined Reardon severity score was significantly greater in the hepatitis C virus (HCV) group than in the controls (6.3 vs. 2.6, respectively), suggesting that being HCV-positive increases the severity of, or risk for, CAD, Dr. Satapathy said.

The researchers defined CAD in two different ways for their analysis. CAD defined as stenosis greater than 50% was found in 44 of the HCV cases (70%) compared with 30 controls (48%). CAD defined as stenosis greater than 75% was found in 42 patients with hepatitis C (67%) compared with 29 controls (46%).

In addition, the prevalence of multivessel coronary artery disease was significantly higher in the HCV patients compared with the controls (57% vs. 16%, respectively). The prevalence of single-vessel involvement was greater in the control group.

"HCV seropositive status is a strong predictor for CAD," Dr. Satapathy said. However, "HCV patients are more likely to remain undertreated with antiplatelet and lipid-lowering agents," he noted.

The study was limited by the retrospective design and small sample size, said Dr. Satapathy. However, the findings suggest that CAD is significantly more common and severe in HCV-positive patients, and this should be considered by clinicians treating these patients, he said.

Dr. Satapathy said he had no financial conflicts to disclose.

Source

Hepatitis C doesn't affect cognitive function of women, but some evidence HIV does

Michael Carter

Published: 08 December 2011

Infection with hepatitis C does not affect the cognitive performance of women with or at risk of HIV, according to data from the Women’s Interagency HIV Study (WIHS) published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

“We were unable to show a significant association between the presence of HCV [hepatitis C virus]…and performance on our cognitive battery nor that there is an interaction between HIV and HCV in their effect on cognitive function,” write the authors.

However, their was some evidence that infection with HIV had an impact on cognition.

A number of earlier studies have suggested that hepatitis C-infected individuals have an increased risk of neurocognitive impairments. Moreover, replicating virus has been found in the brains of patients with the infection. It has also been suggested that co-infection with HIV and hepatitis C could have a worse impact on cognitive function than either virus alone.

Women have been unrepresented in research exploring the impact of hepatitis C on cognition. Therefore, investigators from the WIHS designed a study involving 1338. Just under a fifth (18%) had detectable hepatitis C virus and 67% were infected with HIV.

“To our knowledge this cohort for our study is over twice as large as any previously reported study of the effects of HCV and HIV on cognition,” note the investigators.

The patients were divided into six groups:

• Negative for both HIV and hepatitis C RNA (392 individuals).

• HIV-negative/hepatitis C RNA-positive (42 individuals).

• HIV-positive/hepatitis C RNA-negative (480 individuals).

• AIDS/hepatitis C RNA-negative (241 individuals).

• AIDS/hepatitis C RNA-positive (88 individuals)

The patients had a battery of four tests to assess their cognitive function. The results were controlled for age, ethnicity, depression, liver disease status and current or past drug and alcohol abuse, all of which have been shown to affect cognitive function.

There were significant differences between the patients according to their hepatitis C and/or HIV-infection status.

Individuals infected with hepatitis C were a significant nine years older than women who did not have hepatitis C (p < 0.001). Rates of injecting drug use were also significantly higher among the women with hepatitis C (85% vs. 12%), and hepatitis C-infected women were also significantly more likely to report recent use of cocaine (p < 0.001).

As expected, liver function was significantly poorer in those infected with hepatitis C, and the women with an AIDS diagnosis had lower CD4 cell counts than other individuals (p = 0.001).

After controlling for potential confounders, the investigators failed to find any association between hepatitis C viraemia and cognitive performance.

In their first set of analysis, they established a significant connection between poorer liver function and poorer cognitive function (p < 0.001). However, this relationship disappeared after controlling for factors such as age, ethnicity, depression and general mental health.

Nevertheless, infection with HIV was associated with impaired speed of information processing and perceptual motor ability (p < 0.001).

The investigators do not regard their findings as definitive: “The question of whether HCV has a direct effect on cognition will require future studies with a complete neuropsychological batter, a large control group and a large group of HCV-mono-infected subjects.” They also believe that such studies would need “a cohort that includes both men and women.”

Reference

Crystal H et al. Effects of hepatitis C and HIV on cognition in women: data from the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr, online edition, doi: 10.1097/QAI.0b013e318240566b, 2011 (click herefor the free abstract).

Source

Strong results from Biotron HCV trial

Nearly 90% of patients treated with Biotron's (ASX:BIT) Hepatitis C treatment candidate demonstrated a complete EVR at three month follow-up.

Dylan Bushell-Embling (Australian Life Scientist) 08 December, 2011 10:41

Sydney-based Biotron (ASX:BIT) has presented encouraging results from a trial of the use of its prospective Hepatitis C treatment, when coupled with existing therapies.

Patients treated in a phase IIa trial of Biotron's BIT225 drug candidate, combined with approved standard of care (SOC) treatments, mostly demonstrated improvement at three month follow-up.

Of the subjects to have been treated with BIT225, 87% showed a complete early viral response (EVR) – defined as virus levels in the blood below the level of detection.

This compares to 63% who received only SOC treatments interferon alfa-2b plus ribavirin, and backs up data from the four week point of the study showing significantly reduced levels of HCV virus in BIT225-treated patients.

The extent of virus reduction was dose-dependent, with the higher dose having the most effect.

Patients involved in the trial received either 200mg or 400mg doses of BIT225 for 28 days, and then remained on the SOC treatments for another 44 weeks.

Biotron CEO Dr Michelle Miller said the results of the trial were “extremely encouraging.” She said they also show that BIT225 was generally well-tolerated in patients, with the most common potential side effect being nausea, which may be solved by tweaks to the formulation.

Biotron is also in the middle of a phase 1b/IIa trial for BIT225 as a treatment for HIV.

Biotron (ASX:BIT) shares climbed 18.18% to a seven-month high of $0.130 after the results were released on Wednesday.

Source

Transplant candidates seek 'best quality' livers despite having to remain on waiting list

Public release date: 1-Dec-2011

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

New research reveals that liver transplantation candidates want to be involved in decisions regarding quality of the donor organ, and many are reluctant to accept organs with a higher risk of failure. In fact, more than 42% of patients would choose to remain on the waiting list rather than accept a "lower quality" liver according to the study appearing in the December issue of Liver Transplantation, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

As of November 30, 2011, the Organ Procurement and Transplantation Network (OPTN) reports that 16,124 candidates are on the waiting list to receive a liver, with only 5,375 deceased donor organs recovered through August. Additionally, there is a large variation in quality of deceased donor livers, which is based on donor characteristics such as age, cause of death, and ischemia time. Previous research has shown that donor characteristics can make the difference between a 20% to 40% risk of graft failure by 3 years following transplantation.

"Organ quality is an important issue for all liver transplant candidates, increasingly so, given the aging donor pool and more frequent use of organs that carry a higher risk of failure," explains Dr. Michael Volk with the University of Michigan Health System in Ann Arbor. "The decision to accept or pass on an organ could mean the difference between life and death for patients with end-stage liver disease. Communication of the risks versus benefits of accepting a "lower quality" organ is critical, and understanding patient views on the subject is essential for physicians caring for transplant candidates."

For the current study, researchers tested presentation formats for communicating organ quality risks to patients, and factors that might influence patients' willingness to accept higher risk organs. First, the team conducted interviews with ten patients on the waiting list for liver transplantation to determine their knowledge of organ quality and preferences for accepting organs with greater risk of failure. Based on qualitative information obtained from interviews, the team created a web-based survey which 95 candidates completed.

