An extension of the LIGHTSITE III trial shows that retreatment with photobiomodulation (PBM) may restore and sustain visual gains in patients with intermediate dry age-related macular degeneration (AMD), even after a 20-month interruption. Data from the LIGHTSITE IIIB study, presented at the 2025 American Society of Retina Specialists (ASRS) meeting, demonstrated that patients who resumed PBM after the treatment pause regained approximately 5 letters of best-corrected visual acuity (BCVA), while those who had previously received sham treatment showed stabilization of vision after being switched to active therapy.

LIGHTSITE III was a prospective, double-masked, randomized trial that enrolled 100 patients with intermediate dry AMD across 10 sites in the United States. Participants were randomized to receive either PBM or sham treatment using the Valeda light delivery system (LumiThera), a noninvasive, FDA-authorized device that uses yellow (590 nm), red (660 nm), and near-infrared (850 nm) light to stimulate mitochondrial activity and reduce oxidative stress in retinal tissue. The PBM group showed statistically significant gains in BCVA at 24 months compared to sham, with a favorable safety profile and evidence of slowed disease progression.

Following completion of LIGHTSITE III, the LIGHTSITE IIIB extension study was delayed for approximately 20 months, due to the original study’s conclusion and the time required for regulatory approvals and study setup, explained David Boyer, MD, a senior partner at Retina-Vitreous Associates Medical Group in Los Angeles and adjunct clinical professor of ophthalmology at the University of Southern California Keck School of Medicine, who presented the data on behalf of the study investigators at ASRS. During this intermission, patients received no PBM therapy.

In the extension, 36 participants (63 eyes) from LIGHTSITE III were re-enrolled for 4 additional PBM treatment cycles over 13 months, explained Dr. Boyer, a consultant to LumiThera. Those originally in the LIGHTSITE III sham arm (n=15 eyes) were switched to PBM in the extension study, allowing investigators to assess both continued and newly initiated treatment effects.

Dr. Boyer described the enrolled population as moderate to high risk for AMD progression. “These were not eyes just with small drusen,” he said. Using established disease scoring systems such as the Klein and Ferris models, participants averaged 3.4 risk points, indicating elevated progression risk. More than 50% had hypertension, approximately one-third were current or former smokers, and 40% to 60% had a family history of AMD. “These patients were representative of what we see in real-world practice,” Dr. Boyer noted.

Sustained Vision Gains

Patients who had originally received PBM in LIGHTSITE III lost an average of 2.2 letters during the 20-month treatment gap but regained more than 5 letters from the LIGHTSITE III baseline after resuming therapy in LIGHTSITE IIIB (Figure 1). This visual improvement was sustained over the course of the extension trial. “They went back to basically their 5 letters of improvement overall,” Dr. Boyer said. “They had not lost significant vision, and they improved.”

In contrast, patients from the sham group declined by 5.7 letters during the treatment gap and showed minimal recovery after PBM treatment was initiated in the extension trial. “The sham group stabilized. Their visual acuity did not continue to deteriorate, but they were unable to improve overall,” Dr. Boyer said.

Analysis of the 2 studies suggests that PBM-treated eyes experienced sustained benefit over approximately 54 months, with a cumulative gain of more than 5 letters. By month 13 of LIGHTSITE IIIB, there was a 9.9-letter BCVA gap between eyes originally treated with PBM and those originally assigned to sham.

PBM treatment benefits were more pronounced in patients with lower BCVA at baseline, noted Dr. Boyer. At the start of LIGHTSITE IIIb, patients with BCVA of 70 letters or below saw the greatest improvements. “If you have 20/40 or worse vision…. those are the patients that did well,” Dr. Boyer said. “You can’t expect major vision improvements in these patients who have 20/25 vision.”

In total, >65% of PBM-treated eyes in LIGHTSITE IIIB showed greater than 1-line BCVA improvement, >25% gained 2 lines or more, and >15% gained 3 lines or more. Dr. Boyer emphasized the ceiling effect seen in patients with good baseline vision, noting, “It’s hard to get 5-letter improvements” when starting from 20/25 vision.

Geographic Atrophy as a Limiting Factor

Baseline disease severity, particularly the presence of geographic atrophy (GA), had a significant impact on treatment outcomes (Figure 2). At the start of LIGHTSITE IIIB, 26.3% of PBM-treated eyes and 60% of sham-treated eyes had GA.

“Eyes with no GA showed the minimal best-corrected vision loss,” Dr. Boyer said. “Eyes with GA showed wider variability.” Although PBM-treated eyes without GA regained prior visual gains, those with GA were less responsive. Two eyes in the PBM group with GA lost 25 to 61 letters, skewing the overall data. Excluding those outliers, remaining GA eyes in the PBM group showed modest improvement.

In the sham-to-PBM crossover group, eyes with no GA maintained vision, whereas eyes with GA showed a more variable response to PBM (Figure 3).

PBM was well tolerated across both LIGHTSITE III and the extension study. No significant ocular safety signals were observed. However, 3 patients developed neovascular AMD during LIGHTSITE IIIB. “We know that unfortunately, in this category of patients, the risk is very high,” Dr. Boyer said. “There was no comparator during this period, so it's hard to say—is this the norm? Or is this something that we need to look out for in the future?” He noted that approved GA treatments such as pegcetacoplan (Syfovre; Apellis Pharmaceuticals) and avacincaptad pegol (Izervay; Astellas Pharma) have also shown conversion to neovascular AMD in trials with similar or higher rates than those observed in the LIGHTSITE III trial and extension.

The LIGHTSITE III and IIIB data suggest PBM may have the greatest utility in patients with intermediate AMD without central GA and baseline BCVA of 70 letters or less. “Early and intermediate AMD is where patients are going to get the biggest effect,” said Dr. Boyer said. “However, future research is needed to validate these findings.”

Dr. Boyer noted that LumiThera has begun planning additional PBM studies targeting other retinal conditions, including central serous chorioretinopathy and pigment epithelial detachments. There is also interest in evaluating PBM in eyes with extrafoveal GA. A registry study (EUROLIGHT) is under way in Europe investigating whether the visual benefits of PBM are improved or maintained over time, and a US-based registry is also under discussion.

With Alcon’s recent announcement that it would acquire LumiThera, Dr. Boyer expressed optimism that more rigorous, large-scale studies could be on the horizon. “Hopefully they would continue LumiThera’s dedication to further research studies,” he said. RP