Long-term Follow Up Interim Data Show Nplate Increased and Sustained Platelet Counts in Adult Chronic ITP Patients
Interim Phase 2 MDS Data Also Presented at ASH Annual Meeting
SAN FRANCISCO, December 08, 2008 /PRNewswire-FirstCall/ -- Amgen Inc. today released updated results from the ongoing, open-label extension study of the long-term safety and efficacy of Nplate(TM) (romiplostim) in adult patients with chronic immune thrombocytopenic purpura (ITP). Chronic ITP is a chronic and serious autoimmune disorder characterized by lower than expected platelet counts in the blood, sometimes leading to serious bleeding events. The results were presented today as an oral presentation at the 50th Annual Meeting of the American Society of Hematology (ASH Abstract # 402). Results from a study of Nplate in myelodysplastic syndromes (MDS) also were presented.
"These data show Nplate increased platelet counts in most patients for most of the time, and clinically relevant bleeding was reduced over time," said David J. Kuter, M.D., Chief of Hematology, Massachusetts General Hospital, Boston. "This is significant because Nplate can be a long-term treatment for adult chronic ITP patients, who are at risk of serious bleeding events if their platelet counts drop to less than 30,000 per microliter. These patients have had limited availability to long term treatment options."
These study results showed that overall 74 percent of patients (160/215) achieved a platelet response defined as a platelet count of 50,000 platelets per microliter and doubling of the baseline platelet count (median:17,000 platelets per microliter). A platelet response was achieved by 30 percent (61/207) of patients after the first dose and by 47 percent (94/199) of patients after the third dose. The average treatment period was 76 weeks and the longest duration of treatment was 204 weeks.
Additional key findings from the Extension study show:
-- Platelet counts increased: Platelet counts of Nplate-treated patients were increased from baseline by 20,000 platelets per microliter more than 80 percent of the time in 47 percent of patients and more than half the time in 67 percent of patients.
-- Platelet counts maintained: Platelet count increases of 50,000 platelets per microliter were sustained for greater than or equal to 10, greater than or equal to 25, and greater than or equal to 52 consecutive weeks in 77 percent (127/164), 67 percent (95/141), and 41 percent (48/116) of patients, respectively.
In this study, adverse events (AEs) did not increase with time and were reported in 86 percent of patients, with most mild to moderate in severity. The most common were headache (34 percent), contusion (32 percent), and fatigue (31 percent). Treatment-related and serious AEs were reported in 28 percent and 29 percent of patients, respectively. Treatment-related serious AEs were reported in 7 percent of patients. Five percent of patients (11/215) discontinued treatment due to AEs.
Bone marrow reticulin was present or increased in eight patients with no evidence of progression to collagen fibrosis or chronic idiopathic myelofibrosis. Thrombotic/thromboembolic events were reported in seven patients, of whom six had pre-existing risk factors. To date, one patient developed a neutralizing antibody to Nplate; however, it did not cross react with thrombopoietin and it was absent upon re-testing four months after Nplate treatment was stopped.
This ongoing, open-label study is assessing the safety and efficacy of long-term administration of Nplate in both splenectomized and non-splenectomized adult chronic ITP patients. As of July 2008, 223 patients had enrolled and 215 were treated with Nplate. Sixty-one percent of patients were female and, of the enrolled patients, 44 percent had undergone a splenectomy (removal of the spleen).
Eligible patients had completed a previous ITP Nplate study, with no significant change in medical history. The Nplate starting dose was 1 ug/kg by subcutaneous injection and was adjusted to maintain a platelet count between 50,000 and 200,000 platelets per microliter.
Interim Phase 2 Nplate MDS Data Also Presented (Abstract # 224)
Interim data from an ongoing Phase 2 multicenter, randomized, double-blind, placebo-controlled study evaluating Nplate in patients with low or intermediate risk MDS receiving azacytidine were also presented (n=40). The interim analysis showed that Nplate reduced the incidence of clinically significant, treatment-related thrombocytopenic events and platelet transfusions. Nplate also improved the platelet nadir, defined as the lowest peripheral blood count that occurs secondary to bone marrow suppression, in MDS patients receiving azacytidine.
Each study arm was in combination with azacytidine, and serious AEs were observed in 77 percent of the placebo group, 46 percent of the Nplate 500ug group and 71 percent of the 750ug group. One incident of each of the following events was reported: arthralgia, rash, hypersensitivity, pulmonary hemorrhage, hemorrhage and epistaxis. Two patients in the placebo group died, one of fungal pneumonia and the other of pulmonary hemorrhage. One case of disease progression from MDS to acute myeloid leukemia was observed in the Nplate 500ug treated group.
About Adult ITP
In patients with ITP, platelets -- or blood cells needed to prevent bleeding -- are destroyed by the patient's own immune system. Low platelet counts leave adult ITP patients open to sudden serious bleeding events, making it impossible to arrest blood flow. The risk for serious bleeding events increases when platelet counts drop to less than 30,000 platelets per microliter; normal counts range from 150,000 to 400,000 platelets per microliter. ITP has historically been considered a disease of only platelet destruction although recent data suggest that the body's natural platelet production processes in ITP are also unable to compensate for low levels of platelets in the blood. Increasing the rate of platelet production may address low platelet levels associated with ITP.
Currently available treatments (i.e., corticosteroids, immunglobulins) have limited application due to poor tolerability or transient effects. Surgical therapy (removal of the spleen) is also available to adult patients with chronic ITP, but does not work in all cases. Currently, there are 140,000 treated chronic ITP patients in Europe and the United States (U.S.). ITP affects about twice as many adult women as men.
