Romiplostim in patients with refractory aplastic anaemia previously treated with immunosuppressive therapy: a dose-finding and long-term treatment phase 2 trial.

BACKGROUND: Aplastic anaemia is a rare, life-threatening condition, characterised by pancytopenia with hypocellular bone marrow. Haematopoietic stem cells and most progenitor cells express thrombopoietin receptor (c-MPL). Romiplostim is a peptibody with c-MPL agonist activity that stimulates endogenous thrombopoietin production and leads to promoting the proliferation and differentiation of megakaryocytes in the bone marrow. In this phase 2 trial we aimed to assess the activity and safety of romiplostim in patients with aplastic anaemia who were previously treated with immunosuppressive therapy. METHODS: We did an open-label, phase 2 study including a randomised, parallel, dose-finding part followed by an extension part to evaluate long-term treatment at two clinical centres in Seoul, South Korea. Eligible patients were aged 19 years or older, and had aplastic anaemia confirmed by bone marrow and cytogenetic studies and thrombocytopenia (platelet count ≤30 × 109/L), an Eastern Cooperative Oncology Group performance status score of 2 or lower, and were previously treated with immunosuppressive therapy, including at least one course of antithymocyte globulin plus cyclosporin. In the dose-finding part, patients were randomly assigned to fixed dose cohorts (1, 3, 6, or 10 µg/kg) of subcutaneous romiplostim once weekly for 8 weeks, according to a static allocation procedure after stratification by platelet count. In the extension part of the study, patients continued romiplostim titrated every 4 weeks in single steps (1, 3, 6, 10, 13, 16, and 20 µg/kg once weekly), depending on platelet response and safety up to 1 year (weeks 9-52). Patients who had a platelet response during weeks 46-53 continued dose titration in single steps (3, 6, 10, 13, 16, and 20 µg/kg once weekly) for an additional 2 years (weeks 53-156). The primary endpoint was the proportion of patients achieving a platelet response at week 9 (after completion of the dose-finding part). Activity was assessed per-protocol in all patients evaluable for response at week 9 and safety was assessed in all patients who received at least one dose of romiplostim. This trial is registered with ClinicalTrials.gov, NCT02094417. FINDINGS: Between April 14 and Nov 24, 2014, 35 patients were enrolled and randomly assigned to one of four dose cohorts: romiplostim 1 µg/kg (n=7), 3 µg/kg (n=9), 6 µg/kg (n=9), and 10 µg/kg (n=10). Data cutoff for this final analysis was on April 14, 2018. The median duration of treatment for all patients was 53 weeks (IQR 35-155). Ten (30%) of 33 evaluable patients achieved a platelet response at week 9, including seven (70%) of ten patients in the 10 µg/kg cohort, three (33%) of nine patients in the 6 µg/kg cohort, and no patients in both the 3 µg/kg and 1 µg/kg cohorts. During the extension study, 18 (55%) of 33 evaluable patients had a platelet response during weeks 46-53 and were eligible for continued treatment. Ten (30%) patients maintained a platelet response at 2 and 3 years, of whom nine had an erythroid response and five a neutrophil response, and completed protocol treatment. Treatment-related adverse events occurred in three (9%) of 35 patients, including grade 1 or 2 myalgia, fatigue, and dizziness. 17 (49%) of 35 patients had adverse events of grade 3 or higher; seven (20%) had serious adverse events (one event of febrile neutropenia, cataract, retinal detachment, macular fibrosis, inguinal hernia, appendicitis, cellulitis, tendon injury, and transfusion reaction); and one patient died from sepsis during treatment; none of these events were related to treatment. No patients developed clonal evolution. INTERPRETATION: Romiplostim seems to be active and has a favourable safety profile in patients with refractory aplastic anaemia. 10 µg/kg once weekly might be used as a recommended starting dose in future studies. These findings warrant further investigation. FUNDING: Kyowa Hakko Kirin Korea.

A comparison of the bioequivalence of two formulations of epoetin alfa after subcutaneous injection.

BACKGROUND: The previous formulation of epoetin alfa in Japan was a citrate-buffered protein solution containing gelatin hydrolysate as the protein protective agent. To eliminate pain at injection sites, and the risks of anaphylactic shock and unknown infections by gelatin we have developed a new formulation of phosphate-buffered epoetin alfa, which does not contain gelatin hydrolysate. AIM: To compare the bioequivalence of two formulations of epoetin alfa administered by the subcutaneous route. METHODS: Four separate studies were performed to assess the bioequivalence of two epoetin alfa formulations using different strength and doses, i.e. 750 IU per 0.5 ml x 0.5 ml (= 750 IU per subject), 750 IU per 0.5 ml x 4 ml (= 6000 IU per subject), 6000 IU per 0.5 ml x 0.5 ml (= 6000 IU per subject) and 24,000 IU per 0.5 ml x 0.125 ml (= 6000 IU per subject). Each study was a single-centre, open-label, randomized, two-treatment, two-period, crossover study for which healthy volunteers were enrolled. Bioequivalence was assessed using the confidence interval (CI) of the ratios for the log-transformed, baseline-corrected Cmax and AUC(0,t). Baseline-corrected AUC(0,t) was calculated using the following equation: AUC(0,t) = AUC(0,t), uncorrected -- predose level x observation period. RESULTS: The ratios (gelatin-free/gelatin-containing) for the log-transformed Cmax and AUC(0,t) after 6000 IU per subject injection of three different concentrations of epoetin alfa were well within the usual range for bioequivalence (90% CI 0.8, 1.25). The 90% CI of the ratio for Cmax after 750 IU per subject injection was 0.906, 1.24, which was within the bioequivalence range. However, the ratio for AUC(0,t) was not determined in this lowest dose because of negative AUC(0,t) values obtained in 12/60 cases. The overall safety data were consistent with those expected for a healthy study population, and did not present any concerns suggestive of adverse effects due to either formulation. CONCLUSIONS: The point estimates and 90% CIs of the ratios of Cmax and AUC(0,t) for the gelatin-free/gelatin-containing formulations indicated that the two formulations are bioequivalent.