Novel Approaches in Early and Intermediate AMD: A Mechanistic Deep Dive

Novel Approaches in Early and Intermediate AMD: A Mechanistic Deep Dive 
This supplement summarizes a discussion among retina specialists and scientific experts on advancements in the treatment of early-to-intermediate age-related macular degeneration (AMD). Faculty experts share recent evidence, clinical experiences, and insights into lifestyle modifications, photobiomodulation, and other emerging treatments that may help halt the progression of this vision-threatening disease.

Diana V. Do, MD; David S. Boyer, MD; Janis Eells, PhD; Eleonora M. Lad, MD, PhD; Marion R. Munk, MD, PhD

Management of early-to-intermediate AMD remains centered on evidence-based risk reduction and longitudinal monitoring. Recent advances in photobiomodulation (PBM) have led to an approved treatment option for patients, alongside lifestyle modifications and vitamin supplementation. Additionally, more treatments are being evaluated for clinical efficacy and safety in this patient population, heralding a new era in disease management. A recent roundtable discussion captured insights from experts at the forefront of the scientific innovations driving new treatment interventions for intermediate AMD. These experts share the mechanistic rationale for PBM, review the data establishing its efficacy, and consider its practical application in everyday clinical practice. They also share insights into other emerging treatments and the future of dry AMD management.

Counseling Patients With Early-to-Intermediate AMD
Dr. Do: Welcome everyone. We have brought together a great group of experts in retina to discuss the latest strategies for managing early and intermediate AMD.

Let's start off with an interesting case that we typically encounter in our clinics. This is a 64-year-old man who presents to the clinic with several small- to medium-sized drusen in both eyes. He has a family history of AMD, and he is concerned because his mother had significant vision loss from her advanced AMD. His older brother has geographic atrophy (GA) and has also experienced vision loss. He has heard about a new “light therapy” for AMD and wants to know if he is a candidate and should start treatment.

Dr. Lad, when you have a patient with early or intermediate (eg, multiple medium-sized drusen or 1 large druse) AMD in your clinic, what are some of the first things you counsel your patient about?

Dr. Lad: The first thing I would counsel this patient about, given his family history, is that macular degeneration is multifactorial and complex. While genetics play a role, environmental factors are also strong predictors of progression.¹ So I would advise him to stop smoking if he is currently smoking.² I obtain a smoking history and assess for other modifiable risk factors he can address, such as high blood pressure, excess weight, and maintaining a healthy lifestyle.^3,4 

I check whether the patient is using supplements, specifically the Age-Related Eye Disease Study (AREDS) supplement formulation, and I counsel the patient about their use.^5-7Some people have trouble with them because they're larger pills, so there are chewable replacements that patients could use instead. 

A Mediterranean-style diet is very important because long-term analyses of data from the National Eye Institute AREDS and AREDS2 studies have associated greater adherence with a lower risk of progression to advanced AMD.⁸

In addition, I would counsel him to follow up with a retina specialist approximately every 6 to 9 months, consistent with the standard of care, and to self-monitor at home. He can use an Amsler Grid or electronic home monitoring device to do so.^4,9,10

In addition, regular imaging should be performed to monitor the progression of his disease.⁴ Should the patient convert to neovascular AMD (nAMD), I counsel the patient about available treatments and the importance of early intervention, ideally within 1 to 2 weeks. Should they convert to GA, there are currently injectable complement inhibitor medications available for treatment as well.⁴

Understanding the Pathophysiology of AMD
Dr. Do: That's terrific advice. Dr. Eells, can you briefly describe what is happening on a cellular level as AMD progresses?

