December 11, 2010

A Targeted Approach to Hepatitis C Treatment

Peter Mueller PhD, CSO and EVP of Global R&D; Vertex Pharmaceuticals, Cambridge, Mass.

Drug Discovery & Development - December 01, 2010

Hepatitis C is a serious liver disease caused by the hepatitis C virus (HCV) that affects approximately 170 million people worldwide.1 Up to 3.9 million Americans may be infected with HCV and 75 percent are unaware of their infection.2,3 Hepatitis C can be cured with drug therapy. However, for people infected with the most common form of HCV in the United States (genotype 1), less than half achieve a sustained viral response (SVR), or viral cure, with current therapies.4-6

Without effective treatment, chronic hepatitis C can cause liver failure, liver cancer, and death.1 The need for more effective therapy for people with genotype 1 hepatitis C has led to research into direct-acting antivirals (DAAs) that target viral replication proteins such as the HCV protease and HCV polymerase.

Vertex Pharmaceuticals used a structure-based drug design approach to identify telaprevir, a novel small molecule DAA.7 Telaprevir inhibits a protease essential for viral replication, HCV NS3-4A. The complex formed between telaprevir and HCV NS3-4A is covalent yet reversible, with a slow-on, slow-off process.7 This potent, selective inhibitor significantly reduced HCV RNA levels (an indicator of reduced viral replication) in both cell culture systems and early-phase clinical trials.7,8

To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir-based therapy as part of Phase 2 and Phase 3 clinical trials. Telaprevir was given in combination with pegylated-interferon and ribavirin for the first 12 weeks of treatment followed by pegylated-interferon and ribavirin alone for either 12 or 36 weeks of additional therapy. Telaprevir has been studied in three Phase 3 trials: ADVANCE, ILLUMINATE, and REALIZE. ADVANCE and ILLUMINATE included patients who had never received treatment for hepatitis C (treatment-naïve), whereas REALIZE included patients who had not achieved SVR, or viral cure, after a prior course of interferon-based treatment (treatment-experienced).9-11 REALIZE was the only Phase 3 study of an investigational DAA designed to evaluate all major subgroups of people whose prior treatment was unsuccessful, including those who had a null response (less than a 2-log10 drop in HCV RNA by week 12 of a prior course of treatment) as defined by the U.S. Food and Drug Administration (FDA).6,11,12

The telaprevir Phase 2 study results were published in the New England Journal of Medicine, and Phase 3 results from ADVANCE and ILLUMINATE were presented at the annual meeting of the American Association for the Study of Liver Diseases in October 2010.9,10,13-15

Vertex submitted a new drug application to the FDA in November of 2010 and plans to request priority (6-month) review of the application.

References

1. World Health Organization. Hepatitis C. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index.html. Updated 2002. Accessed August 18, 2010.

2. Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed August 18, 2010.

3. Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed August 18, 2010. This report was commissioned by Vertex Pharmaceuticals.

4. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis in the United States. J Viral Hepat. 2000;7:196-202.

5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Eng J Med. 2002;347(13):975-982.

6. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: An update. Hepatology. 2009;49(4): 1335-1374.

7. Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50(3):899-909.

8. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131(4):997–1002.

9. Jacobson IM, McHutchison JG, Dusheiko GM et al. Telaprevir in combination with Peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study. Hepatology. 2010;52(Suppl 4): 427A. Abstract 211.

10. Vertex Pharmaceuticals Press Release: Vertex Pharmaceuticals to Start Phase 3 'REALIZE' Trial with Telaprevir in Treatment-Failure HCV Patients, August 19, 2008. Available at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=328603. Accessed on August 25, 2010.

11. Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa3a and ribavirin for 34 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of the Phase 3 ILLUMINATE study. Hepatology. 2010;52(Suppl 4):401A. Abstract LB-2.

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

13. McHutchison JG, Everson GT, Gordon SC, et al. and the PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. New Eng J Med. 2009;360(18):1827-1838.

14. Hezode C, Forestier N, Dusheiko G, et al. and the PROVE2 Study Team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. New Eng J Med. 2009;360(18):1839-1850.

15. McHutchison JG, Manns MP, Muir AJ, et al. and the PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. New Eng J Med. 2010;362(14):1292-1303.

