FOR IMMEDIATE RELEASE

Contacts:
Kara Vonasek, Spectrum Science
202-955-6222

Aislinn Raedy, American Society of Hematology
202-776-0544

NEXT GENERATION TREATMENT SHOWS PROMISE FOR MANAGEMENT OF BLOOD CLOTTING DISORDER

(SAN DIEGO, December 6, 2004) – Two studies presented during the 46th Annual Meeting of the American Society of Hematology (ASH) highlight the effects of a promising new pipeline therapy for treatment of immune thrombocytopenic purpura (ITP). ITP is a disorder that affects approximately 20,000 individuals in the United States and 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 and the occurrence of spontaneous bleeding and bruising in the most severe cases.

“ITP is a relatively uncommon disease, but it still affects a significant number of people, both children and adults of all ages,” said Jim George, M.D., President-Elect of the American Society of Hematology and Professor of Medicine at the University of Oklahoma Health Sciences Center, Oklahoma City. “Current treatments are all aimed at decreasing the platelet destruction by the patient’s immune system, and these treatments can cause serious side effects. Many patients require surgery to remove the spleen to control their disease. The new product described below works by an entirely different mechanism – to increase platelet production. It is promising and may provide a much needed, safe, long-term treatment option for people with ITP.”

Normal platelet range for a person without ITP is 150,000 - 400,000 platelets per microliter (µL). Patients with severe cases of ITP have platelet counts under 10,000. Sometimes, platelet counts become so low they are undetectable.

Recent advancements in ITP treatment, such as thrombopoietin (TPO), have shifted the treatment focus from preventing platelet destruction to enhancing platelet production. By targeting and ultimately enhancing the pathway that leads to platelet production, researchers hope to tip the scales in favor of platelet production for patients with ITP and get the body to produce platelets more quickly than they are being destroyed.

Thrombopoietin is the major platelet growth factor responsible for stimulating platelet production under normal conditions, which makes it an important target for clinical research. Scientists have discovered a way to produce a protein that has all of the effects of native thrombopoietin for use in clinical trials. Unfortunately, studies with the early form of thrombopoietin showed less than impressive results due to the fact that some patients developed an immune reaction to the drug.

In the two studies highlighted below, however, scientists explored the safety and efficacy of a next-generation thrombopoietin, AMG531, which appears to overcome the limitations of previous versions and proves promising for treatment of ITP.

An Open-Label, Unit Dose-Finding Study Evaluating the Safety and Platelet Response of Novel Thrombopoietic Protein (AMG531) in Thrombocytopenic Adult Patients with Immune Thrombocytopenic Purpura (ITP) [Abstract 2058]

Researchers from the Royal London Hospital Whitechapel Department of Hematology conducted a phase I, open-label study of novel thrombopoietic agent AMG531, which functions by activating the hormone receptor, or “on-off switch,” necessary for growth and maturation of megakaryocytes, large bone marrow cells that play a very important role in platelet production. Researchers carried out this study to evaluate the safety and efficacy of AMG531, as well as to determine the optimal dose appropriate for follow-up studies. Results showed AMG531 was well-tolerated and capable of increasing platelet counts in patients with ITP when doses equivalent to >1 microgram per kilogram (μg/kg) were given.

A total of 16 patients were enrolled and assigned to one of four dose-sequential treatment arms – 30, 100, 300, or 500 μg respectively – and a fifth confirmatory cohort at 300 μg, which was selected as the most effective dose level during the study and repeated for verification. Patients eligible for the study had been diagnosed with ITP three months prior to study start and had a baseline platelet count of <30,000 platelets per μL (or <50,000 platelets per μL for patients taking corticosteroids). Patients received the study drug at day one and day 15 (or day 22 if platelet counts were >50,000 platelets per μL on day 15) and were then followed for eight weeks.

After a conversion of the μg doses to μg/kg dose equivalents, results showed that 67 percent of patients receiving a dose of >1 μg/kg achieved the secondary platelet response criterion, which was defined as doubling of baseline platelet count. Of these patients, 75 percent had previously undergone surgical removal of the spleen, which suggests that patients during any stage of treatment for ITP, even those without a spleen, may safely respond to treatment with AMG531.

