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 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.

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 DISCLOSURES

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