PHILADELPHIA, Dec. 6 /PRNewswire-FirstCall/ -- GlaxoSmithKline (NYSE: GSK) announced positive safety and efficacy results from RAISE (RAndomized placebo- controlled ITP Study with Eltrombopag), a Phase III study of PROMACTA(R) (eltrombopag) in adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who had received one or more prior ITP therapies. Patients receiving PROMACTA were eight times more likely than those on placebo to maintain platelet counts between 50,000 to 400,000/microliters during a six- month treatment period, thereby reducing patients' bleeding symptoms and their need for concomitant and rescue ITP treatments. These data were presented at the 50th Annual Meeting of the American Society of Hematology (ASH), December 6-9, 2008, in San Francisco, CA.
"PROMACTA is the first approved agent to show that generating platelets can be achieved and maintained with an oral therapy," said Paolo Paoletti, M.D., Senior Vice President of Oncology R&D, GSK. "With the continued emergence of GSK in oncology, we want patients and physicians to continuously benefit from our dedication to developing truly innovative treatments that can help improve patients' lives. PROMACTA is a great example of this commitment."
PROMACTA received accelerated approval from the FDA on November 20 as a thrombopoietin receptor treatment for patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. PROMACTA should not be used in an attempt to normalize platelet counts.
Chronic ITP is a disorder marked by increased platelet destruction and/or inadequate platelet production in the blood, which causes an increased risk of bleeding.(1) Approximately 60,000 individuals in the U.S. have the disorder.(2)
"Patients with chronic ITP often have a difficult time managing their disease. They may experience excessive bruising, bleeding and sometimes more serious hemorrhages that can rarely be fatal. Until recently, ITP patients have had few options well demonstrated to be effective in the long term," said James Bussel, M.D., director of the Platelet Disorders Center, Children's Cancer and Blood Foundation Division of New York Presbyterian/Weill Cornell Medical Center. "As the RAISE study demonstrates, PROMACTA is an important new oral treatment option for ITP patients that is effective in maintaining a hemostatic platelet response."
The RAISE Study (Abstract #400 Presented on December 8, 2008 at 11:45 a.m.)
RAISE, a global, six-month, double-blind, placebo-controlled, Phase III study was designed to evaluate the safety and efficacy of PROMACTA in previously treated adults with chronic ITP and with platelet counts less than 30,000/microliters. The study enrolled 197 patients (PROMACTA: n=135; placebo: n=62) and, of these, approximately 50 percent had platelet counts less than or equal to 15,000/microliters; about 50 percent were receiving simultaneous ITP therapies at randomization; around 35 percent were splenectomized, and more than 50 percent had received at least three prior ITP medications. Patients began once daily treatment with PROMACTA at 50 mg (or matching placebo) with doses individualized based upon each patient's platelet response, ranging from once-daily doses of 25 mg to 75 mg, or less frequently. The baseline median platelet count in both the placebo and the PROMACTA groups was 16,000/microliters.
Throughout the study, the median platelet count in the placebo group never exceeded 30,000/microliters. By contrast, after just one week, patients in the PROMACTA arm experienced a rise in their median platelet count to 36,000/microliters, with median platelet levels subsequently ranging from 52,000 to 91,000/microliters for the remainder of the study, meeting the study's primary endpoint of odds of responding (platelets 50,000 to 400,000/microliters) during the six month treatment period. Patients receiving PROMACTA were eight times more likely to achieve an overall response of increased platelet counts of 50,000 to 400,000/microliters than those taking placebo (Odds ratio = 8.2; 99 percent CI [3.59, 18.73]; p < 0.001). In comparison to the placebo group, significantly fewer patients treated with PROMACTA had any bleeding or clinically significant (WHO Grades 2-4; p < 0.001) bleeding throughout the trial and more patients in the PROMACTA group (59 percent) stopped or reduced their simultaneous ITP medications than in the placebo group (32 percent; p = 0.016). In addition, during the treatment phase of the study, fewer patients in the PROMACTA arm (19 percent) required rescue therapy compared with those in the placebo arm (40 percent, p = 0.001).
The overall incidence of adverse events was similar between the PROMACTA (87 percent) and placebo groups (92 percent), which were mostly mild to moderate in severity. Headache was the most common adverse event in both groups (greater than or equal to 30 percent). Two corticosteroid-associated adverse events (dyspepsia and peripheral edema) were significantly less likely to occur in the PROMACTA group compared to the placebo group; however, a higher incidence of hepatobiliary laboratory abnormalities were reported in patients taking PROMACTA (13 percent) compared with those in the placebo group (7 percent). These abnormalities were not predictive of serious, drug-induced liver injury. One death was reported in the placebo group. There were no clinical or laboratory symptoms suggestive of bone marrow fibrosis in patients taking PROMACTA.
Additional GSK Data Presented at ASH (Abstract #401, Abstract #669)
A post hoc analysis of data from the ongoing EXTEND (Eltrombopag eXTENded Dosing study) trial of refractory and non-refractory ITP patients showed that PROMACTA induced long-lasting platelet count increases and reduced clinically significant bleeding symptoms. The analysis is being presented at ASH on Monday, December 8, 2008 at 12:00 noon, PST.
In addition, data from a survey of ITP patients showed that patients are willing to accept significant risks for treatment side effects in exchange for improved efficacy and convenient administration. The survey results are being presented at ASH on Monday, December 8, 2008 at 4:30 p.m., PST.
PROMACTA 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.
PROMACTA was discovered as a result of a research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals (Nasdaq: LGND). It was developed by GlaxoSmithKline. GSK plans to submit a Marketing Authorization Application (MAA) for eltrombopag in Europe in 2008.
