New Therapy Significantly Increases Platelet Count

Eltrombopag Significantly Improved Platelet Count and Allowed Initiation of Antiviral Therapy in Majority of Hepatitis C Patients

Phase 2 trial data showed that treatment with eltrombopag enabled 91% of hepatitis C patients with thrombocytopenia to initiate interferon therapy[1]

SOURCE: GlaxoSmithKline plc

Increased platelet counts
In hepatitis C patients with platelet counts between 20,000 - 70,000/mL, more than 95% (P <.001) of patients receiving 75mg of eltrombopag achieved the primary endpoint of the trial defined as an increase in platelet count to b %100,000/mL after four weeks of treatment, compared to 0% in the placebo group. Of patients receiving 50mg and 30mg doses, nearly 74% and 75% (respectively) achieved the primary endpoint of the trial.

Initiating antiviral therapy
91% of patients receiving 75mg of eltrombopag initiated antiviral therapy compared to 22% in the placebo group. Of patients receiving 50mg and 30mg of eltrombopag, up to 74% and 71% (respectively) were able to initiate antiviral therapy.

Maintaining antiviral therapy
Of patients initiating antiviral therapy, 65% of these patients completed 12 weeks of antiviral therapy, compared to 6% in the placebo group. Additionally, patients who received 50mg and 30mg of eltrombopag, 53% and 36% (respectively) completed a full 12 week course of antiviral therapy.



BOSTON, MA -- October 30, 2006 -- GlaxoSmithKline plc today announced results from a global phase 2 study of eltrombopag, an investigational non-peptide oral platelet growth factor.

In this study of 74 hepatitis C patients with thrombocytopenia, (a condition where the blood has low platelet levels) more than 95% (P <.001) of patients treated with the highest dose of eltrombopag (75mg) had increased platelet counts. In addition, 71% - 91% of patients in all treatment groups were able to initiate antiviral therapy with pegylated interferon-alpha (IFN) and ribavirin, and 65% were able to be maintained on therapy.1

Full results from this phase 2 study are being presented today at the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, Massachusetts.

Thrombocytopenia is the most common haematological complication in patients with chronic liver disease.[2], [3] It occurs as a result of damage to liver cells that produce thrombopoietin, the body's natural platelet growth factor, or secondary to disease progression to cirrhosis. It is characterised by low platelet counts, leaving patients at risk of spontaneous bruising, mucosal bleeding, and in severe cases, intracranial haemorrhage.

"We are very excited by these results for eltrombopag which may offer hope to patients with hepatitis C currently unable to undergo antiviral therapy due to thrombocytopenia," said Paolo Paoletti, MD, Senior Vice President, Oncology Medicine Development Centre, GSK. "As we move into phase 2I trials for eltrombopag in a variety of conditions where thrombocytopenia is a complicating factor, these data represent a significant milestone for GSK in supportive care and underscore our continued commitment to deliver novel treatments to meet significant unmet medical need."

Pegylated IFN combined with ribavirin is the standard treatment regimen used to control infection with hepatitis C virus (HCV). This regimen is critical to successful management of HCV infection and provides patients with the opportunity for a cure.

Although this treatment regimen is effective in managing HCV it can also cause thrombocytopenia, therefore IFN is to be used with caution in patients who have existing thrombocytopenia (<90,000 platelets/B5L).[4] In order to combat thrombocytopenia in patients with HCV the current clinical management strategy involves delaying, reducing or discontinuing treatment with antiviral therapy.

"Patients with hepatitis C and low platelet counts are normally prevented from initiating antiviral therapy, receive less effective doses of interferon, or need to stop treatment all together," said Professor Geoffrey Dusheiko, Professor of Medicine and an Honorary Consultant at the Centre for Hepatology of the Royal Free and University College School of Medicine, Royal Free Hospital, London. "Without antiviral therapy, patients' clinical outcomes are severely compromised. These data are tremendously exciting and suggest that eltrombopag could be the first oral therapy to increase platelet counts and enable patients with hepatitis C-associated thrombocytopenia to initiate and maintain their antiviral therapy."

