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

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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Abstract

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.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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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

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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