ORLANDO, Fla., Dec. 11 /PRNewswire/ -- The term "bleeding disorder" encompasses a wide range of medical problems that lead to excessive bleeding or excessive clotting. Impaired clotting mechanisms can lead to excessive blood loss during injury or surgery, while a tendency to clot excessively can

put patients at serious risk for venous thromboembolism (clots in the veins which can travel and block blood flow in other body parts, such as the heart and brain). Four studies being presented today at the 48th Annual Meeting of the American Society of Hematology (ASH(TM)) look at potential treatments for controlling a variety of bleeding disorders.

Platelets contribute to the initiation of clotting, and patients with low platelet counts are predisposed to bleeding. People with a platelet deficit may bleed more easily than others, heal more slowly, and bruise more often. Immune thrombocytopenic purpura (ITP) is characterized by an abnormal decrease in the number of platelets and can result in severe internal bleeding. The decrease in platelets occurs when the immune system attacks and destroys the body's own platelets for an unknown reason. ITP is diagnosed in approximately 66 adult cases per one million each year.

"The first two studies being presented today offer doctors a new perspective on the mechanism of developing low platelet counts in the setting of immune-mediated platelet destruction (ITP). Although it has usually been assumed that patients with ITP actively produce platelets in an attempt to compensate for the platelet destruction, two studies today support the hypothesis that impaired production of platelets in the bone marrow contributes to the clinical features of the disease," said Nancy Berliner, MD, Professor of Medicine and Genetics, Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn.

Along with these abstracts, an additional study being presented offers updated results on a promising therapy for ITP that is aimed at negating the immune-mediated platelet destruction.

Blood clotting -- a natural, protective mechanism that is triggered by the body in response to a cut or wound -- is essential to prevent excessive bleeding. When blood clotting is overactive, a clot (or thrombus) forms inside a blood vessel, obstructing the flow of blood through the circulatory system. These clots generally form in one of the large, deep veins of the body, usually in the calf, thigh, knee, or pelvis. The fourth abstract being presented discusses a promising new agent for the prevention of deep-vein clots in high risk surgical patients.

Analysis of Bleeding in Patients with Immune Thrombocytopenic Purpura (ITP): A Randomized, Double-Blind, Placebo-Controlled Trial of Eltrombopag, an Oral Platelet Growth Factor [Abstract #475]

Thrombocytopenia in immune thrombocytopenic purpura (ITP) is due to both increased platelet clearance and inadequate platelet production. Researchers led by a team at New York Presbyterian Hospital's Weill Cornell Medical Center conducted a study to determine whether the use of eltrombopag, an oral medication given to stimulate the production of platelets in the blood, may increase the platelet count and thus prevent or decrease bleeding episodes in patients with ITP.

The safety and efficacy of eltrombopag was evaluated in a double-blind, placebo-controlled, phase II trial of 117 adults with chronic, previously treated ITP and low platelet levels (less than 30,000/mL). Subjects were randomized to placebo (29 patients) or once daily eltrombopag at 30 mg (30 patients), 50 mg (30 patients), or 75 mg (28 patients) for six weeks, and were followed for an additional six weeks. If a patient's platelet count exceeded 200,000/mL during the first six weeks of treatment, study medication was discontinued.

Platelet counts and bleeding were assessed weekly in both the treatment and follow-up periods. The World Health Organization (WHO) bleeding scale was used to measure bleeding severity on a scale of zero to four: grade 0 (no bleeding), grade 1 (mild), grade 2 (moderate), grade 3 (gross), and grade 4 (debilitating blood loss). Preliminary analysis showed a substantial platelet increase and a trend of decreased bleeding (all grades) in participants treated with 50 mg or 75 mg of eltrombopag. These results included:

  * Median platelet counts increased progressively with the doses by the end
    of the treatment: 16,000/mL in the placebo group; and 26,000/mL,
    128,000/mL, and 183,000/mL in the 30 mg, 50 mg, and 75 mg eltrombopag
    arms, respectively.