Dr. Eells: Dry AMD is a progressive neurodegenerative disease that is driven by metabolic stress, chronic inflammation, and cellular atrophy within the outer retina (Figure 1). It's characterized by a breakdown of retinal pigment epithelial (RPE) cells, which are metabolically vulnerable, leading to the death of photoreceptor cells in the central portion of the retina, known as the macula. Although the pathogenesis has not been fully elucidated, considerable evidence supports a role for mitochondrial dysfunction and oxidative stress, which feed on each other, along with activation of the innate immune system at disease onset and throughout disease progression.¹¹

Figure 1. Schematic Progression of AMD
AMD, age-related macular degeneration; BM, Bruch’s membrane; CC, choriocapillaris; CH, choroid; CNV, choroidal neovascularization; GA, geographic atrophy; GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; PR, photoreceptor cells; RPE, retinal pigmented epithelium. 
A-B. Normal eye anatomy and retinal structure. C. Aging changes without AMD, including impaired transport across BM. D. Early/intermediate AMD with drusen formation and inflammation, oxidative stress, and complement activation. E. Late dry AMD (geographic atrophy) characterized by RPE and photoreceptor loss. F. Late wet AMD characterized by CNV. Fundus images courtesy of the Macula Reading Centre, University of Tübingen.
Source: Adapted from Armento, et al.¹²

The pathophysiology of AMD unfolds across several distinct cellular and molecular stages. The metabolic stress and lipofuscin accumulation stage occurs because photoreceptors have an extremely high metabolic rate. In fact, photoreceptors have the highest metabolic activity of any cell type in the body and generate substantial reactive oxygen species. As such, photoreceptors are very reliant upon mitochondrial function and susceptible to mitochondrial dysfunction.¹¹

The underlying RPE layer is responsible for phagocytosing photoreceptor outer segments, which can lead to lysosomal overload when the RPE is metabolically compromised. Along with this overload, oxidative stress and age-related mitochondrial dysfunction impair digestion of the outer segments, leaving behind an undegradable fluorescent lipid-protein product (lipofuscin) inside the RPE cells.¹¹

Lipids and proteins then accumulate within Bruch's membrane, blocking metabolic traffic and causing the RPE to extrude its waste. The extracellular waste deposits, called drusen, collect between the RPE basement membrane and Bruch's membrane. As the deposits coalesce into soft drusen, a physical barrier is created that restricts oxygen and nutrient delivery, further exacerbating the underlying mitochondrial dysfunction.¹¹

The complement system also contributes to AMD pathophysiology. Drusen are highly immunogenic and contain proteins that activate the innate immune system. Local dysregulation of the complement system, particularly involving complement factor H, triggers chronic low-grade inflammation. The inflammatory cascade then recruits microglial cells and macrophages, which release pro-inflammatory cytokines that further damage the tissue.^11,12

The choriocapillaris and RPE rely on each other for survival and daily metabolic maintenance. Vascular dropout occurs early in dry AMD pathology. There is loss of the capillary network of the choroid. The loss of these microvessels exacerbates hypoxia, leading to widespread tissue death and starvation of the RPE cells. Since RPE cells keep photoreceptors alive, the photoreceptors are eventually starved as well.^13,14

Altogether, the compounding damage from the chronic inflammation, ischemia, oxidative stress, and mitochondrial dysfunction leads to apoptosis of the RPE cells. Because photoreceptors rely on the RPE for nutrients, structural support, retinol recycling, and other essential functions, they degenerate in parallel with the RPE, leading to progressive degeneration of the macula. This collective cell death results in demarcated patches of total tissue loss, known as geographic atrophy.^11,13 Once the area expands into the fovea, it causes permanent and irreversible loss of central vision.

Dr. Do: Terrific. Thank you so much for that amazing and detailed explanation of what happens at the cellular level. Dr. Boyer, now that we've learned from Dr. Eells about the mechanisms that lead to advanced AMD, how does this biology inform meaningful endpoints when we're looking at intermediate AMD? 

Dr. Boyer: Dr. Eells gave an outstanding presentation explaining where the problems occur. We are trying to intervene at various stages to prevent the eventual outcome of complete RPE and outer retinal atrophy (cRORA). When you deal with intermediate AMD, endpoints are very different from those used in later stages of disease because you usually cannot achieve significant improvement in vision. When we target the complement system to prevent progression of GA, we rely on microperimetry. For PBM, the Duke Reading Center recently showed improvement in outer segment/inner segment junction morphology with treatment.¹⁵ So anything we can do to improve mitochondrial function, such as increasing cytochrome c oxidase (CcO) concentrations¹⁶ and reducing damage caused by reactive oxygen species,¹⁷ will hopefully translate into improvement in the endpoints we are studying: low-luminance vision deficit, low-luminance vision, microperimetry, and overall vision.