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SeraCare Introduces New HCV Seroconversion Panels

SeraCare Life Sciences, a leading expert in human biologicals and the manufacturer of ACCURUN® controls, introduces two new, highly characterized HCV seroconversion panels designed to help diagnostic manufacturers and clinical laboratories effectively evaluate their HCV test systems.

Milford, MA (PRWEB) December 11, 2010

The safety of the blood supply and the accurate diagnosis of Hepatitis C infection depend on the sensitivity and overall quality of tests for markers of HCV. Test developers, regulators and clinical laboratories require highly characterized panels and control materials to challenge sensitivity accuracy and reproducibility of their assays.

SeraCare Life Sciences, a leading expert in human biologicals and the manufacturer of ACCURUN® controls, introduces two new, highly characterized HCV seroconversion panels designed to help diagnostic manufacturers and clinical laboratories effectively evaluate their HCV test systems. The specimens in each panel are collected from a single individual during the evolution of the immune response to HCV. Accurate detection of early HCV infection is especially important for tests used to screen the blood supply, as HCV is not initially symptomatic upon infection.

The two new seroconversion panels, designated PHV922 and PHV923, each consist of a set of undiluted plasma samples collected from a single individual during seroconversion, the period of time during development of infection and early immune response. PHV922 and PHV923 were collected from deferred plasma donors in different regions of the U.S. over 17 and 23 days respectively, in 2008. PHV922 is HCV genotype 3a; PHV923 is HCV genotype 1a. Both series demonstrate the early evolution of the human immune response to HCV, and contain naturally occurring samples to challenge the sensitivity of tests for HCV antibody.

Data for the SeraCare HCV Seroconversion Panels are available at http://www.seracarepanels.com/. The enhanced online data sheets graphically portray the evolution of the HCV markers, and display test results from multiple test methods for each marker. For additional information call +1 508-244-6400 or visit the webpage at http://www.seracarecatalog.com/, or email info(at)seracare(dot)com.

About SeraCare Life Sciences, Inc.:

SeraCare serves the global life sciences industry by providing vital products and services to facilitate the discovery, development and production of human diagnostics and therapeutics. The Company’s innovative portfolio includes diagnostic controls, plasma-derived reagents and molecular biomarkers, biobanking and contract research services. SeraCare’s quality systems, scientific expertise and state-of-the-art facilities support its customers in meeting the stringent requirements of the highly regulated life sciences industry.

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Hepatitis C: Disease Treatment Insight

December 10, 2010
Writer Toni Brown

MedPredict Market Research, a global provider of pharmaceutical competitive intelligence and market research, has published a new report entitled “Thought Leader Insight & Analysis: Hepatitis C Virus (HCV),” designed to provide critical strategic insight for pharma and biotech companies with a stake in the market for treatments in this disease area.

“This report summarizes the perspectives of renowned thought leaders who specialize in the treatment of hepatitis C,” according to Elizabeth Mathews, MedPredict’s CEO. “We conducted in-depth interviews with these experts immediately following AASLD to understand the effect that the upcoming approvals of telaprevir and boceprevir will have on the treatment of HCV, as well as to gain insight into how combination therapy will address the unmet needs still remaining after the approval of these protease inhibitors.”

Some of the topics discussed by in this report include:
  • Goals of therapy,
  • Who should treat HCV,
  • Unmet needs and favorite future cocktails; interferon-sparing regimens,
  • Warehousing patients in the age of protease inhibitors,
  • Potential for resistance development,
  • Dosing/compliance,
  • IL-28b / CC, CT and TT patients; US, EU and Asian populations,
  • Fibrosis score,
  • Possible reimbursement/bundling strategies,
  • Cost of therapy and duration of treatment, and
  • Side effects: rash vs. anemia. 
Companies/partnerships discussed in this report: Abbott/Enanta, Achillion, Amgen/Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb, Eiger, Gilead, GlaxoSmithKline, Idenix, Medivir/Tibotec, Merck, Novartis, Novartis/Debiopharm, Pfizer, Pharmasset, Roche/Pharmasset, Scynexis, and Vertex.
The full report may be purchased by contacting MedPredict.

About MedPredict

MedPredict maintains a proprietary database of over 1,000 global physician thought leaders. Based on primary interviews with these thought leaders, MedPredict publishes periodic therapeutic area reports to keep clients up-to-date on emerging trends and competitive activity. The reports include thought leader reactions to recent publications and presentations, as well as clinical, regulatory and marketing activity.

