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CLINICAL TRIAL DOWNLOAD: LIGHTSITE III 24-month Photobiomodulation Results

Noninvasive treatment could slow progression in intermediate AMD.

By: Yasha Modi, MD , Matthew W. Russell, MD, Rishi P. Singh, MD, Clark Tedford, PhD
Retinal Physician September 1, 2023 Vol 20, Issue September 2023 Page(s): 47, 48

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Photobiomodulation (PBM), previously referred to as low-level light therapy, has a 50-year history in medical research and has been investigated for treating a host of medical conditions. It is theorized that photons enter tissue and interact with enzyme cytochrome c oxidase located within mitochondria. Through an undefined mechanism, this is believed to increase cellular metabolism. In the body, this may increase wound healing or decrease pain. In the eye, increased cellular metabolism within photoreceptors or the RPE may have beneficial effects in AMD. This has been studied in preclinical and human studies with mixed results. Ultimately, randomized clinical trials with clear primary and secondary outcomes are required to demonstrate the true clinical impact of PBM in AMD.

LumiThera Inc. has been a recent driver of this technology and has established randomized clinical trials to assess the value of this technology in patients with intermediate AMD. Recently, 24-month data from the LIGHTSITE III study were released. To better understand the results, we have asked Drs. Matthew Russell and Rishi Singh of the Cleveland Clinic to share their insights and have asked Clark Tedford, PhD, of LumiThera, to respond.

Matthew W. Russell, MD, and Rishi P. Singh, MD; Cole Eye Institute

By 2040, an estimated 240 million US patients are projected to be afflicted by age-related macular degeneration.1 The advent of anti–vascular endothelial growth factor agents has proven to stave off visual decline in patients with advanced exudative AMD. However, limited options exist for patients hoping to mitigate progression of early and intermediate AMD to more advanced visually threatening stages. While the AREDS vitamin formulations may benefit some patient populations with intermediate AMD, they are not efficacious for all patients, highlighting an unmet need for more modalities to reduce AMD progression.2

Photobiomodulation therapy uses serial illuminations of visible and near infrared spectrum light (590 nm to 1,000 nm) from light-emitting diodes. When targeted in the retinal tissue, PBM may improve photoreceptor mitochondrial function and reduce inflammation, working against 2 pathologic mechanisms of AMD.3,4 Putting PBM and AMD into investigation, the landmark TORPA 1 trial demonstrated visual acuity (VA) improvements in a small cohort of eyes after treatment with PBM.5 Following this work, the TORPA 2 trial examined a larger cohort of AMD eyes, again finding VA improvements from baseline. While promising, the TORPA studies have both been limited by lack of randomization and comparator groups.6

The LIGHTSITE I trial also evaluated PBM in a similar sized cohort as the TORPA 2 trial, but it differed through the use of the Valeda Light Delivery System (LumiThera), which uses slightly differing therapeutic wavelengths and longer treatment duration, and a randomized sham-controlled study design. The LIGHTSITE I trial found increases in VA, but a decline to near baseline values at 6 months, suggesting need for repeat treatment in PBM delivery.7 A reduction in drusen volume relative to a control group was also noted in the PBM arm. In response to these positive findings, the LIGHTSITE II and III trials were set forth to further investigate the efficacy of PBM in management of AMD. The LIGHTSITE II trial, a sham-controlled, prospective, multicenter trial, investigated PBM, finding that PBM-managed eyes showed increases in VA, stable drusen volume, and reductions in geographic atrophy (GA) lesion growth compared to sham-treated eyes.8

The LIGHTSITE III trial has recently released the highest powered, longest duration clinical data to date regarding PBM in patients with AMD. In a sham-controlled, prospective, multicenter fashion, the LIGHTSITE III trial enrolled 100 subjects with intermediate AMD to be treated with PBM over a 24-month period. Initially at 13 months, the LIGHTSIDE III data found that PBM-treated eyes had significantly improved VA of 5.4 letters from baseline. At 24 months, these significant visual changes were found to be sustained, with an average improvement of 5.9 letters from baseline.9 In addition, the PBM-treated eyes showed a reduction in the number of subjects losing >5 letters (7% vs 18%) vs the sham-treated eyes at 24 months, suggesting a slowing of vision loss over the study. Also, significantly fewer PBM-treated than sham-treated eyes were found to progress to GA: 6.8% vs 24%, respectively. The results of the LIGHTSITE III trial are highly encouraging, offering one of the first modalities that may reduce AMD progression and visual decline in early stages of disease.