About Myelodysplastic Syndromes
MDS is a disorder in which the production of blood cells by the bone marrow is disrupted and loses its ability to produce normal cells. There is no curative treatment for MDS, with the exception of bone marrow transplantation, and roughly 70 percent of all patients with MDS encounter complications or progression due to acute myeloid leukemia. MDS affects all ages, from children to adults, with the highest prevalence in those over sixty years of age.
Nplate is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
Nplate, Amgen's first peptibody, is a novel engineered therapeutic fusion protein with attributes of both peptides and antibodies, but is distinct from each. Nplate works similarly to thrombopoietin (TPO), a natural protein in the body. Nplate stimulates the TPO receptor, which is necessary for growth and maturation of bone marrow cells that produce platelets.
Nplate was granted approval for the treatment of adult chronic ITP by the regulatory bodies in Australia in July and the U.S. in August 2008. In November 2008, the European Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending marketing authorization of Nplate in the European Union (EU). Amgen has also filed for regulatory approval of Nplate in Canada and Switzerland, and these applications are currently under review. Nplate has received orphan designation for ITP in the U.S. (2003), EU (2005), Switzerland (2005) and Japan (2006).
Nplate is 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. Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Nplate should not be used in an attempt to normalize platelet counts.
Important Safety Information
Serious adverse reactions associated with Nplate in clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate discontinuation.
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis
-- Nplate administration increases the risk for development or progression of reticulin fiber deposition within the bone marrow.
-- In clinical studies, Nplate was discontinued in four of the 271 patients because of bone marrow reticulin deposition. Six additional patients had reticulin observed upon bone marrow biopsy. All 10 patients with bone marrow reticulin deposition had received Nplate doses greater than or equal to 5 mcg/kg, and 6 received doses greater than or equal to 10 mcg/kg.
-- Progression to marrow fibrosis with cytopenias was not reported in the controlled clinical studies. In the extension study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate therapy.
-- Clinical studies have not excluded a risk of bone marrow fibrosis with cytopenias.
-- Prior to initiation of Nplate examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable Nplate dose, examine peripheral blood smears and CBCs monthly for new or worsening morphological abnormalities (e.g., teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s).
-- If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Nplate and consider a bone marrow biopsy, including staining for fibrosis.
Worsened Thrombocytopenia After Cessation of Nplate
-- Discontinuation of Nplate may result in thrombocytopenia of greater severity than was present prior to Nplate therapy. This worsened thrombocytopenia may increase the patient's risk of bleeding, particularly if Nplate is discontinued while the patient is on anticoagulants or antiplatelet agents.
-- In clinical studies of patients with chronic ITP who had Nplate discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate therapy.
-- This worsened thrombocytopenia resolved within 14 days.
-- Following discontinuation of Nplate, obtain weekly CBCs, including platelet counts, for at least two weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines.
-- Thrombotic/thromboembolic complications may result from excessive increases in platelet counts. Excessive doses of Nplate or medication errors that result in excessive Nplate doses may increase platelet counts to a level that produces thrombotic/thromboembolic complications. In controlled clinical studies, the incidence of thrombotic/thromboembolic complications was similar between Nplate and placebo.
-- To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of greater than or equal to 50 x 10(9)/L.
Lack or Loss of Response to Nplate
-- Hyporesponsiveness or failure to maintain a platelet response with Nplate should prompt a search for causative factors, including neutralizing antibodies to Nplate or bone marrow fibrosis.
-- To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate and thrombopoietin (TPO).
-- Discontinue Nplate if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
Hematological Malignancies and Progression of Malignancy in Patients with a Pre-existing Hematological Malignancy or Myelodysplastic Syndromes (MDS)
-- Nplate stimulation of the TPO receptor on the surface of hematopoietic cells may increase the risk for hematologic malignancies. In controlled clinical studies among patients with chronic ITP, the incidence of hematologic malignancy was low and similar between Nplate and placebo.
-- In a separate single-arm clinical study of 44 patients with myelodysplastic syndromes (MDS), 11 patients were reported as having possible disease progression, among whom 4 patients had confirmation of acute myelogenous leukemia (AML) during follow-up.
-- Nplate is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
-- Monitor CBCs, including platelet counts and peripheral blood smears, prior to initiation, throughout, and following discontinuation of Nplate therapy.
-- Prior to the initiation of Nplate, examine the peripheral blood differential to establish the baseline extent of red and white blood cell abnormalities.
-- Obtain CBCs, including platelet counts and peripheral blood smears, weekly during the dose adjustment phase of Nplate therapy and then monthly following establishment of a stable Nplate dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate.
Nplate Distribution Program
-- Nplate is available only through a restricted distribution program called Nplate(TM) NEXUS (Network of Experts Understanding and Supporting Nplate(TM) and Patients) Program. Under the Nplate(TM) NEXUS Program, only prescribers and patients registered with the program are able to prescribe, administer, and receive Nplate. This program provides educational materials and a mechanism for the proper use of Nplate. To enroll in the Nplate(TM) NEXUS Program, call 1-877-NPLATE1 (1-877-675-2831).
-- In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35 percent of patients receiving Nplate and 32 percent of patients receiving placebo. Headaches were usually of mild or moderate severity.
-- Most common adverse reactions (greater than or equal to 5 percent higher patient incidence in Nplate versus placebo) were Arthralgia (26 percent, 20 percent), Dizziness (17 percent, 0 percent), Insomnia (16 percent, 7 percent), Myalgia (14 percent, 2 percent), Pain in Extremity (13 percent, 5 percent) , Abdominal Pain (11 percent, 0 percent), Shoulder Pain (8 percent, 0 percent), Dyspepsia (7 percent, 0 percent), and Paresthesia (6 percent, 0 percent).
-- As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein.
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Posted: December 2008