Remigromig Meets Primary Endpoint in BRUNELLO Trial

Clinical Report: Remigromig Meets Primary Endpoint in BRUNELLO Trial

Overview

In the phase 2b/3 BRUNELLO trial, both remigromig doses met the prespecified noninferiority endpoint for mean best-corrected visual acuity (BCVA) change at week 52 versus monthly ranibizumab in adults with diabetic macular edema (DME). Neither dose was superior to ranibizumab on the key secondary endpoints, and proliferative diabetic retinopathy (PDR)-related adverse events and treatment discontinuations were more frequent with remigromig.

Background

DME is a cause of visual impairment in people with diabetes, and anti-VEGF intravitreal therapy is a primary pharmacologic treatment approach described in the supplied guideline context. Remigromig is a trispecific, tetravalent antibody designed to activate the Wnt pathway through FZD4 and two LRP5 epitopes, with the intended effect of promoting endothelial tight-junction formation and restoring blood-retinal barrier integrity. The BRUNELLO trial compared this mechanism with monthly ranibizumab, an anti-VEGF therapy. The study is planned for two years, with personalized treatment intervals to be evaluated in its second year.

Data Highlights

Measure	Remigromig 0.5 mg	Remigromig 0.8 mg	Ranibizumab 0.5 mg
Participants assigned	984 adults with DME randomized across three groups
Mean BCVA gain at week 52	9.1 ETDRS letters (multiplicity-adjusted P=.0129)	8.7 ETDRS letters (P=.0222)	11.8 ETDRS letters
Primary endpoint	Met noninferiority	Met noninferiority	Active comparator
PDR-related adverse events	6.7%	6.1%	0.9%
Intraocular inflammation	1.8%	1.5%	1.8%
Adverse events leading to treatment discontinuation	4.9%	4.5%	0.9%

Key Findings

BRUNELLO was a randomized, double-masked phase 2b/3 trial enrolling 984 adults with DME; approximately one-quarter had previously received anti-VEGF therapy.
Participants received monthly intravitreal remigromig 0.5 mg, remigromig 0.8 mg, or ranibizumab 0.5 mg; the primary endpoint was noninferiority in mean BCVA change from baseline at week 52.
At week 52, mean BCVA gains were 9.1 ETDRS letters with remigromig 0.5 mg and 8.7 letters with 0.8 mg, compared with 11.8 letters with ranibizumab; both remigromig results were within the prespecified noninferiority margin.
Neither remigromig dose demonstrated superiority to ranibizumab for visual acuity or central subfield thickness, the key secondary endpoints. OCT case examples presented by Donald J. D’Amico showed retinal-fluid reductions maintained through week 52.
PDR-related adverse events occurred in 6.7% and 6.1% of patients receiving remigromig 0.5 mg and 0.8 mg, respectively, versus 0.9% with ranibizumab. D’Amico said these cases were manageable with standard-of-care treatment and that 85% of affected patients gained vision at one year.
Intraocular inflammation rates were 1.8%, 1.5%, and 1.8%, respectively; no retinal vasculitis was reported. Adverse events led to treatment discontinuation in 4.9%, 4.5%, and 0.9%, respectively.

Clinical Implications

The reported results establish week-52 noninferiority to monthly ranibizumab for both remigromig doses, but do not establish superiority on visual acuity or central subfield thickness. The higher observed frequency of PDR-related events and treatment discontinuations with remigromig should be considered alongside the reported visual and anatomic outcomes; the trial’s second year will evaluate personalized treatment intervals.

Conclusion

BRUNELLO met its primary noninferiority endpoint for both remigromig doses versus ranibizumab at week 52, while reporting more PDR-related adverse events with remigromig. Confirmation in the companion pivotal BAROLO trial was identified by D’Amico as relevant to further development of Wnt pathway activation for DME.