“We may now have a new way to treat DME by activating the Wnt pathway,” Donald J. D’Amico, MD, told an audience of retina specialists Saturday, while presenting positive results from the phase 2b/3 BRUNELLO trial of Merck’s remigromig (MK-3000, formerly Restoret/EYE103). During Retina Subspecialty Day at the American Academy of Ophthalmology 2026 meeting in New Orleans, Dr. D'Amico, chair of ophthalmology at Weill Cornell Medicine, reported that both remigromig doses studied met the trial’s primary endpoint, demonstrating noninferior visual acuity gains compared with monthly ranibizumab in patients with DME. However, proliferative diabetic retinopathy (PDR)–related adverse events occurred more frequently among patients receiving remigromig, he said.
Remigromig is a trispecific, tetravalent antibody designed to activate the Wnt pathway by engaging FZD4 and 2 distinct epitopes of LRP5. Activation of this pathway is intended to restore blood-retinal barrier integrity by promoting endothelial tight junction formation. Dr. D’Amico noted that Wnt signaling is “orthogonal to VEGF,” meaning the 2 pathways operate through distinct molecular mechanisms.
The randomized, double-masked BRUNELLO trial enrolled 984 adults with DME who were assigned to receive monthly intravitreal injections of remigromig 0.5 mg, remigromig 0.8 mg, or ranibizumab 0.5 mg. Approximately one-quarter of participants had previously received anti-VEGF therapy. The primary endpoint was noninferiority in mean change from baseline in best-corrected visual acuity (BCVA) at week 52. The 2-year study will evaluate personalized treatment intervals during its second year.
Both remigromig doses met the primary endpoint. At 1 year, mean BCVA gains were 9.1 ETDRS letters with remigromig 0.5 mg (multiplicity-adjusted P=.0129) and 8.7 letters with remigromig 0.8 mg (P=.0222), compared with 11.8 letters with ranibizumab. The differences were within the prespecified noninferiority margin. However, neither remigromig dose demonstrated superiority to ranibizumab on visual acuity or central subfield thickness, the trial’s key secondary endpoints.
Dr. D'Amico also presented case examples of optical coherence tomography (OCT) images illustrating reductions in retinal fluid among patients receiving either remigromig dose, with anatomic improvements maintained through week 52. The overall adverse-event profiles were generally similar across treatment groups, with intraocular inflammation reported in 1.8% and 1.5% of patients receiving remigromig 0.5 mg and 0.8 mg, respectively, compared with 1.8% receiving ranibizumab. No retinal vasculitis was reported.
However, adverse events indicative of PDR occurred in 6.7% and 6.1% of patients receiving the 2 remigromig doses, respectively, compared with 0.9% of patients receiving ranibizumab. Adverse events led to treatment discontinuation in 4.9%, 4.5%, and 0.9% of patients, respectively. Dr. D’Amico said that the higher rates of PDR-related events might reflect less protection against neovascular progression with remigromig than with ranibizumab, given the therapies' different mechanisms of action. He noted that PDR cases were manageable with standard-of-care treatment and that 85% of affected patients gained vision at 1 year.
Dr. D’Amico characterized remigromig as the first biologic with a novel mechanism of action to demonstrate noninferior visual outcomes to anti-VEGF therapy in DME. He said confirmation in the companion pivotal BAROLO trial would support further development of Wnt pathway activation as a treatment approach for the disease.
Following the presentation, Merck issued a press release saying that it plans to discuss the BRUNELLO results with regulatory authorities. Remigromig is also being evaluated in a phase 2 proof-of-concept study, SUPER TUSCAN, in patients with neovascular age-related macular degeneration and retinal vein occlusion. RP