Novel mechanisms reshaping the phase 3 pipeline in wet and dry AMD

Currently, anti-VEGF therapy remains the backbone of wet age-related macular degeneration (AMD) treatment, and complement inhibition has defined the first approved therapies for geographic atrophy in dry AMD. Since their entrance to clinical practice, these medication classes have defined the standard for disease management; however, their impact has not resulted in a halting of seeking more innovative approaches to AMD.

A wave of phase 3 candidates now in development are testing mechanisms that move beyond both paradigms, from 1-time gene therapies to angiopoietin pathway agonism and even sustained-release platforms designed to reduce injection frequency. Here is where 7 of the most mechanistically distinct candidates stand.

Gene therapy candidates aim to eliminate repeat injections

Ixoberogene soroparvovec (Ixo-vec), developed by Adverum Biotechnologies, is a single intravitreal gene therapy designed to provide continuous intraocular expression of an anti-VEGF protein, potentially eliminating the need for repeat injections after a 1-time treatment.¹ The phase 3 AQUARIUS trial (NCT07482176) is comparing a single dose of Ixo-vec against intravitreal aflibercept in 284 participants with neovascular AMD, with the primary end point measuring mean change in best-corrected visual acuity averaged across weeks 52 and 56.¹

Adverum is now a wholly owned subsidiary of Eli Lilly, and Ixo-vec's phase 3 program includes 2 trials: the US-based ARTEMIS trial (NCT06856577), which completed screening in 2025 with topline data expected in the first quarter of 2027, alongside AQUARIUS. Adverum also presented 5-year extension data at the American Society of Retina Specialists 2026 meeting that show a durable treatment effect.²

RGX-314, also known as surabgene lomparvovec (sura-vec), developed by AbbVie and RegenxBio, uses a similar 1-time gene therapy approach to drive sustained anti-VEGF protein expression, with a suprachoroidal delivery option under investigation alongside subretinal administration.^3,4 The ATMOSPHERE trial (NCT04704921) is evaluating 2 dose levels of RGX-314 against ranibizumab, and the ASCENT trial (NCT05407636) is a second pivotal study in the same program.^3,4 Both trials completed enrollment in October 2025, together randomizing more than 1200 participants across more than 200 sites worldwide, the largest gene therapy program for wet AMD to date, with topline data expected in the fourth quarter of 2026.⁵

4D-150, from 4D Molecular Therapeutics, takes a dual-transgene approach: a single intravitreal injection delivers both an aflibercept-expressing gene and an anti-VEGF-C microRNA, targeting 2 components of the angiogenic pathway simultaneously.⁶ The therapy is being evaluated in a phase 3 trial (NCT06864988) of 400 participants with neovascular AMD against an active comparator.⁶ NCT06864988 refers specifically to 4FRONT-1, the North American trial in treatment-naive patients; a second global trial, 4FRONT-2, includes treatment-experienced patients and also recently completed enrollment. Topline data are expected in the first half of 2027 for 4FRONT-1 and the second half of 2027 for 4FRONT-2.⁷

Tie2 agonism offers a mechanism distinct from VEGF blockade

MK-8748 (also known as EYE201 or Tiespectus), developed by Merck/EyeBiotech, works through a different pathway altogether: Tie2 receptor agonism, which stabilizes retinal blood vessels via the angiopoietin signaling pathway rather than blocking VEGF directly.⁸ The phase 2/3 pivotal MALBEC trial (NCT07440225) is comparing the treatment against aflibercept 2 mg in a 3-arm, 960-participant study, one of the larger trials in the current AMD pipeline.⁸

MALBEC randomly assigns patients in 1:1:1 fashion to 1 of 2 MK-8748 dosing regimens or aflibercept 2 mg, with BCVA change from baseline to year 1 as the primary efficacy end point. Dosing consists of 3 monthly loading injections followed by dosing every 8 weeks through week 48, then response-guided individualized retreatment intervals, with a final assessment at week 96.