The findings show that patients are reluctant to accept higher risk organs, wanting only the "best" organ. Of those completing the survey, 58% would only accept organs with a 25% (or less) risk of graft failure and 18% would only accept the lowest possible risk of 19% at 3 years following transplantation. Women were slightly more accepting of high risk organs than men. Researchers found that risk tolerance was increased by presenting organ quality as "average quality" rather than "best quality," and by providing feedback about the implications of these preferences on the likelihood of receiving a transplant. Additionally, 83% of candidates were found to prefer an equal or dominant role in deciding whether to accept a higher risk organ. This finding is striking given that, in most transplant centers, patient involvement in these decisions is minimal.

"Up until now, it has not been clear how much patients want to be involved in this complicated decision," says Dr. Volk. "Furthermore, explaining the intricacies of this topic to sick patients is easier said than done. Our findings offer transplant physicians some useful guidelines for how to council transplant candidates on issues of organ quality." The authors suggest future studies are needed to develop validated patient education tools that will enhance discussions between physicians and patients in need of liver transplantations.

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This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

Full citation: Patient Decision Making about Organ Quality in Liver Transplantation." Michael L. Volk, Rachel S. Tocco, Shawn J. Pelletier, Brian J. Zikmund-Fisher and Anna S. F. Lok. Liver Transplantation; Published Online: November 29, 2011 (DOI: 10.1002/lt.22437) Print Issue Date: December 2011. http://onlinelibrary.wiley.com/doi/10.1002/lt.22437/abstract.

Author Contact:To arrange an interview with Dr. Volk, please contact Mary Masson with the University of Michigan at mfmasson@med.umich.edu .

About the Journal

Liver Transplantation is published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society . Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AALSD and the ILTS, Liver Transplantation. delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit Liver Transplantation.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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When prophecy fails: How to better predict success in HIV prevention clinical trials

Public release date: 7-Dec-2011

Contact: Lisa Chensvold
lisa_chensvold@med.unc.edu
919-843-5719
University of North Carolina School of Medicine

CHAPEL HILL, N.C. -- New research from the University of North Carolina at Chapel Hill schools of medicine and pharmacy may help explain the failure of some recent clinical trials of prevention of HIV infection, compared to the success of others that used the same drugs.

The study published online December 7, 2011 in the journal Science Translational Medicine, also suggests how to improve the chances for success, even before the research begins. These suggestions are reinforced in an editorial by several of the UNC authors writing in The Lancet, also published online December 7, 2011.

Over the past two years, results from several clinical trials involving pre-exposure prophylaxis (PrEP) for HIV infection have been a mixed bag of successful prevention and futility. Reports described varying degrees of successful HIV infection prevention in four trials and failure in two others. In all the PrEP trials, the drugs used were tenofovir (TFV) and emtricitabine (FTC) in daily oral and/or gel combinations.

These drugs have been shown to be protective against HIV infection in animal PrEP studies and are now being used clinically, and tenofovir is considered the backbone of HIV therapy, both used orally and topically.

The new UNC study looked at drug concentrations in the mucus membrane tissues that are most susceptible to HIV infection: the tissue lining the vagina, cervix and rectum. The study was led by Angela D.M. Kashuba, PharmD, professor in the UNC Eshelman School of Pharmacy and director of the UNC Center for AIDS Research Clinical Pharmacology and Analytic Chemistry Core. She also is a member of the UNC Institute for Global Health & Infectious Diseases.

"We did this study to understand how much drug got into these tissues and how long they lasted over two weeks," Kashuba said. And after giving normal, healthy volunteers a single pill combination of TFV/FTC, "What we found over the next 14 days was somewhat surprising. When a person takes a drug, it doesn't end up in the same concentration in different tissues."

Indeed, concentrations of tenofovir were 100 times higher in rectal tissue than in vaginal or cervical tissue. "And FTC achieved concentrations 10 to 15 times higher in vaginal and cervical tissue than they were in rectal tissue," Kashuba said. "And this raised some questions: because of these discrepancies can the two drugs be used equally well in both populations – women at risk for HIV infection and men at risk for HIV infection? And are the concentrations achieved even after a single dose high enough to prevent HIV infections?"

According to Kashuba, it's clear from the recent clinical studies that drug concentration in tissue may make a difference in effectiveness. For example, in one of the placebo-controlled PrEP clinical trials involving men who have sex with men, the combination of these drugs provided about 44 percent effectiveness overall.

But the half the men given the active form of the drugs had no detectable drug in their system when they were sampled during the study and, therefore, were not taking it consistently every day. Thus, the high tenofovir concentrations in rectal tissue could explain the relatively high efficacy of 44 percent.

Results of a PrEP clinical trial (VOICE) conducted in heterosexual women in Uganda, South Africa and Zimbabwe, also paralleled the UNC findings. The daily tenofovir arm was stopped because no protection was seen for the drug taken daily. "If these women did not take the drug every single day, we think our study supports the fact there would not be good efficacy because tenofovir drug concentrations in the vagina and cervix are so much lower than what we see in rectal tissue, Kashuba said."

The authors of the study and the editorial say adherence to taking the drug as prescribed is crucial. They lament that the only prospective means of measuring adherence now available is what the patient reports. "And so if you ask someone did you take all your doses, most will say yes," Kashuba said "People want to be considered good study participants, and sometimes they just can't remember how many doses they took last week, or in the last month, be it almost all of the doses or half of them."

The UNC researcher points to lessons learned: "Before delving into a clinical trial, we need to keep in mind that when someone takes a pill, you can't assume that the drug gets in all places at the same amount. And before we can select the drugs and the right doses for a clinical trial, we need to know what concentrations in tissue prevent HIV infection. They could be different."

And along with the above, the authors emphasize the need to develop ways to objectively measure drug-taking behavior in clinical studies so that the research can be designed and interpreted correctly.

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The study was funded in part from the National Institutes of Health, the UNC Center for AIDS Research, the UNC TraCS Clinical Translational Research Center, and the Gilead Sciences Investigator Initiated Research Program.

Along with Kashuba, UNC study co-authors from the School of Medicine are Kristine B. Patterson, Heather A. Prince, Nicholas J. Shaheen, and Myron S. Cohen. From the UNC Eshelman School of Pharmacy are Eric Kraft and Amanda J. Jenkins. And from Gilead Sciences, James F. Rooney. Co-authors of the editorial were Kashuba, Patterson, Cohen, and Julie B. Dumond of UNC Eshelman School of Pharmacy.

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Enoxaparin May Prevent Portal Vein Thrombosis in Advanced Cirrhosis

By: M. ALEXANDER OTTO, Internal Medicine News Digital Network

SAN FRANCISCO – The anticoagulant enoxaparin appears to prevent portal vein thrombosis in patients with advanced cirrhosis, based on a small Italian study presented at the annual meeting of the American Association for the Study of Liver Diseases.

In this trial, 6 of 36 patients (17%) randomized to placebo developed partial or complete portal vein thrombosis (PVT) within a year, whereas none of the 34 patients (0%) randomized to 4,000 IU daily of the low-molecular-weight heparin developed PVT.

The analysis indicated that enoxaparin had a significant protective effect (HR 0.218; 95% CI, 0.048-0.994, P = .049) in these patients with advanced cirrhosis.

At enrollment, none of the patients had PVT. The treatment and placebo groups had no significant differences in terms of biochemical or demographic factors at the outset of the trial, which was the first to prospectively investigate whether anticoagulation prevents PVT.

At the meeting, lead investigator Dr. Erica Villa, professor of gastroenterology at the University of Modena and Reggio Emilia in Modena, Italy, said that the results need to be confirmed in larger studies.

All of the subjects had cirrhosis classified as Child-Pugh B7 to C10. The mean age in both groups was 57 years, and the mean MELD (Model for End-Stage Liver Disease) score was approximately 14. Men made up more than 60% of both arms.

