FDA approves GSK's Promacta (Eltrombopag)

GlaxoSmithKline has announced that the United States Food and Drug Administration (FDA) granted accelerated approval for PROMACTA (eltrombopag) for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.

The approval is a significant milestone for PROMACTA and the ITP community, as PROMACTA is the first oral thrombopoietin (TPO) receptor agonist approved for adult patients with chronic ITP. GSK expects PROMACTA to be available by the next week.

"It is very important for chronic ITP patients to have new treatment options to manage the symptoms of this serious and, at times, life-threatening disease. In addition, many people with chronic ITP are concerned about everyday activities for fear of an accidental bump or unanticipated bruise that may lead to bleeding," said Craig Conway, executive director of the Platelet Disorder Support Association. "The approval of this new product represents a promising new treatment option that offers hope to the ITP community."

Shift in Approach

"Preventing platelet destruction has always been the primary means of treating patients with ITP. Recent advances, like the clinical trials of PROMACTA, show that increasing the production of platelets may also play a significant role in treating this disorder," 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. "The entire ITP community, including physicians, patients and their families, may benefit from this shift in thinking and these innovative new treatments."

The new drug application for PROMACTA was supported by the largest database of randomized clinical trial information on investigational therapies for chronic ITP patients. The indication is based on data from two pivotal studies in the short term treatment and one ongoing long-term treatment study of patients with chronic ITP.

"The approval of PROMACTA affirms our commitment to hematology and oncology research, and demonstrates our dedication to developing truly innovative therapies for patients," said Paolo Paoletti, M.D., Senior Vice President of the Oncology Medicine Development Center at GSK. "PROMACTA is a significant step forward in helping patients and physicians better manage the challenges of chronic ITP."

The approval of PROMACTA was supported by an unanimous decision by the FDA's Oncology Drugs Advisory Committee (ODAC) on May 30, 2008, in which the panel voted, 16-0, that PROMACTA demonstrated a favorable risk-benefit profile for the short-term treatment of patients with chronic ITP.

GSK is launching PROMACTA CARES, a single source of information, education and support for healthcare professionals and patients. Prescribers and pharmacies must enroll in PROMACTA CARES before they can prescribe or dispense PROMACTA. Similarly, patients are required to enroll in PROMACTA CARES before they can receive the drug. This program was created in accordance with the FDA's requirements to help assure the appropriate and safe use of PROMACTA, while minimizing risks. PROMACTA CARES is part of an ongoing collaboration between GSK and the FDA to provide a format for appropriate additional data collection.

Additionally, PROMACTA CARES has an optional component: reimbursement support for the uninsured and under-insured as part of GSK's ongoing commitment to providing needed medicines to those who may benefit from assistance. Knowledgeable consultants are available to assist patients and healthcare professionals with disease and product-related questions and to help in obtaining the product. More information regarding PROMACTA CARES can be found by calling 1-877-9-PROMACTA or by visiting www.PROMACTACARES.com . Program hours are 8:30 AM to 8:00 PM ET, Mondays through Fridays.

GSK plans to submit a Marketing Authorization Application (MAA) for eltrombopag in the treatment of chronic ITP in Europe in 2008; the proposed trade name is REVOLADE.

PROMACTA milestones

Following the New Drug Application (NDA) filing for PROMACTA in December 2007, the FDA granted the drug Priority Review in March 2008. In addition, the agency granted PROMACTA orphan drug designation for this indication. This is a special status the FDA grants to products that treat a rare disease or condition, affecting less than 200,000 individuals in the United States.(1)

About ITP

Chronic ITP is a disorder marked by increased platelet destruction and/or inadequate platelet production in the blood, which causes an increased risk of bruising and bleeding.(2,3) There are estimated to be approximately 60,000 individuals diagnosed with chronic ITP in the U.S.(4) People with chronic ITP often bleed from small blood vessels causing bruises, nosebleeds or even fatal intracerebral bleeds, although these are rare.(3)

About PROMACTA

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.

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

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 > / = 3X upper limit of normal (ULN) and are: progressive; or persistent for > / = 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 > / = 50 x 10(9)/L.

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.

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