ITP

ATLANTA—The investigational “peptibody” romiplostim (AMG 531) can increase and sustain platelet counts in splenectomized adult patients with chronic immune thrombocytopenic purpura (ITP) and make it possible for romiplostim-treated patients taking concurrent standard ITP medications such as corticosteroids to top taking them, according to data presented here at the ASH Annual Meeting. Terry Gernsheimer MD, Associate Professor of Medicine in the Division of Hematology at the University of Washington School of Medicine and the Puget Sound Blood Center in Seattle, explained that the agent, which stimulates platelet production at the thrombopoeitin receptor, is an engineered protein that combines the benefits of peptides and antibodies but is different from either. “Romiplostim works similarly to thrombopoeitin, a natural growth factor in the body that helps the proliferation and differentiation of cells in the bone marrow,” Dr. Gernsheimer said in an interview. “Romiplostin contains an active peptide component that plays a central role in boosting platelet counts.” Available therapies for ITP—besides splenectomy—include intravenous immunoglobulin, high-dose steroids, androgens, and newer immunosuppressive medications such as rituximab, and “while their use addresses the first problem of this disease—destruction of platelets by the immune system—it does not touch on the second problem—inadequate platelet production.” ITP historically has been considered a disease of increased platelet self-destruction, but now researchers believe suboptimal platelet production is just as important, Dr. Gernsheimer explained. “For refractory ITP to develop, there must be both platelet self-destruction and inadequate platelet production. The body's natural production processes alone cannot compensate for low levels of blood platelets.” A normal platelet range for an adult without ITP is 150,000 to 400,000 platelets/μL of blood—“the risk of a bleeding event increases as platelet counts drop, especially as they drop below 30,000 platelets/μL,” she said. Romiplostim was designed to increase the output of platelets at a rate that outpaces their destruction by the immune system, she explained. Amgen recently filed for regulatory approval of romiplostim for use in treating thrombocytopenia in adults with chronic ITP in the United States, the European Union, Canada, Australia, and Japan. The drug has had both fast track and orphan designations in all those regions since 2003. Study Details The multicenter, multinational Phase III study Dr. Gernsheimer reported at the ASH meeting involved 63 splenectomized adults with chronic refractory ITP (21 of whom received placebo and 42, romiplostin), a median age of 51 (range of 26 to 88), and a mean baseline platelet count of 13,500 platelets/μL. “These patients had continued to experience low platelet counts after a median of 7.75 years of suffering from chronic ITP and receiving more than five different kinds of treatments, including splenectomy,” Dr. Gernsheimer noted. The starting dose of romiplostim was 1 μg/kg by subcutaneous injection adjusted over the 24-week study period based on weekly platelet response. Patients were allowed to enroll with stable doses of other ITP therapies including androgens or corticosteroids. Among the highlights of the study: None of the patients receiving placebo had a durable response to treatment compared with 38% of romiplostim-treated patients. (Durable response was defined as a weekly platelet count of about 50,000 platelets/μl for more than six of the final eight study weeks.) The overall platelet response rate was 79% in romiplostim-treated patients compared with no response in the placebo group. All patients in the treatment group were able to decrease or stop their other ITP medications compared to 16.7% of those on placebo; and Only 26.2 % of patients receiving romiplostim needed rescue medications compared to 57% in the placebo group. The new agent was well-tolerated, she added, although there were two treatment-related serious adverse events. One patient developed thrombosis, another an increase of reticulin in the bone marrow; both patients stopped taking romiplostin for several months while the problems were treated and cleared up. Some 200,000 Americans and Europeans have been diagnosed with refractory ITP, according to the Platelet Disorders Support Association. More than a score of studies of potential new treatments for this disease were presented at the ASH meeting. Non-splenectomized ITP Patients Results from a second pivotal Phase III romiplostim trial—this one in non-splenectomized ITP patients—also met primary endpoints (Abstract 565). The data were reported in an oral session at ASH and published in the November 29th issue of the New England Journal of Medicine (2007;357: 2237–2247), with James B. Bussel, MD, as first author). “Patients without a splenectomy, or for whom this surgical procedure is not an option, often require steroid or immunoglobulin treatment,” explained David J. Kuter MD, D Phil, Chief of Hematology at Massachusetts General Hospital, who reported the study at the ASH meeting. “This six-month study is very encouraging in that—as occurred during the evaluation of splectomized patients presented earlier—most of the romiplostim-treated patients receiving concurrent ITP medications were able to stop them before the study was over.” This study met its primary endpoint with 61% of patients on romiplostim achieving durable platelet response vs 4.8% of patients on placebo. Also, said Dr. Kuter, overall response was 87.8% in patients taking the study drug vs 14.3% of patients on placebo. Across the study, 17.1% of the romiplostim-treated patients needed rescue medications vs 61.9% of those on placebo. No serious treatment-related adverse events were reported. Long-Term Similarly, an updated interim analysis from an ongoing, open-label extension study involving 136 splectomized and non-splenectomized patients showed that the majority of those receiving romiplostim achieved a long-term platelet response (Abstract #568). “In this study,” pointed out principal investigator James Bussel, MD, Director of Platelet Research at Weill Medical College of Cornell University, “response was defined as a weekly platelet count of 50,000 platelets per microliter, plus doubling of the baseline platelet count.” The longest treatment duration was 122 weeks, the shortest, more than 24 weeks; 22 patients were followed for 96 weeks or longer. Of the 30 patients on concurrent corticosteroids at study entry, 63% discontinued or reduced their steroid therapy through the course of the trial, Dr. Bussel said. “At this time, romiplostim is the only thrombopoietic ITP treatment for which there are more than two years of follow-up data. This latest interim evaluation is promising for the potential of romiplostim as a long-term treatment.” While the novel agent appeared generally well-tolerated, 11 patients experienced serious treatment-related adverse events, which caused three to leave the study. Oral Drug Candidate Another platelet research team from Weill Cornell Medical Center headed by Dr. Bussel reported data on the long-term safety and efficacy of the investigational drug eltrombopag, an oral platelet growth factor to treat ITP made by GlaxoSmithKline (Abstract 566) The study was designed to assess the potential of eltrombopag as an oral treatment for improving platelet numbers in chronic ITP patients. Of treated patients with a baseline platelet count of about 30,000/μL, 73% achieved an improved platelet count of 50,000/μL or more; and the average treatment period for all patients has lasted approximately five months so far, suggesting that the new agent can sustain increased platelet counts over time. “The findings in this study indicate that eltrombopag, once approved, may provide physicians with a different treatment option to improve patients' platelet levels and alleviate their ITP symptoms,” he said. To date, however, the drug has received no regulatory approval in any market. “Eltrombopag was fairly well-tolerated in this study,” Dr. Bussel added. Of the 94 patients who received at least one dose, 83 percent reported at least one adverse event—“but most AE's were mild, with the most common being headache (20 percent),” he said. Chronic Autoimmune Disease Adult ITP is a chronic autoimmune disease characterized by low blood platelet counts leading to easy bruising and bleeding—i.e., thrombocytopenia. Terry Gernsheimer MD, Associate Professor of Medicine in the Division of Hematology at the University of Washington School of Medicine and the Puget Sound Blood Center, noted that romiplostim is being evaluated for its ability to boost platelet output in ITP and sustain platelet levels for as long as needed.”

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