SRI Biosciences, SRI International, Menlo Park, California.
Amgen Inc, Thousand Oaks, California.
Int J Radiat Oncol Biol Phys. 2023 Nov 1;117(3):705-717. doi: 10.1016/j.ijrobp.2023.05.008. Epub 2023 May 22.
Patients exposed to acute high doses of ionizing radiation are susceptible to dose-dependent bone marrow depression with resultant pancytopenia. Romiplostim (RP; Nplate) is a recombinant thrombopoietin receptor agonist protein that promotes progenitor megakaryocyte proliferation and platelet production and is an approved treatment for patients with chronic immune thrombocytopenia. The goal of our study was to evaluate the postirradiation survival and hematologic benefits of a single dose of RP with or without pegfilgrastim (PF; Neulasta, granulocyte colony stimulating factor) by conducting a well-controlled, treatment-concealed, good laboratory practice-compliant study in rhesus macaques that was compliant with the United States Food and Drug Administration Animal Rule regulatory approval pathway.
Irradiated male and female rhesus macaques (20/sex in each of 3 groups: control, RP, and RP + PF) were subcutaneously administered vehicle or RP (5 mg/kg, 10 mL/kg) on day 1 in the presence or absence of 2 doses of PF (0.3 mg/kg, 0.03 mL/kg, days 1 and 8). Total body radiation (680 cGy, 50 cGy/min from cobalt-60 gamma ray source) occurred 24 ± 2 hours previously at a dose targeting 70% lethality for the control cohort over 60 days. The study examined 60-day survival postirradiation as the primary endpoint. Secondary endpoints included incidence, severity, and duration of thrombocytopenia and neutropenia, other hematology parameters, coagulation parameters, and body weight change to provide insights into potential mechanisms of action.
Compared with sham-treated controls, treated animals demonstrated a 40% to 55% survival benefit compared with controls, less severe clinical signs, reduced incidence of thrombocytopenia and/or neutropenia, earlier hematologic recovery, and reduced morbidity from bacterial infection.
These results were pivotal in obtaining Food and Drug Administration approval in January 2021 for RP's new indication as a single administration therapy to increase survival in adults and pediatric patients acutely exposed to myelosuppressive doses of radiation.
接触急性高剂量电离辐射的患者易发生剂量依赖性骨髓抑制，导致全血细胞减少症。罗米司亭（RP；Nplate）是一种重组血小板生成素受体激动剂蛋白，可促进祖细胞巨核细胞增殖和血小板生成，已被批准用于治疗慢性免疫性血小板减少症患者。我们的研究目的是通过在符合美国食品和药物管理局动物规则监管批准途径的恒河猴中进行一项经过良好控制、治疗隐匿、符合良好实验室规范的研究，评估单次给予 RP 联合或不联合培非格司亭（PF；Neulasta，粒细胞集落刺激因子）后的辐射后生存和血液学获益。
照射后的雄性和雌性恒河猴（每组 20 只，共 3 组：对照组、RP 组和 RP+PF 组）在第 1 天分别给予载体或 RP（5mg/kg，10mL/kg），同时或不给予 2 次培非格司亭（0.3mg/kg，0.03mL/kg，第 1 天和第 8 天）。全身照射（钴-60 伽马射线源 680cGy，50cGy/min）在 24±2 小时前进行，照射剂量针对对照组 60 天 70%的致死率。该研究将 60 天辐射后生存作为主要终点进行检测。次要终点包括血小板减少症和中性粒细胞减少症的发生率、严重程度和持续时间、其他血液学参数、凝血参数以及体重变化，以深入了解潜在的作用机制。
与假处理对照组相比，治疗组动物的存活率比对照组提高了 40%至 55%，临床症状较轻，血小板减少症和/或中性粒细胞减少症的发生率降低，血液学恢复较早，细菌感染的发病率降低。
这些结果对 2021 年 1 月获得美国食品和药物管理局批准 RP 作为一种新的适应症具有重要意义，即单次给药治疗急性接触骨髓抑制剂量辐射的成人和儿科患者，以提高生存率。