Merck's decision to advance the therapy into pivotal testing was based on results from the phase 1/2a RIOJA trial (NCT06664502), a 2-part study that evaluated the drug across 3 indications: wet AMD, macular edema secondary to branch retinal vein occlusion, and DME. A second pivotal wet AMD trial (NCT07496567) is expected to begin later in 2026, rounding out a broader late-phase development program for the drug.

New delivery platforms target durability without new molecular targets

Tarcocimab tedromer, paired with a second molecule, tabirafusp tedromer, uses Kodiak Sciences' antibody biopolymer conjugate (ABC) platform, engineered for extended intravitreal durability compared with standard anti-VEGF antibodies. The phase 3 DAYBREAK trial (NCT06556368) is a 3-arm study comparing both molecules against aflibercept in 675 participants with wet AMD.⁹ DAYBREAK has completed enrollment, with topline data now expected in the third quarter of 2026. Kodiak's related DME trials using the same ABC platform, GLEAM and GLIMMER, did not meet their primary endpoints after an unexpected increase in cataracts was observed in treated eyes, a safety signal worth monitoring as DAYBREAK data mature.¹⁰

The axitinib implant, marketed in development as Axpaxli (OTX-TKI), takes a different durability approach: a biodegradable hydrogel implant continuously releases a pan-VEGF receptor tyrosine kinase inhibitor rather than an antibody, aiming to reduce injection frequency through sustained-release pharmacology instead of a longer-acting biologic.^11,12 Ocular Therapeutix has 2 phase 3 trials underway, SOL-1 (NCT06223958) and SOL-R (NCT06495918), evaluating the implant in neovascular AMD.^11,12 SOL-1 has already reported positive topline data: the trial met its superiority primary end point, with 74.1% of Axpaxli-treated patients maintaining vision at week 36 compared with 55.8% on aflibercept (P = .0006), and the company plans to submit a new drug application based on SOL-1 data alone in the fourth quarter of 2026. SOL-R's timeline was extended to the first quarter of 2028 to evaluate additional secondary endpoints.¹³

Dry AMD's lone phase 3 entrant targets mitochondrial dysfunction

While pegcetacoplan and avacincaptad pegol, both complement inhibitors, remain the only approved therapies for geographic atrophy, elamipretide, developed by Stealth BioTherapeutics, represents a mechanistically distinct approach in the phase 3 pipeline.¹⁴ Elamipretide is a mitochondria-targeted peptide that binds cardiolipin, addressing mitochondrial dysfunction implicated in AMD pathogenesis rather than the complement cascade.

The phase 3 ReNEW trial (NCT06373731) is evaluating subcutaneous elamipretide injections in 360 participants with dry AMD, a notably different route of administration from the intravitreal injections used across the rest of the AMD pipeline.¹⁴ ReNEW is now fully enrolled, randomizing participants 2:1 to elamipretide or placebo for 96 weeks, with the primary efficacy end point measuring the rate of change in the macular area of photoreceptor loss via spectral-domain optical coherence tomography and ellipsoid zone mapping. A second phase 3 trial, ReGAIN, is also planned in the same program.¹⁵

What these mechanisms could mean for practice

If successful, gene therapy candidates like Ixo-vec, RGX-314, and 4D-150 could shift wet AMD management away from chronic injection schedules toward a small number of durable treatments. Tie2 agonism and ABC-platform durability approaches offer alternatives for patients who respond incompletely to VEGF blockade alone or who struggle with treatment burden under current regimens. In dry AMD, elamipretide's systemic, subcutaneous route stands apart from the intravitreal complement inhibitors currently approved, potentially offering an option for patients who prefer to avoid repeated eye injections altogether.

