RWC Update: Photobiomodulation for Non-Neovascular AMD; High Definition TRD with NGENUITY 1.5; Retinopathy of Prematurity

Photobiomodulation for Non-Neovascular AMD

A new frontier in treating dry age-related macular degeneration (dry AMD) has emerged with the Food and Drug Administration (FDA) clearance of photobiomodulation (PBM).1 As this innovative approach begins to take shape, questions linger about its potential impact. Our experts share their insights in navigating the nuances of this developing field.

Marion R. Munk, MD, PhD: The management of dry AMD is an evolving field with recent advancements transforming the treatment landscape. Historically, patients with dry AMD had limited options and were typically advised only to make lifestyle changes and take vitamin supplements. Dry AMD patients were monitored for progression of disease and offered anti-vascular endothelial growth factor (anti-VEGF) injections upon advancement to neovascular AMD (nAMD). The limited treatment landscape has been discouraging to patients and providers alike. In recent years, injectable treatments for advanced dry AMD/geographical atrophy (GA) and PBM treatment for early/intermediate stage dry AMD patients have emerged as new and approved therapies for this patient population.

Photobiomodulation is a noninvasive light-based therapy that utilizes specific wavelengths to induce biological changes in the target cells to improve bio-energetic output. This is important in retinal disease as the retina is the most energy-demanding organ in the body and mitochondrial dysfunction has long been linked to degenerative disease states. Interest in the utility of PBM as a treatment for dry AMD has led to considerable research exploring the potential benefit across case reports, pilot, and randomized controlled trials (RCTs). The most robust data for the use of PBM in dry AMD was collected from the LIGHTSITE series of RCTs using the Valeda^® Light Delivery System (Valeda, Lumithera). Valeda delivers multi-wavelength PBM treatment with yellow (590 nm), red (660 nm), and near-infrared (850 nm) wavelengths that act on multiple cellular targets to improve retinal health and vision outcomes. The pivotal 24-month LIGHTSITE III trial evaluated Valeda in intermediate dry AMD patients and showed significant benefit in vision observed with an average vision gain of > 1-line improvement measured via the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart. At month 24, approximately 63.7% of PBM-treated eyes responded with a ≥ 5 letter gain (mean of 8.8 letters), 18.7% of PBM-treated eyes responded with a ≥ 10 letter gain (mean of 12.8 letters), and 4.4% of PBM-treated eyes responded with a ≥ 15 letter gain (mean of 16.3 letters). The trial also showed additional benefits such as a significantly reduced risk to progress from intermediate AMD to GA and an improved quality of life.2–5

In 2024, the FDA authorized marketing of Valeda treatment for dry AMD patients to improve vision.1 Valeda is CE marked in the European Union, UKCA marked in the United Kingdom, and is available in select countries in Latin America. Photobiomodulation represents a new biotechnology and is an important milestone in this field that allows for treatment earlier in the course of disease and represents a unique modality that can improve vision with potential disease-modifying effects.

David Boyer, MD: The LIGHTSITE III trial was a double masked, randomized, sham control multi-center trial that utilized three different wavelengths of light: 590, 660, and 850 nm. These wavelengths have been shown experimentally to improve mitochondria function, boost ATP production, reduce oxidative stress and inflammation, and promote cell survival.

To be included in the study, eyes have to have at least three medium drusen (> 63 μm and ≤ 125 μm in diameter) and/or non-central GA, and vision between 20/32 and 20/100. Exclusion criteria included the presence of a choroidal neovascular membrane or the presence of GA within 1 mm from the center of the fovea. Patients received light therapy 3 times a week for 3 weeks with a resting period of 4 months and retreatment every 4 months utilizing the same criteria. The study included 100 patients that were randomized 2 to 1. The trial met its primary predetermined endpoint of improvement of best-corrected visual acuity (BCVA) at month 21 with a gain of almost 6.2 letters versus sham of 2.4 letters. Best-corrected visual gains, percentage of vision losses, and quality of life measurements all favored the active PBM treated group. Post hoc analysis showed many anatomic improvements, including decreased drusen volume, decreased progression to GA, reduction of progression (iRORA) to complete reticular pseudodrusen-associated with outer retinal atrophy (cRORA), though it is important to remember this was post hoc analysis and the numbers of patients in each group was small. The study showed excellent safety. There were no signs of phototoxicity. There seemed to be a slight increase in conversion to nAMD compared to the sham group, though the conversion rate was similar to other FDA-approved treatments for GA. There are several ongoing studies, including the Eurolight registry, an open-label, retrospective and prospective study with at least 500 patients, as well as the LIGHTSITE 3B study that will provide more longitudinal data to substantiate the efficacy of this noninvasive treatment.2–5 At present, I am treating patients with 20/40 or less vision, large drusen volume, and patients with iRORA not near the fovea, with light therapy.

Eric H. Souied, MD, PhD: The LIGHTSITE studies demonstrated significant results for regression of large drusen and visual acuity. However, these results raise several questions.

The first question is the reproducibility in independent studies and in real life. To answer this question, we made a study on a series of 20 eyes affected with large confluent drusen. In this prospective single-center pilot study, we evaluated the effectiveness of PBM in 20 eyes with dry AMD featuring large soft drusen and/or drusenoid pigment epithelial detachment (dPED). Patients received 10 PBM sessions (two per week for 5 weeks) using the Valeda light delivery system. At 6 months, BCVA significantly improved by an average of 5.5 letters (P = 0.007), and quality of life (QoL) increased by 3.07 Visual Function Questionnaire (VFQ-25) points (P = 0.05). Drusen volume and central drusen thickness decreased significantly. Geographic atrophy showed minimal progression (+ 0.06 mm²), suggesting a potential protective effect. No major adverse events were reported.6 In real life, we still do not understand why PBM shows remarkable effects in some patients and no or mild effects in others.

Second, in parallel to large drusen, PBM therapy was evaluated in patients with reticular pseudodrusen (RPD). Although visual acuity remained stable, a shift in RPD stages was observed: stage 3 RPD decreased whereas stage 1 increased after 6 months, suggesting potential regression of advanced lesions.7

The third issue at hand concerns patient acceptability and their ability to attend multiple treatment sessions per week. Our elderly patients are often dependent on caregivers, and the number of ophthalmology centers currently offering this treatment remains limited.

Expanding the number of centers closer to patients could represent a practical solution. Moreover, alternative treatment protocols—other than the current 3 times per week for 3 weeks schedule—should be evaluated. Finally, to address the variability in therapeutic response, personalized treatment protocols may emerge in the coming years (Figure 1).

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