The retina community eagerly anticipates further data from higher powered PBM studies to assess the clinical efficacy of PBM across different clinical settings and AMD stages. The advantages of at-home treatment with a noninvasive mechanism is of particular interest to address this unmet need.

Clark E. Tedford, PhD; LumiThera, Inc.

The development of treatments for early to intermediate dry AMD is paramount. The earlier that treatment can begin, the better the opportunity to slow or stop disease progression. Once patients advance to later stage GA, their ophthalmologists are only addressing slowing of further vision loss. The improvement or recovery of vision is only possible if we treat tissue before it is gone. The halting or slowing of vision loss is very important in the maintaince of the quality of life for patients with AMD.

The Valeda Light Delivery System was developed using PBM. Valeda is CE Marked in Europe and available in select countries in Latin America. Valeda is not FDA approved. Valeda has a unique beam delivery system that targets the retinal tissue with a column of expanding light to treat the retina with a multiwavelength approach. Each of the 3 wavelengths has been shown to target different mechanisms important in the underlying etiology of AMD. The mitochondrial target, cytochrome c oxidase, is a key photoacceptor, and stimulation can help restore the mitochondrial gradient that promotes adenosine triphosphate production. This approach can reset metabolic activity, and repeat treatments can provide sustained benefits, as shown in the clinical trials.

Although PBM is well established in other therapeutic areas, its use in ophthalmology is still evolving. The 24 months of sustained benefits in vision and the slowing of progression to new GA seen in patients in the LIGHTSITE III trial is exciting. Valeda is a noninvasive treatment and provides an option for patients to be treated earlier in the disease cycle. We hope to continue to develop the use of Valeda as a platform for various ocular indications and continue to expand and optimize its benefits in AMD patients. RP

Yasha Modi, MD, is a retina specialist in the department of ophthalmology at NYU Langone Health Center in New York, New York. He reports consultancy to Allergan, Alimera, Genentech, Thea, and Zeiss. Matthew W. Russell, MD, is a resident physician at Cleveland Clinic Cole Eye Institute in Cleveland, Ohio. He reports no relevant disclosures. Rishi P. Singh, MD, is a staff physician and president at Cleveland Clinic Martin Hospital in Stuart, Florida. He reports no relevant disclosures. Clark Tedford, PhD, is the founder, president, and CEO of LumiThera. Reach Dr. Modi at yasha.modi@gmail.com.

REFERENCES

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  6. Merry GF, Munk MR, Dotson RS, Walker MG, Devenyi RG. Photobiomodulation reduces drusen volume and improves visual acuity and contrast sensitivity in dry age-related macular degeneration. Acta Ophthalmol. 2017;95(4):e270-e277. doi:10.1111/aos.13354
  7. 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. doi:10.1097/IAE.0000000000002632
  8. Burton B, Parodi MB, Jürgens I, et al. LIGHTSITE II randomized multicenter trial: evaluation of multiwavelength photobiomodulation in non-exudative age-related macular degeneration. Ophthalmol Ther. 2023;12(2):953-968. doi:10.1007/s40123-022-00640-6
  9. Study of photobiomodulation to treat dry age-related macular degeneration (LIGHTSITE III). Clinicaltrials.gov identifier: NCT04065490. Updated February 5, 2021. Accessed July 10, 2023. https://clinicaltrials.gov/ct2/show/NCT04065490

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