From Intermediate AMD to Geographic Atrophy: Biomarkers, Endpoints, and a Roadmap for Next-Generation Clinical Trials.

Age-related macular degeneration (AMD) is a leading cause of irreversible legal blindness worldwide. Treatments exist for late-stage AMD, but none exists for the intermediate stage (iAMD), which precedes significant vision loss. A therapy tested in iAMD would aim to prevent or slow progression to late-stage disease, meaning geographic atrophy or exudative neovascular AMD. The difficulty is that iAMD can persist for five years or longer before it progresses, whereas a trial must reach an answer within approximately two years. Such a trial therefore has to do two things at once: enroll the eyes most likely to progress within that window, and measure an endpoint that moves when progression slows. This review identifies the enrichment and endpoint criteria that make this possible. An enrichment biomarker must predict progression, be reproducibly measured, and be deployable across sites within two years. Optical coherence tomography (OCT) is the best instrument for this purpose because it is well tolerated, quantitative, and already available wherever iAMD trials are run. A single OCT acquisition can measure drusen area and volume, photoreceptor band integrity, hyperreflective foci, calcified drusen, and reticular pseudodrusen. For the endpoint, the onset and growth of large hypertransmission defects and the progressive loss of the outer retinal bands provide continuous structural measures that can be paired with microperimetry to capture function. Drawing on natural history data to model progression and statistical power, we propose a configurable trial design in which OCT both enriches for high-risk eyes and supplies the endpoint.