NEW ORLEANS, Dec. 6 Amgen Inc. (Nasdaq: AMGN) today announced results from three studies on the safety and efficacy of Nplate® (romiplostim) in adult patients with myelodysplastic syndromes (MDS). MDS is a pre-leukemic condition in which early blood forming cells in the bone marrow are unable to mature normally, thereby limiting their ability to produce normal mature blood elements, which can lead to low platelet counts. The results of the studies were presented at the 2009 American Society of Hematology (ASH) Annual Meeting and Exposition (ASH Abstracts #1769, #1770 and #2765).
Interim Results from Long-Term Open-Label Extension Study of Nplate in MDS (Abstract #2765)
The ongoing, open-label extension study was designed to evaluate the safety and efficacy of Nplate in lower risk MDS patients. The primary endpoints of the interim study for presentation at ASH evaluated adverse event rates with long-term use of Nplate and incidence of antibody development to Nplate and/or thrombopoietin (TPO). Secondary endpoints evaluated the incidence of bleeding events and platelet response during the study period.
Nplate was generally well-tolerated, with the majority of patients (n=28) achieving a platelet response (61 percent) for eight or more consecutive weeks. The primary endpoint evaluating adverse event rates was met, with most patients experiencing adverse events that were mild to moderate with the most common being epistaxis (36 percent), arthralgia (29 percent), anemia (21 percent) and cough (21 percent). The co-primary endpoint was also met, as no neutralizing antibodies to Nplate or TPO were observed, nor progression to acute myeloid leukemia (AML). In addition, no cases of bone marrow fibrosis were reported.
Results for the secondary endpoint showed that 64 percent of patients (n=18) reported one or more bleeding events and 21 percent of patients (n=6) reported one or more clinically significant bleeding events. In the study, 29 percent of patients (n=8) received platelet transfusions. Frequency of bleeding events and platelet transfusions decreased over time. Bleeding events were evaluated on Common Terminology Criteria for Adverse Events (CTCAE) grades one to four, and clinically significant bleeding events were evaluated on CTCAE grades three and over, serious adverse events or any bleeding adverse event requiring intervention.
The data also showed that Nplate was effective with over half (54 percent) of patients (n=28) achieving a platelet response by week three and 61 percent achieving a durable platelet response overall (for eight or more consecutive weeks), meeting the additional secondary endpoint. Platelet response was defined as an absolute platelet increase of greater than or equal to 30,000 platelets per microliter for patients starting with less than 20,000 platelets per microliter, or an increase from less than 20,000 platelets per microliter to over 20,000 platelets per microliter and by at least 100 percent. The study showed that 82 percent of patients (n=28) had a platelet response and the median platelet response lasted 30 weeks.
"Both the safety and efficacy data are important given the limited treatment options available for those who suffer from low platelet counts due to MDS," said Dr. Hagop Kantarjian, Professor of Medicine and Chairman of the Department of Leukemia at The University of Texas M.D. Anderson Cancer Center.
This long-term, follow-up, open-label global extension study included lower risk MDS patients who had completed a previous Nplate study and who had platelet counts of less than 50,000 platelets per microliter with no signs of disease progression. Patients received Nplate doses of 250 micrograms, 500 micrograms, 750 micrograms, or 1500 micrograms weekly or every two weeks based on previous dosing, with adjustments between 250 micrograms and 1000 micrograms.
Additional Phase 2 Nplate MDS Data (Abstract #1769 and #1770)
Data from two separate Phase 2 studies showed that patients with low and intermediate risk MDS currently receiving either decitabine or lenalidomide showed reduced incidence of clinically significant thrombocytopenic events and platelet transfusions with the addition of Nplate treatment.
In the study that examined patients with low and intermediate risk MDS receiving decitabine in combination with Nplate (Abstract #1769), the primary endpoint evaluated the incidence of clinically significant thrombocytopenic events as defined by platelet counts of less than 50,000 platelets per microliter by the third week of treatment, or receipt of platelet transfusions at any time during the study period.
The data showed that the primary endpoint was reached in 79 percent (n=14) of placebo patients and 80 percent (n=15) of Nplate patients and after the first cycle of treatment, median platelet counts at the beginning of each decitabine cycle were lower in placebo-treated patients than in Nplate-treated patients. In the last cycle, 30 percent of placebo treated patients (n=10) and 55 percent of Nplate treated patients (n=11) had reached median platelet count. In addition, results showed decreased platelet transfusions in Nplate-treated patients compared to placebo (47 percent vs. 57 percent, respectively).
