HORNBILL: BI 764524治疗糖尿病黄斑缺血的安全性、耐受性和早期药效学的首次人体I/IIa期研究

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science Pub Date : 2025-03-28 DOI:10.1016/j.xops.2025.100781

Quan Dong Nguyen MD, MSc , Chirag Jhaveri MD , Maged Habib MD , Yasir J. Sepah MBBS , Khaled Nassar MD, PhD , Bartlomiej Krawczyk PhD , Gudrun Simons PhD , Andrea Giani MD , Elizabeth Pearce PhD , Martin Gliem MD , Mohamed Ahmed MBBCh, MD , Sobha Sivaprasad DM , HORNBILL Study Group

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引用次数: 0

摘要

目的报告玻璃体内抗信号蛋白3A抗体治疗糖尿病性黄斑缺血（DMI）患者的安全性和早期药效学结果。DesignHORNBILL是BI 764524的I/IIa期研究，由非随机、开放标签、非控制、单次上升剂量（SRD）和屏蔽、随机、假控制、多剂量（MD）部分组成。参与者：患有DMI和稳定型糖尿病视网膜病变（DR）的成年人接受全视网膜光凝治疗，无中心累及的糖尿病黄斑水肿。方法12名受试者在SRD部分接受单次IVT剂量BI 764524 0.5 mg （n = 3）、1.0 mg （n = 3）或2.5 mg （n = 6）。31名参与者每隔4周接受3次IVT剂量的BI 764524 2.5 mg （n = 21）或假手术（n = 10），并在MD部分随访至第22周。主要结局指标SRD的主要终点是发生剂量限制事件的受试者数量；次要终点评估药物相关和眼部不良事件（ae）。主要MD终点是发生药物相关ae的受试者数量；次要终点包括中央凹无血管区（FAZ）面积、最佳矫正视力（BCVA）和中央亚场厚度（CST）与基线相比的变化。结果SRD未报告剂量限制事件或药物相关不良事件；MD部分选用最高试验剂量（2.5 mg）。在MD部分，报告了2例研究者评估的药物相关ae（玻璃体飞蚊和γ -谷氨酰转移酶升高）。无眼内炎症或视网膜血管闭塞性炎病例发生。第12周（末次注射后4周），BI 764524组调整后平均FAZ面积变化为- 0.004 mm2， sham组为+0.019 mm2。第22周（末次注射后14周），BI 764524组调整后平均FAZ面积变化为- 0.001 mm2， sham组为+0.010 mm2。未发生相关BCVA和CST变化。结论shornbill满足主要安全指标；所有评估的BI 764524剂量耐受性良好。这些发现支持BI 764524在DR和视网膜非灌注患者中的进一步研究。财务披露专有或商业披露可在本文末尾的脚注和披露中找到。

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HORNBILL: A First-in-Human Phase I/IIa Study of the Safety, Tolerability, and Early Pharmacodynamics of BI 764524 for Diabetic Macular Ischemia

Objective

To report safety and early pharmacodynamic results from a first-in-human trial of intravitreal (IVT) anti-semaphorin 3A antibody in participants with diabetic macular ischemia (DMI).

Design

HORNBILL, a phase I/IIa study of BI 764524, comprised a nonrandomized, open-label, uncontrolled, single-rising-dose (SRD) and masked, randomized, sham-controlled, multiple-dose (MD) parts.

Participants

Adults with DMI and stable diabetic retinopathy (DR) treated with pan-retinal photocoagulation and without center-involving diabetic macular edema.

Methods

Twelve participants received single IVT doses of BI 764524 0.5 mg (n = 3), 1.0 mg (n = 3), or 2.5 mg (n = 6) in the SRD part. Thirty-one participants received 3 IVT doses of BI 764524 2.5 mg (n = 21) or sham procedures (n = 10) at 4-week intervals and were followed to week 22 in the MD part.

Main Outcome Measures

The primary SRD end point was the number of participants with dose-limiting events; secondary end points assessed drug-related and ocular adverse events (AEs). The primary MD end point was the number of participants with drug-related AEs; secondary end points included changes from baseline in foveal avascular zone (FAZ) area, best-corrected visual acuity (BCVA), and central subfield thickness (CST).

Results

No dose-limiting events or drug-related AEs were reported with SRD; the highest tested dose (2.5 mg) was selected for the MD part. In the MD part, 2 investigator-assessed drug-related AEs (vitreous floaters and increased gamma-glutamyl transferase) were reported. No intraocular inflammation or occlusive retinal vasculitis cases occurred. At week 12 (4 weeks after the final injection), the adjusted mean FAZ area change was −0.004 mm² in the BI 764524 group and +0.019 mm² with sham. At week 22 (14 weeks after the final injection), the adjusted mean FAZ area change was −0.001 mm² in the BI 764524 group and +0.010 mm² with sham. No relevant BCVA and CST changes occurred.

Conclusions

HORNBILL met the primary safety end points; all evaluated BI 764524 doses were well tolerated. These findings support further investigation of BI 764524 in participants with DR and retinal nonperfusion.