In this Evidence Based Retina episode, Rishi P. Singh, MD, FASRS, sits down with Donald J. D'Amico, MD, to discuss 1-year results from BRUNELLO, the pivotal trial comparing the Wnt pathway agonist Remigromig with ranibizumab in diabetic macular edema (DME).
Dr. D'Amico is professor and chair of the Israel Englander Department of Ophthalmology at Weill Cornell Medical College and ophthalmologist-in-chief at NewYork-Presbyterian Hospital, and he presented the BRUNELLO data at the American Academy of Ophthalmology 2026 annual meeting.1
Remigromig fast facts
- Among adults with diabetes, the global prevalence of clinically significant macular edema is 4.07%, corresponding to an estimated 18.83 million people in 2020 and projected to reach 28.61 million by 2045.2
- An estimated 40% of eyes with DME show no response or a suboptimal response to anti-vascular endothelial growth factor (VEGF) therapy.3
- Norrin, the retina's native ligand for frizzled class receptor 4 (FZD4), forms and maintains the blood-retinal barrier (BRB) via an FZD4/LRP5/TSPAN12 receptor complex. A tetravalent FZD4-LRP5 agonist antibody reversed VEGF-induced endothelial permeability in vitro and restored retinal barrier function in Tspan12-knockout mice.4
- In adult mice whose barrier failed to develop, the same agonist partially induced a new BRB without stimulating angiogenesis.5
- Remigromig (MK-3000, formerly Restoret/EYE103; Merck) is a trispecific, tetravalent antibody that activates the Wnt pathway by binding FZD4 and two distinct LRP5 epitopes, promoting endothelial tight-junction formation.6
- In the phase 1b/2a AMARONE trial, Remigromig monotherapy in 26 patients with treatment-naive DME produced a mean best-corrected visual acuity (BCVA) gain of 11.2 letters and a mean retinal thickness reduction of 143 µm at week 12, with no drug-related adverse events or intraocular inflammation.7
What BRUNELLO shows
BRUNELLO (NCT06571045) is the first pivotal trial in which a biologic with a novel, non-anti-VEGF mechanism demonstrated noninferior visual outcomes versus anti-VEGF therapy. This randomized, double-masked, phase 2b/3 trial enrolled 984 adults with type 1 or type 2 diabetes, hemoglobin A1c of 12% or lower, an ETDRS letter score of 75 to 24, and central subfield thickness (CST) of 325 µm or greater.1
Patients were randomized 1:1:1 to receive monthly intravitreal Remigromig 0.5 mg, Remigromig 0.8 mg, or ranibizumab 0.5 mg through year 1, followed by personalized treatment intervals in year 2.1 About one-quarter had received prior anti-VEGF therapy.6 The primary endpoint was noninferiority in mean BCVA change at week 52; key secondary endpoints tested superiority to ranibizumab for BCVA and CST.1
Efficacy at week 52
Mean BCVA gains from baseline were:1,6
- Remigromig 0.5 mg: 9.1 letters (multiplicity-adjusted P=0.0129)
- Remigromig 0.8 mg: 8.7 letters (P=0.0222)
- Ranibizumab 0.5 mg: 11.8 letters
Both doses met the prespecified noninferiority margin, but neither was superior to ranibizumab for BCVA or CST.6 Dr. D'Amico characterized the between-arm differences as not clinically meaningful, and OCT case examples showed fluid reductions maintained through week 52.6,8
"But nevertheless, statistically, it met its endpoint. This is the first time a non-VEGF agent has demonstrated comparable efficacy in diabetic macular edema.”—Donald J. D'Amico, MD
Safety
Adverse event (AE) rates for Remigromig 0.5 mg, Remigromig 0.8 mg, and ranibizumab, respectively, were:6
- Intraocular inflammation: 1.8%, 1.5%, and 1.8%, with no retinal vasculitis
- Proliferative diabetic retinopathy (PDR)–related AEs: 6.7%, 6.1%, and 0.9%
- Discontinuation due to AEs: 4.9%, 4.5%, and 0.9%
Dr. D'Amico explained that the PDR imbalance may reflect the mechanistic distinction between Remigromig and anti-VEGF therapy: Wnt activation targets BRB integrity and is not designed as an anti-neovascular therapy, so it may offer less protection against neovascular progression than ranibizumab.6,8
PDR cases were generally manageable with standard-of-care treatment, and 85% of affected patients gained vision at 1 year.6 He added that, allowing for the limits of cross-trial comparison, the Remigromig PDR rates compare favorably with the sham and laser control arms of RISE/RIDE and VISTA/VIVID.1
What BAROLO must answer
BAROLO (NCT06957080), the companion pivotal trial of similar size and design, is expected to report within several months and will support subgroup analyses that BRUNELLO alone cannot.6,8
In the interview, Dr. D'Amico identified the questions BAROLO and later studies must address:
- Response in previously-treated eyes and in eyes with macular ischemia
- Durability beyond monthly dosing, which BRUNELLO's second year of personalized intervals will begin to address
- Whether Remigromig belongs as monotherapy, in sequence with anti-VEGF, or in combination
Remigromig is also being evaluated in neovascular AMD and retinal vein occlusion in the phase 2 proof-of-concept SUPER TUSCAN study.6
"This drug was given every month for obvious reasons. That's the baseline needed in order to obtain approval of a brand new agent."—Donald J. D'Amico, MD
In closing
BRUNELLO supports further evaluation of Wnt pathway activation and BRB restoration as a viable therapeutic target in DME, not a replacement for anti-VEGF therapy.
The PDR findings highlight the importance of considering retinopathy severity, in addition to macular fluid, as Remigromig's potential role and appropriate patient population are further evaluated.
Whether its early role is monotherapy, an option for incomplete anti-VEGF responders, or a combination partner depends on BAROLO and on BRUNELLO's second-year data.
"Yet this has consistently been able to show in this study, and hopefully the next one, that it's a standalone pathway for treating these patients."—Rishi P. Singh, MD, FASRS
This article was produced by our editorial team in collaboration with subject-matter experts. AI may have been used as an editorial tool under the direction of human editors, who reviewed and approved all content.