Enoxaparin appeared to provide significant protection against decompensation – defined as new-onset ascites, hepatic encephalopathy, or variceal bleeding – and death. Four enoxaparin patients (12%) decompensated during treatment, whereas 22 (61%) in the placebo arm decompensated. The difference persisted even after treatment with enoxaparin ended at 12 months.

Similarly, although 10 patients died in the enoxaparin group – 4 from sepsis, 2 from progressive liver failure, 3 from hepatocellular carcinoma, and 1 from variceal bleeding – 16 died in the placebo group. These deaths were due to sepsis in seven patients, progressive liver failure in another seven, hepatocellular carcinoma in one, and variceal bleeding in one.

There were no hemorrhagic or other treatment-related adverse events in the enoxaparin group, although asymptomatic thrombocytopenia led to the withdrawal of one patient 3 months into the trial. Three enoxaparin patients had liver transplants while on the drug, and Dr. Villa noted that they did not need extra blood transfusions.

Dr. Villa said she had no disclosures. She said the study was funded internally, and not by a company that makes enoxaparin.

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A Possible Sea Change in Cirrhosis Treatment

Enoxaparin "could certainly become a treatment for people who are at high risk for portal vein thrombosis. We don’t know enough about this; there may be side effects just like with other drugs, but [the findings are] exciting," said Dr. Jake Liang.

If this approach holds up to additional testing, it would signal "a sea change" in the treatment of advanced cirrhosis. "We treat thousands of people with cirrhosis; this would advocate that you should put them on this very expensive medicine" even if there’s no evidence of PVT, said Dr. Willscott Naugler.

Dr. Naugler is assistant professor of medicine at Oregon Health and Science University in Portland. Dr. Liang is president of the American Association for the Study of Liver Diseases and chief of the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases

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Genes modify the risk of liver disease among alcoholics

Public release date: 6-Dec-2011

Contact: R Curtis Ellison
ellison@bu.edu
508-333-1256
Boston University Medical Center

It has been widely observed that only a small percentage of alcoholics develop cirrhosis of the liver, the most advanced form of alcoholic liver disease (ALD); the reason why all alcoholics do not develop such disease is not known. The present study from Spain, that includes original work and a meta-analysis, evaluates whether genetic polymorphisms that determine levels of glutathione-S-transferases (GST) relate to the risk of developing ALD among alcoholics. Alcoholics with certain genetic GST polymorphisms were found to be at significant excess risk for such liver disease in comparison with alcoholics without these polymorphisms.

As stated by the authors, the theory that these enzymes may affect risk is based on the ability of certain GST alleles to detoxify harmful ethanol metabolites in the liver by conjugating acetaldehyde and ROS to reduced glutathione. The specific polymorphisms that the authors found to be associated with increased liver disease are among those that would be expected to lower the activity of the corresponding GST enzymes; this would permit higher levels of toxic metabolites of alcohol and oxidative stress to be present for longer periods of time after excessive alcohol consumption.

Some Forum reviewers thought that while the study was well done, the authors were unclear how these data could directly lead to "potential therapeutic targets" for liver disease in alcoholics. Nevertheless, the original study and meta-analysis provide important data on how specific genetic factors relate to the development of liver disease among alcoholics and could theoretically lead to better strategies for the prevention and treatment of alcoholic liver disease.

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Reference: Marcos M, Pastor I, Chamorro A-J, Ciria-Abad S, González-Sarmiento R, Laso F-J. Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease. Aliment Pharmacol Ther 2011;34:1159.

Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Francesco Orlandi, MD, Dept. of Gastroenterology, Università degli Studi di Ancona, Italy

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Arne Svilaas, MD, PhD, General Practice & Lipidology, Oslo University Hospital, Oslo, Norway

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

For the detailed critique of this paper by the International Scientific Forum on Alcohol Research, go to http://www.bu.edu/alcohol-forum or http://www.bu.edu/alcohol-forum/critique-063-genes-modify-the-risk-of-liver-disease-among-alcoholics-5-december-2011/

The specialists who are members of the Forum are happy to respond to questions from Health Editors regarding emerging research on alcohol and health and will offer an independent opinion in context with other research on the subject

Helena Conibear co Director
The International Scientific Forum on Alcohol Research
helena@alcoholforum4profs.org

Professor R Curtis Ellison co Director
The International Scientific Forum on Alcohol Research
ellison@bu.edu
http://www.alcoholforum4profs.org
http://www.bu.edu/alcohol-forum
Tel UK: 44-1300-320869

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Nonalcoholic Fatty Liver Disease Not so Deadly

Jim Kling

December 6, 2011 — Nonalcoholic fatty liver disease is not associated with increased all-cause or cardiovascular mortality, according to a study published online November 18 in the British Medical Journal.

Nonalcoholic fatty liver disease is present in as much as 30% of the population and is a leading cause of chronic liver disease. It includes a number of conditions including steatosis, nonalcoholic steatohepatitis, fibrosis, and cirrhosis. It can also cause hepatocellular carcinoma and is associated with some cardiovascular risk factors.

Despite these trends, previous studies have shown inconsistent association between nonalcoholic fatty liver disease and mortality. The studies were small and either used highly selected patient populations or used liver enzyme measurements as surrogate markers for nonalcoholic fatty liver disease.

The researchers conducted a prospective cohort study using the US Third National Health and Nutrition Examination Survey (1988 - 1994), with follow-up to 2006. The study included 11,371 adults aged 20 to 74 years who were assessed for nonalcoholic fatty liver disease by the presence of moderate to severe steatosis (diagnosed by ultrasound) and normal levels of enzyme levels. Participants with steatosis and raised liver enzymes were classified as having nonalcoholic steatohepatitis. Mortality was categorized by all causes, cardiovascular disease, cancer, and liver disease.

Nonalcoholic steatohepatitis was present in 3.1% of the population, whereas nonalcoholic fatty liver disease was present in 16.4% of the participants. After adjustment for sex, race/ethnicity, education, smoking, alcohol consumption, physical activity, body mass index, hypertension, hypercholesterolemia, and diabetes, the researchers found that among participants with nonalcoholic fatty liver disease, the hazard ratio (compared with that of those patients without steatosis) for all-cause mortality was 0.92 (95% confidence interval [CI], 0.78 to 1.09). For cardiovascular disease, the ratio was 0.86 (95% CI, 0.67 - 1.12). The hazard ratio for cancer was 0.92 (95% CI, 0.67 - 1.27), and for liver disease it was 0.64 (95% CI, 0.12 - 3.59).

Participants with nonalcoholic steatohepatitis had the following adjusted hazard ratios compared with participants without stenosis: all-cause mortality, 0.80 (95% CI, 0.52 - 1.22); cardiovascular disease, 0.59 (95% CI, 0.29 - 1.20); cancer, 0.53 (95% CI, 0.26 - 1.10); and liver disease, 1.17 (95% CI, 0.15 - 8.93).

The study had several limitations, including the fact that it relied on raised liver enzymes in the presence of steatosis to define nonalcoholic fatty liver disease, rather than liver autopsies. There was no measure of change in nonalcoholic fatty liver disease over time, and some data were self-reported. In addition, follow-up time may not have been long enough to determine the association between nonalcoholic fatty liver disease and liver-related mortality.

The researchers recommend that the study be repeated in the general population, using improved, noninvasive assessment tools and finer staging of nonalcoholic fatty liver disease.

The authors have disclosed no relevant financial relationships.

