Issued: Tuesday 24 September 2013, London UK
GlaxoSmithKline plc announced today that the European Commission has granted an additional indication for Revolade™ (eltrombopag) as a treatment for low platelet counts (thrombocytopenia) in adult patients with chronic hepatitis C infection, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon (IFN)-based therapy.1
Thrombocytopenia (platelet count ≤150Gi/L) can occur in people with chronic hepatitis C infection as a consequence of liver damage.2 It is also a common side effect of peginterferon (pIFN)-based therapy.3,4
25 percent of patients with chronic hepatitis C have thrombocytopenia5 and up to nine percent of patients are severely thrombocytopenic (platelet count <50Gi/L).6
Thrombocytopenia may prevent the initiation5 and maintenance of pIFN-based treatment, thereby reducing a patient's chances of achieving a sustained virologic response (SVR)*7 - the primary goal of hepatitis C treatment.
"Until now, prescribers were without an option for treating low platelet counts in patients with chronic hepatitis C infection" said Paolo Paoletti, President, GlaxoSmithKline Oncology. "Today's announcement is important as it means that healthcare professionals can now use Revolade to help patients start and stay on interferon therapy which will facilitate achieving the best outcome for these individuals - that being a sustained virologic response."
The ENABLE clinical trials
The marketing authorisation granted to eltrombopag is based on results from ENABLE-1 and -2 (Eltrombopag to INitiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE), two Phase III global, multicentre, two-part studies (n=1,520), that comprised an open-label pre-antiviral treatment phase and a randomised, double-blind, placebo-controlled antiviral treatment phase. Eighty percent of the patients had bridging fibrosis or cirrhosis.1,8 ENABLE-1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE-2 utilised peginterferon alfa-2b plus ribavirin.1
Phase III clinical studies demonstrated that eltrombopag may achieve and maintain target platelet counts in chronic hepatitis C patients with associated thrombocytopenia.8,9
* where the hepatitis C virus remains undetectable for six months - following completion of antiviral therapy
Eltrombopag enabled 95 percent of patients with chronic hepatitis C-associated thrombocytopenia to achieve platelet counts sufficient for initiation of pIFN-based therapy.1,8-10
§ Eltrombopag enabled more patients to maintain pIFN-based therapy without dose reduction compared to placebo (45 percent vs 27 percent).1
§ Eltrombopag enabled approximately one in five patients who, because of thrombocytopenia, were previously ineligible or poor candidates for pIFN-based therapy to achieve SVR.1,8,9
The Phase III clinical studies showed an increased risk of adverse events, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic hepatitis C patients with advanced chronic liver disease, as defined by low albumin levels ≤ 35 g/L or MELD (model for end-stage liver disease) score ≥ 10, when treated with eltrombopag in combination with IFN-based therapy.1
§ Eltrombopag may cause hepatotoxicity. Eltrombopag in combination with IFN and ribavirin, in patients with chronic hepatitis C infection, may increase the risk of hepatic decompensation.1
§ An increase in platelet counts with eltrombopag may heighten the risk of thrombotic/thromboembolic complications.1
§ Serious adverse events were more common in patients treated with eltrombopag.11,12
NOTES TO EDITORS
Eltrombopag, marketed under the brand name Revolade™ in Europe and most ex-US countries, and Promacta® in the U.S., is an oral thrombopoietin receptor agonist licensed in over 90 countries around the world as a treatment for thrombocytopenia in adult patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP).
Eltrombopag, indicated in adult patients as a once-daily oral therapy, was approved for chronic hepatitis C-associated thrombocytopenia by the European Commission on Thursday 19 September 2013. Promacta®/RevoladeTM is approved for chronic hepatitis C associated thrombocytopenia in Argentina, Australia, Bangladesh, Pakistan, Philippines and the US.
The most important serious adverse reactions identified in the ITP or chronic hepatitis C-associated thrombocytopenia trials were hepatotoxicity, including hepatic decompensation events and thrombotic/thromboembolic events.
The most common adverse reactions (experienced by at least 10 percent of patients) of any grade in the ITP or chronic hepatitis C-associated thrombocytopenia trials included; headache, anaemia, decreased appetite, insomnia, cough, nausea, diarrhoea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza like illness, asthenia, chills and peripheral oedema.
Important safety information for eltrombopag
There is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic hepatitis C patients with advanced chronic liver disease, as defined by low albumin levels ≤ 35 g/L or model for end-stage liver disease (MELD) score ≥ 10, when treated with eltrombopag in combination with IFN-based therapy. Treatment with eltrombopag in these patients should be initiated only by physicians experienced in the management of advanced hepatitis C, and only when the risks of thrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered clinically indicated, close monitoring of these patients is required.
Risk of hepatotoxicity
Eltrombopag administration can cause abnormal liver function. Liver enzyme elevations have been reported in the ITP and hepatitis C populations. Most patients being treated with eltrombopag in combination with pIFN/ribavirin will experience indirect hyperbilirubinaemia. Hepatic enzymes should be measured prior to the initiation of eltrombopag therapy. Discontinue therapy if liver enzymes do not stabilise or are accompanied by worsening liver function.
Hepatic decompensation (use with IFN)
Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation when receiving alpha-IFN therapy. Hepatic decompensation was reported in controlled clinical studies in thrombocytopenic patients with hepatitis C treated with eltrombopag in combination with pIFN-based antiviral therapy. Patients should be monitored closely for signs and symptoms suggestive of hepatic decompensation, in particular, ascites, hepatic encephalopathy and variceal haemorrhage. Eltrombopag therapy should be terminated if antiviral therapy is discontinued for hepatic decompensation. Patients with poor liver function at baseline [albumin ≤ 35g/L or MELD score ≥ 10] should be closely monitored.
Venous and arterial thrombotic/thromboembolic complications have occurred with eltrombopag therapy. Portal vein thrombosis was the most common thromboembolic event reported in controlled clinical studies in thrombocytopenic patients with hepatitis C. Patients with poor liver function at baseline are at increased risk of thromboembolic events. Patients should be monitored closely for signs and symptoms suggestive of thromboembolic events.
Combination with direct acting antiviral agents
Safety and efficacy have not been established in combination with direct acting antiviral agents approved for treatment of chronic hepatitis C infection.
For the EU Summary of Product Characteristics for Revolade™ and full US Prescribing Information, including BOXED WARNING and Medication Guide for Promacta® please visit http://www.gsk.com/products/index.htm.
GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com
Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK' s operations are described under Item 3.D 'Risk factors' in the company's Annual Report on Form 20-F for 2012.
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3. Pegasys Summary of Product Characteristics March 2013.
4. Pegintron Summary of Product Characteristics May 2012.
5. Giannini EG et al. Liver Int 2012;32(6):1113-1119.
6. Behnava B et al. Hep Mon 2006;6(2):67-69.
7. Everson GT et al. Hepatol 2006;44:1675-1684.
8. Dusheiko G et al. Poster session presented at: The 47th Annual Meeting of the European Association for the Study of the Liver [EASL]. Barcelona, Spain. Apr 18-12 2012.
9. Afdhal N et al. Poster session presented at: The 62nd Annual Meeting of the American Association for the Study of Liver Diseases [AASLD]. San Francisco, CA, USA. Nov 4-8 2011.
10. Giannini EG et al. Expert Opin Pharmacother 2013;14(5):669-678.
11. ENABLE-1 Clinical Trials. Identifier TPL108390. Accessed January 2013.
12. ENABLE-2 Clinical Trials. Identifier TPL108390. Accessed January 2013.
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