Important Safety Information
PROMACTA may cause hepatotoxicity. Patients receiving therapy with PROMACTA must have regular monitoring of serum liver tests (see Laboratory Monitoring below). Discontinue PROMACTA if ALT levels increase to greater than or equal to 3X upper limit of normal (ULN) and are: progressive; or persistent for greater than or equal to 4 weeks, or; accompanied by increased direct bilirubin; or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. Reinitiating treatment with PROMACTA is not recommended and should be considered only with close medical supervision and under exceptional circumstances where the potential benefit outweighs the risk.
Because of the risk for hepatotoxicity and other risks, PROMACTA is available only through a restricted distribution program called PROMACTA CARES. Under the PROMACTA CARES Program, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive PROMACTA. To enroll in the PROMACTA CARES Program, call 1-877-9-PROMACTA.
Warnings and Precautions:
Additional safety information regarding Risk of Hepatotoxicity: Reinitiating treatment with PROMACTA is not recommended. If the potential benefit for reinitiating PROMACTA treatment is considered to outweigh the risk for hepatotoxicity, then cautiously reintroduce PROMACTA and measure serum liver tests weekly during the dose adjustment phase. If liver test abnormalities persist, worsen or recur, then permanently discontinue PROMACTA. Exercise caution when administering PROMACTA to patients with hepatic disease. Use a lower starting dose of PROMACTA in patients with moderate to severe hepatic disease and monitor closely.
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis: PROMACTA is a thrombopoietin (TPO) receptor agonist and TPO receptor agonists increase the risk for development or progression of reticulin fibers within the bone marrow. Prior to initiation of PROMACTA, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of PROMACTA, perform CBC with WBC differential monthly. If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with PROMACTA and consider a bone marrow biopsy, including staining for fibrosis.
Worsened Thrombocytopenia and Hemorrhage Risk After PROMACTA Cessation: Discontinuation of PROMACTA may result in thrombocytopenia of greater severity than was present prior to therapy with PROMACTA. This worsened thrombocytopenia may increase the patient's risk of bleeding, particularly if PROMACTA is discontinued while the patient is on anticoagulants or antiplatelet agents. In the controlled clinical studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 10% and 6% of the PROMACTA and placebo groups, respectively. Serious hemorrhagic events requiring the use of supportive ITP medications occurred in 3 severely thrombocytopenic patients within one month following the discontinuation of PROMACTA; none were reported among the placebo group. Following discontinuation of PROMACTA, obtain weekly CBCs, including platelet counts for at least 4 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines.
Thrombotic/Thromboembolic Complications: Thrombotic/thromboembolic complications may result from excessive increases in platelet counts. Excessive doses of PROMACTA or medication errors that result in excessive doses of PROMACTA may increase platelet counts to a level that produces thrombotic/thromboembolic complications. In the controlled clinical studies, one thrombotic/thromboembolic complication was reported within the group that received PROMACTA and none within the placebo group. Seven patients experienced thrombotic/thromboembolic complications in the extension study. Use caution when administering PROMACTA to patients with known risk factors for thromboembolism. To minimize the risk for thrombotic/thromboembolic complications, do not use PROMACTA in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of greater than or equal to 50,000/microliters.
Malignancies and Progression of Malignancies: Stimulation of the TPO receptor on the surface of hematopoietic cells may increase the risk for hematologic malignancies. PROMACTA is not indicated for the treatment of thrombocytopenia due to causes of thrombocytopenia (e.g., myelodysplasia or chemotherapy) other than chronic ITP.
Laboratory Monitoring: Complete Blood Counts (CBCs) -- Monitor CBCs, including platelet counts and WBC differentials prior to initiation, throughout, and following discontinuation of PROMACTA therapy. Prior to the initiation of PROMACTA, examine the peripheral blood differential to establish the extent of red and white blood cell abnormalities. Obtain CBCs, including platelet counts and peripheral blood smears, weekly during the dose adjustment phase of therapy with PROMACTA and then monthly following establishment of a stable dose of PROMACTA. Obtain CBCs, including platelet counts, weekly for at least 4 weeks following discontinuation of PROMACTA. Liver tests: Monitor serum liver tests (ALT, AST, total and fractionated bilirubin) prior to initiation of PROMACTA, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. If abnormal levels are detected, repeat the tests within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until the abnormality(ies) resolve, stabilize, or return to baseline levels. Discontinue PROMACTA for the development of clinically important liver test abnormalities.
Cataracts: In the controlled clinical studies, cataracts developed or worsened in five patients (5%) who received 50 mg PROMACTA daily and two placebo-group patients (3%). In the extension study, cataracts developed or worsened in 4% of patients who underwent ocular examination prior to therapy with PROMACTA. Cataracts were observed in toxicology studies of eltrombopag in rodents. Perform a baseline ocular examination prior to administration of PROMACTA and, during therapy with PROMACTA, regularly monitor patients for signs and symptoms of cataracts.
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 company information, visit GlaxoSmithKline at www.gsk.com.
Cautionary statement regarding forward-looking statements
Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, 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 'Risk Factors' in the 'Business Review' in the company' s Annual Report on Form 20-F for 2007.
Note to Editors
PROMACTA(R) is a registered trademark of GlaxoSmithKline group of companies in the United States.
REVOLADE(R) is a registered trademark of GlaxoSmithKline group of companies and is the proposed trade name in Europe.
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1. National Heart, Lung, and Blood Institute. Diseases and Conditions Index. http://www.nhlbi.nih.gov/health/dci/Diseases/Itp/ITP_WhatIs.html. Accessed November 12, 2007.
2. Feudjo-Tepie M, Robinson N, Bennett D. Prevalence estimates of adult chronic idiopathic thrombocytopenic purpura (ITP). J Thromb Haemost. 2008; 6(4): 711 - 712.
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