BMJ. Published online November 18, 2011. Full text

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Fatty livers are in overdrive

Public release date: 6-Dec-2011

Contact: Elisabeth (Lisa) Lyons
elyons@cell.com
617-386-2121
Cell Press

When our livers become loaded with fat, it isn't because they are slacking. A new study of human patients in the December Cell Metabolism shows that fatty livers actually burn more fat, not less. All that "hard work" may be at the root of the organ damage that comes with nonalcoholic fatty liver disease (NAFLD), a condition associated with insulin resistance that affects about one in three in the U.S. population.

The findings represent a paradigm shift in the connection between metabolism and fatty liver disease, as it was previously thought that fatty livers burned less fat.

"Our overwhelming goal is to try to understand what happens in those with fatty liver," says Jeffrey Browning of the University of Texas Southwestern Medical Center. "By understanding what leads to the onset and progression of the disease, we hope we can come up with therapies that actually work."

Most studies of people with insulin resistance have focused on the more accessible skeletal muscle. Those studies show that the mitochondria that power skeletal muscle cells work at a slower pace in the context of metabolic syndrome, including insulin resistance and fatty liver. Browning and his colleague Shawn Burgess weren't so sure that muscle could tell you much about what might be happening in other organs, including the liver.

"Unless skeletal muscle is working, it doesn't have much of an energy requirement," Browning explained. "The liver is always working." The liver breaks down fat and makes glucose and ketone bodies that fuel the rest of our bodies, including our hearts and our brains.

In the new study, the researchers used a special method that allowed them to trace metabolic inputs and outputs in the human liver in people with low and high levels of triglyceride fats in their livers. Those studies show that people with fatty livers are breaking down lipids 50 percent faster and producing glucose 30 percent faster in comparison to those with healthy livers.

That increased demand on the liver suggests a link between fatty liver, oxidative stress, and liver damage. Browning says that means therapies including antioxidants like vitamin E might help protect the liver.

The researchers now hope to explore how metabolism shifts over the course of the disease. One day the tracer technique they have developed might even help to identify those patients at the greatest risk of progressing to the point of liver transplantation.

"A third of the population has fatty liver, and it is difficult to look at them and tell anything without a liver biopsy," Browning says. The trouble is all those biopsies would simply overwhelm the health care system.

Perhaps most important, the findings show that researchers need to rethink what insulin resistance means for the functioning of mitochondria throughout the body. "Skeletal muscle is very different from the liver," he says.

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Telaprevir for the treatment of chronic hepatitis C infection

Summary

Expert Review of Anti-infective Therapy
December 2011, Vol. 9, No. 12, Pages 1105-1114 , DOI 10.1586/eri.11.133
(doi:10.1586/eri.11.133)

Drug Profile

Andrew J Muir

Telaprevir is an NS3/4A protease inhibitor that has recently received US FDA approval for the treatment of chronic HCV infection. Telaprevir is given in combination with peg-IFN-α and ribavirin and is indicated for both treatment-naive and treatment-experienced patients with genotype 1 infection. Along with the other first generation NS3/4A protease inhibitor boceprevir, these combination regimens have immediately become the standard of care for genotype 1 patients. The adverse event profile for the combination regimen remains dominated by peg-IFN-α and ribavirin, but there is additional anemia and rash with telaprevir. Owing to telaprevir’s metabolism by the CYP3/4A pathway, drug–drug interactions could lead to toxicity from other medications or decreased efficacy of telaprevir. Viral resistance can develop during treatment with telaprevir, and patients will need to be educated on their role in adherence to minimize the risk of resistance and improve their chances of cure of HCV infection.

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New Data Reported on INX-189, HCV Nucleotide

top-line safety and antiviral data from its ongoing clinical trial designed to evaluate additional doses of INX-189, an oral nucleotide polymerase inhibitor being developed to treat chronic infections caused by hepatitis C virus (HCV), administered as monotherapy or in combination with ribavirin (RBV) for seven days.

Inhibitex Reports Recent Clinical and Corporate Developments

AASLD: Antiviral Activity and Safety of INX-08189, a Nucleotide Polymerase Inhibitor, Following 7-Days of Oral Therapy in Naïve Genotype-1 HCV Patients - (11/07/11)

Inhibitex Nucelotide INX-189 Higher Dosing Increases Viral Load Reduction - Inhibitex reports third quarter financial results and recent corporate developments - (11/07/11)

Inhibitex Commences Dosing of Phase 2 Clinical Trial of INX-189 in HCV Infected Genotype 2/3 Patients - (11/04/11)
Released: 11/29/11 07:00 AM EST

Inhibitex, Inc. (NASDAQ:INHX) (the "Company") today announced several recent clinical and corporate developments, including top-line safety and antiviral data from its ongoing clinical trial designed to evaluate additional doses of INX-189, an oral nucleotide polymerase inhibitor being developed to treat chronic infections caused by hepatitis C virus (HCV), administered as monotherapy or in combination with ribavirin (RBV) for seven days.

"We believe the significant increase in antiviral activity demonstrated with 100 mg INX-189 in combination with RBV, as compared to 100 mg INX-189 dosed as monotherapy, further confirms the antiviral synergy between INX-189 and RBV that we have consistently observed in preclinical and clinical results to-date," stated Dr. Joseph Patti, Senior Vice President and CSO of Inhibitex, Inc. "We look forward to further exploring this antiviral synergy with 200 mg of INX-189 and expanding the scope of our ongoing and planned Phase 2 clinical trials to include interferon-free combinations of INX-189 with other antiviral agents in HCV genotype 1, 2, and 3 patients in 2012."

Recent Corporate Developments

INX-189 for Chronic Hepatitis C - The Company today reported top-line safety and antiviral data from an ongoing Phase 1b extension trial of INX-189, which is designed to further evaluate the safety, tolerability, pharmacokinetics and antiviral activity of various doses of INX-189, administered as monotherapy or in combination with RBV, for seven days in treatment-naïve patients infected with chronic HCV genotype 1. In the ongoing trial, 100 mg INX-189, dosed once-daily for seven days in combination with RBV, continued to demonstrate potent and dose-dependent synergistic antiviral activity with a median HCV RNA reduction from baseline of -3.79 log10 IU/mL. Further, 100 mg INX-189 in combination with RBV was well tolerated and there were no serious adverse events. For comparison purposes, in a clinical trial completed earlier this year, 100 mg INX-189 dosed as monotherapy once-daily for seven days resulted in a median -2.53 log10 IU/mL reduction in HCV RNA levels. In this same clinical trial, the Company also reported antiviral data indicating that INX-189, when dosed once-daily at 9 and 25 mg in combination with RBV for seven days, demonstrated dose-dependent, synergistic antiviral activity.

The Company also reported today that, subject to regulatory review, it plans to further expand its ongoing Phase 1b extension trial to evaluate once-daily doses of 200 mg INX-189 in combination with RBV; 300 mg INX-189 as monotherapy; and 200 mg INX-005 (a single isomer of INX-189) as monotherapy, respectively, for seven days. The Company anticipates that the Phase 1b extension trial will be completed in the first quarter of 2012.

Additionally, the Company reported that it plans to submit a protocol amendment this quarter to its ongoing Phase 2 study in genotype 2 and 3 HCV-infected patients to include the evaluation of 100 mg and 200 mg of INX-189 dosed once-daily in combination with RBV for 12 weeks.

Financing Activity - The Company reported today that it had recently sold a total of 1,949,015 shares of common stock at an average price per share of $10.25 for total gross proceeds of $19,983,396 through its at-the-market (ATM) financing vehicle. The Company entered into a $20 million ATM financing arrangement with McNicoll, Lewis & Vlak LLC (MLV) in November 2010, which provides it the opportunity to sell registered shares into the open market through MLV from time-to-time under its effective shelf registration. After commissions, the Company received $19,383,274 in net proceeds. The intended use of the net proceeds is to support the expansion of the Company's planned Phase 2 program for INX-189 in 2012 and for general corporate purposes.