  * Incidence of bleeding events during treatment decreased in association
    with the dose: 10 percent in the placebo group compared to 16 percent,
    3 percent, and 4 percent in the 30 mg, 50 mg, and 75 mg treatment arms,
    respectively.

  * Bleeding events occurring in treatment follow-up were reduced, with
    14 percent for placebo patients, and 13 percent, 10 percent, and
    7 percent in those taking 30 mg, 50 mg, and 75 mg of eltrombopag,
    respectively.

"Although a relatively uncommon disease, immune thrombocytopenic purpura is a serious disease and requires effective and safe treatment," said James B. Bussel, MD, Professor in the Division of Pediatric Hematology/Oncology, New York Presbyterian Hospital, Weill Cornell Medical Center, New York City. "Based on the encouraging efficacy and safety data generated by this study, several phase III studies with eltrombopag have been initiated and we expect to see similarly positive results."

Single and Multiple Oral Doses of AKR-501 (YM477) Increase the Platelet Count in Healthy Volunteers [Abstract #477]

Currently, severe thrombocytopenia (reduced platelet count) is managed with platelet transfusions from a donor. Despite their effectiveness in resolving the condition, approximately 30 percent of the transfusions are associated with serious complications. New therapies are under investigation to improve platelet count, such as AKR-501, an orally active thrombopoietin receptor agonist, that helps to increase platelet production through stimulation and differentiation of bone marrow cells that break off into large numbers of platelets. Preliminary research suggests that the drug may be at least 30-fold more potent than other treatments with a similar mechanism of action.

Working with 60 healthy volunteers, researchers evaluated the safety and pharmacokinetic (drug concentrations) and pharmacodynamic (platelet counts) activity of AKR-501 administered in single and multiple oral doses with a primary goal of evoking a 50 percent or greater increase in the baseline platelet count. All subjects were evaluated based on their peripheral blood platelet counts (PBPC) at the start of the study.

In the single-dose arm, 63 subjects were randomized to receive increasing dose amounts (1, 3, 10, 20, 50, 75, and 100 mg) of AKR-501 or a placebo. In the multiple-dose arm, 45 subjects received increasing dose amounts (3, 10, 20, 50, and 100 mg) of AKR-501 or placebo, administered daily for 14 days. The drug was well tolerated in both the single- and multiple-dose studies with no serious drug-related adverse experiences reported at any dose.

The protocol-defined endpoint of a greater-than-50-percent increase over baseline platelet count was achieved in five of six volunteers given a single dose of 100 mg of AKR-501 and in all six volunteers given daily doses of 10 mg for 14 days or 20 mg for 10 days (multiple-dose cohorts). Dose escalation was stopped on day 10 for participants in the 20 mg treatment arm when six of the volunteers showed a platelet count of more than 500,000/mL. In comparison, a normal adult platelet count can range from 150,000 to 450,000/mL.

"The medical community is starting to take thrombocytopenia more seriously, and these data suggest that AKR-501 is a promising candidate for use in the prevention and treatment of thrombocytopenia in a whole host of diseases -- either as a substitute for, or in combination with, platelet transfusion," said Robert E. Desjardins, MD, President and CEO of the drug development company, AkaRx, Inc., Paramus, N.J., and lead investigator of this study. "These are the first clinical results on AKR-501 that show it may be a safe thrombopoietic agent that may lessen or eliminate the need for platelet transfusions, benefiting patient health, and, possibly, lowering health care costs."

Rituximab Is an Alternative to Splenectomy in Adults with Chronic Immune Thrombocytopenic Purpura: Results of a Multicenter Prospective Phase 2 Study [Abstract #478]

Current research suggests that about half of patients with ITP respond well to rituximab, a monoclonal antibody approved to treat B-cell non-Hodgkin lymphoma, and another 25 to 40 percent experience a sustained response. Based on these encouraging results, investigators at Henri Mondor Hospital in Creteil, France, assessed the safety and efficacy of rituximab in an extended population of adults with chronic ITP who also have low platelet counts and are eligible candidates for a splenectomy.