Hepatitis C Prevalence
The World Health Organization (WHO) estimates that about 180 million people are infected with hepatitis C globally.[5] Three to four million new cases are diagnosed each year and 70% of these individuals go on to develop chronic hepatitis.5 Hepatitis C is to blame for 50 - 76% of all liver cancers and two thirds of all liver transplants in the developed world.5

About Thrombocytopenia and Hepatitis C
A reduction in platelet count to a level <150,000/mL 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.[6] 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. The severity of thrombocytopenia varies and mild to moderate cases may resolve spontaneously without treatment, however severe thrombocytopenia can be associated with significant morbidity and mortality.[7],[8]

Study Design1
The phase 2, multi-centre, randomised, double-blind, placebo-controlled, dose-ranging trial enrolled 74 patients with hepatitis C virus-associated thrombocytopenia. Eligible patients had compensated cirrhosis and platelet counts between 20,000 - 70,000/mL. They were randomly assigned to one of four treatment groups: 30, 50 or 75mg of eltrombopag or placebo. During Part One of the study, patients were given eltrombopag once a day for four weeks. Those subjects who achieved a target platelet count (>70,000/mL for Pegasys and >100,000/mL for PEG-Intron) were then eligible to enter Part Two of the study where they continued with their randomised dose of eltrombopag in addition to antiviral therapy with IFN and ribavirin.

Study Results1

Safety information
Adverse events (AEs) were reported by 17% of patients in the placebo group compared with 21% receiving 30mg of eltrombopag, 42% on 50mg and 26% on 75mg during the first 4 weeks of therapy. The most common AEs were headache, dry mouth, nausea and diarrhoea. Two serious adverse events (SAEs) were reported on treatment - neither were considered to be related to the study drug. Three subjects experienced four SAEs during follow up (when treatment with eltrombopag had been stopped); one patient experienced abdominal pain and renal failure; one patient reported myositis (muscular inflammation); one other patient reported thrombocytopenia - the only SAE considered to be related to the study drug. Following the introduction of antiviral therapy, the adverse events reported reflect those expected with interferon and ribavirin therapy.

Increased platelet counts
In hepatitis C patients with platelet counts between 20,000 - 70,000/mL, more than 95% (P <.001) of patients receiving 75mg of eltrombopag achieved the primary endpoint of the trial defined as an increase in platelet count to b %100,000/mL after four weeks of treatment, compared to 0% in the placebo group. Of patients receiving 50mg and 30mg doses, nearly 74% and 75% (respectively) achieved the primary endpoint of the trial.

Initiating antiviral therapy
91% of patients receiving 75mg of eltrombopag initiated antiviral therapy compared to 22% in the placebo group. Of patients receiving 50mg and 30mg of eltrombopag, up to 74% and 71% (respectively) were able to initiate antiviral therapy.

Maintaining antiviral therapy
Of patients initiating antiviral therapy, 65% of these patients completed 12 weeks of antiviral therapy, compared to 6% in the placebo group. Additionally, patients who received 50mg and 30mg of eltrombopag, 53% and 36% (respectively) completed a full 12 week course of antiviral therapy.

About Eltrombopag
Eltrombopag is an investigational non-peptide small molecule 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. Eltrombopag is a small molecule, which is administered orally, as a tablet once daily. Eltrombopag was discovered as the result of research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals. It is being developed by GlaxoSmithKline. These data strongly justify further evaluation of eltrombopag for a longer duration in this patient population.


REFERENCES:
[1] JG McHutchison et al. Efficacy and safety of eltrombopag an oral platelet growth factor in subjects with HCV-associated thrombocytopenia: final results from a phase II multicenter, randomized, placebo controlled, double-blind, dose-ranging study. Abstract presented at the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
[2] Aref S, Mabed M, Selim T, et al. Thrombopoietin (TPO) levels in hepatic patients with thrombocytopenia. Hematology. 2004;9:351-356.
[3] Koruk M, Onuk MD, Akcay F, Savas MC. Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis, and its relationship with circulating thrombocyte counts. Hepatogastroenterology. 2002;49:1645-1648
[4] PegasysB. (peginterferon alfa-2a) prescribing information. Nutley, N J: Hoffmann-La Roche Inc; 2003.
[5] World Health Organisation. http://www.who.int/vaccine_research/diseas.../en/index2.html
[6] 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.
[7] Kaushansky K. The thrombocytopenia of cancer: prospects for effective cytokine therapy. Hematol Oncol Clin North Am. 1996;10:431-455.
[8] Demetri GD. Targeted approaches for the treatment of thrombocytopenia. Oncologist. 2001;6 (suppl 5):15-23.