About Inhibitex

Inhibitex, Inc. is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company's clinical-stage pipeline includes two Phase 2 development programs for which it has retained all future rights: INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic HCV infections, and FV-100, a nucleoside analogue in development for the treatment of shingles-associated pain. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM¨ protein platform to Pfizer for the development of a staphylococcal vaccine, which is currently being evaluated in a Phase 1/2 clinical trial. For additional information about the Company, please visit www.inhibitex.com.

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INX-189 Continues to Shape Up as a Very Potent Nuke
"Y. Katherine Xu - William Blair & Company, L.L.C."

· Before the markets opened on Tuesday, Inhibitex reported data from an additional arm in the Phase Ib study of its lead nuke (nucleotide polymerase inhibitor) candidate INX-189 in combination with ribavirin (R). Viral load drop at 7 days from the INX-189 100 mg QD+R combo was 3.79 logs, versus 2.53 logs for monotherapy INX-189 at 100 mg QD, demonstrating again the synergy between the two compounds, as R usually could contribute 0.5 log drop on its own. Earlier data from the Phase Ib study demonstrated dose-dependent additive/synergistic antiviral activity with 9 mg and 25 mg QD doses of INX-189 in combination with R; at the current dose of 100 mg, the synergy appears to be stronger. We summarize the 7-day viral kinetic activity from the Phase Ib study to date in table 1. In addition, the combination was determined to be safe and well tolerated, with no serious adverse events (SAEs).

· Further expansion of Phase Ib study to climb up the dose on monotherapy as well as combo therapy with R, as expected. Inhibitex plans to amend the ongoing Phase Ib study to include three additional 7-day treatment cohorts 1) INX-189 200 mg QD+R; 2) monotherapy INX-189 300 mg QD; and 3) monotherapy INX-005 (single isomer of INX-189) 200 mg QD.

· The monotherapy potency and the synergy with R demonstrated to date are encouraging; looking to match up PSI-7977 of Pharmasset and Gilead. As summarized in table 1, so far INX-189 monotherapy at 200 mg QD monotherapy produced 4.25 log drop, and 100 mg QD+R produced 3.79 log. Going forward, the 300 mg QD monotherapy and the 200 mg QD+R combo could produce higher viral load drops, approaching the 4.7 log drop demonstrated by Pharmasset's PSI-7977. We note that a potent nuke in combination with R, as demonstrated by Pharmasset, could become a stand-alone therapy.

· Expansion of the ongoing Phase IIb study by adding interferon-free, INX-189+R arms, following Pharmasset's footstep. Initiated in September 2011, the ongoing 12-week Phase IIb study planned to enroll and randomize 90 treatment-naïve GT2/3 into four cohorts 1) INX-189 25 mg QD +P/R (PEG-interferon+ribavirin) (n=25); 2) INX-189 50 mg QD + P/R (n=25); 3) INX-189 100 mg QD + P/R (n=25); or 4) placebo+P/R (n=15). Inhibitex will submit a protocol amendment by year end to include two additional interferon-free cohorts to the study: 1) 100 mg QD +R and 2) 200 mg QD +R. Completion of enrollment of the first four cohorts is expected by year end, and preliminary rapid virologic response (RVR) and early virologic response (EVR) data are anticipated by first quarter 2012.

· With such potency demonstrated, safety is now the gating point for INX-189's commercial viability. Should INX-189 demonstrate satisfactory 12-week safety, the probability of INX-189 eventually becoming commercially viable will be dramatically increased, in our opinion. .....We expect 12-week safety data from the first four cohorts of the Phase IIb study in the beginning of second quarter 2012; however, we would not be fully convinced of the safety profile until we see the full 12-week safety data from the planned interferon-free 200 mg QD of INX-189+R cohort. Such data may be available during the second half of 2012.

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Inhibitex jumps as company expands drug testing

Shares of Inhibitex Inc. climbed Tuesday after the company said it plans to expand studies of its experimental hepatitis C drug.

THE SPARK: The Atlanta company said it will ask the Food and Drug Administration for authorization to expand a mid-stage trial of its drug INX-189. Inhibitex wants to test larger doses of the drug and also wants to test a combination of INX-189 and ribavirin, a standard hepatitis C treatment. The regimen would exclude pegylated interferon, also a standard drug used in hepatitis C treatment.

The patients in the trial have genotype 2 or 3 hepatitis C. They are currently getting as much as 100 milligrams of INX-189 per day in the 12-week study. If the new trial design is approved, some patients will get 100 milligrams and 200 milligrams per day.

The company said it sold $20 million in stock to fund expansion of the trial.

Inhibitex also said it will expand a shorter early-stage trial of the drug to include 200-milligram and 300-milligram doses of INX-189. It will test the drug by itself, in combination with ribavirin, and combined with a second drug it is developing.

THE BIG PICTURE: Inhibitex is a development-stage company. It has no products on the market and INX-189 is its most advanced product. The drug is given by mouth and it is considered a promising treatment for hepatitis C. The chronic form of the disease can cause severe liver damage and is the primary cause of liver transplants in the U.S. The disease is expected to become a larger public health problem as baby boomers age.

Several companies are studying hepatitis C treatment regimens that don't include pegylated interferon, a drug that is administered by injection and can cause severe side effects. Inhibitex's decision to test INX-189 without interferon suggests the company thinks INX-189 will also be just as effective without interferon, matching the convenience and lower side effects of other experimental hepatitis C drugs.

SHARE ACTION: Inhibitex stock rose $1.62, or 14.2 percent, to $13.02 in morning trading. Earlier the shares reached an all-time high of $13.94. The stock doubled in value on Nov. 4 after Inhibitex said a 200-milligram dose of INX-189 reduced virus levels in patients during an early clinical trial.

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Inhibitex Soars as Investors Chase Hepatitis Drug Developers
excerpted

http://www.minyanville.com, By Brett Chase Nov 29, 2011 1:20 pm

Gilead's $11 billion planned takeover of Pharmasset is generating investor excitement for rivals. Achillion and Idenix also rising.

The conventional wisdom after Gilead Sciences' (GILD) recently announced $11 billion takeover of hepatitis drug developer Pharmasset (VRUS) is that similar companies will be gobbled up for big prices.

The deal gave a boost to the already rising stocks of three smaller companies developing their own treatments for the liver-wasting virus hepatitis C: Inhibitex (INHX), Achillion Pharmaceuticals (ACHN) and Idenix Pharmaceuticals (IDIX).

But one only need look at the large players in various stages of developing their own hepatitis treatments to find potential suitors. Merck (MRK), for instance, beat Vertex to market with its new hepatitis treatment Victrelis by about a week but that product is being trounced by Incivek. (See Vertex Hepatitis Drug Beats Estimates.) Other big companies studying treatments include Vertex's development partner Johnson & Johnson (JNJ), Bristol-Myers Squibb (BMY), Abbott Laboratories (ABT), Novartis (NVS), Roche and Boehringer Ingelheim.

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Boceprevir Case Study

Download the PDF here

Hepatology december 2011
Haripriya Maddur and Paul Y. Kwo
From the Gastroenterology/Hepatology Division, Indiana University School of Medicine, Indianapolis, IN

Received October 24, 2011; accepted October 25, 2011.
Address reprint requests to: Paul Y. Kwo, M.D.,
Gastroenterology/Hepatology

Division, Indiana University School of Medicine, 975 West Walnut, IB 327,

Indianapolis, IN 46202-5121. E-mail: pkwo@iupui.edu; fax: 317-274-3106

Boc, boceprevir; HCV, hepatitis C virus; IL-28, interleukin-28; PCR, polymerase chain reaction; PR, pegylated interferon and ribavirin; SPRINT-2, Serine Protease Inhibitor Therapy 2; SVR, sustained virological response.

