Therapeutic Class ReviewSM Blood Modifiers: Platelet Growth Factors eltrombopag (Promacta) and romiplostim (Nplate) July 2009

Executive Summary
Background Chronic immune (idiopathic) thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by persistent low platelet counts due to antibody-mediated platelet destruction in the spleen. Chronic ITP affects about 60,000 people in the U.S.[1] Standard treatments include corticosteroids, immunoglobulins, and splenectomy. Therapy for refractory ITP includes: danazol, rituximab, immunosuppressant agents (e.g., cyclosporine, azathioprine), chemotherapeutic agents (e.g., cyclophosphamide, vincristine), dapsone, IV/PO corticosteroids, anti-rho D, and interferon, among others. Professional guidelines acknowledge that their recommendations are not largely evidence-based and are mainly driven by expert consensus. [3] The goal of management for ITP is to maintain a safe platelet count level and prevent serious hemorrhage and platelet transfusions while minimizing toxicity from therapies. [10]. The goal platelet count, sometimes as low as 20,000/mm3, varies from patient to patient depending on the symptoms and comorbidities. Eltrombopag (Promacta), an oral formulation, and romiplostim (Nplate), an injectable product, are thrombopoietin receptor agonists. These have been FDA-approved to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Due to risk of serious side effects, eltrombopag (Promacta) and romiplostim (Nplate) are available only through restricted distribution programs called PROMACTA CARES and NEXUS, respectively, which require patients and prescribers to register. Evidence Promacta The evidence from one 6-month randomized controlled trials (RCT) comparing eltrombopag (Promacta) with placebo in 197 patients with chronic ITP has uncertain validity due to a primary endpoint of uncertain clinical relevance. A 6-week RCT in 114 patients was also not reliable due to high drop-out rates of up to 32% and a primary endpoint of uncertain clinical relevance. Unreliable evidence from one 80-week open-label study in 207 patients with chronic ITP suggests that the effectiveness of eltrombopag (Promacta) may decrease over time. Nplate
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Evidence from two possibly useful 6-month RCTs comparing romiplostim (Nplate) to placebo in 125 patients with chronic ITP has shown: - For every two non-splenectomized patients who received romiplostim (Nplate), one patient maintained platelet counts above 50,000/mm3 for 6 weeks during the last 8 weeks of the trial. - For every three splenectomized patients who received romiplostim (Nplate), one patient maintained platelet counts above 50,000/mm3 for 6 weeks during the last 8 weeks of the trial Unreliable evidence from an extension open-label study of up to 122 weeks in 137 patients with chronic ITP suggests that romiplostim (Nplate)s effectiveness may decrease over time. There are no studies that evaluate the efficacy of eltrombopag (Promacta) or romiplostim (Nplate) compared to standard therapies. Therefore, there is no evidence that eltrombopag (Promacta) or romiplostim (Nplate) is more effective or safer than other treatment options for chronic ITP.

Safety
eltrombopag (Promacta) Common adverse events Nausea, vomiting, menorrhagia, myalgia, paresthesia, cataract, dyspepsia, ecchymosis, thrombocytopenia, increased ALT/AST and conjunctival hemorrhage.

romiplostim (Nplate) Headache, arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, and paresthesia.

Rare but serious side effects

Reticulin formation and increased risk for bone marrow fibrosis. Thrombocytopenia worse than baseline and risk of bleeding following discontinuation of medication. Thrombotic/thromboembolic complications. Increased risk for progression of underlying hematological malignancies Hepatotoxicity (Promacta is being studied in Hepatitis C thrombocytopenia).

Reticulin formation and increased risk for bone marrow fibrosis. Thrombocytopenia worse than baseline and risk of bleeding following discontinuation of medication. Thrombotic/thromboembolic complications. Increased risk for progression of underlying hematological malignancies Lack or loss of response to romiplostim (Nplate)

Practical Formulary Considerations

Eltrombopag (Promacta) Cost Romiplostim (Nplate) These new medications are significantly more costly than the generic alternatives and comparable to the intravenous brand name options (IVIG, rituximab) Safety There is a very high risk for significant adverse effects from treatment with eltrombopag (Promacta) and romiplostim (Nplate) that may outweigh the benefit. Disease severity Chronic ITP is generally not life-threatening and can be managed in most patients. The disease is debilitating in a small subset of patients who are very refractory. Potential of clinical benefit Eltrombopag (Promacta) has uncertain effectiveness and questionable long-term benefit. Romiplostim (Nplate) is effective in increasing platelet counts for the initial 6month period. Sustainability of the benefit is questionable.

Other treatment options

There are other alternative options that are widely accepted by experts and published in national and international guidelines.
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Risk of offlabel uses

There is potential for use in the treatment of other thrombocytopenias where there is little reliable evidence.

