PHILADELPHIA, Dec. 6 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) thrombocytopenicpurpura (ITP) who had received one or more prior ITP therapies. Patientsreceiving PROMACTA were eight times more likely than those on placebo tomaintain platelet counts between 50,000 to 400,000/microliters during a six-month treatment period, thereby reducing patients' bleeding symptoms and theirneed for concomitant and rescue ITP treatments. These data were presented atthe 50th Annual Meeting of the American Society of Hematology (ASH), December6-9, 2008, in San Francisco, CA.
"PROMACTA is the first approved agent to show that generating plateletscan be achieved and maintained with an oral therapy," said Paolo Paoletti,M.D., Senior Vice President of Oncology R&D, GSK. "With the continuedemergence of GSK in oncology, we want patients and physicians to continuouslybenefit from our dedication to developing truly innovative treatments that canhelp improve patients' lives. PROMACTA is a great example of this commitment."
PROMACTA received accelerated approval from the FDA on November 20 as athrombopoietin receptor treatment for patients with chronic ITP who have hadan insufficient response to corticosteroids, immunoglobulins or splenectomy.PROMACTA should be used only in patients with ITP whose degree ofthrombocytopenia 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/orinadequate platelet production in the blood, which causes an increased risk ofbleeding.(1) Approximately 60,000 individuals in the U.S. have thedisorder.(2)
"Patients with chronic ITP often have a difficult time managing theirdisease. They may experience excessive bruising, bleeding and sometimes moreserious hemorrhages that can rarely be fatal. Until recently, ITP patientshave had few options well demonstrated to be effective in the long term," saidJames Bussel, M.D., director of the Platelet Disorders Center, Children'sCancer and Blood Foundation Division of New York Presbyterian/Weill CornellMedical Center. "As the RAISE study demonstrates, PROMACTA is an important neworal treatment option for ITP patients that is effective in maintaining ahemostatic platelet response."
The RAISE Study (Abstract #400 Presented on December 8, 2008 at 11:45a.m.)
RAISE, a global, six-month, double-blind, placebo-controlled, Phase IIIstudy was designed to evaluate the safety and efficacy of PROMACTA inpreviously treated adults with chronic ITP and with platelet counts less than30,000/microliters. The study enrolled 197 patients (PROMACTA: n=135; placebo:n=62) and, of these, approximately 50 percent had platelet counts less than orequal to 15,000/microliters; about 50 percent were receiving simultaneous ITPtherapies at randomization; around 35 percent were splenectomized, and morethan 50 percent had received at least three prior ITP medications. Patientsbegan once daily treatment with PROMACTA at 50 mg (or matching placebo) withdoses individualized based upon each patient's platelet response, ranging fromonce-daily doses of 25 mg to 75 mg, or less frequently. The baseline medianplatelet count in both the placebo and the PROMACTA groups was16,000/microliters.
Throughout the study, the median platelet count in the placebo group neverexceeded 30,000/microliters. By contrast, after just one week, patients in thePROMACTA arm experienced a rise in their median platelet count to36,000/microliters, with median platelet levels subsequently ranging from52,000 to 91,000/microliters for the remainder of the study, meeting thestudy's primary endpoint of odds of responding (platelets 50,000 to400,000/microliters) during the six month treatment period. Patients receivingPROMACTA were eight times more likely to achieve an overall response ofincreased platelet counts of 50,000 to 400,000/microliters than those takingplacebo (Odds ratio = 8.2; 99 percent CI [3.59, 18.73]; p < 0.001). Incomparison to the placebo group, significantly fewer patients treated withPROMACTA 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 theplacebo group (32 percent; p = 0.016). In addition, during the treatment phaseof the study, fewer patients in the PROMACTA arm (19 percent) required rescuetherapy 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 tomoderate in severity. Headache was the most common adverse event in bothgroups (greater than or equal to 30 percent). Two corticosteroid-associatedadverse events (dyspepsia and peripheral edema) were significantly less likelyto occur in the PROMACTA group compared to the placebo group; however, ahigher incidence of hepatobiliary laboratory abnormalities were reported inpatients taking PROMACTA (13 percent) compared with those in the placebo group(7 percent). These abnormalities were not predictive of serious, drug-inducedliver injury. One death was reported in the placebo group. There were noclinical or laboratory symptoms suggestive of bone marrow fibrosis in patientstaking PROMACTA.
Additional GSK Data Presented at ASH (Abstract #401, Abstract #669)
A post hoc analysis of data from the ongoing EXTEND (Eltrombopag eXTENdedDosing study) trial of refractory and non-refractory ITP patients showed thatPROMACTA induced long-lasting platelet count increases and reduced clinicallysignificant bleeding symptoms. The analysis is being presented at ASH onMonday, December 8, 2008 at 12:00 noon, PST.
In addition, data from a survey of ITP patients showed that patients arewilling to accept significant risks for treatment side effects in exchange forimproved efficacy and convenient administration. The survey results are beingpresented at ASH on Monday, December 8, 2008 at 4:30 p.m., PST.
PROMACTA is an oral, non-peptide thrombopoietin receptor agonist that hasbeen shown in pre-clinical research and clinical trials to stimulate theproliferation and differentiation of megakaryocytes, the bone marrow cellsthat give rise to blood platelets.
PROMACTA was discovered as a result of a research collaboration betweenGlaxoSmithKline and Ligand Pharmaceuticals (Nasdaq: LGND). It was developed byGlaxoSmithKline. 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 withPROMACTA must have regular monitoring of serum liver tests (see LaboratoryMonitoring below). Discontinue PROMACTA if ALT levels increase to greater thanor equal to 3X upper limit of normal (ULN) and are: progressive; or persistentfor greater than or equal to 4 weeks, or; accompanied by increased directbilirubin; or accompanied by clinical symptoms of liver injury or evidence forhepatic decompensation. Reinitiating treatment with PROMACTA is notrecommended and should be considered only with close medical supervision andunder exceptional circumstances where the potential benefit outweighs therisk.
