GlaxoSmithKline (GSK) today announced the commencement of two parallel Phase III studies to assess the clinical benefits of its investigational compound Promacta^®/Revolade™ (eltrombopag) in hepatitis C-associated thrombocytopenia, a condition characterised by decreased platelet counts. The studies, ENABLE 1 and ENABLE 2 (Eltrombopag to INitiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE), will measure the ability of eltrombopag to raise platelet counts sufficiently enough to enable the initiation of antiviral therapy and to allow sustained antiviral therapy in thrombocytopenic hepatitis C patients. The clinical benefit of eltrombopag will be measured by the proportion of subjects who are able to achieve sustained virological response (SVR).

SVR is defined as an undetectable viral load of hepatitis C for a period of six months post-treatment and is the desired outcome of antiviral therapy. SVR is a determination that the hepatitis C virus is no longer replicating — a status that is viewed clinically to be an eradication of the virus and a decreased risk of disease progression.¹

“The launch of both ENABLE trials is of great interest to many investigators in the field,” said John McHutchison, MD, Professor of Medicine and Associate Director, Duke Clinical Research Institute, Durham, North Carolina, US. “Thrombocytopenia is a complicating factor in hepatitis C treatment. Not only can it interfere with the administration of effective doses of antiviral therapy, but in some cases treatment may be terminated or not started at all. In a previous Phase II study, eltrombopag, compared to placebo, increased platelet counts and allowed more patients to complete the first 12 weeks of antiviral therapy, giving them an opportunity to achieve an SVR. ENABLE will investigate the effect of eltrombopag over a 12-month treatment period to determine how it may help patients to achieve SVR, which in clinical terms is considered a cure for hepatitis C, as well as better understand any related toxicities or tolerability issues.”

Thrombocytopenia in patients with chronic hepatitis C virus (HCV) can occur as a result of damage to liver cells that produce thrombopoietin (the body’s natural platelet growth factor), or due to disease progression from cirrhosis. It may also occur as a consequence of antiviral (interferon) therapy used to treat HCV infection. ^{2, 3}

Combination antiviral treatment (peginterferon plus ribavirin) is the standard regimen used to control HCV infection.ⁱ This approach is critical for successful management of HCV and provides patients with the potential for a cure.

Eltrombopag is an investigational oral, non-peptide platelet growth factor. The ENABLE trials will investigate if eltrombopag will allow patients a greater opportunity to maximize the dose and duration of their antiviral therapy, thus improving the likelihood of achieving SVR. The ability to achieve and maintain SVR not only provides patients with clinical benefits, but is also shown to have a positive impact on quality of life with significant improvements in perceived wellness, vitality, social functioning and health distress.⁴

In addition, a Phase II subgroup analysis evaluating eltrombopag in hepatitis C patients will be presented at the forthcoming 58^th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, Massachusetts.⁵

Study design

ENABLE 1 and ENABLE 2 are parallel, multi-center, two-part studies. Each consists of an open-label pre-antiviral treatment phase (Part 1) and a randomized, double-blind, placebo controlled, antiviral treatment phase (Part 2). Both studies will enroll approximately 750 patients with chronic hepatitis C infection (quantifiable HCV RNA) with baseline platelet counts of <75,000/μL. In Part 1 of the study all subjects will receive open-label eltrombopag in increasing doses for up to nine weeks before being randomized to double-blind eltrombopag or matched placebo in combination with antiviral therapy for up to 48 weeks (Part 2). ENABLE 1 will administer peginterferon alfa-2a plus ribavirin, while ENABLE 2 will investigate the use of peginterferon alfa-2b plus ribavirin. SVR rates will be assessed along with safety and quality of life outcomes.

Hepatitis C prevalence

The World Health Organization (WHO) estimates that about 180 million people are infected with hepatitis C globally. ⁶ Three to four million new cases are diagnosed each year and 70% of these individuals go on to develop chronic hepatitis.⁴ Hepatitis C is to blame for 50 — 76% of all liver cancers and two thirds of all liver transplants in the developed world.⁶

About thrombocytopenia and hepatitis C

A reduction in platelet count to a level <150,000/μL is the defining characteristic of any type of thrombocytopenia and diagnosis can be confirmed following a routine blood test. Thrombocytopenia occurs in 5% - 10% of all patients hospitalised for any cause.⁷ The severity of thrombocytopenia varies. Mild to moderate cases may resolve spontaneously without treatment, however severe thrombocytopenia can be associated with significant morbidity and mortality.^{2, 8} The cause of thrombocytopenia associated with hepatitis C is multi-factorial: inadequate thrombopoietin production by damaged liver, bone marrow suppression by interferon or viruses (HCV), sequestration of platelets in the spleen, and increased platelet destruction from an associated autoimmune process.

About eltrombopag

Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has been shown in pre-clinical research and clinical trials to stimulate the proliferation and differentiation of megakaryocytes, the bone marrow cells that give rise to blood platelets, and thus can be considered a platelet growth factor. The safety profile will be further examined in ongoing clinical trials. Eltrombopag was discovered as a result of research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals. It is being developed by GlaxoSmithKline.

Eltrombopag is an investigational compound that has not received regulatory approval in any market for any indication at this time.

About GlaxoSmithKline

GlaxoSmithKline is one of the world’s leading research-based pharmaceutical and healthcare companies. GlaxoSmithKline is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information visit www.gsk.com.

Notes to editors

Revolade™ and Promacta^® are registered trade marks of the GlaxoSmithKline group of companies.

Promacta^® is the proposed registered trademark to be used in the United States.

Revolade™ is the proposed trade mark for use in certain European countries.

To access the latest GSK Oncology media materials, visit www.gskcancermedia.com

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REFERENCES

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1. Alberti A, Clumeck N, Collins S, et al. Short statement of the first European consensus conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. Journal of Hepatology 2005;42:615—624.

2. Kaushansky K. The thrombocytopenia of cancer: prospects for effective cytokine therapy. Hematol Oncol Clin North Am. 1996;10:431-455.

3. Ong JP, Younossi ZM. Managing the hematological side effects of antiviral therapy for chronic hepatitis C: Anemia, neutropenia, and thrombocytopenia. ClevelandClin Journal of Medicine. 2004;71(suppl 3):S17-S21.

4. Bonkovsky HL, Woolley JM. The Consensus Interferon Study Group. Reduction of health-related quality of life in HCV and improvement with interferon therapy. Hepatology. 1999;29(1):277-279.

5. Afdhal NH, McHutchison JG, Shiffman ML, et al. Eltrombopag raises platelet counts in two weeks in patients with HCV and significant thrombocytopenia. Abstract #42. Presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases. November 2-6, 2007. Boston, MA. Presented November 4, 2007.

6. World Health Organisation. http://www.who.int/vaccine_research/diseases/viral_cancers/en/index2.html. Accessed 18 July 2007.

7. Mocharnuk R. Growth factors in granulocytopenia and thrombocytopenia. Presented at: 44th Annual Meeting of the American Society of Hematology; December 6—10, 2002; Philadelphia, Pa.

8. Demetri GD. Targeted approaches for the treatment of thrombocytopenia. Oncologist. 2001;6 (suppl 5):15-23.