BI 836880，VEGF/ANG-2抑制剂的综合生物标志物和建模方法支持剂量查找
Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor
影响因子:7.50000
分区:医学2区 Top / 医学：研究与实验2区
发表日期:2024 Oct 14
作者:
Sascha Keller, Ulrich Kunz, Ulrike Schmid, Jack Beusmans, Martin Büchert, Min He, Girish Jayadeva, Christophe Le Tourneau, Doreen Luedtke, Heiko G Niessen, Zohra Oum'hamed, Sina Pleiner, Xiaoning Wang, Ralph Graeser
摘要
BI 836880是一种人源化的双特异性纳米蛋白®，与血管内皮生长因子（VEGF）和Angiopoietin-2（ANG-2）结合并阻断血管内皮生长因子（VEGF）。 A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880.Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard治疗没有可靠的有效。研究了两个剂量时间表，分别为3周（Q3W）或每周一次（QW），剂量为40毫克。在一种全面的生物标记方法中，对可溶性药效学标记（免费和总血浆VEGF-A和ANG-2）以及循环血管生成因子（可溶性VEGF3，可溶性vegf3，可溶性TIE2和胎盘生长因子等）进行了分析，以评估Q3W剂量的外围血液中的目标参与目标。基于人群的药代动力学/药效学（POPPK/PD）模型是使用有限的I期数据集构建的，以通过模拟来支持剂量发现。为了证明肿瘤中的药物活性，应用了动态对比增强的磁共振成像（DCE-MRI）。DCE-MRI扫描支持肿瘤中的靶标参与。自由VEGF-A在所有剂量上都耗尽，而自由Ang-2依赖性剂量依赖性降低，大多数患者从360 mg Q3W开始耗尽。虽然总VEGF-A水平依赖剂量依赖性，达到360 mg Q3W的饱和度，但总的ANG-2水平增加，但没有平稳。血管生成生物标志物显示≥360mg Q3W的剂量变化。 POPPK/PD建模表明，在大多数患者中，稳定状态下稳定的剂量≥360mg Q3W导致抑制自由ANG-2> 90％。通过将剂量增加到≥500mg Q3W，> 90％的患者预计将达到这一水平。多个目标参与标记的全面分析支持BI 836880 720 mg Q3W作为生物学相关的单一疗法剂量时间表。NCT02674152和NCT02689505。
Abstract
BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880.Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied.DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level.The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule.NCT02674152 and NCT02689505.