First Worldwide Clinical Trial for Diabetic Macular Ischemia​ Treatment Achieves Primary Safety Endpoints

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The first ever clinical trial conducted to evaluate an experimental treatment for diabetic macular ischemia (DMI) showed positive findings for Boehringer Ingelheim’s novel humanized monoclonal anti-Sema3A antibody BI 764524.¹ In the Phase I/IIa HORNBILL trial (NCT04424290), investigators found that the intravitreal administration of single and multiple doses of the drug was well tolerated and achieved the primary safety endpoints, with early signs of potential efficacy, according to Boehringer Ingelheim.

“Vision loss associated with retinal conditions such as diabetic retinopathy (DR) 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, said in a press release. “We’re looking forward to start a Phase IIb study to further explore the safety and efficacy of BI 764524.”¹

DMI, a potential complication of diabetes mellitus, has been linked to risk factors such as poor glycemic control and high blood pressure. Understanding of the disease’s pathogenesis, progression, consequences, and treatment options have been limited to date.²

“Since this disease damages the retina, loss of vision is an inevitable consequence that can progressively worsen over time. Also, DMI has been implicated as a risk factor for retinal edema and progressive (DR),” wrote the authors of a study published by Cureus. “Until now, no defined treatment protocol has been devised. The only available treatments focus on the management of risk factors (hyperglycemia and hypertension). Still, many aspects of DMI remain poorly studied and understood.”²

The multipart trial evaluated the tolerability of BI 764524 in patients with DR with DMI who were previously administered panretinal photocoagulation. The trial was comprised of a nonrandomized single rising dose (SRD) portion (N=12) followed by a randomized multiple dosing (MD) portion (N=31).

In the open-label, SRD portion, 12 patients with a mean age of 61.8 years were administered intravitreal BI 764524 at doses of 0.5 mg (n=3), 1.0 mg (n=3), and 2.5 mg (n=6). The primary endpoint of this portion was the number of patients experiencing dose-limiting events (DLEs), with secondary endpoints that included the number of patients reporting drug-related adverse events (AEs) and any ocular AEs.

There were no DLEs reported in the SRD portion, while five ocular AEs in the study eye were reported by four patients, none of which were associated with BI 764524. The highest tested dose of the drug was deemed safe and was subsequently applied to the MD portion.

The masked, sham-controlled, MD portion randomly assigned 31 patients with a mean age of 59.5 years to three intravitreal doses of BI 764524 at a dose of 2.5 mg (n=21) or sham injection procedures (n=10) at four-week intervals of baseline, week four, and week eight, followed by 14 weeks of follow-up until week 22. This portion’s primary endpoint was the number of patients reporting drug-related AEs, with secondary endpoints that included the number of patients reporting ocular AEs, change from baseline in foveal avascular zone (FAZ) area, best corrected visual acuity (BCVA), and central retinal thickness (CRT).

Seven patients in this portion reported ocular AEs, with three patients administered BI 764524 reporting four AEs in the study eye, and four patients reporting six AEs for sham, one of which, vitreous floater, was deemed related to the study drug. No cases of intraocular inflammation or occlusive retinal vasculitis were reported.

Mean BCVA at baseline was 65.2 letters, mean FAZ area was 0.65 mm, and mean CRT was 252 mm. The study achieved the pre-specified criterion for early efficacy of FAZ area stabilization compared with sham at week 16. There were no relevant changes reported for the other secondary efficacy endpoints across the short trial.

According to the study investigators, these findings indicate that BI 764524 may have a positive effect on retinal non-perfusion and potentially stop capillary loss from progressing. As a result, investigators plan to start recruiting patients later this year for the Phase IIb CRIMSON trial, which will further evaluate the safety and efficacy of BI 764524 in patients with DR.

“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 (DR) from developing irreversible and vision-threatening complications, such as DMI,” principal and coordinating investigator Quan Dong Nguyen, MD, MSc, FARVO, FASRS, professor of Ophthalmology at the Byers Eye Institute, and professor of Medicine and of Pediatrics at Stanford School of Medicine, said in a press release. “Retinal non-perfusion is a key driver of vision loss in people living with diabetic retinopathy. However, until the HORNBILL study, retinal non-perfusion has not been explored as a potential treatment target.”¹

References

​​1. Boehringer Ingelheim shares positive results from the first study worldwide in diabetic macular ischemia​. News release. Boehringer Ingelheim. May 6, 2024. Accessed May 7, 2024. https://www.boehringer-ingelheim.com/science-innovation/human-health-innovation/positive-results-diabetic-macular-ischemia-treatment

2. Usman M. An Overview of Our Current Understanding of Diabetic Macular Ischemia (DMI). Cureus. 2018 Jul 30;10(7):e3064. doi: 10.7759/cureus.3064. PMID: 30280060; PMCID: PMC6166915.