On November 20, 2008, the US Food and Drug Administration (FDA) granted accelerated approval for eltrombopag (Promacta Tablets, GlaxoSmithKline) for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulin therapy, or splenectomy.
Eltrombopag is a chemically synthesized thrombopoietin (TPO) receptor agonist for oral administration. The drug interacts with the transmembrane domain of the TPO receptor (also known as cMPL), leading to increased platelet production by megakaryocytes in the bone marrow. The marketing approval was based upon demonstration of a favorable risk-to-benefit profile, where the major benefit pertained to demonstration of a clinically important increase in blood platelets among a population of patients with chronic ITP relatively refractory to prior therapies. Among this patient population, FDA regarded a durable platelet response as an established surrogate for clinical benefit. This determination was based upon the well-characterized pathophysiology of chronic ITP, including the etiologic role of severe thrombocytopenia in hemorrhage.
Clinical and Regulatory Background
ITP is generally regarded as a disorder characterized by autoantibody-induced platelet destruction, thrombocytopenia, and “inappropriately” reduced platelet production. Acute ITP occurs predominantly among children and is generally self-limited. Chronic ITP occurs mainly among adults, and spontaneous recovery is uncommon. The overall incidence of ITP among adults has been estimated to range from 1.6 to 6.6 per 100,000 persons/year of observation. The frequency of death from hemorrhage in patients with platelet counts below 30 × 109/L has been estimated to range between 1.6% and 3.9% per patient-year, although this risk is importantly affected by age as well as the degree and duration of thrombocytopenia. Intracranial hemorrhage is generally recognized as the most serious and life-threatening complication.[6,7]
The diagnosis of ITP is based mainly upon the detection of thrombocytopenia—the laboratory hallmark of the condition—and the exclusion of secondary causes of the thrombocytopenia. The major goal of chronic ITP therapy is to reduce the risk for hemorrhage. Hemorrhagic risk generally correlates with severity of thrombocytopenia; generally, medical treatment is initiated for platelet counts below 30 × 109/L. In the face of a hemostatic challenge such as surgery, platelet counts ≥ 50 × 109/L may be necessary to minimize hemorrhagic risk.
The therapy for most patients with chronic ITP predominantly consists of medications intended to increase platelet counts. Corticosteroids, generally the initial therapy, produce durable platelet responses in many patients. Other medications that have been shown to increase platelet counts, mostly for a relatively short period of time, consist of intravenous immunoglobulins (IVIG) and anti-D immunoglobulin. Failure to respond sufficiently to these medications may result in the use of various other immunomodulatory medications (such as rituximab [Rituxan] or azathioprine) as well as the performance of splenectomy. Splenectomy may result in a durable platelet response, although some patients remain refractory to the procedure. Few therapeutic options have proven beneficial in the refractory setting.
The thrombocytopenia in chronic ITP is thought to result primarily from enhanced platelet destruction. However, reduced platelet formation is also proposed as a contributor to the thrombocytopenia, as evidenced by “inappropriately” low TPO blood levels among patients with chronic ITP. Additionally, in vitro studies have found evidence for deficient platelet production in patients with ITP. Consequently, the development of TPO-receptor agonist molecules prompted manufacturers to explore the use of these molecules among patients with chronic ITP. In August 2008, FDA approved one of these molecules, romiplostim (Nplate), a biologic product for the treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.[13,14]
The clinical development of eltrombopag was targeted toward two potential clinical uses of the drug among patients with relatively refractory chronic ITP: first, as “short-term,” episodic therapy for patients experiencing an acute hemorrhage risk, and second, as “long-term” therapy for patients at continuous risk for hemorrhage. Initial clinical studies showed that eltrombopag increased platelet counts in a dose-related manner among healthy subjects and patients with chronic ITP. With the manufacturer’s initial focus on use of the drug among patients with chronic ITP, FDA designated eltrombopag as an orphan drug, based on the rarity of the condition (a condition affecting less than 200,000 Americans). In December 2007, the manufacturer submitted a New Drug Application (NDA) focused on approval of the drug for short-term treatment among previously treated patients with chronic ITP.
1. Bussel JB, Cheng G, Saleh MN, et al: Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 357:2237-2247, 2007.
2. Stevens W, Koene H, Zwaginga JJ, et al: Chronic idiopathic thrombocytopenic purpura: Present strategy, guidelines and new insights. Netherland J Med 64:356-363, 2006.
3. Cines DB, Bussel JB, Liebman HA: The ITP syndrome: Pathogenic and clinical diversity. Blood 113:6511-6521, 2009.
4. Neylon AJ, Saunders PW, Howard MR, et al: Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: A prospective study of a population-based cohort of 245 patients. Br J Haematol 112:966-974, 2003.
5. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, et al: The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 160:1630-1638, 2000.
6. Mueller-Eckhardt C: Idiopathic thrombocytopenic purpura (ITP); clinical and immunologic considerations. Semin Thromb Hemost 3:125-159, 1997.
7. McCrae KR, Bussel JB, Mannucci PM, et al: Platelets: An update on diagnosis and management of thrombocytopenic disorders. Hematology Am Soc Hematol Educ Program 282-305, 2001.
8. ASH ITP Practice Guidelines Panel: Diagnosis and treatment of idiopathic thrombocytopenic purpura: Recommendations of the American Society of Hematology. Ann Intern Med 126:319-326, 1997.
9. Bussel JB, Graziano JN, Kimberly RP, et al: Intravenous anti-D treatment of immune thrombocytopenic purpura: Analysis of efficacy, toxicity and mechanism of effect. Blood 77:1884-1893, 1991.
10. Gurcan HM, Keskin DB, Stern JN, et al: A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 9:10-25, 2009.
11. Aledort LM, Hayward CP, Chen MG, et al: Prospective screening of 205 patients with ITP, including diagnosis, serological markers and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol 76:205-213, 2004.
12. Parker RI, Siegel RS, Ratajczak MZ, et al: Deficient in vitro megakaryocytopoiesis and decreased in vivo platelet turnover in children and young adults with chronic thrombocytopenia. J Pediatr Hematol Oncol 20:196-201, 1998.
13. Bussel JB, Kuter DJ, Pullarkat V, et al: Safety and efficacy of long term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 113:2161-2171, 2009.
14. Kuter DJ, Bussel JB, Lyons RM, et al: Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomized controlled trial. Lancet 371:395-403, 2008.
15. Bussel JB, Cheng G, Saleh MN, et al: Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 357:2237-2247, 2007.
16. Cines DB, Blanchette VS: Immune thrombocytopenic purpura. N Engl J Med 346:995-1008, 2002.
17. Page LK, Psaila B, Provan D, et al: The immune thrombocytopenic purpura (ITP) bleeding score: Assessment of bleeding in patients with ITP. Br J Haematol 138:245-248, 2007.
18. British Committee for Standards in Hematology, General Hematology Task Force: Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 120:574-596, 2003.