Mechanism of Action of Photobiomodulation
Dr. Do: Now that you brought up the subject of PBM, I wanted to ask Dr. Eells, how does PBM work to slow AMD progression?

Dr. Eells: We've known for more than 60 years that exposure of cells to low-energy photon radiation in the far-red (FR) to near-infrared (NIR) range of the spectrum, which we call PBM, restores the function of damaged mitochondria, upregulates the production of cytoprotective factors, and prevents apoptotic and necrotic cell death (Figure 2).^18,19 Clinically, it's been applied in the treatment of soft tissue injuries and wound healing.^20,21 More recent studies have demonstrated that PBM is applicable to retinal injury and disease and that FR to NIR photons penetrate diseased tissues, including the retina.^22,23

Figure 2. Mechanism of PBM in Retinal Cells
FR, far-red; NIR, near-infrared; PBM, photobiomodulation.
Radiation in the FR/NIR range restores damaged mitochondria and activates signaling pathways that produce cytoprotective factors that culminate in cell survival.
Source: Valter, et al.¹⁹

The therapeutic effects are hypothesized, based on a substantial body of evidence, to result from intracellular signaling pathways triggered when FR and NIR photons are absorbed by the mitochondrial photoacceptor CcO. Think of it sort of like the photosynthesis of the eye. The photoacceptor, CcO, is a key enzyme in the mitochondrial electron transport chain. CcO activation culminates in improved mitochondrial energy metabolism, activation of transcription factors, increased synthesis of cytoprotective factors, and improved cell survival. Investigations in numerous experimental models of retinal injury and disease have supported the therapeutic benefit of PBM.^18,19

Mitochondria contain most of the chromophores that absorb light in the FR to NIR spectrum. CcO has absorption sites for both FR and NIR wavelengths, and when you stimulate those sites, the activity of the enzyme increases. Light stimulation modifies the redox state and increases the proton gradient, making the mitochondria work better. It also increases mitochondrial membrane potential, which drives adenosine triphosphate synthesis, meaning the mitochondria are making more energy. Mitochondria then undergo repair, switching the cellular metabolism in the cell away from glycolysis, which is not very efficient, towards oxidative phosphorylation.^18,19

PBM also photodissociates nitric oxide from complex IV of the electron transport chain, which acts as a brake on electron transport from CcO. This activates transcription factors, leading to changes in gene transcription. So not only do you make mitochondria more effective and more productive, but you turn on a whole series of transcription factors that also activate cytoprotective genes, and particularly important ones in disease states, genes that promote cell survival, reduce oxidative stress, and decrease inflammation.^18,19

A number of these are antioxidant genes that are turned on, including superoxide dismutase, catalase, and glutathione peroxidase. Anti-apoptotic genes are turned on, and interestingly, correspondingly, the pro-cell death genes are turned off. So B-cell lymphoma 2(BCL2)-associated X protein (BAX), which is a pro-cell death pathway, is turned down and BCL2 is turned up.^18,24 Survivin/baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) is turned up.¹⁸

There are also genes encoding anti-inflammatory cytokines, along with a corresponding downregulation of pro-inflammatory cytokines. We've seen this in several studies that we've done where interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) are decreased, whereas expression of the anti-inflammatory cytokines IL-10 and transforming growth factor beta (TGF-β) is turned on.²⁵

Chaperones and protective structural proteins including crystallins are upregulated by PBM. In addition, PBM stimulates the expression of brain-derived neurotrophic factor and basic fibroblast growth factor.²⁶ Thus, there is a profound series of modifications that increase cell survival and enhance cell resilience. By targeting this underlying mitochondrial dysfunction, we can therapeutically move away from late-stage symptom management toward active cellular preservation.¹⁹

The clinical relevance in terms of this mechanism is that mitochondrial resuscitation increases the activity of the mitochondria within the cell and improves survival of both the RPE and photoreceptor cells. The reduction in oxidative stress decreases damage to the RPE. Suppression of apoptosis maintains cell survival.²⁶ And what this leads to is improvement in visual acuity, the prevention of vision loss, and anatomic preservation.^19,27 So it fits in mechanistically from a cellular basis all the way up to the measurement of vision.

