Merck’s experimental eye drug remigromig has matched standard anti-VEGF therapy in a pivotal clinical trial for diabetic macular edema (DME), marking a potential breakthrough in the search for new treatments for a disease that threatens the vision of millions of people worldwide.
However, the one-year results from the Phase 2b/3 BRUNELLO study also revealed higher rates of proliferative diabetic retinopathy and treatment discontinuations among patients receiving remigromig than among those treated with ranibizumab, highlighting safety findings that warrant further investigation.
The study evaluated remigromig (MK-3000, formerly EYE103), an investigational antibody designed to activate the Wnt pathway, which plays a role in repairing and maintaining the blood-retinal barrier.
The trial met its primary endpoint, with both remigromig doses independently demonstrating non-inferiority to monthly ranibizumab in improving best-corrected visual acuity after one year.
Patients receiving the 0.5 mg dose of remigromig gained an average of 9.1 letters on a standardized vision chart, while those receiving the 0.8 mg dose gained 8.7 letters. Patients treated with ranibizumab gained 11.8 letters.
Although the numerical gains were higher with ranibizumab, the differences fell within the study’s prespecified non-inferiority margin and were not considered clinically meaningful. Neither remigromig dose demonstrated superiority over the established treatment on the secondary endpoints.
Merck described remigromig as the first biologic with a novel mechanism of action to demonstrate non-inferior visual acuity compared with anti-VEGF therapy in a pivotal DME trial.
The efficacy findings were accompanied by differences in adverse events that could influence the drug’s future development.
Proliferative diabetic retinopathy (PDR), an advanced form of diabetic eye disease involving abnormal blood vessel growth, was reported more frequently among patients receiving remigromig.
PDR-related adverse events occurred in 6.7% of patients receiving the 0.5 mg dose and 6.1% of those receiving the 0.8 mg dose, compared with 0.9% among patients treated with ranibizumab. The figures included new-onset PDR.
Treatment discontinuations due to adverse events were also higher in both remigromig groups, at 4.9% for the 0.5 mg dose and 4.5% for the 0.8 mg dose, versus 0.9% for ranibizumab.
Merck said additional analyses are underway to better understand the findings. The company noted that PDR cases were generally manageable with standard-of-care treatment and suggested the rates may reflect the natural progression of DME, given that remigromig targets repair and maintenance of the blood-retinal barrier rather than directly suppressing the growth of new blood vessels.
Despite advances in DME treatment, a substantial proportion of patients continue to experience persistent disease or inadequate responses to existing therapies.
“Although anti-VEGF therapies remain the foundation of treatment for diabetic macular edema, up to two thirds of patients fail to achieve clinically meaningful vision gains after one year, underscoring the need to explore new biological pathways,” said Donald J. D’Amico, chair of Ophthalmology at Weill Cornell Medicine, Ophthalmologist-in-Chief, New York-Presbyterian Hospital and presenting author of the BRUNELLO study.
“These findings ‒ which demonstrate for the first time that a biologic targeting the Wnt pathway can achieve visual acuity comparable to an established anti-VEGF therapy ‒ support continued evaluation of this novel approach as we look forward to additional Phase 3 results from the BAROLO study.”
DME occurs when damaged retinal blood vessels leak fluid into the macula, the central part of the retina responsible for detailed vision. The resulting swelling can impair reading, driving and other everyday activities.
An estimated 1.6 million people in the United States live with DME. Merck says up to 40% of patients continue to have disease activity after six months of treatment, either because they do not respond or respond only partially.
“Despite important advances in care, up to 40% of patients with diabetic macular edema have persistent disease activity after six months of treatment, meaning that they do not respond or only partially respond to therapy, underscoring the need for new therapeutic approaches,” said David Guyer, founder, chief executive officer and president of EyeBio, a wholly owned subsidiary of Merck.
“The BRUNELLO study provides important evidence that activating the Wnt pathway, which is involved in the repair and maintenance of the blood-retinal barrier, may offer a potential new way to help patients with DME and expand treatment options for retinal specialists and their patients.”
Unlike conventional anti-VEGF treatments, which target vascular endothelial growth factor to limit abnormal blood vessel growth and leakage, remigromig is designed to activate the Wnt pathway to support the integrity of the blood-retinal barrier.
The approach could offer an alternative biological strategy for patients whose disease remains difficult to control with current treatments. However, the BRUNELLO results do not establish that remigromig is superior to existing therapy, and its safety profile requires further assessment.