Case Scenario

A 52-year-old male executive who is asymptomatic is evaluated for abnormal liver biochemical tests. The aspartate aminotransferase level is 138 U/L, and the alanine aminotransferase level is 164 U/L; the bilirubin, alkaline phosphatase, and albumin levels and the complete blood counts are normal. The international normalized ratio is 1.1, and the serum creatinine level is 0.9 mg/dL. The hepatitis C virus (HCV) RNA level is 1,600,000 IU/mL, and the genotype is 1B. The patient has read about boceprevir and wants to know whether he is a candidate for treatment with this drug. He also wants to know whether he really requires liver biopsy before the initiation of treatment.

Will you use boceprevir in this patient? How will you determine whether he is responding to the drug, how long will you give him the medication, and how will you monitor him for side effects? How will you determine that treatment-related anemia is related to boceprevir and is not related to ribavirin? Which side effects of boceprevir will warrant the discontinuation of treatment? Will your approach vary with the genotype for the interleukin-28 (IL-28) polymorphism?

The Problem

Chronic HCV affects approximately 170 million people worldwide.1 HCV, the most common blood-borne infection in the United States, is a major cause of chronic liver disease, which can lead to death from liver failure or hepatocellular carcinoma.2-4 For the past decade, therapy for HCV infection has entailed the use of pegylated interferon and ribavirin (PR). Although the sustained virological response (SVR) rates with this treatment regimen have been as high as 80% for genotypes 2 and 3, the rates for genotype 1 have been less favorable (approximately 40%-50%).4-6 In May 2011, the Food and Drug Administration approved two direct-acting antiviral agents, telaprevir and boceprevir, for the treatment of HCV genotype 1 in both previously untreated patients and patients who failed to achieve SVR with PR.7 When they are added to the standard of care (PR), SVR rates for genotype 1 infections are markedly improved in patients who have not been treated; SVR rates of 63% to 75% have recently been reported.8, 9 Boceprevir is not currently recommended for HCV genotype 2 or 3 infections.

Boceprevir

The current treatment regimens with direct-acting antiviral agents incorporate nonstructural protein 3 protease inhibitors in conjunction with PR. Boceprevir is a linear peptidomimetic keto amide serine protease inhibitor that binds reversibly to the HCV nonstructural protein 3 active site.10 In the recently reported Serine Protease Inhibitor Therapy 2 (SPRINT-2) study,10 the addition of boceprevir to pegylated interferon alfa-2b and ribavirin significantly improved SVR rates in nonblack patients from 38% for patients with just PR to 67% for patients with 24 weeks of boceprevir in response-guided treatment arms (28 or 48 weeks of therapy according to viral clearance). Patients who received 48 weeks of treatment (i.e., 44 weeks of boceprevir with PR after a 4-week PR lead-in period) achieved an SVR rate of 68% (Supporting Fig. 1).

The side effects associated with the addition of boceprevir to PR include increased rates of dysgeusia, neutropenia, and anemia. Dysgeusia that is observed when boceprevir is added to the standard of care is usually mild and rarely, if ever, requires the discontinuation of therapy. Although neutropenia may lead to infections in those receiving PR, severe infections are infrequent, and treatment cessation is rarely warranted. Anemia associated with triple therapy (PR and boceprevir) is primarily driven by ribavirin-related hemolytic anemia, which begins during the 4-week PR lead-in period and is responsible for the majority of the hemoglobin decline.11 Anemia associated with boceprevir typically contributes an additional decline of 1 g/dL to the decline associated with ribavirin therapy. Anemia associated with boceprevir is thought to be due to the bone marrow-suppressive effect of the drug, whereas anemia associated with ribavirin is attributed to hemolysis. Similar to the development of anemia with PR therapy, the development of anemia with boceprevir-based treatment is associated with higher SVR rates.12 In the SPRINT-2 trial, dose modifications due to anemia were required almost twice as often for patients on boceprevir regimens versus the PR control groups (21% versus 13%). However, the rates of discontinuation due to adverse events were not significantly different for the patients on boceprevir-containing regimens (13%) and the PR controls (12%), and discontinuation due to anemia was rare as well (2% for the patients on boceprevir-containing regimens and 1% for the PR controls). It should be emphasized that erythropoietin supplementation was used in the trial.

Drug interactions are significant with boceprevir and are discussed in the next section.

Monitoring for Drug-Related Side Effects

Boceprevir is primarily metabolized by two pathways: the aldo-keto reductase pathway and the cytochrome P450 3A4 pathway. Importantly, it is a reversible inhibitor of cytochrome P450 3A4. All individuals who are candidates for boceprevir therapy require an assessment of drug-drug interactions (Supporting Table 1).

Before therapy is started, thyroid-stimulating hormone levels must be determined, and pregnancy testing is required for women of child-bearing potential. Additionally, complete blood count monitoring should be performed before treatment initiation, at weeks 2, 4, 6, 8, and 12, and monthly thereafter.

The management of anemia involves ribavirin dose reductions (200 mg/day) when hemoglobin levels decline to <10 g/dL in patients without underlying cardiovascular disease or when there is a >2 g/dL drop in hemoglobin levels over any 4-week interval during the treatment course (including the 4-week lead-in period). If the hemoglobin concentration declines to <8.5 g/dL, ribavirin should be discontinued. The boceprevir dose should never be reduced during ribavirin or interferon dose modifications. Additionally, if the discontinuation of either interferon or ribavirin is required, all three treatments should be discontinued to prevent potential boceprevir resistance.

Areas of Uncertainty

Need for Liver Biopsy Before Treatment.

A liver biopsy sample provides important information about the prognosis and the urgency of treatment and excludes other forms of liver disease.13 The degree of fibrosis has also been shown to be an independent predictor of the response to therapy. In patients with HCV genotype 1 infections, the need for liver biopsy is less compelling because of the higher SVR rates observed with the addition of boceprevir to the standard of care. However, information about advanced fibrosis from a pretreatment liver biopsy sample may be used to predict the response to therapy, even with the advent of newer direct-acting antiviral agents. Indeed, in the SPRINT-2 study, the SVR rates of patients with F3/F4 fibrosis in the boceprevir arms were only 41% to 52%. If a patient's liver biopsy sample reveals mild fibrosis (F0-F2), there is a higher chance of SVR (67% in the SPRINT-2 study) with boceprevir-based treatment. A finding of minimal fibrosis may reduce the urgency of therapy, and the patient could await possible newer therapies. On the other hand, if the liver biopsy sample demonstrates cirrhosis, 48 weeks of treatment is recommended.

Testing for IL-28 Polymorphisms.

The SVR rates for PR-treated HCV genotype 1 patients with the IL-28 CC genotype were more than 2-fold greater than the rates for patients with the CT or TT genotype.14-15 Data regarding the use of IL-28B with the addition of direct-acting antiviral agents to PR are emerging, and as the discovery of IL-28B occurred after the large phase 3 trials with telaprevir and boceprevir had been initiated, we will need to wait for more complete data sets in naive patients. In the SPRINT-2 trial, IL-28 data were available for 62% of the patients (653/1048). The addition of boceprevir was associated with higher SVR rates for the patients with the IL-28 CT and TT genotypes (Supporting Fig. 1).16 Those with the IL-28 CC genotype had SVR rates comparable to those of the controls, but 88% of these individuals cleared the virus by week 8 and were eligible for short-term (28-week) therapy.