Dr. Munk: I would also add that although much of the mechanistic evidence for PBM centers on the absorption of FR and NIR light by CcO, the 590-nm yellow wavelength is also thought to contribute to the therapeutic response. Yellow light has been shown to reduce oxidative stress and inflammatory signaling in retinal cells, improve retinal homeostasis, and provide complementary effects through photobiomodulatory pathways that extend beyond direct CcO activation, although its precise molecular targets remain less well defined than those of FR and NIR light.^19,22,28

Dr. Do: Dr. Boyer, how do you counsel patients when discussing PBM?

Dr. Boyer: The biggest problem, whenever a patient undergoes treatment, is making sure they have realistic expectations and understand what treatment entails. Some patients may present with a single druse and 20/20 vision. I'm not sure those patients would be candidates for treatment. But patients with significant drusen volume and vision of 20/40 or worse may benefit. I explain to patients that the data showed an average 5-letter improvement,²⁷ but individual responses vary. Some patients may gain 10 letters, whereas others may lose 5 letters, so they have to be realistic about what they can expect. Their vision may remain stable, which is a very positive feature. It also takes time. Treatment needs to continue for at least 1 year to see visual improvement. We do look at other factors, such as drusen volume, and explain that if there is an improvement in drusen volume without the formation of cRORA, that is a positive finding. So I try to make patient expectations reasonable.

Clinical Evidence for Photobiomodulation
Dr. Do: Great. The LIGHTSITE III pivotal trial evaluated the efficacy and safety of multiwavelength PBM. Dr. Boyer, can you explain to us which types of patients were included in this clinical trial along with the design of the trial?

Dr. Boyer: A total of 100 participants and 148 eyes were randomized 2:1 to receive PBM or an active sham. Patients included in the trial had at least 1 druse >63µm and a visual acuity between 20/32 and 20/100. Many of these patients had a fairly significant degree of intermediate AMD with pigment alterations and drusen, but only a small number of eyes had non-center involving GA at baseline, so they were eligible for treatment (Table).²⁷

Table. LIGHTSITE III Inclusion/Exclusion Criteria

AMD, age-related macular degeneration; AREDS, Age-Related Eye Disease Study; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; GA, geographic atrophy; nAMD, neovascular age-related macular degeneration; VEGF, vascular endothelial growth factor.
Source: Boyer, et al.²⁷

During the trial, participants received 3 treatments per week for 3 to 5 weeks, for a total of 9 treatments, and the treatment cycle was repeated every 4 months over a 2-year period. After 13 months, the primary endpoint was met, with PBM-treated patients gaining 5.4 letters (standard error [SE], 0.96; standard deviation [SD], 9.15), whereas sham-treated patients gained 3.0 letters (SE, 1.13; SD, 8.30; P= 0.02). Approximately 55% of PBM-treated eyes (n = 91) had a ≥5-letter gain compared with 26.4% of sham-treated eyes (n = 54). Among the 138 eyes with drusen at baseline, no change in drusen volume was seen in PBM-treated eyes (0.006 mm³). In comparison, drusen volume increased in the sham group (0.049 mm³). It should be noted that the sham group was not a typical negative control group because those eyes received a small amount of light.²⁷

Dr. Do: Dr. Lad, can you describe a bit more about the active sham treatment because, as Dr. Boyer mentioned, these patients in the active sham arm actually did receive a little bit of light therapy, and in the beginning of the clinical trial, they also had a mild improvement in their vision.

Dr. Lad: The sham group actually was an active control group. The patients received 2 out of 3 wavelengths of light. The third one, the 850-nm wavelength, was not included. The intensity of the 2 wavelengths was 50-fold and 100-fold lower than that of the active group, which is why the sham-treated patients also had a response, as you mentioned.²⁷

Dr. Do: We discussed that visual acuity was the primary endpoint of the LIGHTSITE III clinical trial. Dr. Lad, can you explain to us what were the vision outcomes?