For more information contact:
Elizabeth Mathews
MedPredict
513.271.1924

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`Natural killers' unleashed to search and destroy cancer

Doctors at the University of Miami are treating liver cancer patients by giving immune-system cells more muscle in the lab to recognize and attack their cancer cells.

BY FRED TASKER
ftasker@MiamiHerald.com

They're called ``natural killer cells'' but they're a part of the human immune system that helps save lives. Now doctors from Miami and Japan have developed new ways to pump up the cells to attack cancer even more aggressively.

Encarnacion Miranda, a 58-year-old car salesman from Key Largo, is counting on the cells -- which exist in healthy livers -- to save his life. He's the first patient in a clinical trial at the University of Miami of 25 liver patients seeking Food and Drug Administration approval of the new treatment.

``It's scary,'' Miranda said Thursday, during an announcement of the medical trial. ``But I feel really good.''

Miranda's liver had been dogging him since 1979, when he contracted hepatitis C from a blood transfusion. By October 2009, chronic exhaustion forced him to give up his favorite sport, fishing for yellowtail snapper in the Florida Keys. That's when he learned his hepatitis had become liver cancer.

Doctors gave Miranda a liver transplant. But, knowing that liver cancer recurs in up to 20 percent of cases due to tumor cells left hiding in the body, they went further. Before the transplant, they took blood from the donated liver, extracted the natural killer immune cells from it, then cultured and expanded them in laboratory flasks for four days to increase their power against any remaining cancer cells. They fed them intravenously back into Miranda's new liver.

Doctors say the killer cells, which recognize cancer cells as alien and try to destroy them, also will help fight any remaining hepatitis C. They aren't sure yet whether their findings on natural killer cell expansion might be broadened to work in other organs and combat other cancers.

The procedure was studied for four years at the University of Hiroshima. Dr. Masahiro Ohira performed the procedure on 24 patients; 22 survived cancer-free for more than three years. It cut in half the recurrence of cancer.

``The killer cells act like smart bombs in going after the cancer,'' Ohira said.

Miranda is grateful to the team at the University of Miami Medical School that worked with him at Jackson Memorial Medical Center.

``I was up and walking three days after my [Oct. 19] transplant,'' he said. ``Yesterday I walked six miles.''

Treating Miranda was actually far more complicated than his recovery would indicate. When his three liver tumors were found, they were too big to permit a transplant. So the team from UM used several courses of chemotherapy and radio-frequency ablation -- the use of radio-frequency waves to destroy tumor tissue -- to attack them, finally reducing them enough to make possible the transplant.

When a donor liver became available, the doctors flushed out some of its natural killer cells before transplanting it into Miranda. Ohira put the cells into a laboratory flask and applied an agent known to increase the cells' potency, even though it doesn't increase their number.

``It increases their activity against cancer and hepatitis C by four times,'' he said.

The team included Dr. Andreas Tzakis, director of the Liver Transplant Program, Ohira, now a research associate in the UM Department of Surgery and Drs. Seigo Nishida and David Levi, professors of clinical surgery at UM.

``They're my heroes,'' Miranda said. ``They never gave up.''

Miranda's prognosis?

``We think it's good,'' Tzakis said. ``Of course there are no guarantees.''

Miranda says he has far more energy now.

``Last year I was so exhausted I felt like I was passing away. Today I feel like a new person.''

Miranda's doctors say by next year he and his companion of 14 years, Linda Cozby, can return to catching yellowtail snapper.

Miranda grinned.

``Next year is only three weeks away.''

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Fat Index Associated With Liver Damage in Hep C Patients

Last Updated: December 09, 2010

The visceral adiposity index, a score that combines body mass index, waist circumference, triglycerides, and high-density lipoprotein levels, is associated with liver damage and viral load in patients with genotype 1 chronic hepatitis C, according to a study in the November issue of Hepatology.

THURSDAY, Dec. 9 (HealthDay News) -- The visceral adiposity index (VAI), a score that combines body mass index, waist circumference, triglycerides, and high-density lipoprotein levels, is associated with liver damage and viral load in patients with genotype 1 chronic hepatitis C (G1 CHC), according to a study in the November issue of Hepatology.

