Photobiomodulation Shows Vision Gains in Dry AMD at 24 Months

In the LIGHTSITE III trial, multiwavelength photobiomodulation produced a +6.2 letter BCVA gain at month 21, with 61.5% of treated eyes gaining at least five letters. Investigators also reported lower progression to geographic atrophy versus sham at 24 months. However, an accompanying editorial called the findings promising, but emphasized limitations in sample size, controls and long-term interpretation. Click image to enlarge. Renewed attention to geographic atrophy (GA) in recent years has focused on new treatment interventions, including two injectable therapies and the photobiomodulation (PBM) procedure. PBM’s primary proposed mechanism is mitochondrial photoacceptor activation, which produces a biological response that results in stabilization of metabolic function and cytoprotection. It’s been an attractive treatment strategy for degenerative ocular disorders. Studies such as LIGHTSITE I and II provided foundational evidence of the benefits of multiwavelength PBM in eyes with dry age-related macular degeneration (AMD), and LIGHTSITE III further followed those effects over a 24-month duration, results of which have recently been published in Retina.1 LIGHTSITE III used a double-masked, randomized prospective study design, enrolling patients with a diagnosis of dry AMD who were then treated with PBM at varying wavelengths (590nm, 660nm and 850nm) or sham. Treatment series included nine PBM or sham treatments delivered three times per week, over three to five weeks every four months for 24 months. A total of 148 eyes (100 subjects) with dry AMD were randomized into the study. According to the topline results, the study met the prespecified best-corrected visual acuity (BCVA) efficacy endpoint at month 21 with a significant difference between treatment groups and a +6.2 letter gain after PBM. At month 21, 61.5% of treated eyes showed ≥5 letter gain, 23.1% showed ≥10, and 4.4% showed ≥15 letter gains. A favorable safety profile was observed with no signs of phototoxicity. At least one ocular-specific adverse event (AE) was observed in 38 study eyes from 32 subjects. This number was similar between groups (sham: 25.5%; PBM: 25.8%). Disease progression to GA showed a significant decrease in incidence (sham, 24% vs. PBM, 6.8%) after PBM treatment at month 24. Nine study eyes progressed to later-stage nAMD during the 24-month study: two sham-treated eyes (3.6%) and seven PBM-treated eyes (7.5%). In addition, three nonstudy eyes (8.3%) progressed to nAMD.“The higher frequency of >5 letter BCVA gains in the PBM group and greater loss of >5 letters in the sham group over time highlight that PBM promotes vision recovery and also reduces progressive decline,” the authors wrote in their paper. “Both are important components of treating a degenerative disease such as AMD for which a loss of two to three letters per year (intermediate AMD) and development of GA with irreversible loss of retinal tissue is projected.”Some inherent limitations noted by the authors include the sham treatment, which served as an active control delivering a low fluence of PBM. “Even with a significant fluence reduction, sham treatment activates photoacceptors and is anticipated to produce a small biologic effect paralleling a high-dose/low-dose study design within the treatment groups,” they wrote.” Moderate effects observed in the sham group reduced over time, with a one-letter change from baseline observed at month 24. Subject sensitivity may account for enhanced response variability at lower-dose PBM.”An editorial in Retina calls these results promising, but says it raises familiar questions.2 The editorial’s author noted that the results should not be dismissed, pointing out one notable difference: “Most interventional strategies have targeted structural outcomes, without restoring vision or with functional outcomes trending worse in treatment versus control. Against that background, a persistent mean BCVA separation of roughly four to five letters over two years, plus a rightward shift in responder distributions, deserves attention.”In terms of skepticism, the editorial highlights the sample size and event counts. “Although 100 subjects were enrolled, analyses are eye-based with partial bilateral enrollment, increasing reliance on modeling to account for within-subject correlation,” he wrote. “Attrition was nontrivial (73% of subjects available at month 24, with discontinuations more frequent in sham), and missing data were addressed with multiple imputation for primary BCVA analyses, with last observation carried forward used in certain sensitivity and secondary/ exploratory analyses.” Such shortcomings complicate the interpretation of the findings, he wrote. “Furthermore, there is no evidence presented that the last observation carried forward results were distributed across comparable time points in the progression of the disease for the two groups.”The fact that the sham was not inert complicates interpretation in both directions, the editorial author continued, adding that the baseline age imbalance (sham group was roughly three years older) and baseline acuity and “room to improve” remain central. Next, he wrote that “disease modification” requires a higher bar. “The low event numbers for incident GA and neovascular conversion make estimates fragile,” he wrote. “Thus, the GA incidence signal is interesting, but not multiplicity-controlled. Several anatomic trends are directionally favorable yet exploratory.” Finally, treatment time-burden was substantial, wrote the author, who noted the nine in-office sessions every four months (54 sessions over two years).The editorial concluded: “LIGHTSITE III at 24 months provides randomized evidence to date that multiwavelength PBM may be able to improve BCVA in dry AMD, with a safety profile that is encouraging and intriguing but lacking definitive anatomic signals. Light can be medicine. The opportunity now is to ensure that it is also evidence-based medicine, illuminated by replication, refined by phenotyping and safeguarded by long-term vigilance.”Click here for the journal source and here for the commentary. Glenn J, Jaffe MD, David Boyer MD, et al. Long-term efficacy and safety of photobiomodulation in dry age-related macular degeneration (LIGHTSITE III: 24-month analysis). Retina. April 24, 2026. [Epub ahead of print.]Vavvas, DG. Photobiomodulation in dry age-related macular degeneration: Promising signal, familiar questions. Retina. April 24, 2026. [Epub ahead of print.]  This article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.