Testing for IL-28 polymorphisms could be used for counseling patients. If a patient has the IL-28 CC genotype, he may require only 28 weeks of therapy instead of 48 weeks. If he has the IL-28 CT or TT genotype, the addition of boceprevir will substantially improve his chances of SVR in comparison with just PR therapy. However, we could also use a week 4 viral decline after the PR lead-in period as a marker because an HCV decline at 4 weeks appears to be a stronger predictor of SVR than the IL-28 status.

Use of Erythropoiesis-Stimulating Agents.

In the SPRINT-2 study, 43% of the patients receiving boceprevir-based therapy received erythropoiesis-stimulating agents, whereas only 24% of the PR-receiving controls did. Thromboembolic events have been associated with the use of erythropoiesis-stimulating agents in patients with peginterferon-alfa-treated HCV, and these agents are not approved for the treatment of ribavirin-related anemia. In the SPRINT-2 study, similar SVR rates were observed regardless of the anemia management strategies, which included ribavirin dose reductions, erythropoiesis-stimulating agents, both ribavirin dose reductions and erythropoiesis-stimulating agents, and no dose modifications.12 These findings call into question the precise role of erythropoiesis-stimulating agents when antiviral agents are used for the treatment of HCV. A large, prospective, randomized trial evaluating the use of an erythropoiesis-stimulating agent versus ribavirin dose reduction in patients receiving boceprevir with PR is fully enrolled (ClinicalTrials.gov identifier: NCT01023035) and should address this important question.

Recommendations

This patient is clearly a candidate for therapy with boceprevir and PR and has a high possibility of achieving SVR. Liver biopsy, although it is not required, may help with prognostication. IL-28 testing may be helpful, especially if the patient is interested in truncating therapy with no compromise in the chance of achieving SVR. The treatment will entail a 4-week lead-in period with PR alone and then the addition of boceprevir (800 mg every 7-9 hours) with a light meal or snack, and his viral load response during the treatment will determine the treatment duration. The viral load can be reduced during the lead-in period before the addition of boceprevir, and this period can be used to assess the responsiveness to interferon/ribavirin and to predict the likelihood of SVR resistance. Indeed, if the viral decline is >1 log10 at the end of week 4, this patient has a >80% chance of achieving SVR with a response-guided treatment paradigm (Supporting Table 1). However, if the viral decline during the lead is <1 log10, then he is poorly responsive to interferon and will require PR and boceprevir for 44 weeks. HCV RNA levels should be determined at weeks 4, 8, 12, and 24 of therapy and at the end of the treatment course. When HCV RNA is undetectable by polymerase chain reaction (PCR) at weeks 8 and 24 of treatment with assay with lower limit of detection (LLOD) of 10-15 IU/ml (weeks 4 and 20 of boceprevir therapy), the treatment can be completed after 28 weeks (Fig. 1). If, however, HCV RNA is detectable by PCR at week 8 but is undetectable at week 24 (with PCR test with LOD <10-15 IU/ml), treatment with boceprevir should be continued until week 36 and should be followed by PR alone until week 48. The continuation of therapy despite these parameters will lead to a marked increase in the risk of resistance-associated variants.

Careful management of anemia will be required, but the preliminary data suggest that the anemia management strategy will not affect SVR rates. Finally, the measurement of viral levels at weeks 4, 8, 12, and 24 and adherence to futility rules will maximize SVR rates and minimize the emergence of resistance-associated variants.
Boceprevir is marketed in the United States as Victrelis by Merck. It is supplied as oral capsules at a strength of 200 mg. The cost for 24 weeks of boceprevir is approximately $25,000, and the cost for 44 weeks of therapy is approximately $46,000. The total cost of 28 weeks of triple therapy (including boceprevir) is $55,000, and the total cost of 48 weeks of therapy is approximately $101,000.

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Drug-resistant Hepatitis C

29/11/2011 00:53:00

Research into range of mutations provides clues to improve treatment
 
A team of international researchers, led by Matthias Götte from McGill’s Department of Microbiology and Immunology, believes it has found a key factor in understanding why certain drug-resistant strains of the hepatitis C virus are seen so frequently, while others are rarely detected.
 
It has been estimated that 170 million people around the world are infected with the hepatitis C virus (HCV). Close to 300,000 of them live in Canada. Chronic infection with the virus is associated with severe liver disease, including cirrhosis and cancer. Unlike hepatitis A and B, there is currently no vaccine to prevent people from catching the disease. Although new medications show great promise in curing HCV infection, the virus is able to develop resistance to each class of antiviral drugs. And as a result, treatment may fail.
 
It was already known that humans are not infected by a single species of virus, but rather by billions of different, mutant viruses that sometimes differ from one another only by a single nucleotide, i.e. the basic building blocks of viral RNA. The researchers have now demonstrated that the viral polymerase, the enzyme responsible for copying sequences from RNA, is inaccurate in the way it replicates these sequences and as a result generates mutations when connecting one nucleotide after the other. “The surprising finding we had is that some mutations are much more easily made than others,” says Götte.
 
They next submitted HCV RNA samples taken from infected patients to sequence analyses and were able to distinguish between rare and common types of mutations. Together, the data suggest that the bar for the development of drug resistance is much higher if rare mutations are involved. This study has therefore important implications for the development of potent drug combinations that are less likely to result in the emergence of resistance.
 
The research was funded by: Cancer Research Society, Canadian Institutes of Health Research
 
Career awards and stipends were provided by: Fonds de Recherche en santé du Québec, Canadian Institutes of Health Research, and the National Canadian Research Training Program in Hepatitis C.
 
The paper describing the research was published by the Proceedings of the National Academy of Sciences (PNAS).
 
To read an abstract of the paper: http://www.pnas.org

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Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127, and Ribavirin in Patients With Chronic HCV Infection

Gastroenterology
Volume 141, Issue 6 , Pages 2047-2055, December 2011

Stefan Zeuzem, Tarik Asselah, Peter Angus, Jean–Pierre Zarski, Dominique Larrey, Beat Müllhaupt, Ed Gane, Marcus Schuchmann, Ansgar Lohse, Stanislas Pol, Jean–Pierre Bronowicki, Stuart Roberts, Keikawus Arasteh, Fabien Zoulim, Markus Heim, Jerry O. Stern, George Kukolj, Gerhard Nehmiz, Carla Haefner, Wulf Otto Boecher

Received 3 June 2011; accepted 30 August 2011. published online 16 September 2011.

Abstract

Background & Aims

Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin.

Methods

Thirty-two treatment-naïve patients with chronic HCV genotype 1 infection were randomly assigned to groups that were given 400 mg or 600 mg BI 207127 3 times daily plus 120 mg BI 201335 once daily and 1000 to 1200 mg/day ribavirin for 4 weeks. The primary efficacy end point was virologic response (HCV RNA level <25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4 weeks of assigned combination therapy.

Results

In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed in patients with genotype-1b compared with genotype-1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among genotypes. One patient in the group given 400 mg 3 times daily had virologic breakthrough (≥1 log₁₀ rebound in HCV RNA) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely.

Conclusions

The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.

Source

Spotlight On Hepatitis-C Market

By Zacks Investment Research on December 6, 2011

Is the hepatitis-C market the next Mecca for the pharma/biotech sector? It seems so if we go by the flurry of activity and heightened interest in this market in the past few quarters. The hepatitis-C virus (HCV) market seems to have caught the eye of several pharma/biotech companies – as evident by the deals being signed for the development of drugs for the treatment of HCV.

We are talking about the recent announcements made by big players like Johnson & Johnson (NYSE:JNJ), Bristol-Myers Squibb (NYSE:BMY) and Gilead Sciences, Inc. (NASDAQ:GILD). All three companies have made it clear they want a piece of the HCV market pie.

