Charles Miller, MD, PhD, on DME research and the initiation of the phase 2b/3 BRUNELLO trial

On September 4, 2024, Merck and EyeBio announced that the companies have initiated the Phase 2b/3 BRUNELLO trial (NCT06571045) to evaluate the candidate MK-3000, formerly known as EYE103 for the treatment of patients with diabetic macular edema (DME).¹ According to a press release issued by the companies, MK-3000 is a “tri-specific antibody that acts as an agonist of the Wingless-related integration site (Wnt) signaling pathway”¹ The release also states that MK-3000 is administered via intravitreal injection.¹

The decision to initiate this trial follows the results of the phase 1/2 AMARONE (NCT05919693) trial, which were announced in February of 2024.²

The National Library of Medicine’s website, ClinicalTrials.gov, lists specific details on this upcoming trial.

• Expected enrollment will be approximately 960 patients.³
• Patients will be randomized 1:1:1 to receive a low-dose, high dose, or 0.5 mg ranibizumab, administered via intravitreal injection.³
• The projected completion will be on or around the end of 2027.³

The unmet need in DME

To discuss this research, Sydney M. Crago, Managing Editor for Ophthalmology Times, spoke to Charles Miller, MD, PhD, Associate Vice President, Clinical Development at EyeBio, a wholly-owned subsidiary of Merck & Co, Inc., Rahway, New Jersey, United States. In this conversation, Miller highlighted the unmet need in DME treatment and the growing population of patients with diabetes. He said, “While anti-VEGF drugs have helped, 40–60% of DME patients still experience persistent edema. MK-3000 aims to address this unmet need with a new mechanism of action.”

Miller also noted that he believes the ophthalmology field is focused on the importance vision has on quality of life. He said, “where I think the field is going is offering patients additional therapeutic options to help maximize visual outcomes. When we talk about visual outcomes specifically for DME patients, we're talking about patients who are working age, and so maximizing those visual outcomes is really critical for helping them maximize their quality of life.”

As for the work that Miller and his team are doing to be a part of the innovation in treating patients with DME, he noted that MK-3000 brings new potential to the space. He said, “MK-3000 represents a technical advance for the field. If approved, MK3000 would represent the first Wnt agonist molecule to be used in this space, so that's an exciting technical advance.”

The use of AI in clinical trials

When asked how the advancements of the pharmaceutical space can be supported by the coinciding advancements in digital tools like machine learning and AI algorithms, he highlighted the role that technology will have in future clinical trial research. “Machine learning or AI driven image analysis, these are techniques that we at EyeBio and Merck, in partnership, have sought to bring to bear in the clinical trial setting. I don't think there's any question that [they can be used] as tools for rough analysis for these existing data sets, but also more prospective efforts like being applied toward patient selection. As we move into future clinical trials, these will all be made easier and more efficient by the introduction of those tools.”

A review of the AMARONE trial

The conversation also discussed the results of the phase 1/2 trial for MK-3000, known as the AMARONE trial. According to Miller, the trial evaluated "33 patients with predominantly DME, but also included 5 patients with wet AMD. In part 1 of the AMARONE study, patients received multiple ascending doses of MK-3000, and then in part 2, researchers carried forward the 2 highest doses tested, since there were no dose limiting toxicities."

As for the results of this research, Miller stated that, "Across patients in both parts of the study with DME, when they received 3 monthly injections [of MK-3000], so an injection every 4 weeks for 12 weeks, we saw a mean improvement in vision of more than 11 letters and a mean reduction in CST of more than 140 microns." This notable improvement aligns with the companies' announcement of their plans to continue research with the BRUNELLO trial.

References:

1. Merck and EyeBio Announce Initiation of Phase 2b/3 Clinical Trial for Restoret™ for the Treatment of Diabetic Macular Edema. Merck. News Release. September 4, 2024. Accessed October 2, 2025. https://www.merck.com/news/merck-and-eyebio-announce-initiation-of-phase-2b-3-clinical-trial-for-restoret-for-the-treatment-of-diabetic-macular-edema/

2. EyeBio Announces Positive Visual, Anatomic and Safety Data from First-in-Human Ph1b/2a AMARONE Trial of Restoret at Macula Society Annual Meeting. www.businesswire.com. Published February 13, 2024. Accessed February 13, 2024. https://www.businesswire.com/news/home/20240212626117/en/EyeBio-Announces-Positive-Visual-Anatomic-and-Safety-Data-from-First-in-Human-Ph1b2a-AMARONE-Trial-of-Restoret-at-Macula-Society-Annual-Meeting

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). Accessed October 2, 2025. https://clinicaltrials.gov/study/NCT06571045.