Age-related macular degeneration (AMD) is a progressive retinal disease and is the leading cause of severe vision loss in older adults.1,2 The disease exists in 2 forms: dry or nonexudative AMD, which progresses slowly, and wet or exudative AMD, which can lead to more rapid vision loss. The intermediate stage of dry AMD is characterized by the presence of larger drusen and/or pigmentary changes in the retina, but without the advanced features of late AMD such as geographic atrophy (GA) or choroidal neovascularization (CNV).1 Notably, this stage offers a critical window of opportunity for therapeutic intervention before irreversible vision loss occurs.
There are treatments available for wet AMD and for GA; however, the therapeutic options for the early to intermediate stages of dry AMD remain limited. The primary intervention typically consists of antioxidant supplementation, which has shown only modest efficacy in delaying disease progression.1,2
Photobiomodulation (PBM) is an innovative, noninvasive biotechnology that uses low-level light to promote cellular health and function.3-5 This technique uses specific wavelengths of light, ranging from visible to near-infrared spectrum (500 nm to 1,000 nm), allowing high penetration to stimulate beneficial cellular responses in targeted tissues.3-5 Photobiomodulation is based on the fundamental principle that certain molecules within cells can absorb light energy.6-8 When cells are exposed to specific wavelengths of light, this absorption process can trigger the activation of native cellular molecules. This activation, in turn, has the potential to influence and modulate a variety of biochemical reactions and metabolic processes within the cell.6-8
Figure 1. Representative imaging of macular drusen reduction from a LIGHTSITE I trial participant following photobiomodulation (PBM) treatment. Compared to baseline imaging (top), a significant reduction in macular drusen volume was observed at month 12 (bottom) following 2 series of PBM treatment. The patient also showed a gain of >5 BCVA letters. Image from Markowitz SN, Devenyi RG, Munk MR, et al. A double-masked, randomized, sham-controlled, single-center study with photobiomodulation for the treatment of dry age-related macular degeneration. Retina. 2020;40(8):1471-1482. doi:10.1097/IAE.0000000000002632. Used with permission.
In November 2024, the US Food and Drug Administration (FDA) authorized marketing of LumiThera’s Valeda Light Delivery System, an innovative medical device designed to administer multiwavelength PBM therapy, as the first approved treatment for vision loss in dry AMD patients. The Valeda system uses 3 specific wavelengths of light: yellow (590 nm), red (660 nm), and near-infrared (850 nm). These wavelengths were carefully chosen for their ability to interact with multiple biologic targets.9 The selection of these wavelengths is based on their capacity to engage various components of the mitochondrial electron transport chain and to interact with other biologic systems relevant to the treatment of ocular conditions. By targeting multiple molecular substrates of the mitochondrial electron transport chain, the Valeda system aims to provide a comprehensive approach to treating retinal diseases, particularly dry AMD.8,9
Mechanism of Action
The therapeutic effects of PBM are wavelength-dependent, whereby selective light frequencies facilitate interaction with cellular components and enhance mitochondrial activity.6-8 Stimulation of the mitochondrial respiratory chain stabilizes metabolic function and initiates signaling cascades that promote cellular proliferation and cytoprotection.6-8 A key player in this process is cytochrome C oxidase, which acts as a primary photoacceptor for light in the far red to near infrared range. When activated by PBM, cytochrome C oxidase enhances the electron transport pathway, boosting ATP production, which is the cell’s primary energy source.6,10-13
Other studies have shown that PBM can reduce various markers of cellular inflammation, including expression of glial fibrillary acidic protein, a key indicator of glial cell activation in response to retinal stress or injury. Similarly, reductions in vimentin, another intermediate filament protein associated with cellular stress, have been noted. The expression of inflammatory enzymes such as cyclooxygenase has also been shown to decrease following PBM treatment.14-16
Additionally, researchers have reported reductions in proinflammatory signaling molecules, including calcitonin and tumor necrosis factor. Oxidative stress markers like 4-hydroxynonenal have been found to decrease, indicating a potential protective effect against oxidative damage. Furthermore, studies have shown a reduction in intracellular adhesion molecules and downregulation of complement C3 in the outer retina, which play a role in inflammatory cell recruitment.14-16 Collectively, these findings suggest that PBM may exert its therapeutic effects by targeting mitochondrial dysfunction, oxidative stress, and inflammation within the retinal pigment epithelium (RPE), which are key pathologic features of AMD.14-16
Previous Studies Show Success
Previous studies have shown improved structural and functional visual outcomes with PBM treatment. Ivandic et al provided the first evidence of PMB therapy for AMD in 2008, encompassing all forms of the disease. The study showed significant improvements in BCVA and reduction in various AMD-related signs, including pigment accumulation, drusen, macular edema, and retinal bleeding.17 The Toronto and Oak Ridge PBM studies (TORPA I and II) also demonstrated improvements in BCVA and contrast sensitivity, along with reduction in drusen volume after PBM therapy.18
A 2022 retrospective observational case series by Le et al examined the effects of multiwavelength PBM using the Valeda system in eyes with reticular pseudodrusen (RPD).19 In this report, PBM stabilized RPD and reduced both stage 2 and stage 3 RPD. There was also no progression of RPD into more advanced stages during the study period.19 Benlahbib et al further showed the efficacy and safety of PBM for treating large soft drusen as well as drusenoid pigment epithelial detachments in eyes with intermediate AMD.20 Nevertheless, these studies had various limitations, including different stages of disease without distinction between intermediate and late AMD, lack of a control group, and short-term follow-up without long-term outcomes.