Dr. Lad: In the 24-month analysis, there were significant improvements in best-corrected visual acuity, and these were sustained throughout the study. There was a mean gain of 5.4 letters compared with sham after 13 months (Figure 3).²⁷ At month 24, PBM significantly reduced vision loss by 53% (HR, 0.47; P < 0.02) and GA onset in dry AMD by 73% (HR, 0.27; P < 0.006), findings that were clinically meaningful for our participants (Figure 4).²⁹ Also, the incidence of new GA was 24% in the sham-treated eyes and 6.8% in the PBM-treated eyes (P= 0.007), suggesting reduced progression to more advanced forms of AMD. So GA occurrence was significantly higher in the sham versus the PBM group at both time points, although the sham, as we discussed, was an active sham.³⁰

Figure 3. LIGHTSITE III: Mean Change From Baseline in BCVA
BCVA, best-corrected visual acuity; BL, baseline; PBM, photobiomodulation; Tx, treatment.
Least squares means are presented using multiple imputation. *P < 0.05 between groups. ^P < 0.0001 within group.
Source: Boyer, et al.²⁷

Figure 4. Cumulative Incidence of GA in the LIGHTSITE III Trial
GA, geographic atrophy; PBM, photobiomodulation.
The cumulative percentage of participants who developed incident GA was lower in the PBM group than in the sham group at Month 13 (P = 0.024) and Month 24 (P= 0.007).
Source: Jaffe, et al.²⁹

In addition, PBM treatment demonstrated a stabilizing effect on macular drusen volume in the treated eyes, and this is very important because drusen are a hallmark feature of dry AMD, and drusen volume increases with progression toward advanced AMD. The observed stability in drusen volume in the PBM-treated eyes, compared with an increase in the sham-treated eyes, indicated that PBM might slow or even halt one of the key pathologic processes in AMD that we discussed earlier.^27,30

Dr. Do: Dr. Boyer, it seems that this new therapy met its primary endpoint in improving vision. Dr. Lad mentioned a smaller analysis looking at incident GA. What can we take from that data since it was in a smaller number of patients?

Dr. Boyer: I think that these post hoc analyses were very interesting. They all favored PBM, showing overall improvement in various factors, including incident incomplete RPE and outer retinal atrophy (iRORA) and conversion of iRORA to cRORA.³⁰ So I think this should enable us to do a larger study to determine whether this is an outcome truly associated with PBM. I think it is encouraging, but as you pointed out, very few patients were involved. It wasn't designed or statistically powered to support those types of conclusions.

Dr. Munk: Importantly, a lower incidence of GA was observed in the PBM group despite a greater proportion of eyes with subretinal drusenoid deposits (58% vs 42%), a recognized independent risk factor for GA development.³¹

Safety of Photobiomodulation

Dr. Do: And when we look at any new therapy, we're always concerned about safety. Dr. Lad, are there any safety signals with PBM that were detected in the LIGHTSITE III study?

Dr. Lad: The safety profile of PBM was excellent. However, at least 1 ocular-specific adverse event was observed in 38 study eyes, representing 25.7% of eyes from 32 participants. The number of eyes with at least 1 adverse event was similar between the sham and PBM-treated groups. Four ocular-specific adverse events, with an average incidence of 2.7%, which is quite small, were considered treatment related. These included dry eye (5.7%), punctate keratitis (5.7%), visual perseveration (persistence or the reappearance of the visual image, 2.9%), and application-site warmth (1.5%). None of these ocular-specific adverse events led to study discontinuation in any of the patients.³⁰

A total of 7 (7.5%) ocular-specific serious adverse events were reported in the PBM-treated group, all involving nAMD. In the sham-treated group, there were 3 ocular-specific serious adverse events: 1 eye with cystoid macular edema and 2 with nAMD. In the non-study eyes, there were 3 (8.3%) ocular-specific serious adverse events of nAMD that were reported. However, none of the serious adverse events were considered treatment related.