Secondary endpoints were also met with results showing that treatment was generally well-tolerated in lower-risk MDS patients (all patients in the Nplate and placebo groups experienced at least one adverse event) with improved MDS treatment response after four cycles compared to placebo (47 percent vs. 36 percent, respectively) and decreased bleeding events (27 percent vs. 43 percent, respectively) in Nplate-treated patients compared to placebo. Adverse events were mild to moderate with similar treatment-related adverse events between patients taking Nplate and placebo (33 percent vs. 21 percent, respectively). Similar findings have been reported for use of Nplate in combination with azacytidine (vidaza).
The other study (Abstract #1770) examined patients with low and intermediate risk MDS receiving lenalidomide in combination with Nplate. The objective of the study was to evaluate the effect of Nplate on the incidence of clinically significant thrombocytopenic events and the overall safety and efficacy of Nplate in combination with lenalidomide. The data showed that treatment was generally well-tolerated with a comparable incidence of adverse events between all treatment groups with most frequent adverse events (appearing in greater than or equal to 10 percent of patients) in patients taking Nplate vs. placebo being diarrhea (38.5 percent vs. 45.5 percent, respectively), thrombocytopenia (16.3 percent vs. 36.4 percent), rash (34.7 percent vs. 27.3 percent), edema peripheral (30.8 percent vs. 27.3 percent) and dizziness (11.6 percent vs. 27.3 percent). Data also showed increased platelet counts (31.5 percent vs. 17 percent) and reduced the need for platelet transfusions (19 percent vs. 25 percent) compared to placebo. Adverse events were mild to moderate with similar rates of adverse events between patients taking Nplate and placebo (100 percent vs. 91 percent).
Both studies were multi-center, randomized, double-blind, placebo controlled studies that involved low and intermediate risk MDS patients receiving Nplate and decitabine (n=28) or lenalidomide (n=39). Patients received four 28-day cycles of decitabine or lenalidomide in addition to Nplate or placebo. At the end of treatment, there was an optional open-label extension period for patients taking the study drug and Nplate. MDS treatment response (complete response, partial response, stable disease, progressive disease or unknown) was determined by the investigator based on modified MDS Investigator Working Group (IWG) guidelines.
About Myelodysplastic Syndromes
MDS is a disorder in which the production of normal blood cells by the bone marrow is disrupted. 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 adult chronic ITP.
Nplate was the first platelet producer approved in the European Union (EU), Canada, Australia, Russia and the United States (U.S.). Nplate was granted approval for chronic ITP by the regulatory bodies in Australia, Canada, Europe, Russia and the U.S. Nplate also has received orphan designation for chronic ITP in the U.S. (2003), the EU (2005), Switzerland (2005) and Japan (2006).
Nplate is the first treatment specifically developed for chronic ITP. It is also being investigated for potential use in pediatric ITP, MDS and CIT.
In the U.S., Nplate is indicated for the treatment of thrombocytopenia in patients with chronic 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.
In the EU, Nplate is indicated for the treatment of splenectomized adult ITP patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins). Nplate may be considered as a second-line treatment for adult non-splenectomized ITP patients for whom surgery is contra-indicated.
Nplate was named as a recipient of the U.S. Prix Galien 2009 "Best Biotechnology Product" award and also received the 2009 Scrip Awards for "Best New Drug."
Important U.S. Nplate Safety Information
Serious adverse reactions associated with Nplate in clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Nplate discontinuation. Additional risks include bone marrow fibrosis, thrombotic/thromboembolic complications, lack or loss of response to Nplate, and hematological malignancies and progression of malignancy in patients with a pre-existing hematological malignancy or MDS. Nplate is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
Nplate is available only through a restricted distribution program called Nplate NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program.
In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction.
Important EU Nplate Safety Information
The most common side effects are headache, fatigue, arthralgia, myalgia, injection site bruising, injection site pain, peripheral edema, dizziness, muscle spasms, nausea, contusion, diarrhea, bone marrow disorder, influenza like illness, insomnia and pruritus.
Reoccurrence of thrombocytopenia and bleeding after cessation of treatment and increased bone marrow reticulin have been associated with Nplate treatment in the clinical trials. Thrombotic/thromboembolic complications, progression of existing hematopoietic malignancies or MDS, and effects on red and white blood cells are all potential risks associated with Nplate treatment. As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein.
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