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Immune thrombocytopenic purpura: AMG 531 increases platelets

Interim results from an open-label study have shown that long-term administration ( up to 48 weeks ) of its investigational therapy AMG 531 was generally well-tolerated and stimulated platelet production in patients with immune thrombocytopenic purpura ( ITP ).

Overall, 85 percent of patients in the study ( 29 of 34 ) achieved a platelet response, defined as doubling of the baseline platelet count and at least 50,000 platelets per microliter of blood.

Immune thrombocytopenic purpura is characterized by an immune system malfunction that recognizes the body's own platelets as foreign and destroys them, potentially resulting in dangerously low platelet counts ( less than 30,000 platelets per microliter ).
Platelets are specialized blood cells that help prevent and stop bleeding by participating in clotting. Normal platelet range for a person without ITP is 150,000 to 400,000 platelets per microliter.

AMG 531 is a first-in-class investigational protein called a peptibody, which contains two component regions. AMG 531 works similarly to thrombopoietin ( TPO ), a natural protein in the body. The active peptide component of AMG 531 stimulates the TPO receptor, or "on-off switch," which is necessary for growth and maturation of bone marrow cells and plays a very important role in platelet production. The carrier component contains a portion of natural immunoglobulin called the constant or Fc component, which increases the half-life of AMG 531.

" Traditional therapies for immune thrombocytopenic purpura have focused on diminishing platelet destruction by suppressing the immune system, beginning with the use of steroids, followed by surgical removal of the spleen and more intensive immunosuppression. These treatments have potentially serious side effects. For ITP patients who do not respond to these therapies, there are no effective treatment options," said James George, at the University of Oklahoma Health Sciences Center, Oklahoma City. " The long-term study results show that AMG 531 administered as an individualized weekly dose resulted in a durable platelet response. If approved, AMG 531 may provide an important therapeutic option for ITP patients, potentially enabling patients to taper off long-term steroid therapy."

Interim results were presented for 34 patients treated with AMG 531 for up to 48 weeks. Twenty-eight patients had undergone splenectomy before study entry and eight were receiving concurrent corticosteroids for ITP. Overall, 47 percent of patients ( n=16 ) had a durable platelet response, defined as platelet response at six or more weeks between weeks 18 through 25. Of the eight patients on concurrent corticosteroids, 50 percent ( n=4 ) discontinued corticosteroid treatment and 25 percent ( n=2 ) had at least a 50 percent dose reduction.

" It is exciting that most patients in this study achieved platelet counts of greater than 50,000 per microliter, despite how refractory they were, from a starting count of approximately 18,000," said James B. Bussel, at the Weill Cornell Medical Center, New York. " This is important because it suggests that AMG 531 may stimulate platelet production faster than the immune system can destroy them, enabling patients to sustain a satisfactory platelet count with ongoing AMG 531 treatment."

In this study, AMG 531 was generally well-tolerated.
The most frequently reported adverse events were headache, upper respiratory infection and fatigue. Serious adverse events reported as treatment related include bone pain ( n=1 ); anemia ( n=1 ); and vaginal hemorrhage ( n=1 ).
Additionally, there was one reported case of diffuse reticulin formation in the bone marrow reported as myelofibrosis.
Reticulin formation is hypothesized as due to excessive accumulation of megakaryocytes in the bone marrow. Follow-up bone marrow biopsies reveal that the reticulin is improving.
No neutralizing antibodies have been detected to date.

Source: American Society of Hematology ( ASH ) 47th Annual Meeting, 2005