How MK-8748's tie2 agonism differs from anti-VEGF blockade in wet AMD

For decades, treatment for wet age-related macular degeneration (AMD) has centered on blocking VEGF signaling. MK-8748 (Tiespectus; EyeBio/Merck) takes a different approach, pairing VEGF inhibition with direct activation of the Tie2 receptor. Jonathan Gloth, MD, a retina specialist at InVision EyeCare in Lakewood, NJ, discussed how the dual mechanism compares with anti-VEGF monotherapy and existing Tie2-pathway therapies.

Gloth compared the mechanism to faricimab (Vabysmo; Genentech), which inhibits angiopoietin-2 (Ang-2) to indirectly support Tie2 signaling. MK-8748 instead directly activates Ang-1, the receptor's natural agonist. "I expect similar results, potentially even better than with faricimab," Gloth told Modern Retina, noting the added mechanism targets endothelial cell tight junctions to reduce vascular permeability.

Gloth said this Ang-1 agonism is designed to stabilize choroidal neovascular membranes and reduce leakage from abnormal vessels, with the goal of drier retinas and longer intervals between injections for patients with wet AMD. MK-8748 is currently being evaluated in 2 pivotal phase 2b/3 trials, MALBEC (NCT07440225) and TORRONTES (NCT07496567), each a randomized, double-masked, 3-arm study comparing 2 dose regimens of MK-8748 with aflibercept 2
mg (Eylea; Regeneron).¹ The trials follow positive phase 1/2a RIOJA (NCT06664502) findings across wet AMD, branch retinal vein occlusion-related macular edema, and diabetic macular edema.¹

What does an unstable vessel look like versus a stabilized one?

Asked to describe the clinical distinction between an unstable and a stabilized vessel, Gloth pointed to imaging findings retina specialists monitor at every visit. Unstable vessels manifest with leakage on OCT or OCTA, or with intraretinal, subretinal, or sub-RPE fluid on presentation.

When a patient with previously stable disease presents with new fluid, Gloth said the response is typically a shorter treatment interval or a change in therapy. "We want that vascular stability," he said, "we want lack of fluid or leakage." Gloth said this fluid-driven decision-making underscores why retina specialists rely on imaging at every visit, rather than symptoms alone, to guide treatment intervals.

Reference
1. Merck & Co, Inc. Merck announces initiation of pivotal phase 2b/3 trial evaluating MK-8748 (Tiespectus), an investigational bispecific Tie2 agonist/VEGF inhibitor, for the treatment of neovascular age-related macular degeneration. News release. Merck & Co, Inc; April 2, 2026. Accessed August 24, 2026.