Because of the risk for hepatotoxicity and other risks, PROMACTA isavailable only through a restricted distribution program called PROMACTACARES. Under the PROMACTA CARES Program, only prescribers, pharmacies, andpatients registered with the program are able to prescribe, dispense, andreceive PROMACTA. To enroll in the PROMACTA CARES Program, call1-877-9-PROMACTA.
Warnings and Precautions:
Additional safety information regarding Risk of Hepatotoxicity:Reinitiating treatment with PROMACTA is not recommended. If the potentialbenefit for reinitiating PROMACTA treatment is considered to outweigh the riskfor hepatotoxicity, then cautiously reintroduce PROMACTA and measure serumliver tests weekly during the dose adjustment phase. If liver testabnormalities 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 severehepatic disease and monitor closely.
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis:PROMACTA is a thrombopoietin (TPO) receptor agonist and TPO receptor agonistsincrease the risk for development or progression of reticulin fibers withinthe bone marrow. Prior to initiation of PROMACTA, examine the peripheral bloodsmear closely to establish a baseline level of cellular morphologicabnormalities. Following identification of a stable dose of PROMACTA, performCBC with WBC differential monthly. If the patient develops new or worseningmorphological abnormalities or cytopenia(s), discontinue treatment withPROMACTA 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 severitythan was present prior to therapy with PROMACTA. This worsenedthrombocytopenia may increase the patient's risk of bleeding, particularly ifPROMACTA is discontinued while the patient is on anticoagulants orantiplatelet agents. In the controlled clinical studies, transient decreasesin platelet counts to levels lower than baseline were observed followingdiscontinuation of treatment in 10% and 6% of the PROMACTA and placebo groups,respectively. Serious hemorrhagic events requiring the use of supportive ITPmedications occurred in 3 severely thrombocytopenic patients within one monthfollowing the discontinuation of PROMACTA; none were reported among theplacebo group. Following discontinuation of PROMACTA, obtain weekly CBCs,including platelet counts for at least 4 weeks and consider alternativetreatments for worsening thrombocytopenia, according to current treatmentguidelines.
Thrombotic/Thromboembolic Complications: Thrombotic/thromboemboliccomplications may result from excessive increases in platelet counts.Excessive doses of PROMACTA or medication errors that result in excessivedoses of PROMACTA may increase platelet counts to a level that producesthrombotic/thromboembolic complications. In the controlled clinical studies,one thrombotic/thromboembolic complication was reported within the group thatreceived PROMACTA and none within the placebo group. Seven patientsexperienced thrombotic/thromboembolic complications in the extension study.Use caution when administering PROMACTA to patients with known risk factorsfor thromboembolism. To minimize the risk for thrombotic/thromboemboliccomplications, do not use PROMACTA in an attempt to normalize platelet counts.Follow the dose adjustment guidelines to achieve and maintain a platelet countof greater than or equal to 50,000/microliters.
Malignancies and Progression of Malignancies: Stimulation of the TPOreceptor on the surface of hematopoietic cells may increase the risk forhematologic malignancies. PROMACTA is not indicated for the treatment ofthrombocytopenia due to causes of thrombocytopenia (e.g., myelodysplasia orchemotherapy) 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 theinitiation of PROMACTA, examine the peripheral blood differential to establishthe extent of red and white blood cell abnormalities. Obtain CBCs, includingplatelet counts and peripheral blood smears, weekly during the dose adjustmentphase of therapy with PROMACTA and then monthly following establishment of astable dose of PROMACTA. Obtain CBCs, including platelet counts, weekly for atleast 4 weeks following discontinuation of PROMACTA. Liver tests: Monitorserum liver tests (ALT, AST, total and fractionated bilirubin) prior toinitiation of PROMACTA, every 2 weeks during the dose adjustment phase, andmonthly following establishment of a stable dose. If abnormal levels aredetected, repeat the tests within 3 to 5 days. If the abnormalities areconfirmed, monitor serum liver tests weekly until the abnormality(ies)resolve, stabilize, or return to baseline levels. Discontinue PROMACTA for thedevelopment of clinically important liver test abnormalities.
Cataracts: In the controlled clinical studies, cataracts developed orworsened in five patients (5%) who received 50 mg PROMACTA daily and twoplacebo-group patients (3%). In the extension study, cataracts developed orworsened in 4% of patients who underwent ocular examination prior to therapywith PROMACTA. Cataracts were observed in toxicology studies of eltrombopag inrodents. Perform a baseline ocular examination prior to administration ofPROMACTA and, during therapy with PROMACTA, regularly monitor patients forsigns and symptoms of cataracts.
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Under the safe harbor provisions of the U.S. Private Securities LitigationReform Act of 1995, GSK cautions investors that any forward-looking statementsor projections made by GSK, including those made in this announcement, aresubject to risks and uncertainties that may cause actual results to differmaterially from those projected. Factors that may affect GSK' s operations aredescribed under 'Risk Factors' in the 'Business Review' in the company' sAnnual Report on Form 20-F for 2007.
Note to Editors
PROMACTA(R) is a registered trademark of GlaxoSmithKline group ofcompanies in the United States.
REVOLADE(R) is a registered trademark of GlaxoSmithKline group ofcompanies and is the proposed trade name in Europe.
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1. National Heart, Lung, and Blood Institute. Diseases and ConditionsIndex. 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 adultchronic idiopathic thrombocytopenic purpura (ITP). J Thromb Haemost. 2008;6(4): 711 - 712.