Remigromig's DME Non-Inferiority Masked by Proliferative Safety Signal: Approval Path Uncertain

Merck's Remigromig Meets Primary Endpoint in Pivotal DME Trial

Merck announced positive topline results from the pivotal Phase 2b/3 BRUNELLO trial, evaluating remigromig (MK-3000) in adults with diabetic macular edema (DME). The investigational tetravalent, tri-specific antibody, designed to activate the Wnt pathway, demonstrated non-inferiority to active control 0.5 mg ranibizumab for mean change from baseline in best-corrected visual acuity (BCVA) at week 52. Both 0.5 mg and 0.8 mg doses of remigromig were generally well tolerated, though higher rates of proliferative diabetic retinopathy, vitreous hemorrhage, and treatment discontinuations due to adverse events were observed in the remigromig arms.

• Remigromig achieved its primary endpoint by demonstrating non-inferiority to ranibizumab in improving best-corrected visual acuity (BCVA) from baseline at week 52. This outcome was consistent across both tested doses (0.5 mg and 0.8 mg) in patients with diabetic macular edema, marking a significant efficacy milestone for this novel therapeutic approach.
• The safety profile of remigromig showed it was generally well tolerated. However, the trial observed higher incidences of specific adverse events, including proliferative diabetic retinopathy, vitreous hemorrhage, and treatment discontinuations, in the remigromig treatment arms compared to the ranibizumab control. Further detailed analyses are currently underway to fully characterize these findings.
• This trial represents a crucial advancement as remigromig is the first new mechanism of action in 20 years to achieve Phase 3 results demonstrating non-inferiority to anti-VEGF therapy for DME. This offers a potential new treatment option for the up to 40% of DME patients who do not fully respond to existing therapies, addressing a significant unmet medical need.

Addressing Unmet Needs in DME with a Novel Wnt Pathway Agonist

Despite advances in pharmacological and laser-based interventions, the management of diabetic macular edema (DME) remains constrained by persistent efficacy gaps, treatment burden, and safety trade-offs. No single modality addresses all dimensions of the disease, leaving meaningful unmet need across patient subgroups.

• Persistent and refractory DME under anti-VEGF therapy. A substantial proportion of patients fail to achieve adequate response to anti-VEGF agents. In a retrospective cohort of patients with DME recalcitrant to bevacizumab who switched to aflibercept, mean central macular thickness (CMT) decreased from 473 ± 146 μm to 349 ± 85 μm (p < 0.001) and mean visual acuity (VA) improved from 0.55 ± 0.32 to 0.46 ± 0.33 logMAR (p = 0.038) — yet 12 eyes (24%) demonstrated absence of macular edema, implying the majority retained residual edema even after switching agents. Similarly, in a separate cohort switching from bevacizumab to aflibercept over one year, mean CMT decreased from 428.32 ± 84.89 μm to 275.54 ± 50.24 μm, confirming that switching can yield benefit but does not universally resolve disease.

• OCT biomarkers as predictors of corticosteroid response in refractory DME. Among patients with DME refractory to anti-VEGF who were switched to intravitreal corticosteroids, post-switch results showed no statistically significant improvement in best corrected visual acuity (BCVA) at three-month follow-up (p = .048/0.096), though mean CMT decreased significantly from 486.3 (SD = 159) μm to 369.3 (SD = 129) μm (p < .001). Disorganization of retinal inner layers (DRIL), present in 62.5% of patients at baseline, was the tomographic characteristic able to influence significantly both CMT and BCVA final results (p = .02 and 0.012, respectively), underscoring that structural retinal damage limits functional recovery even when anatomical edema is reduced.

• High treatment burden and its impact on patients and caregivers. Frequent intravitreal injections impose a substantial clinical and psychosocial burden. In a prospective real-world study of 41 patients with previously treated DME receiving the fluocinolone acetonide intravitreal implant (Iluvien), 46.3% of patients required caregiver accompaniment at baseline and 61% reported pre-injection anxiety (median duration 2 days). Clinic visits declined from 5.8 ± 1.6 to 3.7 ± 1.5 per year (p < 0.001) following implant use, highlighting that even with long-acting therapies, visit frequency remains a meaningful burden.

• IOP elevation and cataract progression as safety limitations of corticosteroid implants. Long-acting corticosteroid implants carry significant ocular safety risks. In a 3-year multicenter randomized controlled trial of the 0.59-mg fluocinolone acetonide (FA) intravitreal implant, intraocular pressure (IOP) ≥30 mmHg was recorded in 61.4% of implanted eyes (versus 5.8% in the standard-of-care group) at any time, and 33.8% required surgery for ocular hypertension by 4 years. Of implanted phakic eyes, 91% had cataract extraction by 4 years (versus 20% in the standard-of-care group), representing a major safety liability that limits broader use.

• Limitations of laser-based alternatives. Macular laser photocoagulation, while cost-effective and relevant in low-resource settings, carries inherent efficacy and safety constraints. A systematic review and meta-analysis of 14 randomized controlled trials (514 eyes receiving conventional laser, 574 receiving subthreshold laser) found that subthreshold laser likely results in no difference to BCVA compared with conventional laser (moderate GRADE certainty), and conventional laser demonstrated only a small, statistically significant improvement in central retinal thickness (low GRADE certainty) — a magnitude unlikely to be clinically important. Conventional laser has also been associated with central vision loss due to macular edema and peripheral visual field loss resulting from extensive inner retinal scarring.

BRUNELLO: Remigromig's Efficacy and Safety in Diabetic Macular Edema

Recent clinical evidence across DME has evaluated a range of interventions — from established anti-VEGF agents to corticosteroid implants and novel delivery platforms — offering comparative insights into efficacy and safety profiles relevant to the broader treatment landscape.

Wnt Pathway's Entry into DME: Promise and Peril

The announcement of positive topline results for Merck's remigromig in diabetic macular edema (DME) marks a significant moment, as it introduces a novel therapeutic approach targeting the Wnt pathway into a field largely dominated by anti-VEGF agents. While anti-VEGFs have proven highly effective in improving visual acuity and reducing macular thickness by inhibiting the VEGF-A pathway, remigromig's distinct mechanism could offer a new avenue for patients, particularly those who may not respond optimally to current standards of care. The trial demonstrated non-inferiority to ranibizumab, a well-established anti-VEGF, in improving visual acuity, which is a crucial benchmark for any new DME therapy.

However, the path forward for remigromig is not without considerable challenges. The observed higher rates of proliferative diabetic retinopathy (PDR) and vitreous hemorrhage (VH) in the remigromig arms are critical safety signals. These are severe complications of diabetic retinopathy that anti-VEGF therapies are known to prevent or mitigate. Furthermore, increased treatment discontinuations due to adverse events could impact long-term patient adherence and real-world outcomes. This safety profile will necessitate careful patient selection and robust risk-benefit discussions, potentially limiting its initial use to specific patient subsets or later lines of therapy.

The competitive landscape for DME is also rapidly evolving. Beyond ranibizumab, newer anti-VEGFs like faricimab, which targets both VEGF-A and angiopoietin-2, and aflibercept 8mg, offer extended dosing intervals, reducing the burden of frequent injections. The emergence of biosimilars for existing anti-VEGFs further intensifies pricing pressure and market competition. For remigromig to carve out a meaningful market share, it will need to clearly differentiate itself, perhaps by demonstrating superior efficacy in specific patient populations, a unique safety advantage in certain contexts, or a more durable response that outweighs the current safety concerns. The Wnt pathway's potential is intriguing, but its clinical utility will ultimately hinge on a compelling overall value proposition.