LIGHTSITE Trials
LIGHTSITE I was the first double-masked, randomized, sham-controlled, parallel-group clinical trial to evaluate the efficacy of PBM in patients with dry AMD.21 The study enrolled both intermediate and late-stage dry AMD patients as the first evaluation of PBM safety and efficacy. Patients in the earlier stages of dry AMD responded more favorably to PBM compared to those with advanced disease and extensive central tissue loss. There was a significant improvement in contrast sensitivity immediately after PBM treatment, with benefits extending up to 12 months. PBM-treated subjects exhibited a mean BCVA letter score gain of 4 letters immediately after each treatment series at 1 month and 7 months. Approximately 50% of PBM-treated participants achieved a ≥5-letter improvement compared to 13.6% in the sham group. High responders (≥5-letter gain) showed an average improvement of 8 letters after initial treatment. There were statistically significant reductions in central drusen volume and thickness in PBM-treated patients (Figure 1). In addition, the VFQ-25 quality of life measures showed improvement at 12 months. Importantly, there were no reported device-related adverse events.21
LIGHTSITE II further investigated the safety and efficacy of PBM therapy in eyes with intermediate AMD.22 The study included 44 subjects with nonexudative AMD, comprising 53 eyes in total. The study’s primary endpoint was the change in BCVA from the initial baseline measurement to the 9-month follow-up assessment. Notably, 35.3% of PBM-treated eyes achieved a ≥5-letter improvement at 9-month follow-up. The study also revealed interesting anatomic findings. Although the PBM-treated group maintained stable macular drusen volume over time, the sham-treated group experienced increases. Both PBM and sham groups exhibited GA lesion growth during the trial. However, the PBM group showed 20% less growth over a 10-month period, suggesting potential disease-modifying effects of the treatment.22
More recently, LIGHTSITE III further expanded upon the therapeutic role of PBM in eyes with early/intermediate dry AMD.23 Relative to LIGHTSITE I and II, LIGHTSITE III enrolled a larger sample size with novel structural and functional parameters and a longer follow-up. In this prospective, randomized, controlled trial, subjects received either multiwavelength PBM (91 eyes) or sham treatment (54 eyes). The PBM therapy used light at 3 specific wavelengths: 590 nm, 660 nm, and 850 nm. Each treatment cycle consisted of 9 sessions conducted over a period of 3 to 5 weeks. These cycles were repeated at 4-month intervals throughout the study’s total duration of 24 months. This design allowed for multiple treatment cycles over the 2-year study period to assess both the short-term and long-term effects of PBM therapy compared to sham. For masking purposes, the sham treatment group received a markedly decreased dose of light (50 to 100 times lower dose) at 590 nm and 660 nm. The consistent spacing of treatment cycles and the extended study duration provided a comprehensive evaluation of PBM’s efficacy and safety profile over time.23
LIGHTSITE III results at 13 months showed statistically significant improvements in BCVA across multiple time points during the first 4 treatment series compared to sham.23 These results were based on 100 (148 eyes) treated patients with intermediate AMD >50 years of age with BCVA of 50 to 75 letters. Among the PBM-treated eyes, 55% demonstrated a mean increase of nearly 2 lines in BCVA. PBM showed potential in preventing progressive decline in visual function without reduced outcome scores, supporting its safety profile. Notably, the PMB group demonstrated a significant decrease in new onset GA in comparison to the sham group (6.8% vs 24% of eyes, respectively). In addition, PBM treatment demonstrated a stabilizing effect on macular drusen volume in treated eyes. In contrast, eyes receiving sham treatment exhibited a tendency toward increased drusen volume over the course of the study period.
This difference in drusen volume progression suggests that PBM may have a protective effect against the accumulation of drusen, a hallmark feature of AMD. The observed stability in drusen volume in PBM-treated eyes, compared to the increasing trend in sham-treated eyes, indicates that PBM might slow down or potentially halt one of the key pathologic processes in AMD. This finding is particularly significant, because drusen accumulation is associated with disease progression in AMD, and controlling this process could potentially slow the advancement of the condition. Data from the 24-month analysis showed significant improvements in BCVA that were sustained throughout the duration of the study, with a mean gain of 5.9 letters compared to sham. At month 24, PBM significantly reduced vision loss by 53% and GA onset in dry AMD by 73%. New GA occurrence was 24% in sham eyes and 6.8% in PBM eyes. In addition, new GA occurrence was significantly higher in the sham group vs the PBM group at both time points.24,25 Taken together, these results underscore the promising potential of PBM as a novel, noninvasive treatment approach for early to intermediate dry AMD, demonstrating both functional and structural benefits without compromising safety. These findings align with and extend prior research using the same 3 wavelengths delivered by the Valeda Light Delivery System, confirming clinical improvements in dry AMD after PBM treatment.23-25
There were no significant safety signals in the LIGHTSITE trials. The most common adverse events reported included foreign body sensation, increases tearing, eye discomfort, blepharitis, conjunctival hemorrhage, and posterior vitreous detachment.
Conclusion and Future Directions
Photobiomodulation appears to offer a safe treatment for intermediate AMD. The results suggest potential anatomic improvements, a decrease of visual loss, and even an improvement in the visual acuity in many patients. A registry study (EUROLIGHT) is underway to see if these visual benefits are improved or maintained over time. The LIGHTSITE IIIB extension study is currently in progress, building upon the findings of the previous LIGHTSITE III trial. This new study employs an open-label design, meaning all participants will receive the active treatment. The extension study will run for 13 months, during which participants will undergo 4 additional series of PBM treatments.25 We hope these findings will further elucidate the sustained benefits and potential disease-modifying effects of PBM in dry AMD disease progression. RP
References
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