These data indicate that AMG531 is a well-tolerated, effective treatment option for patients with ITP. Dosing by weight seems most appropriate for this patient population, and doses >1 μg/kg appear to be most effective for follow-up studies.

“The results are gratifying and show that our approach to the stimulation of platelet production does indeed favorably alter the platelet count without further intensifying platelet destruction,” said Adrian Newland, M.D., of the Department of Hematology, Royal London Hospital Whitechapel, and lead investigator of this study. “More studies on the long-term effects of this drug are necessary, but given its safety and efficacy profile, AMG531 could potentially be a long-term maintenance therapy for patients who have already lost their spleen, or an effective alternative to surgery, obviating the need for a splenectomy.”

No safety concerns were identified during the trial. Headache was the most frequently reported adverse event, which is common with recombinant protein products. Given that this is a platelet-specific treatment, other platelet parameters such as hemoglobin, white blood cell, blood chemistry, and coagulation variables were monitored for possible problems. No clinically significant, on-study changes were observed, and most importantly, no anti-thrombopoietin antibodies were detected, which was the problem with earlier-generation thrombopoietin.

A Phase-II Placebo Controlled Study Evaluating the Platelet Response and Safety of Weekly Dosing with a Novel Thrombopoietic Protein (AMG531) in Thrombocytopenic Adult Patients with Immune Thrombocytopenic Purpura (ITP) [Abstract 511]

Researchers from Massachusetts General Hospital led a multicenter, randomized, double blind, placebo-controlled, phase II study to determine an appropriate weekly dose of AMG531 that would produce an acceptable safety profile while elevating platelet counts to an adequate level. Patients were randomized into a placebo group and two dose cohorts, 1 μg/kg and 3 μg/kg, respectively. The dose cohorts were treated weekly with AMG531 for six weeks. Results showed that while a platelet response was observed with both dose levels, patients on the 1 μg/kg dose maintained counts within the target range of >50,000 platelets per μL but <450,000 platelets per μL. However, response variability suggests that individual dose adjustments might be necessary to achieve the optimal outcome for each patient.

Twenty-one patients were enrolled in the study, treated for six weeks, and followed for an additional six weeks post-study. Safety was evaluated in all patients and efficacy was evaluated in 20 patients. Seven of the eight (88 percent) patients receiving the 1 μg/kg dose achieved the desired platelet count compared to three of eight (38 percent) patients in the 3 μg/kg group. However, there were two other patients in the 3 μg/kg group who exceeded 450,000 platelets per μL, which is the upper limit of the desired range, and were forced to discontinue.

Eligibility requirements included a baseline platelet count of <30,000 platelets per μL (or <50,000 platelets per μL for patients taking corticosteroids), an ITP diagnosis three months prior to study start, and one previous ITP treatment with no history of thrombosis.

AMG531 appeared to be well tolerated at both doses for weekly treatments over an extended period of time, but the 1 μg/kg dose more effectively maintained platelet counts within the desired range.

“We have seen a response rate that is higher than any other treatment currently available for ITP. If this therapy continues to be as effective as it looks in this study, then we will be able to offer a novel way of treating ITP that is equivalent to the way in which we treat anemia with erythropoietin,” said David Kuter, M.D., D.Phil., of Massachusetts General Hospital, and lead investigator of this study. “We are now starting a randomized, placebo-controlled, phase III licensing trial, and ongoing, longitudinal studies are being undertaken to address its long-term utility and safety.”

No safety concerns were identified aside from one instance of transient thrombocytopenia. The most frequently reported adverse events attributable to the drug were headache and mouth sores. White blood cells, blood chemistry, and coagulation variables remained stable. Notably, no anti-AMG531 or anti-TPO antibodies were detected. Platelet counts dropped after stopping drug therapy. Splenectomy status and concomitant use of corticosteroids did not appear to affect platelet response.

The American Society of Hematology is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

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