General Information

Eltrombopag olamine is a small molecule thrombopoietin receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the thrombopoietin receptor (also known as cMpl), leading to increased platelet production.

Promacta is specifically indicated 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.

Mechanism of Action

Eltrombopag is an orally bioavailable, small-molecule thrombopoietin receptor agonist that interacts with the transmembrane domain of the human thrombopoietin receptor. It initiates signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.

Side Effects

Adverse events associated with the use of Promacta may include, but are not limited to, the following:

• Hemorrhage
• Nausea
• Vomiting
• Menorrhagia
• Myalgia
• Paresthesia
• Cataract

Dosing/Administration

Promacta is supplied as a tablet designed for oral administration. The recommended initial dose of the drug is 50 mg once daily except in patients who are of East Asian ancestry or who have moderate to severe hepatic impairment. In this population, and for patients with moderate or severe hepatic impairment, the recommended initial dose of Promacta is 25 mg once daily. Promacta should be adjusted to achieve and maintain a platelet count >50 x 109/L as necessary to reduce the risk for bleeding. The dosing of Promacta should not exceed 75 mg daily.

Clinical Trial Results

FDA Approval
FDA approval of Promacta was based on the results of three clinical trials: two randomized double-blind, placebo-controlled studies and an open-label extension study.

Studies 1 and 2
Study 1 randomized 114 subjects to Promacta 50 mg or placebo. Study 2 randomized 117 subjects to placebo or one of three dose regimens of Promacta: 30 mg, 50 mg, or 75 mg, each administered daily. Promacta was administered over a maximum treatment period of six weeks, followed by six weeks off therapy. Promacta or placebo were discontinued if the platelet count exceeded 200 x 10(9)/L. The primary efficacy end point was response rate, defined as a shift from a baseline platelet count of 50 x 10(9)/L at any time during the treatment period. In Study 1, the response rate was met by 59 percent in the Promacta (50 mg) arm compared to 16 percent in the placebo group (p 200 x 10(9)/L in 3 percent and 27 percent of the patients, respectively.

Extension Study
This open-label, single-arm study enrolled any subjects who had completed a prior trial with Promacta. The trial was designed to decrease the dose or eliminate the need for any concomitant ITP medications. Promacta was administered to 109 subjects; 74 completed three months of treatment, 53 completed six months and three patients completed one year of therapy. The median baseline platelet count was 18 x 10(9)/L prior to administration of Promacta. Median platelet counts at 3, 6 and 9 months on study were 74 x 109/L, 67 x 10(9)/L and 95 x 10(9)/L, respectively. The median daily dose of Promacta following six months of therapy was 50 mg (n=53); the median daily dose was also 50 mg among patients with no change in the dose regimen of Promacta over two months or more of therapy (n=45).

Ongoing Study Commitments

• GlaxoSmithKline has agreed to complete trial TRA102537, a randomized, double blind, placebo-controlled phase 3 study, to evaluate the efficacy, safety and tolerability of eltrombopag, a thrombopoietin receptor agonist, administered for six months as oral tablets once daily in adult subjects with previously treated chronic idiopathic thrombocytopenic purpura (ITP).
  Protocol submission: completed
  Trial start date: underway
  Final report submission: November 2009

• GlaxoSmithKline has agreed to complete trial TRA108057, an open-label repeat dosing study of eltrombopag olamine in adult subjects, with chronic idiopathic thrombocytopenic purpura (ITP).
  Protocol submission: completed
  Trial start date: underway
  Final report submission: April 2009

• GlaxoSmithKline has agreed to develop and maintain a prospective, observational pregnancy exposure registry study conducted in the United States that compares the pregnancy and fetal outcomes of women exposed to Promacta Tablets during pregnancy to an unexposed control population. The registry will detect and record major and minor congenital anomalies, spontaneous abortions, stillbirths, elective terminations, adverse effects on immune system development, platelet number and function, neoplasm formation, bone marrow reticulin formation, thrombotic events and any serious pregnancy outcomes. These events will also be assessed among infants through at least the first year of life.
  Final protocol submission: May 2009
  Study start date: November 2009
  First interim report submission: November 2010, then annually
  Final report submission: November 2019

• GlaxoSmithKline has agreed to conduct a milk-only lactation study in the subset of women enrolled in the pregnancy registry who choose to breastfeed their infants. This study will be designed to detect the presence and concentration of Promacta Tablets in breast milk and any effects on milk production and composition. The study will include a symptom diary for mothers to record any adverse effects in the breastfeeding infants.
  Final protocol submission: May 2009
  Study start date: November 2009
  First interim report submission: November 2010, then annually
  Final report submission: November 2019

• GlaxoSmithKline has agreed to conduct trial TRA105325 entitled, EXTEND (Eltrombopag extended dosing study): an extension study of eltrombopag olamine in adults, with idiopathic thrombocytopenic purpura (ITP), previously enrolled in an eltrombopag study. The protocol for this trial was previously submitted to FDA and the study is currently active. The protocol will be modified to include performance of bone marrow examinations prior to the initiation of Promacta (eltrombopag) Tablets, following 12 months of Promacta Tablets therapy as well as following the completion of 24 months of Promacta Tablets therapy; enrollment will continue until these data are obtained from at least 150 patients. An interim report will contain, in addition to any other items, results of bone marrow evaluations for patients who have completed bone marrow evaluations at baseline and following 12 months of Promacta Tablets therapy.
  Protocol modification submission: January 2009
  First interim report submission: January 2012
  Final report submission: January 2014