Remigromig noninferior to ranibizumab in phase 2b/3 BRUNELLO DME trial

What did the BRUNELLO trial show for remigromig in diabetic macular edema?

Both doses of remigromig (MK-3000, formerly EYE103; Merck) met the primary end point of the pivotal phase 2b/3 BRUNELLO trial in adults with diabetic macular edema (DME), Merck announced September 24, 2026.¹ At week 52, the 0.5-mg and 0.8-mg doses each independently demonstrated noninferiority to 0.5-mg ranibizumab for mean change from baseline in best-corrected visual acuity (BCVA).¹

Remigromig is an investigational tetravalent, tri-specific antibody designed to activate the Wingless-related integration site (Wnt) pathway, which is involved in repair and maintenance of the blood-retinal barrier. BRUNELLO is the first of two phase 2b/3 trials of the agent in DME.¹ Merck and EyeBio, now a wholly owned Merck subsidiary, announced the trial's initiation in 2024 on the basis of results from the open-label phase 1/2 AMARONE study, when the agent was referred to as Restoret.²

BRUNELLO (NCT06571045) is a randomized, double-masked, multicenter trial comparing two dose levels of intravitreal remigromig with active control ranibizumab (Lucentis) in adults with DME.^1,3 The trial enrolled 984 participants, who were randomized 1:1:1 to 0.5 mg remigromig, 0.8 mg remigromig, or 0.5 mg ranibizumab every four weeks for the first year. In year 2, treatment frequency will shift according to a personalized treatment interval algorithm.¹

Eligible participants were adults 18 years or older with type 1 or type 2 diabetes, a hemoglobin A1c of 12% or less, and a decrease in vision in the study eye attributed primarily to DME.³ The primary end point is mean change in BCVA from baseline to week 52 in the study eye, measured with standardized Early Treatment Diabetic Retinopathy Study (ETDRS) testing.¹

Merck did not report mean letter gains, between-group differences, the noninferiority margin, or P values in the topline announcement.¹ Donald J. D'Amico, MD, chair of ophthalmology at Weill Cornell Medicine, will present the year 1 results at the American Academy of Ophthalmology (AAO) 2026 Annual Meeting in New Orleans on October 10.^1,4 Merck also plans to discuss the findings with regulatory authorities.¹

Remigromig safety profile and adverse events in BRUNELLO

According to Merck, both remigromig doses were generally well tolerated. However, higher rates of proliferative diabetic retinopathy (PDR), vitreous hemorrhage, and treatment discontinuations due to adverse events were observed in the remigromig arms compared with ranibizumab. The company stated further analyses to characterize these findings are underway.¹

The topline announcement did not include event counts or percentages by treatment arm. It also did not report rates of intraocular inflammation, endophthalmitis, retinal detachment, or intraocular pressure elevation. Secondary end point data, including anatomic outcomes, were likewise not disclosed.¹

"Despite available therapies, up to 40% of patients with diabetic macular edema do not fully respond and remain at risk of continued vision loss," said David Guyer, MD, founder, chief executive officer, and president of EyeBio, in the announcement.^1,2

Dean Y. Li, president of Merck Research Laboratories, described remigromig as a potential first novel mechanism of action for retinal vascular diseases in more than two decades.¹ A second pivotal phase 2b/3 trial, BAROLO (NCT06957080), is ongoing in patients with DME.¹ Remigromig is also under evaluation in the phase 2 SUPER TUSCAN proof-of-concept study (NCT07205887) in patients with neovascular age-related macular degeneration and macular edema secondary to retinal vein occlusion.¹

Merck is separately developing MK-8748 (Tiespectus; EYE201), a bispecific antibody designed to activate the Tie2 pathway and inhibit VEGF.¹ The agent is in two pivotal phase 2b/3 trials for neovascular age-related macular degeneration, TORRONTES (NCT07496567) and MALBEC (NCT07440225), and two pivotal phase 3 trials for DME, SANGIOVESE (NCT07705555) and SYRAH (NCT07705607).¹

References
1. Merck. Merck's remigromig, a tri-specific agonist of the Wingless-related integration site (Wnt) pathway, met primary endpoint in the pivotal phase 2b/3 BRUNELLO study of adults with diabetic macular edema. Published September 24, 2026. Accessed September 24, 2026. https://www.merck.com/news/mercks-remigromig-a-tri-specific-agonist-of-the-wingless-related-integration-site-wnt-pathway-met-primary-endpoint-in-the-pivotal-phase-2b-3-brunello-study-of-adults-with-diabetic-macular/
2. Harp MD. Merck and EyeBio announce initiation of phase 2b/3 BRUNELLO trial evaluating MK-3000 for treatment of diabetic macular edema. Ophthalmology Times. September 5, 2024. Accessed September 24, 2026. https://www.ophthalmologytimes.com/view/merck-and-eyebio-announce-initiation-of-phase-2b-3-brunello-trial-evaluating-mk-3000-for-treatment-of-diabetic-macular-edema
3. 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 identifier: NCT06571045. Accessed September 24, 2026. https://clinicaltrials.gov/study/NCT06571045
4. Donald J. D'Amico, MD. Weill Cornell Medicine. Accessed September 24, 2026. https://weillcornell.org/djdamico