Romiplostim is a peptibody protein that increases platelet production by binding to and activating the thrombopoietin receptor. Patients with MDS frequently develop clinically significant thrombocytopenia (CST) or other bleeding problems for which transfusion has long been the only available treatment. Three studies presented at ASH suggest that romiplostim might be a safe, effective method for increasing platelet counts in MDS patients and that further trials are warranted.
New Orleans, LA — On the heels of winning the 2009 Scrip Award for “Best New Drug” and the U.S. Prix Galien 2009 “Best Biotechnology Product” for romiplostim (Nplate), Amgen has announced results from three studies in patients with myelodysplastic syndromes (MDS), presented at the 51st ASH Annual Meeting. Romiplostim is a peptibody protein that increases platelet production by binding to and activating the thrombopoietin receptor. Patients with MDS frequently develop clinically significant thrombocytopenia (CST) or other bleeding problems for which transfusion has long been the only available treatment. These three studies suggest that romiplostim might be a safe, effective method for increasing platelet counts in MDS patients and that further trials are warranted.
Dose-Escalation Investigation of Romiplostim
An ongoing extension open-label phase 1/2 study investigated the safety and efficacy of romiplostim in 28 patients with median baseline platelets of 31 x 109/L; 32% had platelets <20 x 109/L. In the parent study, patients received doses of romiplostim ranging from 250 µg up to 1500 µg weekly or every 2 weeks, with dose escalation permitted up to a maximum of 1000 µg per week in patients with inadequate response after 4 weeks of therapy. The majority of patients (24) patients demonstrated platelet response; a 4-week washout period followed prior to initiating the open-label extension study.
In the extension study, the median duration of treatment was 41 weeks at a median weekly dose of 748 µg. All patients received at least 8 weeks of romiplostim. Investigators described adverse events as “mild to moderate.” The most common adverse events were epistaxis (36%), arthralgia (29%), anemia (21%), and cough (21%). In addition, no neutralizing antibodies to romiplostim or thrombopoietin were observed and none of the patients progressed to acute myeloid leukemia (AML) or experienced bone marrow fibrosis. Adverse events resulted in 6 patients withdrawing from the study, with 3 patients having an increase in blast cells and 1 patient developing chronic myeloid leukemia. Peripheral blasts disappeared after treatment discontinuation. One patient, who had a history of chronic obstructive pulmonary disease and congestive heart failure, died from fatal pulmonary fibrosis after initiating treatment.
Secondary endpoints included the rate of bleeding events and platelet response. The majority of patients (n = 18) experienced at least one bleeding event, and 6 patients had one or more clinically significant bleeding events. In addition, 8 patients required platelet transfusions.
Regarding efficacy, 54% of patients achieved platelet response by week 3 and 61% achieved platelet response persisting for at least 8 consecutive weeks, meeting the secondary endpoint. Researchers defined platelet response as “an absolute platelet increase of ≥30,000 platelets per microliter for patients starting with <20,000 platelets per microliter or an increase from <20,000 platelets per microliter to >20,000 platelets per microliter and by at least 100%.” Data showed 82% of patients had a platelet response lasting a median of 30 weeks.
In a press release, co-author Hagop Kantarjian, professor of Medicine and chairman of the Department of Leukemia at the University of Texas M. D. Anderson Cancer Center, said, “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.” The researchers concluded romiplostim had an acceptable toxicity profile in patients with thrombocytopenic MDS. ASH Abstract 2765.
Romiplostim versus Placebo
The other studies were phase II multicenter randomized clinical trials that found adding romiplostim to decitabine or lenalidomide (Revlimid) in patients with low- or intermediate-risk MDS reduced the incidence of CST and the need for platelet transfusions. Both studies found romiplostim to be well-tolerated and recommended additional investigation but noted that data interpretation was limited by each study’s small sample size.
In one study, 39 patients (median age, 74 y) were randomized to receive 4 cycles of subcutaneous placebo, 500 µg of romiplostim, or 750 µg of romiplostim in addition to standard treatment with lenalidomide. At study outset, 15 patients (30%) had platelet counts <50 x 109/L, and 7 (18%) had del(5q).
The incidence of adverse events was comparable between the different groups. Patients in the placebo arm had a higher incidence of diarrhea, at 45.5% versus 38.5% for patients taking romiplostim; thrombocytopenia, observed in 36.4% of patients taking placebo compared with 16.3% of patients on romiplostim; and dizziness, observed in 27.3% of patients on placebo compared with 11.6% for patients receiving romiplostim. Romiplostim was associated with higher rates of rash (34.7% vs 27.3%, respectively) and peripheral edema (30.8% vs 27.3%).
Compared to placebo, patients taking romiplostim had increased platelet counts (31.5% vs 17%, respectively) and were less likely to require platelet transfusion (19% vs 25%, respectively). No deaths were reported, and 12 patients discontinued the study, including 1 in the romiplostim group who progressed to AML. ASH Abstract 1770.
In the third study, 29 patients were randomized nearly 1:1 to receive placebo or 750 µg romiplostim in addition to decitabine at a standard or modified dose. Nine patients in the placebo group and 10 in the romiplostim group completed 4 cycles of decitabine.
After the first treatment cycle, patients in the placebo group had lower median platelet counts at the beginning of each subsequent cycle compared with those receiving romiplostim. In the last cycle, 30% of patients taking placebo and 55% of romiplostim-treated patients reached median platelet count. In addition, more patients on placebo required platelet transfusions than patients taking romiplostim (57% vs 47%, respectively). The placebo group also had a higher incidence of bleeding events than the romiplostim group (43% vs 27%).
Only 36% (n = 5) of patients in the placebo group achieved complete or partial response compared with 47% (n = 7) in the romiplostim group. All patients experienced at least 1 adverse event with a slightly higher rate in the placebo group than the romiplostim group (57% vs 53%, respectively). One patient in each group had progression to AML, and 2 patients in each group died. Neither death in the romiplostim arm was considered related to the investigational treatment. ASH Abstract 1769.
Dislcosure: Amgen provided funding for these studies.