HORNBILL: BI 764524 Meets Safety Endpoints in Diabetic Macular Ischemia

Quan Dong Nguyen, MD, Msc

Credit: Stanford University

Positive results from the phase 1/2a HORNBILL study found BI 764524 was well-tolerated after intravitreal administration of single and multiple doses in patients with diabetic macular ischemia (DMI), achieving its primary safety endpoints.¹

Presented at the Association for Research in Vision and Ophthalmology (ARVO) 2024 Meeting, HORNBILL, the first-ever study investigating a potential treatment for DMI, also identified early signs of potential efficacy with BI 764524 treatment.

“The results from the HORNBILL study are really encouraging. They suggest there may be a pathway for earlier intervention that could decrease the risk of, and maybe even prevent, people with diabetic retinopathy from developing irreversible and vision-threatening complications, such as DMI,” principal trial investigator Quan Dong Nguyen, MD, Msc, a professor of ophthalmology at the Byers Eye Institute, said in a statement.²

A frequent complication of diabetic retinopathy, DMI can lead to slowly progressing, irreversible vision loss.³ The complication develops when the light-sensitive tissue of the central retina does not receive adequate blood supply over a long duration. No currently approved treatment exists for DMI, suggesting an unmet need for a serious condition.^`

Current standard of care treatment for advanced DR can include intravitreal anti-vascular endothelial growth factor (VEGF) or invasive laser treatment. Despite the availability of effective treatments, those with DR often progress to later disease stages.³ In HORNBILL, investigators examined BI 764524, a humanized monoclonal anti-Sema3A antibody.¹

The treatment uses a novel mechanism of action by inhibiting the Sema3A pathway to re-vascularize ischemic areas and override the limitations of anti-VEGF and laser treatments, suggesting the potential to address retinal non-perfusion in retinal diseases.

HORNBILL included two parts, including a single-rising dose (SRD; n = 12) and a multiple-dose (MD; n = 32) phase, with BI 764524 administered via intravitreal injection. In the single-rising phase, patients received 0.5 (n = 3), 1.0 (n = 3), or 2.5 mg (n = 6) doses of BI 764524.

For the SRD phase, the primary endpoint was the number of dose-limiting events (DLEs); Secondary endpoints included the number of patients with drug-related adverse events (AEs) and any ocular AEs.

Upon analysis, patients, with a mean age of 61.8 years, reported no DLEs in the SRD phase. Investigators identified 5 ocular AEs in four patients in the study eye, but none were determined to be related to the study drug. The highest tested dose (2.5 mg) was considered safe and applied in the multiple-dosing phase.

In the randomized, masked, sham-controlled, MD phase, patients received 3 intravitreal doses of BI 764524 2.5 mg (n = 21) or sham injection procedures (n = 10) at 4-week intervals to week 8, with follow-up taking place until the end of the study at week 22.

The primary endpoint was the number of patients with drug-related AEs, with secondary endpoints consisting of the number of patients with ocular AEs, change from baseline in foveal avascular zone (FAZ) area, best-corrected visual acuity (BCVA), and central retinal thickness (CRT).

In the MD phase, 7 patients, with a mean age of 59.5 years, experienced ocular AEs, including four AEs in the BI 764524 group and six AEs in the sham group. A single event (vitreous floater) was reported as related to the study drug.

Safety data also demonstrated one systemic AE, an increase determined to be related to the study drug by the investigator. Notably, investigators identified no cases of intraocular inflammation or occlusive retinal vasculitis.

At baseline, the mean BCVA was 65.2 letters, the mean FAZ area was 0.65 mm, and the mean CRT was 252 mm. Upon analysis, HORNBILL met its pre-specified criterion for early efficacy of FAZ area stabilization versus sham at week 16 (P < .20). Over the trial period, other secondary efficacy endpoints exhibited no notable change.

Boehringer Ingelheim has indicated a phase IIb trial, CRIMSON, will begin recruiting later in 2024 to assess further the safety and efficacy of BI 764524 in patients with DR.²

“Vision loss associated with retinal conditions such as diabetic retinopathy and DMI has a devastating impact on quality of life. Today’s results are an important step towards achieving our aspiration of developing precision therapies delivering the right treatment for the right patient at the right time to prevent vision loss before irreversible damage occurs,” Ulrike Graefe-Mody, PhD, head of retinal health at Boehringer Ingelheim, added in a statement.²

References

1. _{Nguyen QD, Jhaveri C, Habib MS, Pearce E, Nassar K, Krawczyk B, Giliem M, Sivaprasad S. Outcomes of the HORNBILL study: a Phase I/IIa trial investigating BI 764524 in patients with diabetic macular ischemia. Paper presented at the Association for Research in Vision and Ophthalmology (ARVO) 2024 Meeting, May 5–9, 2024.}
2. _{Boehringer Ingelheim. Boehringer Ingelheim shares positive results from the first study worldwide in diabetic macular ischemia. GlobeNewswire News Room. May 6, 2024. Accessed May 6, 2024. https://www.globenewswire.com/news-release/2024/05/06/2875619/0/en/Boehringer-Ingelheim-shares-positive-results-from-the-first-study-worldwide-in-diabetic-macular-ischemia.html.}
3. _{Sim DA, Keane PA, Zarranz-Ventura J, et al. The effects of macular ischemia on visual acuity in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2013;54(3):2353-2360. Published 2013 Mar 28. doi:10.1167/iovs.12-11103}