Johnson & Johnson’s Tibotec Pharmaceuticals and Bristol-Myers Squibb recently announced that they have decided to join forces for the development of Bristol-Myers’ daclatasvir (BMS-790052) in combination with Tibotec’s TMC435, for the treatment of chronic HCV. What the partners are aiming to do is create an oral once-daily interferon-free cocktail treatment for HCV patients.

Bristol-Myers and Johnson & Johnson’s announcement comes on the heels of Gilead’s announcement regarding its intention to buy Pharmasset, Inc. (NASDAQ:VRUS), a company focused on developing HCV treatments. We think the main attraction for Gilead in this $11 billion deal is Pharmasset’s HCV pipeline. Lead candidate PSI-7977 is currently in two phase III studies, with a third phase III study scheduled to commence in the first half of 2012. Successful development could lead to US approval in 2014 thereby making Gilead a front-runner in the oral once-daily interferon-free cocktail treatment HCV market.

We note that both TMC435 and daclatasvir are being evaluated separately in combination with Pharmasset’s PSI-7977.

The Allure of the HCV Market

HCV is a hot development area which has come into the limelight with the launch of two new treatments – Vertex Pharmaceuticals’ (NASDAQ:VRTX) Incivek and Merck’s (NYSE:MRK) Victrelis. Both drugs gained approval in the US earlier this year. Incivek, which was launched in May 2011, posted a whopping $419.6 million in sales in the first full quarter of its launch.

So, with two new recently launched products in the market, why is the HCV market considered so attractive? Firstly, it is estimated that about 170 million people suffer from HCV infection across the world. However, the treated population is much lower. In major markets like the US, EU, Japan, Australia, Turkey, Canada, etc. only 200,000 HCV patients out of a total of more than 12 million are estimated to receive treatment each year. This means a huge number of HCV patients go untreated, leaving the field open for new treatments.

Secondly, the current standard of care comes with several side effects which make it difficult for patients to remain on treatment. A 48-week course of both peg-interferon (peg-INF – weekly injections) and ribavirin (RBV – oral drug), are the standard treatment for genotype 1 HCV infection. However, this treatment regimen is associated with significant side-effects like fatigue, flu-like symptoms, rash, depression and anemia.

With a large number of HCV patients failing to achieve a sustained viral response (SVR) on the current standard of care, there are several patients who would be open to treatment with new and potentially more effective therapies.

These factors have made the HCV market an attractive commercial opportunity for pharma and biotech companies. Victrelis and Incivek are examples of the changing treatment regimen in the HCV market. Both are protease inhibitors which when added to the standard of care reduce the treatment period and also improve the treatment outcome. However, both need to be administered with peg-IFN and RBV – this leaves the path open for the introduction of treatments with fewer side effects.

Cocktail Therapy – The Next Big Thing in HCV

Companies like Johnson & Johnson and Gilead are trying to develop the next crop of drugs, which are expected to change the treatment paradigm for HCV patients by providing them with all-oral treatment regimens. The aim is to develop a treatment which does not require the administration of interferon, thereby doing away with a whole range of side effects. The treatment duration will also be shorter.

Treatments being developed include HCV polymerase inhibitors and HCV NS5A inhibitors. The future HCV market will most likely consist of cocktail treatment regimens developed by combining different oral treatments.

Vertex Pharma has also recognized the need to continually evolve the HCV treatment pattern and is developing an all-oral combination of VX-222 (a polymerase inhibitor) and Incivek without peg-IFN.

Who Will Win the Rat Race?

With several companies pursuing cocktail therapies for HCV, it will be interesting to see which of these companies will be the first to hit the market with a new treatment option. Currently, it looks like Gilead might be the front-runner assuming the Pharmasset acquisition goes through.

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The FAIR Foundation strongly rebukes President Obama for his World AIDS Day pledge of $50 million more for HIV/AIDS

In an candid Opinion Editorial entitled "Are You Serious??", the FAIR Foundation has issued an open letter to President Obama chastizing him for his World AIDS Day pledge of another $50 million for HIV/AIDS.

Palm Desert, California (PRWEB) December 06, 2011

In an candid Opinion Editorial entitled "Are You Serious??", the FAIR Foundation has issued an open letter to President Obama chastising him for his World AIDS Day pledge of another $50 million for HIV/AIDS.

The FAIR Foundation opinion editorial questions if Obama has forgotten that his 2012 HIV/AIDS budget request of taxpayer dollars is already $28.3 billion and asks if the President has been told by his administration that over one-third of a trillion dollars has been spent on HIV disease since its inception.

FAIR also asks the President if he is aware that his National Institutes of Health (NIH) is spending less than $200 per patient in research on virtually every disease, including over 6,000 rare illnesses that receive pennies, while the NIH is spending over $3,000 research dollars on behalf of every patient with HIV/AIDS?

FAIR's letter points out that President Obama has been crisscrossing the country calling for fairness in taxes paid by all Americans and FAIR inquires of the President if he thinks the numbers above are “fair” to non-HIV patients.

A member of the FAIR Foundation’s Board of Directors, Ray Hill, also addresses the President. The letter points out that Hill was one of the most strident HIV/AIDS patient advocates who, for decades, fought for increased HIV funding. He was arrested for his advocacy and he eventually won his legal case in the United States Supreme Court (U.S. Supreme Court—Houston v. Hill, 482 U.S. 451) when Supreme Court Justice William Brennan labeled Mr. Hill a "Citizen Provocateur." The American Civil Liberties Union (ACLU) awarded Ray its Lifetime Achievement Award for advancing the rights of gay, lesbian and transgender citizens, and he has been voted "gay hero" seven years in a row by the gay community of Houston, Texas.

Hill speaks to the President: “The funding for HIV has become a jobs program with billions of wasted dollars going to administrators in the USA and abroad. It is time for HIV funding to be reduced and redirected to other illnesses that have not had such exorbitant funding.”

FAIR’s letter states that FAIR supports efforts to provide the excellent HIV medicine to patients in poor countries; however FAIR is disgusted at the glee expressed by rock singer Bono at the President’s announcement ceremony when Bono celebrated this increased spending by “every taxpayer in this country.”

In FAIR’s letter to Obama, FAIR points out that in addition to the billions he is forcing taxpayers to spend on HIV/AIDS, billions more are spent annually on behalf of HIV/AIDS by others, including the 50 states, pharmaceutical companies and non-profit organizations such as the Bill and Melinda Gates Foundation.

FAIR then suggests that since Mr. Gates and Mr. Warren Buffet wish to pay more of their combined $90 billion dollars to our country’s treasury, Obama should give them a call and ask them for this extra $50 million he has just pledged.

FAIR's letter continues, “We realize it is an election year and, as the LA Times article states, you are trying to “renew the devotion of the liberal base” that helped elect you but we submit that such blatant pandering is an insult to all HIV/AIDS activists, including our Ray Hill.”

FAIR asks one last question: “Did you not see the results of the 2010 mid-term elections? Please allow us to remind you: American citizens assessed the trillion dollars spent by the Bush administration and the Congress at that time, the four trillion dollars you and your Congress have spent, and then these fed up citizens shouted within their voting booths and booted a majority of the big spenders out of Congress.”

FAIR's letter to the President reminds him that these voters are returning in 11 months and of their message to him and to Congress: STOP SPENDING TAXPAYER DOLLARS.

You may read the FAIR Foundation's rebuke of President Obama below or by clicking here.

The FAIR Foundation is a national non-profit organization with thousands of members and millions of supporters in all fifty states and the District of Columbia. FAIR's Board of Directors consists of twenty-seven transplant surgeons, medical directors and patient advocates.

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