Petrov Aleksandr, Makarenko Igor, Belova Bella, Melikyan Anait, Saparova Valeria, Peskov Kirill, Kudryashova Nataliya, Kovalik Vladislav, Gefen Maria, Khokhlov Alexandr, Drai Roman
R&D Center, GEROPHARM, Saint-Petersburg, Russia.
Federal State Budgetary Scientific Institution Moscow State University of Medicine and Dentistry named after A. I. Evdokimov, Moscow, Russia.
Clin Pharmacol Drug Dev. 2025 Feb;14(2):116-126. doi: 10.1002/cpdd.1494. Epub 2024 Dec 19.
During biosimilar drug development, conducting a clinical trial of biosimilar efficacy in patients may become necessary in the presence of residual uncertainty regarding the biosimilarity of the drugs. In the development of the biosimilar romiplostim GP40141, we aimed to use a model-based in silico clinical trial (ISCT) approach to optimize the planned biosimilar efficacy trial in patients with immune thrombocytopenia. The population pharmacokinetic/pharmacodynamic model for healthy volunteers was modified and validated to describe platelet dynamics in patients with immune thrombocytopenia. ISCTs were then conducted using the modified model for various expected scenarios of biosimilar efficacy trials. Statistical analysis of the simulation results was subsequently used to confirm the appropriateness of the chosen design for evaluating the planned efficacy end points. Since the planned trial includes both patients naïve to therapy with thrombopoietin receptor agonists and nonnaïve patients, various expected ratios of naïve to nonnaïve patients (1:1, 1:2, 1:3) and the percentage of nonnaïve patients who previously received eltrombopag (0% or 30%) were assessed across 200 ISCTs performed for each scenario. The obtained estimates of empirical power for the equivalence test of platelet response/durable platelet response by the 10th/26th week between the test and reference groups were not less than 94%, regardless of the scenario. Differences in power between the 10- and 26-week end points did not exceed 4%. The analysis of ISCT results allowed for an effective reduction of uncertainty in the biosimilar development of GP40141, demonstrating the appropriateness of using the 10-week efficacy end point as the primary one.
在生物类似药研发过程中，如果药物的生物相似性仍存在不确定性，那么对患者进行生物类似药疗效的临床试验可能就变得必要。在生物类似药罗米司亭GP40141的研发中，我们旨在采用基于模型的计算机模拟临床试验（ISCT）方法，来优化针对免疫性血小板减少症患者计划开展的生物类似药疗效试验。对健康志愿者的群体药代动力学/药效学模型进行了修改和验证，以描述免疫性血小板减少症患者的血小板动态变化。然后使用修改后的模型针对生物类似药疗效试验的各种预期场景进行计算机模拟临床试验。随后对模拟结果进行统计分析，以确认所选择的设计对于评估计划的疗效终点是否合适。由于计划开展的试验纳入了既往未接受过血小板生成素受体激动剂治疗的患者和非初治患者，因此在针对每种场景进行的200次计算机模拟临床试验中，评估了初治患者与非初治患者的各种预期比例（1:1、1:2、1:3）以及既往接受过艾曲泊帕治疗的非初治患者的百分比（0%或30%）。无论在哪种场景下，试验组与参照组之间在第10周/第26周时血小板反应/持久血小板反应等效性检验的经验性检验效能估计值均不低于94%。第10周和第26周终点之间的效能差异不超过4%。对计算机模拟临床试验结果的分析有效降低了GP40141生物类似药研发中的不确定性，证明了将第10周疗效终点作为主要终点的合理性。
