全面的生物标志物和建模方法，支持 BI 836880（一种 VEGF/Ang-2 抑制剂）的剂量发现。
Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor.
机构信息
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Metrum Research Group, Tariffville, CT, USA.
出版信息
J Transl Med. 2024 Oct 14;22(1):934. doi: 10.1186/s12967-024-05612-x.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule.
TRIAL REGISTRATION
NCT02674152 and NCT02689505.
背景
BI 836880 是一种人源化的双特异性纳米抗体®，可与血管内皮生长因子（VEGF）和血管生成素-2（Ang-2）结合并阻断其功能。本文介绍了一种全面的生物标志物和建模方法，为 BI 836880 的剂量选择提供了支持。
方法
两项 I 期剂量递增研究（1336.1[NCT02674152]，1336.6[NCT02689505]）评估了 BI 836880 在局部晚期或转移性实体瘤成人患者中的应用，这些患者对标准治疗无反应或标准治疗不可靠有效。研究了两种给药方案，3 周（q3w）或每周一次（qw），起始剂量为 40mg。在全面的生物标志物方法中，分析了可溶的药效动力学标志物（游离和总血浆 VEGF-A 和 Ang-2）以及循环血管生成因子（可溶性 VEGF3、可溶性 Tie2 和胎盘生长因子等），以评估 q3w 剂量时外周血中的靶标结合情况。使用有限的 I 期数据集构建基于人群的药代动力学/药效学（PopPK/PD）模型，以模拟支持剂量选择。为了证明肿瘤中的药物活性，应用了动态对比增强磁共振成像（DCE-MRI）。
结果
DCE-MRI 扫描支持肿瘤中的靶标结合。所有剂量下游离 VEGF-A 均被耗尽，而游离 Ang-2 则呈剂量依赖性下降，从 360mg q3w 起，大多数患者的 Ang-2 下降至耗尽水平。虽然总 VEGF-A 水平呈剂量依赖性增加，并在 360mg q3w 时达到饱和，但总 Ang-2 水平增加，但未达到平台期。血管生成生物标志物显示从 360mg q3w 及以上剂量开始发生变化。PopPK/PD 模型表明，360mg q3w 及以上剂量可使大多数患者在稳态时游离 Ang-2 抑制率>90%。增加剂量至 500mg q3w 及以上，预计>90%的患者将达到这一水平。
结论
多种靶标结合标志物的综合分析支持 BI 836880 720mg q3w 作为一种具有生物学意义的单药治疗剂量方案。
试验注册
NCT02674152 和 NCT02689505。
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