Merck’s BRUNELLO trial found remigromig non-inferior to ranibizumab in DME, but higher PDR-related adverse events raise important safety questions.
Written By: Mayuresh Salvi, PharmD
Reviewed By: Pharmacally Editorial Team
Remigromig (MK-3000, formerly EYE103), an investigational tetravalent, tri-specific antibody designed to activate the Wingless-related integration site (Wnt) pathway, met its primary non-inferiority endpoint against ranibizumab 0.5 mg at one year in the pivotal Phase 2b/3 BRUNELLO trial (NCT06571045) in adults with diabetic macular edema (DME). However, Merck reported higher rates of proliferative diabetic retinopathy (PDR)-related adverse events and discontinuations due to adverse events with remigromig. The results were presented at the American Academy of Ophthalmology (AAO) 2026 Annual Meeting on October 10.
Study Design and Efficacy
BRUNELLO randomized 984 participants in a 1:1:1 ratio to remigromig 0.5 mg, remigromig 0.8 mg, or ranibizumab 0.5 mg. All treatments were administered by intravitreal injection every four weeks during the first year. In year two, treatment frequency will follow a personalized treatment interval algorithm.
The primary endpoint was mean change from baseline in best-corrected visual acuity (BCVA) at week 52, measured using standardized Early Treatment Diabetic Retinopathy Study (ETDRS) testing. Key secondary endpoints assessed superiority over ranibizumab for BCVA and central subfield thickness (CST) changes.
At week 52, mean BCVA gains were +9.1 letters with remigromig 0.5 mg (95% CI, 8.1–10.1; multiplicity-adjusted p=0.0129), +8.7 letters with remigromig 0.8 mg (95% CI, 7.7–9.8; p=0.0222), and +11.8 letters with ranibizumab (95% CI, 10.7–12.8).
Both remigromig doses met the prespecified non-inferiority endpoint. Nevertheless, the numerical gains favoured ranibizumab by 2.7 and 3.1 letters, respectively. Non-inferiority does not establish equivalent efficacy or superiority, and no secondary endpoint demonstrated superiority over ranibizumab. Merck did not disclose the numerical non-inferiority margin, limiting independent assessment of this component of the analysis.
PDR-Related Events Raise Safety Concerns
PDR-related adverse events occurred in 6.7% of patients receiving remigromig 0.5 mg and 6.1% receiving 0.8 mg, compared with 0.9% receiving ranibizumab. Discontinuations due to adverse events were 4.9%, 4.5% and 0.9%, respectively.
The PDR-related category included specified adverse-event terms covering PDR, vitreous haemorrhage, iris and retinal neovascularization, neovascular glaucoma, and neovascularization. These percentages therefore represent a composite category, not confirmed PDR incidence alone. Merck’s earlier topline announcement also identified higher rates of vitreous haemorrhage with remigromig.
The company described both doses as generally well tolerated and stated that PDR cases were generally manageable with standard-of-care treatment. However, the announcement did not provide absolute event counts, individual event breakdowns, severity distributions, event timing or baseline retinopathy severity by treatment arm.
Clinical Evidence From BRUNELLO
The central BRUNELLO finding is the combination of non-inferior visual-acuity outcomes and higher PDR-related event rates with remigromig. This imbalance warrants further investigation, particularly because remigromig activates the Wnt pathway to support blood-retinal barrier repair and maintenance, whereas ranibizumab inhibits VEGF-mediated signalling.
Merck suggested that the events might reflect natural disease progression rather than a treatment effect. However, the available data cannot establish the cause, and the difference in mechanisms alone does not demonstrate that Wnt pathway activation contributed to the observed events.
The absence of detailed safety data limits assessment of the clinical significance of the imbalance. Detailed CST results and second-year findings were also not reported in the announcement.
Safety Assessment and Future Clinical Evidence
Merck plans to discuss the results with regulatory authorities. The ongoing pivotal Phase 2b/3 BAROLO study (NCT06957080) will provide additional evidence in DME, while the Phase 2 SUPER TUSCAN study (NCT07205887) evaluates remigromig in neovascular age-related macular degeneration and retinal vein occlusion.
Further analyses must clarify the PDR-related safety signal, establish the clinical relevance of the visual-acuity findings and determine whether personalized treatment intervals offer a practical advantage. For now, BRUNELLO supports continued investigation of remigromig but does not establish superiority over ranibizumab or demonstrate a benefit from less frequent dosing.
References
Merck & Co., Inc. Merck Presents One-Year Results from the Pivotal Phase 2b/3 BRUNELLO Study Evaluating Remigromig, a Tri-specific Agonist of the Wingless-related Integration Site (Wnt) Pathway, in Adults with Diabetic Macular Edema at AAO 2026. October 10, 2026
A Study to Evaluate the Efficacy and Safety of 2 Doses of EYE103 Compared with Ranibizumab (0.5 mg) in Participants with DME (BRUNELLO), ClinicalTrials.gov ID NCT06571045
About the Writer
Mayuresh Sunil Salvi (Linkedin) is a PharmD professional and healthcare writer with a strong interest in pharmacovigilance, drug safety, and emerging medical research. He is passionate about exploring new drug discoveries, clinical research, and advances in evidence-based medicine. His interests also include ward rounds, prescription audits, and treatment analysis to support rational pharmacotherapy and improved patient care.