Promacta®/Revolade® (eltrombopag) Significantly Increased Platelet Counts And Reduced Bleeding In Long-Term Study Of Patients With Chronic ITP

Main Category: Blood / Hematology
Also Included In: Clinical Trials / Drug Trials
Article Date: 08 Dec 2008 - 3:00 PDT

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GlaxoSmithKline (GSK) announced positive safety and efficacy results from RAISE (RAndomized placebo-controlled ITP Study with Eltrombopag), a Phase III study of Promacta®/Revolade® (eltrombopag) in adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who had received one or more prior ITP therapies. Patients receiving eltrombopag were eight times more likely than those on placebo to maintain platelet counts between 50-400,000/L 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.

"Eltrombopag 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. Eltrombopag is a great example of this commitment."

Eltrombopag received accelerated approval by 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. Eltrombopag should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. Eltrombopag should not be used in an attempt to normalize platelet counts. GSK submitted a Marketing Authorisation Application (MAA) for eltrombopag in Europe and other international markets in early December 2008.

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, eltrombopag 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 eltrombopag in previously treated adults with chronic ITP and with platelet counts less than 30,000/μL. The study enrolled 197 patients (eltrombopag: n=135; placebo: n=62) and, of these, approximately 50 percent had platelet counts less than or equal to 15,000/μL; 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 eltrombopag 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 eltrombopag groups was 16,000/μL.

Throughout the study, the median platelet count in the placebo group never exceeded 30,000/μL. By contrast, after just one week, patients in the eltrombopag arm experienced a rise in their median platelet count to 36,000/μL, with median platelet levels subsequently ranging from 52,000 to 91,000/μL for the remainder of the study, meeting the study's primary endpoint of odds of responding (platelets 50,000 to 400,000/μL) during the six month treatment period. Patients receiving eltrombopag were eight times more likely to achieve an overall response of increased platelet counts of 50,000 to 400,000/μL 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 eltrombopag had any bleeding or clinically significant (WHO Grades 2-4; p < 0.001) bleeding throughout the trial and more patients in the eltrombopag 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 eltrombopag 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 eltrombopag (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 (≥30 percent). Two corticosteroid-associated adverse events (dyspepsia and peripheral edema) were significantly less likely to occur in the eltrombopag group compared to the placebo group; however, a higher incidence of hepatobiliary laboratory abnormalities were reported in patients taking eltrombopag (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 eltrombopag.

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 eltrombopag 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 p.m., 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.

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.

Eltrombopag was discovered as a result of a research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals (NASDAQ: LGND). It was developed by GlaxoSmithKline.

The compound is also being studied for thrombocytopenia associated with chronic hepatitis C virus, chronic liver disease and oncology-related thrombocytopenia.

About GlaxoSmithKline

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.

Promacta® is a registered trademark of GlaxoSmithKline group of companies in the United States.
Revolade® is a registered trademark of GlaxoSmithKline group of companies and is the proposed trade name in Europe.

References:

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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