Over the course of 21 months, 60 patients were evaluated in a prospective, phase II study. At the start of the trial, the patients had ITP for an average of 4.8 years, with mean platelet counts of 16+10x109/L. All participants who did not undergo a splenectomy discontinued current ITP treatments and were given four weekly intravenous infusions of rituximab (375 mg/m2).

Treatment success in the study was defined as a platelet count greater than 50x109/L, with a level at least twice that of the patient's initial count.

One year after the first infusion, success was achieved in 24 patients (40 percent). Among 24 long-term responders, platelet counts at one year were greater than 150x109/L in 18 patients, and between 50 and 150 x109/L in six patients. Two other patients had an incomplete response as defined by platelet count success standards (between 30 and 50 x109/L), but did see their count double over the one-year period. Fifty-seven percent (34 patients) failed to respond, and among those patients, 18 had already undergone splenectomy.

"Current treatments aim to decrease platelet destruction by the patient's immune system, many requiring surgery to remove the spleen to control their disease," said Bertrand Godeau, MD, Professor, Department of Internal Medicine, Henri Mondor Hospital, Creteil, France. "Rituximab appears to be a safe and effective splenectomy-sparing strategy in adults with chronic immune thrombocytopenic purpura, leading to a significant and lasting response in a measurable number of cases."

A New Oral Aniticoagulant, Dabigatran Etexilate, Is Effective and Safe in Preventing Venous Thromboembolism after Total Knee Replacement Surgery (The RE-MODEL Trial) [Abstract #573]

Venous thromboembolic events (VTE), common conditions that are difficult to detect in many patients, are a serious risk after surgical procedures. Major operations -- particularly orthopedic procedures in the hips and legs -- increase a patient's risk of developing these conditions, including deep vein thrombosis (DVT), the formation of a blood clot that may partially or completely block a blood vessel. Dabigatran etexilate is an oral, direct clotting inhibitor in clinical development for the prevention and treatment of VTE following orthopedic surgery.

In this phase III study of dabigatran etexilate to prevent DVT after total knee replacement, researchers from Sahlgrenska-Ostra University Hospital in Gothenburg, Sweden, randomized 2,076 orthopedic patients to one of three treatment arms: 150 or 220 mg daily of dabigatran etexilate one to four hours after surgery or 40 mg daily of subcutaneous enoxaparin (another commonly used anticoagulant) starting 12 hours prior to surgery.

Efficacy outcomes were evaluated in 75 percent of patients (1,541 patients) and were measured by a composite of total VTE and all-cause mortality during the treatment period. Not all patients could be evaluated for efficacy because some patients were not undergoing venography and, for others, the quality of the venography was not sufficient. Total VTE and death rates were comparable in the three groups, occurring in 40.5, 36.4, and 37.7 percent of patients receiving 150 or 220 mg dabigatran etexilate and 40 mg enoxaparin, respectively. Safety was evaluated for all patients receiving study treatment, showing no significant difference in the rate of major bleeding among the three treatment groups (1.3, 1.5, and 1.3 percent, respectively, among the 150 or 220 mg dabigatran etexilate and 40 mg enoxaparin groups). Elevated liver function test results occurred in 3.7, 2.8, and 4.0 percent of patients in the 150 or 220 mg dabigatran etexilate and 40 mg enoxaparin study groups.

"Although considerable progress has been made in the treatment of VTE, new advancements are emerging that have the potential to rapidly change the therapeutic scenario," said Bengt I. Eriksson, MD, PhD, Department of Orthopedics, Sahlgrenska-Ostra University Hospital, Gothenburg, Sweden. "The analysis of these phase III data confirms that once-daily dabigatran etexilate, given early in the postoperative period, was as safe and effective as the standard of care in preventing venous thromboembolism for patients undergoing total knee replacement surgery."

The American Society of Hematology (http://www.hematology.org/) 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.

CONTACT: Leslie Humbel of Spectrum Science Communications, +1-202-955-6222, lhumbel@spectrumscience.com; or Laura Stark of American Society of Hematology, +1-202-776-0544, lstark@hematology.org; On-site (12/8-12/12): +1-407-685-5405

Web site: http://www.hematology.org/