MK-8748's dual mechanism: Margaret A. Chang, MD, on retinal disease

Anti-VEGF therapy remains the backbone of care for retinal vascular disease, but a meaningful subset of patients continues to lose vision or accumulate fluid despite regular injections, and treatment burden remains a persistent barrier for many others. That unmet need has renewed interest in the angiopoietin/Tie2 pathway, a vascular stability mechanism distinct from VEGF signaling; direct activation of the Tie2 receptor can reduce vascular permeability and inflammation, offering a complementary route to disease control rather than another way to simply block VEGF.

That rationale underlies MK-8748 (Tiespectus; EyeBio/Merck), a bispecific antibody that directly agonizes Tie2 while also inhibiting VEGF.¹ Two pivotal wet age-related macular degeneration (AMD) trials—MALBEC (NCT07440225) and TORRONTES (NCT07496567)—are now evaluating the molecule, each a randomized, double-masked, 3-arm study comparing 2 dose regimens of MK-8748 against aflibercept 2 mg (Eylea; Regeneron).^2,3 As previously reported in Modern Retina, dosing in MALBEC begins with 3 monthly loading injections, continues every 8 weeks through week 48, then shifts to an individualized, response-guided retreatment schedule through a final assessment at week 96, with change in best-corrected visual acuity (BCVA) from baseline to year 1 serving as the primary efficacy end point.² TORRONTES follows the same pivotal, 3-arm design against aflibercept 2 mg.³ The pivotal program builds on phase 1/2a RIOJA (NCT06664502) data spanning wet AMD, diabetic macular edema (DME), and macular edema secondary to branch retinal vein occlusion (BRVO); in a first-in-human, multiple ascending dose cohort of 12 treatment-naive patients with BRVO, patients gained a mean of 16.7 letters of BCVA and saw central subfield thickness drop by a mean of 157.8 µm at 12 weeks.⁴

To unpack what this dual mechanism could mean for patients, and what data would actually need to show to change practice, Modern Retina spoke with Margaret A. Chang, MD, MS, a senior partner at Retina Consultants Medical Group, part of Retina Consultants of America, in Sacramento, California. Chang serves as a principal investigator on multiple retinal clinical trials. She also sits on the steering committee of several phase 3 studies and holds a master's degree in biostatistics, giving her particular insight into how trial end points translate into clinical decision-making. In the following Q&A, Chang discusses the biological rationale for pairing Tie2 agonism with VEGF inhibition, what a MALBEC readout would need to show on both vision and retreatment frequency to change patient management, what a positive wet AMD result would or would not suggest about extending the mechanism to other retinal vascular diseases, and which patient populations beyond wet AMD stand to benefit most from a dual-pathway approach.

Modern Retina: What is the biological rationale for pairing direct Tie2 activation with VEGF inhibition in a single molecule, rather than relying on VEGF suppression alone?

Margaret A. Chang, MD, MS: Activating Tie2 directly has the added benefit of stabilizing retinal vasculature by decreasing vascular permeability and decreasing inflammation. As we all know, anti-VEGF agents work very well for our patients with retinal vascular disease, but there is a definite subset of the population in which VEGF inhibition alone is not enough to control disease activity or to allow extension of treatment intervals.

Modern Retina: MALBEC's primary end point is BCVA change at Year 1, but dosing runs through week 96 under an individualized, response-guided retreatment schedule after the initial loading phase—what would a result need to show on both fronts (vision outcome and retreatment frequency) to actually change how patients are managed?

Chang: When comparing our current therapies, we often look at decreasing treatment burden. However, if there is a signal for improvement in visual outcome with a new therapy, patient management may significantly shift, even if retreatment frequency does not change.

Modern Retina: Both trials are enrolling patients with wet AMD specifically—what would a positive readout here suggest, or not suggest, about extending this mechanism to other retinal vascular diseases like DME or RVO-related edema?

Chang: Most new therapies for retinal vascular diseases start with trials for neovascular AMD. A bispecific agent such as this one that is a direct tie2 agonist in addition to anti-VEGF would hopefully show even better efficacy in diseases with significant vascular permeability such as DME and vein occlusion.

Modern Retina: Beyond wet AMD, what patient populations or disease states seem best positioned to benefit from this kind of dual-pathway approach?

Chang: Diabetic macular edema and retinal vein occlusion come to mind, but it certainly is possible that other retinal vascular diseases such as macular telangiectasia, or ischemic diseases such as diabetic retinopathy would also benefit.

References
1. Merck Announces Initiation of Pivotal Phase 2b/3 Trial Evaluating MK-8748 (Tiespectus). Merck.com. April 2, 2026. Available at: https://www.merck.com/news/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/
2. Merck launches phase 2b/3 MALBEC trial of MK-8748 in wet AMD. Ophthalmology Times. Available at: https://www.ophthalmologytimes.com/view/merck-launches-phase-2b-3-malbec-trial-of-mk-8748-in-wet-amd
3. New Clinical Trials Available at Texas Retina. Texas Retina Associates. May 1, 2026. Available at: https://www.texasretina.com/2026/05/01/new-clinical-trials-available-at-texas-retina-6
4. Tiespectus improves vision and retinal thickness in BRVO. Retinal Physician. October 20, 2025. Available at: https://www.retinalphysician.com/issues/2025/october/aao25/
5. Margaret A. Chang, MD, MS. American Society of Retina Specialists find-a-specialist profile. Available at: https://www.asrs.org/find-a-specialist/profile/2542