Nguyen Quan Dong, Jhaveri Chirag, Habib Maged, Sepah Yasir J, Nassar Khaled, Krawczyk Bartlomiej, Simons Gudrun, Giani Andrea, Pearce Elizabeth, Gliem Martin, Ahmed Mohamed, Sivaprasad Sobha
Byers Eye Institute, Stanford University School of Medicine, Stanford, California.
Retina Consultants of Austin, Austin, Texas.
Ophthalmol Sci. 2025 Mar 28;5(5):100781. doi: 10.1016/j.xops.2025.100781. eCollection 2025 Sep-Oct.
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).
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.
Adults with DMI and stable diabetic retinopathy (DR) treated with pan-retinal photocoagulation and without center-involving diabetic macular edema.
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.
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).
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 mm in the BI 764524 group and +0.019 mm with sham. At week 22 (14 weeks after the final injection), the adjusted mean FAZ area change was -0.001 mm in the BI 764524 group and +0.010 mm with sham. No relevant BCVA and CST changes occurred.
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.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
报告玻璃体内注射抗信号素3A抗体用于糖尿病性黄斑缺血（DMI）患者的首次人体试验的安全性和早期药效学结果。
犀鸟研究（HORNBILL）是一项关于BI 764524的I/IIa期研究，包括非随机、开放标签、非对照、单剂量递增（SRD）部分以及盲法、随机、假手术对照、多剂量（MD）部分。
患有DMI且糖尿病视网膜病变（DR）稳定、接受过全视网膜光凝治疗且无累及黄斑中心的糖尿病性黄斑水肿的成年人。
在SRD部分，12名参与者接受了单次玻璃体内注射BI 764524，剂量分别为0.5毫克（n = 3）、1.0毫克（n = 3）或2.5毫克（n = 6）。在MD部分，31名参与者接受了3次玻璃体内注射BI 764524，剂量为2.5毫克（n = 21）或假手术（n = 10），每4周一次，随访至第22周。
SRD的主要终点是出现剂量限制事件的参与者数量；次要终点评估与药物相关的和眼部不良事件（AE）。MD的主要终点是出现与药物相关AE的参与者数量；次要终点包括黄斑无血管区（FAZ）面积、最佳矫正视力（BCVA）和中心子野厚度（CST）相对于基线的变化。
SRD部分未报告剂量限制事件或与药物相关的AE；MD部分选择了最高测试剂量（2.5毫克）。在MD部分，报告了2例研究者评估的与药物相关的AE（玻璃体飞蚊症和γ-谷氨酰转移酶升高）。未发生眼内炎症或闭塞性视网膜血管炎病例。在第12周（最后一次注射后4周），BI 764524组调整后的平均FAZ面积变化为-0.004平方毫米，假手术组为+0.019平方毫米。在第22周（最后一次注射后14周），BI 764524组调整后的平均FAZ面积变化为-0.001平方毫米，假手术组为+0.010平方毫米。未发生相关的BCVA和CST变化。
犀鸟研究达到了主要安全性终点；所有评估的BI 764524剂量耐受性良好。这些发现支持对BI