Product Value Eltrombopag (Promacta) and romiplostim (Nplate) may be of value for third or fourth line treatment in patients with refractory chronic ITP. There are many other treatments available, and there is no evidence of improved efficacy or safety over these less costly alternative treatments. The adverse effects of other treatments are known and generally manageable. Eltrombopag (Promacta): Evidence suggests that eltrombopag (Promacta) may increase platelet counts in patients with chronic ITP. Eltrombopag (Promacta) appears to have less value than Nplate due to more potential drug-drug interactions. Due to risk of rare but serious side effects and uncertain long term benefit, eltrombopag (Promacta) should only be reserved for refractory patients when other treatments options have been ineffective. Romiplostim (Nplate): Romiplostim (Nplate) may maintain platelet counts above 50,000/mm3 in onethird to one-half of chronic ITP patients. It may provide value in patients who have had insufficient response to standard therapies. Its value past 6 months is still unknown. Romiplostim (Nplate) has risk of rare but serious side effects that need to be weighed against its benefit. Decision Maintain non-preferred/non-formulary status of eltrombopag (Promacta) and romiplostim (Nplate) because: There is no evidence of improved efficacy or safety over less costly alternative treatments. There is the potential of serious side effects. The adverse effects of other treatments are known and generally manageable. Long term effects of eltrombopag (Promacta) and romiplostim (Nplate) are unknown. There is risk for use in other thrombocytopenias where there is no reliable evidence that supports its efficacy and safety.

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I. Products
Drug Products
Eltrombopag (Promacta)

FDA approval a
Nov. 20/ 2008

Patent expirationc
n/a

FDA approved indications

Thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy Thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy

Usual Dose/Route
50mg po QD

Potential off-label use

Thrombocytopenia secondary to chemotherapy, HIV, hepatitis, blood loss, and conditions other than ITP. Thrombocytopenia secondary to chemotherapy, HIV, hepatitis, blood loss, and conditions other than ITP. Conditions/ diseases with underlying inflammation.

Romiplostim (Nplate)1

Aug 22 /2008

n/a

Initial dose 1 mcg/kg SQ once weekly Adjust weekly dose by increments of 1 mcg/kg to achieve and maintain a platelet 9 count 50 x 10 /L

Prednisone [5] (generic)

Approved Prior to Jan 1, 1982

Expired

Adrenal insufficiency, allergic disorder, asthma, collagen disease, disease of endocrine system, disorder of the eye, disorder of gastrointestinal tract, disorder of hematopoietic structure, disorder of respiratory system, disorder of skin, acute multiple sclerosis, ITP, Hodgkins disease, NonHodgkin lymphoma, hypercalcemia of malignancy, nephrotic syndrome, mycosis fungoides, inflammatory disorder of musculoskeletal system, trichinosis, tuberculosis of meninges, polymyositis, leukemia, neoplastic disease Cerebral edema, allergic disorder, asthma, disease of endocrine system, disorder of the eye, disorder of gastrointestinal tract, disorder of hematopoietic structure, disorder of respiratory system, disorder of skin, acute multiple sclerosis, transplanted organ rejection, nephrotic syndrome, inflammatory disorder of musculoskeletal system, trichinosis, tuberculosis of meninges, neoplastic disease Prophylaxis of bacterial infectious disease, Bcell chronic lymphocytic leukemia, prophylaxis of hepatitis A, ITP, Kawasaki disease, measles prophylaxis, primary immune deficiency disorder, prophylaxis of rubella contact in pregnancy, varicella prophylaxis.

1mg/kg/day

Methylprednisolon e [5] (generic)

Feb 21, 1984

Expired

1mg/kg/day

Conditions/ diseases with underlying inflammation.

Intravenous IVIG (Iveegam , Gamunex, Privigen, Gammagard liquid ) [5]

a

Approved Prior to Jan 1, 1982

Expired

1 to 2 gm/kg divided into equal amounts and given over 2 to 5 days.

Systemic lupus erythematosus, immune mediated neutropenia, solid organ transplantation, myasthenia gravis, conditions with underlying immunodeficiency.

Date applies to approval date for the original brand name medication where there are now generics available.

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References 1. Product Dossier: Promacta (eltrombopag). GlaxoSmithKline: Research Triangle Park, NC; January 2009. 2. Promacta (eltrombopag) Product Information. GlaxoSmithKline, Research Triangle Park, NC, November 2008. 3. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88: 340. 4. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007;357: 22372247.George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88: 340. 5. GlaxoSmithKline Press Release Detail 2008. Available at: http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10127.htm Accessed December 2008. 6. GlaxoSmithKline Press Release Detail 2008. Available at: http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10135.htm. Accessed January 2009 7. FDA Center for Drug Evaluation and Treatment. Approval package for application number NDA 022291 (eltrombopag); Medical Review. Available at: http://www.fda.gov/cder/foi/nda/2008/022291s000_TOC.htm. Accessed February 25, 2009. 8. Klasco RK (Ed): DRUGDEX System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com (cited: January 2009) 9. Drug Facts and Comparisons. Drug Facts and Comparisons 4.0 [online]. 2009. Available from Wolters Kluwer Health, Inc. Accessed January 2009. 10. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Guideline. British Journal of Hematology. 2003;120:574 596 11. Product Dossier: NplateTM (romiplostim). Amgen, Inc: Thousand Oaks, CA; 2008. 12. Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al.Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomized controlled trial. Lancet. 2008;371(9610):395-403. 13. Bussel JB, Provan , Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomized, doubleblind, placebo-controlled trial. Lancet 2009; 373: 64148 14. Nplate (Romiplostim) Product Information. Amgen Inc. Thousand Oaks, CA, March 2008. 15. Newland C, Sanz MA, Bourgeois E, et al. Evaluating the long-term efficacy of romiplostim (AMG 531) in patients with chronic immune thrombocytopenic purpura (ITP) during an open-label extension study. Haematologica. 2008;93(suppl 1):377. Abstract 0945 16. Gammagard Liquid [package insert]. Westlake Village, CA.: Baxter Healthcare Corporation; April 2005. 17. Prescribing Information. Gammagard (Immune Globulin [Intravenous]), Baxter Healthcare

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