[Edaily Reporter NA EUN-KYUNG ] The focus of research into treatments for wet age-related macular degeneration is shifting from preventing abnormal blood vessel growth to stabilizing the damaged blood vessels themselves. This approach involves directly activating the vascular endothelial cell-specific tyrosine kinase receptor 2 (TIE2 receptor) to regulate vascular stability, while maintaining the existing vascular endothelial growth factor (VEGF) inhibition mechanism.

In this field, two candidate compounds originating from Korean companies are competing against each other. #Ingenia Therapeutics’ IGT-427 is currently undergoing late-stage clinical trials by U.S.-based MSD, while MMT-205—jointly developed by curacle co., ltd.(365270)and MapTix—has been licensed to U.S.-based Memento Medicine and is preparing to enter clinical trials.

According to MSD’s official research and development (R&D) pipeline released on the 20th, the age-related macular degeneration (AMD) candidate MK-8748 (IGT-427), originally developed by Ingenia Therapeutics, is currently undergoing pivotal Phase 2b and 3 clinical trials—MALBEC and TORRONTES—for wet age-related macular degeneration. MSD announced the initiation of the MALBEC trial on April 2, and the TORRONTES trial began enrolling its first patient on the 15th of the same month.

From “Preventing Abnormal Vessel Formation” to “Normalizing Damaged Vessels

” Wet age-related macular degeneration is a condition in which abnormal new blood vessels form beneath the macula, leading to the leakage of blood and fluid and resulting in impaired central vision. Currently, intravitreal injections that block VEGF are used as the standard of care. Lucentis ushered in the era of anti-VEGF therapy, while Eylea and high-dose Eylea extended the interval between doses by prolonging the duration of the drug’s effect.

However, limitations remain, such as the need for repeated intravitreal injections and the fact that edema and vascular leakage are not sufficiently controlled in some patients. Consequently, recent development efforts have split into two main areas: long-acting technologies designed to extend the interval between injections, and multi-mechanism therapies that target vascular stabilization pathways other than VEGF.

TIE2 is primarily expressed in vascular endothelial cells, where it plays a role in maintaining the integrity of the blood vessel wall and preventing blood components from leaking into surrounding tissues. While VEGF inhibition blocks signals that cause abnormal neovascularization and leakage, TIE2 activation strengthens the connections between endothelial cells, thereby stabilizing the damaged vascular barrier.

Roche’s Bavismo (active ingredient: faricimab) is the first commercially available drug to utilize the TIE2 pathway by simultaneously inhibiting VEGF and angiopoietin-2 (Ang2). However, it does so indirectly by removing Ang2, which interferes with TIE2 activation. AXT107, a peptide candidate from U.S.-based Asclepius Therapeutics, is also undergoing Phase 1 and 2a clinical trials for wet age-related macular degeneration by inhibiting VEGF receptor-2 and activating TIE2; however, it differs from MK-8748 and MMT-205—which directly stimulate the TIE2 receptor—in that it acts via integrins.

Among the candidates that combine direct TIE2 activation and VEGF inhibition into a single bispecific antibody, MK-8748—originally developed by Ingenia Therapeutics—is the farthest along, currently in pivotal Phase 2b and 3 clinical trials. MMT-205, discovered by curacle co., ltd. and MapTix, is a later-stage candidate currently in development with the goal of entering clinical trials in 2027; although it lags behind in the clinical development timeline, it belongs to the next generation of competitors sharing the same mechanism of action.

Ingenia Enters Late-Stage Clinical Trials with TIE2 Preservation and Direct Activation

IGT-427 was licensed to iBio in 2022; following MSD’s acquisition of iA, Inc., it is currently being developed under the names MK-8748 and Tiespectus. MSD has entered pivotal Phase 2b and 3 clinical trials comparing the efficacy and safety of IGT-427 with Eylea for wet age-related macular degeneration and is expanding its late-stage development scope to include diabetic macular edema.

IGT-427 is a bispecific antibody that combines VEGF inhibition with direct activation of TIE2. IGT-427 recognizes a different site on TIE2 than where angiopoietin-1 (Ang1) and Ang2 bind. The company explains that even if Ang2 levels increase in a disease state, IGT-427 can activate TIE2 without competing for the same binding site.

An official from Ingenia Therapeutics explained, “IGT-427 is designed to inhibit the phenomenon where TIE2 on the cell surface is cleaved off by proteases,” adding, “By combining VEGF inhibition with direct TIE2 activation, we can prevent abnormal blood vessel formation and leakage while simultaneously stabilizing the blood vessels themselves.” The goal is to preserve the cell-surface TIE2, which actually transmits signals, while minimizing the “sink effect”—where the drug is consumed by soluble TIE2 that has been released from the cells. However, whether this unique approach will actually lead to improved vision in patients and extended dosing intervals must be confirmed in late-stage clinical trials.

curacle co., ltd. and Maptics Prepare to Enter Clinical Trials with “Triple-Function” Approach

MMT-205, developed by curacle co., ltd. and Maptics, is also a bispecific antibody that combines VEGF inhibition with direct TIE2 activation. The two companies transferred the global rights to MMT-205 to U.S.-based Memento this year. Memento has secured a Series A investment of $93 million (approximately 130 billion won) and is preparing to submit an Investigational New Drug (IND) application, with the goal of entering clinical trials in 2027.

Curacle co., ltd. and Maptics explain that MMT-205 possesses a triple function: it blocks the action of Ang2 in addition to inhibiting VEGF and directly activating TIE2. While its mechanism of action is similar to that of Ingenia, there is a key difference: IGT-427 has progressed to late-stage clinical trials following initial patient data, whereas MMT-205 is still in the preclinical stage.

Whether direct TIE2 activation will establish itself as the new standard of care for age-related macular degeneration depends on the late-stage clinical results of MK-8748. To demonstrate the clinical value of adding TIE2, the treatment must improve vision more than the existing Eylea, stably reduce intra-retinal fluid, and extend the interval between injections.

In the retinal disease treatment market, which is growing to a scale of tens of trillions of won, anti-VEGF is expected to remain a core treatment pillar. Meanwhile, competition is intensifying to address vascular instability and persistent leakage—issues that existing treatments have failed to resolve—through TIE2 activation. While anti-VEGF therapies have focused on preventing the formation of abnormal new blood vessels, next-generation treatments aim to stabilize the damaged blood-retinal barrier to reduce leakage. This is why MK-8748, originally developed by Ingenia, and MMT-205, originally developed by curacle co., ltd. and Maptics, are attracting attention.

David Gayer, CEO of iBio, Inc., stated, “Despite currently available treatments, many patients with wet age-related macular degeneration remain at risk of further vision loss due to persistent vascular leakage.” He added, “MK-8748’s differentiated dual mechanism—which directly activates TIE2 and inhibits VEGF—has the potential to serve as a new therapeutic approach for maintaining the stability of retinal blood vessels.”