Regarding the incidence of progression to later-stage nAMD during the 24-month study, 2 of the sham-treated eyes and 7 of the PBM-treated eyes had progression to nAMD. In addition, 3 non-study eyes progressed to nAMD.³⁰ A total of 16 participants were randomized with a fellow non-study eye that had nAMD at screening, meaning those study eyes carried a high baseline risk of conversion.^4,30 However, the prevalence of these high-risk eyes was 3-fold higher in the PBM group than in the sham group, so it's important to consider that the imbalance may have contributed to the observed rates of conversion to nAMD. Of the study eyes that converted to nAMD, 66.7% were at high risk for conversion. On average, the conversion to nAMD occurred approximately 79 days after the last PBM treatment and 54.4 days after the last sham treatment.³⁰

Dr. Munk: LIGHTSITE II results actually pointed in the opposite direction: the overall conversion rate to nAMD or macular neovascularization was lower in the PBM group (2.9%, n = 34 eyes) than in the sham group (5.3%, n = 19 eyes) and comparable to the fellow eyes not enrolled in the study (2.9%, n = 35 eyes). Although neither LIGHTSITE II nor LIGHTSITE III was powered to evaluate conversion to nAMD, the available evidence is overall reassuring and does not support the hypothesis that PBM increases the risk of progression to nAMD.³²

Dr. Boyer: So people have to be evaluated, and it may be helpful to perform optical coherence tomography angiography before initiating PBM to rule out occult choroidal neovascularization, as a small percentage of people did go on to develop nAMD.

Dr. Eells: In the animal studies that we've done, we have seen virtually no adverse effects with PBM.^22,23,33,34 The same appears to apply to studies of traumatic brain injury. There is a whole series of excellent studies being conducted in football players and in patients with post-traumatic brain injury. There have been no adverse effects and a very positive response in terms of slowing or stopping some of the degeneration and improving the psychological outcomes.^35-37 So it is a pretty amazing approach. PBM is time consuming. The PBM treatment schedule requires patients to be in the clinic for 9 treatment sessions. The sessions are 5 to 10 minutes each and are administered 3 times per week for 3 to 5 weeks. For maintenance, the 9-session series is repeated every 4 months. 

Long-Term Outcomes From LIGHTSITE IIIB
Dr. Do: Dr. Boyer, can you tell us a little bit about LIGHTSITE IIIB? What was that clinical trial, and how is that different from LIGHTSITE III?

Dr. Boyer: LIGHTSITE IIIB was an extension trial. After 24 months, patients were no longer treated, but investigators began to realize the importance of continued treatment. So treatment was reinstituted after approximately 20 months. During that period, we saw that the sham group had a marked decrease in vision (Figure 5). There was a slight 2-letter decrease overall in the treated group, but when PBM was reinstituted, vision improved to a mean gain of 5 letters. It's also important to point out that patients with visual acuity worse than 20/40 experienced greater improvements in vision than patients with relatively good vision, likely because of the ceiling effect seen in patients with excellent baseline vision.^38,39

Figure 5. Mean Change in BCVA: LIGHTSIDE III and IIIB
BCVA, best-corrected visual acuity; LT3 BL, LIGHTSITE III baseline; PBM, photobiomodulation; Tx, treatment.
Mean BCVA letter score change from the LIGHTSITE III baseline is shown for participants who received PBM or sham treatment during LIGHTSITE III and for those who continued PBM (PBM/PBM) or crossed over from sham to PBM (Sham/PBM) during the LIGHTSITE IIIB extension following an approximately 20-month treatment interruption.
Source: Adapted from Do, et al.³⁸

Dr. Do: Dr. Munk, can you tell us about the real-world data being collected for PBM?

Dr. Munk: To complement the randomized LIGHTSITE trials, the ongoing EUROLIGHT registry is evaluating the long-term safety and real-world effectiveness of multi-wavelength PBM in routine clinical practice. This multicenter, prospective-retrospective registry aims to enroll at least 500 patients across the United States and Europe. In addition to longitudinal visual acuity outcomes, the study systematically collects optical coherence tomography and fundus autofluorescence imaging, treatment patterns, and safety data to further characterize the anatomical and functional effects of PBM in a real-world setting.⁴⁰

Integrating PBM Into Clinical Practice
Dr. Do: Let's go back to our original case. That was the patient who has medium and some small drusen, and he was asking if he was a candidate for PBM. Dr. Boyer, how do you advise patients when to start PBM?