References

1. ClinicalTrials.gov. Efficacy and Safety Study of Ixoberogene Soroparvovec (Ixo-vec) in Participants With Neovascular Age-related Macular Degeneration (AQUARIUS). NCT07482176. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT07482176

2. Eyes On Eye Care. Adverum reports 5-year extension data on wet AMD gene therapy. Published July 28, 2026. Accessed August 6, 2026. https://glance.eyesoneyecare.com/stories/2026-07-28/adverum-reports-5-year-extension-data-on-wet-amd-gene-therapy/

3. ClinicalTrials.gov. Pivotal 1 Study of RGX-314 Gene Therapy in Participants With nAMD (ATMOSPHERE). NCT04704921. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT04704921

4. ClinicalTrials.gov. Pivotal 2 Study of RGX-314 Gene Therapy in Participants With nAMD (ASCENT). NCT05407636. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT05407636

5. Ophthalmology Management. Regenxbio Completes Enrollment in Phase 3 Pivotal Gene Therapy Trials for Wet AMD. Published October 6, 2025. Accessed August 6, 2026. https://www.ophthalmologymanagement.com/news/2025/regenxbio-completes-enrollment-in-phase-3-pivotal-gene-therapy-trials-for-wet-amd/

6. ClinicalTrials.gov. 4D-150 in Patients With Macular Neovascularization Secondary to Age-Related Macular Degeneration. NCT06864988. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT06864988

7. 4D Molecular Therapeutics, Inc. 4DMT Completes Enrollment for 4FRONT-2 Global Phase 3 Clinical Trial of 4D-150 in Wet AMD. News release. Published June 29, 2026. Accessed August 6, 2026. https://www.globenewswire.com/news-release/2026/06/29/3318897/0/en/4DMT-Completes-Enrollment-for-4FRONT-2-Global-Phase-3-Clinical-Trial-of-4D-150-in-Wet-AMD.html

8. ClinicalTrials.gov. A Clinical Trial of EYE201/MK-8748 in People With Macular Degeneration (MALBEC). NCT07440225. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT07440225

9. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Tarcocimab Tedromer and Tabirafusp Tedromer Compared to Aflibercept in Participants With Neovascular (Wet) Age-Related Macular Degeneration (wAMD) (DAYBREAK). NCT06556368. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT06556368

10. Kodiak Sciences Inc. Kodiak Sciences Announces Recent Business Highlights and Fourth Quarter and Full Year 2025 Financial Results. Published March 31, 2026. Accessed August 6, 2026. https://kodiak.gcs-web.com/news-releases/news-release-details/kodiak-sciences-announces-recent-business-highlights-and-2

11. ClinicalTrials.gov. Study to Evaluate the Efficacy and Safety of Intravitreal OTX-TKI (Axitinib Implant) in Subjects With Neovascular Age-Related Macular Degeneration (SOL-1). NCT06223958. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT06223958

12. ClinicalTrials.gov. Study to Evaluate the Efficacy and Safety of Intravitreal OTX-TKI (Axitinib Implant) in Subjects With Neovascular Age-Related Macular Degeneration (SOL-R). NCT06495918. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT06495918

13. Ocular Therapeutix, Inc. Ocular Therapeutix Announces Additional Positive Week 52 Data from Landmark SOL-1 Phase 3 Trial of AXPAXLI in Wet AMD. News release. Published April 13, 2026. Accessed August 6, 2026. https://www.globenewswire.com/news-release/2026/04/13/3272358/0/en/ocular-therapeutix-announces-additional-positive-week-52-data-from-landmark-sol-1-phase-3-trial-of-axpaxli-in-wet-amd.html

14. ClinicalTrials.gov. ReNEW: Phase 3 Study of Efficacy, Safety, and Pharmacokinetics of Subcutaneous Injections of Elamipretide in Subjects With Dry Age-Related Macular Degeneration. NCT06373731. Accessed August 5, 2026. https://clinicaltrials.gov/study/NCT06373731

15. Stealth BioTherapeutics Inc. Stealth BioTherapeutics Provides Commercial and R&D Pipeline Update and Outlines 2026 Strategic Priorities. Published January 6, 2026. Accessed August 6, 2026. https://www.prnewswire.com/news-releases/stealth-biotherapeutics-provides-commercial-and-rd-pipeline-update-and-outlines-2026-strategic-priorities-302653243.html