Salvatore Petta, M.D., of the University of Palermo in Italy, and colleagues performed liver biopsies on 236 patients with G1 CHC and conducted examinations to assess for steatosis, evidence of liver damage (such as necroinflammatory activity and fibrosis), and viral loads. The researchers also conducted metabolic and anthropometric tests and computed each subject's VAI.

The researchers found that VAI scores were independently associated with homeostasis model assessment score, hepatitis C virus (HCV) RNA levels, necroinflammatory activity, and steatosis. Also, in regression analyses, insulin resistance, higher VAI score, and fibrosis all were associated with moderate to severe steatosis, while older age, higher VAI score, and fibrosis were independently associated with steatosis of at least 30 percent, and older age, higher VAI score, and fibrosis were independently related to moderate to severe necroinflammatory activity.

"In conclusion, VAI, a new index of both fat function and distribution, appears to be independently associated with steatosis and necroinflammatory activity in G1 CHC patients and has a direct correlation with HCV viral load. These data suggest a direct role of adipose tissue in liver damage and a possible interference of HCV with adipocyte function. Experimental studies are needed to determine the mechanisms responsible for these associations," the authors write.

Abstract
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Cambridge, UK, December 8th - Lab21 Limited, the Cambridge, UK-based specialist in personalised medicine has secured new patents in Europe and the USA relating to Hepatitis C and its SelahDOTS™ fluorescent nanoparticles, as it continues to expand its intellectual property portfolio.

The hepatitis C patent extends an existing patent, and refers to technology allowing the genotypic identification of drug resistant mutations in the 4 major global genotypes of HCV. With the imminent launch of a series of new small molecule therapies in HCV, this technology will allow accurate monitoring of when drug resistance appears in individual patients, improving patient care.

The SelahDOTS™ nanoparticles technology covers a generic approach to the development of new diagnostic and imaging reagents using carbon-based non-toxic nanoparticles. This platform technology has multiple applications in clinical diagnostics and was originally developed through a licence from Clemson University. The grant of the patent now allows Lab21 to develop a series of new product and service applications in areas such as in vivo imaging, immunodiagnostics and point-of-care biomarker analysis,

The securing of these patents builds on Lab21’s growing intellectual property portfolio as it expands its competitive proprietary position in pharmacogenetic markers, disease markers and its assay technology.

Dr Berwyn Clarke, CSO at Lab21 commented: ‘The HCV patent further strengthens our portfolio in the important HCV diagnostic area while the nanoparticle platform technology has potential to transform the ways in which particulate diagnostics are used, particularly in vivo, where particle-related toxicity has been a significant problem. Additionally we are seeing early development progress in incorporating the SelahDOTS™ technology in our own new molecular and protein based assays.’

Graham Mullis, Lab21 CEO added: ‘The development of an extensive intellectual property portfolio will be an important part of Lab21’s strategy as we continue to grow. Patents such as these will ensure we are able to remain uniquely competitive and ensure we are able to provide our customers with the most advanced products and services in the markets we choose to serve.’

For further information: Lab21 Graham Mullis, CEO Dr Berwyn Clarke, CSDO t: +44 (0)1223 395461 e: graham.mullis@lab-21.com

For media and investor enquiries: College Hill Tony Stephenson/Gemma Howe/Nicole Yost t: +44 (0)20 7866 7864 m: +44 (0)7989 855113 e: lab21@collegehill.com

About Lab21 Lab21 is a global provider of state-of-the-art diagnostic products and services, supporting blood bank screening, medical diagnostics and drug discovery. Its customers include international healthcare providers, pharmaceutical and biotechnology companies. The product division of the Company manufactures immunodiagnostic kits and reagents that are distributed into 110 international countries and is focused on infectious diseases for the blood-banking market. The service division has a growing test portfolio providing companion diagnostics and high technology molecular assays for the growing integration of personalised medicine into healthcare. These services are currently in infectious diseases, oncology and pharmacogenetics areas with emerging interests in cardiovascular and metabolic disease. Lab21's clinical reference laboratory and corporate office is based in Cambridge and has additional UK sites in Newmarket, Bridport, Liverpool and Ipswich. It also has operations in South Carolina, USA. The Company's investors include Merlin Biosciences, Nexus Medical Partners, Medicis Capital, Rowan Dartington and Kreos Capital. Website: http://www.lab21.com/

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