The LIGHTSITE III trial, a randomized, controlled, multicenter study, evaluated the use of multiwavelength photobiomodulation therapy for patients with nonexudative (dry) age-related macular degeneration. The study aimed to assess whether photobiomodulation could improve visual function, slow disease progression, and reduce the incidence of geographic atrophy over a 13-month period.
The trial investigated the Valeda Light Delivery System (LumiThera, Inc.), which delivers photobiomodulation (PBM) at 590 nm, 660 nm, and 850 nm, targeting mitochondrial dysfunction and oxidative stress—both of which are implicated in age-related macular degeneration (AMD) progression.
The patient population included 100 patients (148 study eyes) with early to intermediate dry AMD enrolled across 10 US clinical sites. Patients were assigned in a 2:1 ratio to receive either PBM therapy or sham treatment. PBM-treated eyes received 9 treatment sessions every 4 months for the study duration. Sham-treated eyes received identical sessions without active PBM exposure. Follow-up was after 13 months.
The primary endpoint was change in best-corrected visual acuity (BCVA) from baseline. Secondary outcomes included low-luminance BCVA, contrast sensitivity (CS), reading speed, macular drusen volume and geographic atrophy (GA) progression, and rates of new GA lesion formation.
Findings were published in Retina. PBM-treated eyes showed a statistically significant +5.4 letter gain in BCVA, while sham-treated eyes gained +3.0 letters. The between-group difference was +2.4 letters, favoring PBM. Gains of at least 5 letters were seen in 55% of PBM eyes vs 40.8% of sham eyes. Gains of at least 10 letters occurred in 26.4% of PBM eyes compared with 14.9% of sham eyes. Patients who were younger than 75 years showed a stronger visual acuity response to PBM than older participants. Participants with better baseline BCVA still demonstrated significant visual gains, indicating that PBM therapy may be beneficial across different disease severities.
PBM therapy also significantly improved contrast sensitivity, and PBM-treated eyes demonstrated better reading performance, which suggested functional benefits beyond BCVA improvements.
PBM-treated eyes exhibited a significantly lower rate of new-onset GA, and 1.1% of PBM-treated eyes developed new GA lesions, compared with 10% in the sham group. The odds ratio for GA reduction was 9.4, favoring PBM. Eyes with more extensive drusen accumulation at baseline appeared to have a greater reduction in drusen volume with PBM treatment.
Macular drusen volume remained stable in PBM eyes, while sham-treated eyes showed an increase.
No treatment-related serious adverse events (SAEs) were reported. The most common mild adverse event was dry eye symptoms, which were reported in both groups.
Treatment compliance was high in both groups: 88.2% of PBM-treated eyes completed all therapy sessions and 74.5% of sham-treated eyes completed all follow-ups.
Led by David Boyer, MD, of Retina Vitreous Associates Medical Group in Beverly Hills, California, the researchers acknowledged LIGHTSITE III’s limitations including small sample size, which might limit the generalizability of the findings. The primary efficacy analysis at 13 months may not be sufficient to fully assess the long-term benefits or durability of PBM therapy in dry AMD, but the ongoing 24-month analysis will be important for evaluating long-term safety and efficacy. While the study found a lower incidence of new GA lesions in PBM-treated eyes, it did not fully quantify or analyze GA progression rates in those with existing GA. The study used a sham treatment for the control group, for which patients may still have experienced a placebo effect, particularly in subjective measures such as reading speed and contrast sensitivity. The study population primarily included early-to-intermediate dry AMD patients, which may not represent all AMD demographics, including those with advanced disease or different genetic backgrounds. Finally, LIGHTSITE III did not compare PBM therapy with other established AMD management strategies, such as AREDS2 supplementation, lifestyle modifications, or emerging pharmacologic treatments.
Given these limitations, the investigators suggested that future studies should explore PBM efficacy in a broader patient population, evaluate PBM as an adjunctive therapy alongside existing treatments, and assess whether PBM can slow the expansion of GA lesions in patients with more advanced dry AMD. Additional research is also needed to determine whether certain patient subgroups derive greater benefit from PBM therapy.
In response to the FDA’s authorization for marketing of the Valeda Light Delivery System, Srinivas Sadda, MD, of Doheny Eye Institute in Pasadena, California, and the David Geffen School of Medicine at the University of California in Los Angeles, provided a perspective on LIGHTSITE III recently in JAMA Ophthalmology. Specifically, Dr. Sadda noted, “inconsistencies may undermine confidence in the results. For example, it is unclear when participants were dropped from the study over the 13 months. The impact of these dropouts on study results, including secondary and safety outcomes, is uncertain.”
Other concerns included the age of sham participants—who were older, on average, than PBM participants by 3 years—and whether their age influenced outcomes. Dr Sadda also noted that specific delivery of therapy was not specified in LIGHTSITE III, and while percentages of patients who completed the therapy sessions were high, he raised questions about monitoring during treatment sessions for further compliance.
Dr Sadda also suggested a regression to the mean effect related to visual acuity gains. Regarding anatomic outcomes he wrote, “While no change was noted in PBM eyes, drusen volume showed an increase in sham eyes. However, mean increase in sham eyes was approximately 0.05 mm3, which is not a statistically significant difference between groups and not likely clinically meaningful.” Conversion to neovascular AMD will be important to monitor in years 2 and 3, he noted, given the rate of conversion in the PBM group compared to sham and nonstudy eyes.
He concluded in agreement with the LIGHTSITE III investigators that more data are needed to give the best recommendations to patients.