Dr. Boyer: Well, I usually like to see some degree of visual loss. I don't think patients with 20/20 vision are going to appreciate an improvement. Many patients with 20/20 would remain 20/20 for years without treatment. If I saw large semisoft drusen that I felt were a precursor to iRORA or cRORA, I might recommend treatment, explaining that their vision may remain the same, but we're trying to reduce progression to GA and visual loss.

Patients with visual decline due to AMD, let's say 20/30 or 20/40, are the patients I would recommend treatment for because I think they may achieve some degree of visual improvement or stabilization. However, I don't recommend it for people with 20/20 vision, although that might be a highly personal choice.

Dr. Do: Dr. Lad, in this case, the patient did have decreased vision due to his underlying intermediate AMD, and he decided to start PBM. How should we counsel patients who want to proceed with treatment, and can they continue their AREDS vitamins during the treatment?

Dr. Lad: Yes, during PBM treatment, I would counsel patients to continue all their existing management strategies, which are mainly lifestyle interventions. Those include the AREDS vitamins and maintaining good nutritional support through a Mediterranean diet.⁴ Risk factor optimization, again, including controlling hypertension and maintaining a healthy weight, is crucial.³ They should maintain their scheduled follow-up visits unless they notice new symptoms during self-monitoring with either the Amsler grid or an electronic home monitoring device, which could alert them to return to the clinic sooner for evaluation and treatment.

If only 1 eye is treated with PBM, it is important to coordinate care for the other eye. We have patients who might have advanced GA receiving complement inhibitor injections in the fellow eye or patients with nAMD in the fellow eye who are receiving anti-vascular endothelial growth factor (VEGF), so coordination is needed between visits so the fellow eye can be managed adequately as well.

Dr. Do: We understand that PBM requires multiple treatments over the course of therapy. Dr. Boyer, what happens if patients miss appointments, and how can we counsel them on that?

Dr. Boyer: Well, I think for any treatment, we really emphasize the importance of trying to maintain the treatment intervals used in the studies. We treat 3 times a week over a period of 3 weeks. But if a patient misses a treatment, it certainly can be made up during that week. Let's say they are treated 3 times a week during the first week, and they miss 1 treatment in the second week, so they only receive 2 treatments. They can receive 4 treatments the following week. I think the important thing is that you have to set the expectation that this is a time-intensive but safe treatment that has the potential to improve vision and possibly reduce further visual loss over time. 

Dr. Do: And Dr. Lad, what are some tips you have for integrating PBM into routine clinical practice?

Dr. Lad: It is important to consider our clinic workflow, especially since in retina we are so busy with the management of patients requiring injections. Fortunately, PBM treatment does not require any anesthesia, which would delay clinic flow, or medications such as dilating agents, which would also cause delays. These treatments are performed under physician supervision, but they are administered by trained ophthalmic technicians, nurses, or certified assistants. This depends on state regulations, but it is much easier to integrate PBM into the clinical workflow than many of our other procedures. I would recommend setting aside specific PBM appointment windows for these treatments to avoid disrupting the normal workflow, such as injection clinics or regularly scheduled new patient or follow-up appointments.

Dr. Do: Terrific. Let's discuss another case. A patient who has intermediate AMD in 1 eye and nAMD in the fellow eye requiring intravitreal anti-VEGF injections every 2 months. Dr. Lad, you mentioned coordinating care. In this scenario, how do you manage the 9 visits for PBM with the injection visits for the fellow eye?

Dr. Lad: That's a great question. As I think through this, it helps tremendously that PBM is administered by our highly trained ophthalmic technicians. So I almost consider those visits to be independent. Otherwise, I would maintain the normal flow of treatment for the fellow eye with nAMD, and I would monitor that treatment interval. Most of us utilize a treat-and-extend paradigm for nAMD, so we inject the patients until the retinal fluid is stabilized and ideally resolved, and then we slowly extend the interval. That is critical for achieving the best outcomes in the fellow eye. In parallel, ophthalmic technicians can administer PBM to the fellow eye with dry AMD. So it does help to have separate appointments, and they can be scheduled and coded separately within our clinic workflow to make this happen. 

