Long-Term Safety Profile of Romiplostim in Patients with Chronic Immune Thrombocytopenia (ITP).
Authors: Liebman Howard , Henry David , Lefrere Francois , Viallard Jean-Francois , Lichtin Alan , George James , Sanz Miguel , Zhang Kathy , Rutstein Mark 
Published: October 2019

Romiplostim is an investigational Fc-peptide fusion protein (peptibody) that increases platelet production by a mechanism similar to thrombopoietin (TPO). Previous analyses have shown that romiplostim raises and sustains platelet counts, and reduces concomitant chronic Immune Thrombocytopenic Purpura (ITP) medications and rescue medications. Romiplostim use is also associated with a decrease in the incidence and severity of bleeding events over time. We report a pooled analysis of safety from 8 romiplostim clinical studies in adult patients with ITP, including data up to July 13, 2007. Eligible patients that were enrolled in the 7 parent studies were able to enroll in the extension study. The mean age of the 229 patients (65% female) evaluated was 51 years, 135 (59%) had been splenectomized and all patients had received at least 1 prior ITP treatment. The median baseline platelet count was 14 x 109/L. In early studies the dosage varied with the study; however, in the phase III trials and extension study, romiplostim was given as a weekly subcutaneous injection with a dose starting at 1ug/kg and titrations to maintain platelet counts ≥ 50 x 109/L. The number of patients receiving romiplostim was 219 and the number of patients receiving placebo in parent studies was 46 (36 patients who started on placebo and later received romiplostim were counted in both treatment groups). The median treatment duration was 54 weeks (range 1–162), with 16% (36) of patients exposed to romiplostim for > 2 years. Ten percent (22/229) of patients discontinued their parent ITP study including 6 (3%) due to adverse events (AEs), 4 (2%) withdrew consent, and 4 (2%) died. Of the 4 patients who died, 2 were in the romiplostim group and 2 were in the placebo group. Twenty percent (29/229) of patients discontinued during entire follow up period. Since the time spent by patients receiving romiplostim or placebo was not equal, it is important to adjust the AEs for study duration. While patients were receiving romiplostim they had a lower study duration-adjusted event rate than while they were receiving placebo (Table). The most frequently reported AEs (duration-adjusted rates per 100-patient years, romiplostim vs placebo) were: headache, (116 vs 162), contusion (92 vs 137), and epistaxis (67 vs 91). The rate of bleeding events was lower in the romiplostim group than the placebo group. Thrombotic events occurred at a similar rate in romiplostim and placebo patients. No clear association between platelet count and thrombotic events was observed. The presence of or an increase in bone marrow reticulin was reported in 10 romiplostim-treated patients, which decreased in several patients after treatment discontinuation, with no evidence of chronic idiopathic myelofibrosis attributable to romiplostim. One patient developed neutralizing antibodies to romiplostim (absent on retesting 4 months after drug cessation), with no cross-reactive antibodies to TPO. This integrated analysis provides the longest duration of safety information reported for ITP patients treated with a TPO mimetic, with some patients treated for up to 162 weeks. Romiplostim appeared to be well-tolerated and the frequency of AEs did not increase with time on treatment.

Romiplostim N=219 Pt-yr=270 Placebo N=46 Pt-yr=20 AE = adverse event, Pt-yr = Total patient years on study, n = Number of AEs, r = Study duration adjusted event rate per 100 patient-years (no. events/Pt-yr * 100) r(n) r(n) AEs 1789 (4818) 2274 (450) Serious AEs 77 (207) 121 (24) Treatment-Related AEs 197 (530) 202 (40) Treatment-Related Serious AEs 14 (37) 0 Deaths 3 (8) 15 (3) Bleeding Events Any grade 314 (846) 490 (97) ≥grade2 85 (228) 147 (29) ≥grade3 15 (41) 30 (6) Thrombotic Events Any 8 (21) 10 (2) Venous 5 (13) 10 (2) Arterial 3 (8) 0