支持BI 836880剂量探索的全面生物标志物与模型分析方法——一种VEGF/Ang-2抑制剂

Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor

Journal of Translational Medicine

影响因子:7.5

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

DOI: 10.1186/s12967-024-05612-x

摘要

BI 836880是一种人源化双特异性纳米抗体®，能够结合并阻断血管内皮生长因子（VEGF）和血管生成素-2（Ang-2）。本文提出了一种支持BI 836880剂量探索的全面生物标志物与模型方法。两项I期剂量递增研究（1336.1 [NCT02674152]，1336.6 [NCT02689505]）评估了BI 836880在确认的局部晚期或转移性实体瘤成人患者中的疗效，这些患者对标准治疗无反应或标准治疗效果不可靠。研究涉及两种剂量方案：每3周一次（q3w）或每周一次（qw），起始剂量为40 mg。在全面的生物标志物分析中，分析了可溶性药效动力学标志物（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），以评估外周血中的靶点结合情况。利用有限的I期数据建立了基于群体的药代动力学/药效动力学（PopPK/PD）模型，通过模拟支持剂量优化。为了验证药物在肿瘤中的活性，还采用了动态对比增强磁共振成像（DCE-MRI）。DCE-MRI结果显示，靶点在肿瘤中得到充分结合。游离VEGF-A在所有剂量下均被耗竭，而游离Ang-2剂量依赖性下降，从360 mg q3w开始大部分患者达到耗竭状态。尽管总VEGF-A水平随剂量增加而升高，并在360 mg q3w时达到饱和，总Ang-2水平也升高但未达到平台。血管生成生物标志物在≥360 mg q3w剂量下发生变化。PopPK/PD模型显示，剂量≥360 mg q3w能在大多数患者中实现>90%的游离Ang-2在稳态下的抑制。增加剂量至≥500 mg q3w，预计可使超过90%的患者达到此水平。这些多靶点结合标志物的全面分析支持720 mg q3w作为BI 836880的具有生物学意义的单药剂量方案。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.