Dr. Do: Dr. Boyer, we see many patients who have non-central GA, and they also have large- and medium-sized drusen. Do you consider PBM for those patients? And how do you counsel them?

Dr. Boyer: We have 2 FDA-approved treatments for GA, and I think you have to offer that to the patient. The post-hoc analysis of the LIGHTSITE III trial did demonstrate a reduction in progression toward the fovea, as well as a reduction in progression from iRORA to cRORA, but it was not powered to determine whether patients with small areas of GA should be treated with PBM.³⁰ Although patients with small areas of GA may benefit, if the area is larger and I think it is going to impact their vision, I still recommend complement inhibitor therapy, as it is the only FDA-approved treatment strategy. 

Dr. Do: Dr. Eells, I wanted to ask you again, because you are such an expert in AMD. When people have non-central GA, do you think the mechanism of action of PBM might be beneficial to slow down the progression of the atrophy? 

Dr. Eells: Yes, I do. I think that pathophysiology is essentially the same whether it's off-center or, unfortunately, on-center, and I think that PBM does slow the damage. Even though there are differences throughout the retina in terms of its metabolism in different areas and cell populations, the benefit in non-central GA is definitely there.^15,30 I would even add that light treatment works best if you institute it when the dysfunction is starting, before the damage is manifested. The problem is that treating people before they actually have a visual deficit is challenging. And yet, over time, that may turn out to be the best thing we can possibly do: actually prevent the onset of disease. It's just that we do not currently have the tools to assess the subtle changes that are occurring. 

Future Directions in Early AMD
Dr. Do: PBM appears to be the beginning of a new era of treatments for intermediate AMD. Dr. Eells, what else is in the pipeline for clinical research?

Dr. Eells: There are several things in the pipeline. In the area of energy medicine, which has become a relatively new approach, a transpalpebral microcurrent device is placed on the eyelid and provides a low-level alternating pulsed direct current to the upper eyelid. That restores the transepithelial potential of the RPE, which is essential for maintaining RPE function.^41,42

It also activates mitochondria, and that doesn't really surprise me. I think whether you activate mitochondria with light or with an electrical stimulus, energy is energy, and it activates neuronal pathways. There are some trials going on right now, and the early outcomes look very positive.⁴³

So I think that the idea of moving away from drugs and perhaps toward using energy as a therapeutic modality makes a tremendous amount of sense and gives you new tools, because another wonderful thing with PBM, and probably also the transpalpebral microcurrent device, is that you can combine either approach with whatever pharmacologic agent you're using and target the system at different sites of action.

Another area with tremendous development, which goes back to the original link between complement factor H and AMD risk, is complement inhibition. We now know that as many as 60% of AMD cases are linked to dysfunction within the complement system.^12,44 We also now appreciate the interplay between the innate immune system and the complement system, including formation of the membrane attack complex and its effects on retinal cells.¹²

There are a number of drugs being studied for the management of GA.⁴⁵ To prevent progression of early-to-intermediate AMD, iptacopan inhibits factor B to block the amplification of C3.⁴⁶ Immunologists have brought important insights to ophthalmology by investigating alternative complement pathways and other pathways that may be harnessed to prevent retinal damage.¹² And again, you could use complement inhibition in concert with electrical or light stimulation.

Summary
Dr. Do: We’ve heard some great insights on PBM. I think this treatment is a terrific new option for our patients. We've discussed that select patients with intermediate AMD may benefit from PBM, along with continued lifestyle modifications to decrease the risk of AMD progression. We've also discussed how PBM shifts cellular metabolic activity to upregulate cytoprotective pathways, increase mitochondrial biogenesis, and modulate inflammation to improve photoreceptor and RPE survival. In addition, the data show that with regular treatment, vision may improve, drusen volume may be maintained or decreased in select patients, and the risk of disease progression may be reduced. Other treatments are also in development for early-to-intermediate AMD. And I think, as we’ve discussed, we're entering an era of earlier intervention to help prevent vision loss. I'd like to thank our wonderful panelists, Drs. Eells, Lad, Munk, and Boyer, for joining me in this educational event. 

References