Christina Kaiser Marko, PhD, and Joan W. Miller, MD

When Joan Miller, MD, finished her vitreoretinal fellowship in 1991, the field of retina was primarily surgical. While surgical advances had greatly improved outcomes in retinal detachment, diabetic retinopathy, and epiretinal membrane, treatment for age-related macular degeneration (AMD)— a leading cause of blindness—was virtually nonexistent.

We treated choroidal neovascularization (CNV) in neovascular AMD with laser photocoagulation, but laser destroyed the neural retina, CNV usually recurred, and treatment of subfoveal CNV led to immediate vision loss and a scotoma that possibly was slightly better than natural history. [1,2]

Photodynamic therapy (PDT), a technology being developed for cancer treatment, had the potential to achieve more-selective damage to CNV, preserving the overlying neurosensory retina. PDT relies on low-intensity light exposure of tissues treated with photosensitizers to produce photochemical effects. Several investigators had studied PDT using various photosensitizers, including rose bengal and chloroaluminum sulfonated phthalocyanine (CASPc), to treat experimental CNV in animal models, but the selectivity was not addressed and/or the photosensitizers had other side effects. [3-7]

As a first-year faculty member at Massachusetts Eye and Ear, Dr. Miller became interested in benzoporphyrin derivative (BPD or verteporfin), a lipophilic photosensitizer being tested in clinical trials for cutaneous metastatic tumors. If one could demonstrate effective, selective treatment of CNV using verteporfin PDT, there was potential to move to clinical trials in neovascular AMD. First, however, a slit lamp laser delivery system would be required for the range of spot size and powers needed to treat CNV. Dr. Miller worked with Coherent Medical Lasers to build a prototype system. QLT Phototherapeutics, Inc., provided the photosensitizer, which was not clinical grade, and required dimethylsulfoxide (DMSO) as a solvent.

Dr. Miller and her team performed their first experiments using an irradiance of 150 mW/cm2—the same irradiance used in both the skin cancer clinical trials and PDT of experimental choroidal melanoma. At this irradiance, she found the 16-minute treatment time too long to maintain focus on a macular lesion and determined that these laser parameters would never be practical for CNV treatment.

Increasing the irradiance to shorten the treatment time went against the teaching of experts at the time, but Dr. Miller speculated that the choroid would act as a heat sink, and she proceeded to test higher irradiances—up to 1800 mW/cm2. They performed comprehensive experiments, testing photosensitizer dose, light irradiance and fluence, and time of laser application after photosensitizer infusion; and the team investigated the effects on CNV lesions, normal retina/choroid, and the optic nerve using fundus photography, fluorescein angiography, and histopathology.[8-10]

Importantly, by using experimental parameters of 6 mg/m2 verteporfin dose, irradiance of 600 mW/cm2, and fluence of 150 J/cm2 to treat normal retina and experimental CNV, Dr. Miller and her team were able to achieve CNV closure while avoiding significant damage to the outer retina. These investigations in experimental CNV and normal retina correlated very closely with subsequent results in clinical trials—and provided essential support for the new drug application (NDA) submission to the US Food and Drug Administration (FDA). Many research fellows contributed to these efforts, including Drs. Michal Kramer, Deeba Husain, Robert Haimovici, and Martin Reinke, and technicians Rachel Moulton, Edward Connolly, and Norman Michaud.  

Based on the success of these experiments, Dr. Miller and the clinical investigators designed phase 1/2 clinical trials to evaluate the safety and short-term efficacy of verteporfin PDT for subfoveal CNV in AMD and other conditions. The Wilmer Reading Center, initially led by Dr. Susan Bressler and subsequently by Dr. Neil Bressler, provided image interpretation for the trials.

The phase 1/2 trials used an irradiance of 600 mW/cm2, but varied the verteporfin dose (6 or 12 mg/m2), time of infusion (5 or 10 minutes), time of laser light application after start of infusion (10, 15, 20, or 30 minutes), and fluence (50 to 150 J/cm2). Dr. Miller performed the first treatment of a patient with CNV using verteporfin PDT at Mass. Eye and Ear in 1995, and these first trials were carried out at Mass. Eye and Ear (Dr. Miller as principal investigator (PI)); in Lubeck, Germany (Dr. Ursula Schmidt-Erfurth as PI); Lausanne, Switzerland (Dr. Michel Sickenberg as PI); and Geneva, Switzerland (Dr. Constantin Pournaras as PI).

A maximum tolerated fluence (150 J/cm2) was identified as it led to retinal vessel occlusion, and a minimal fluence (25 J/cm2) yielded inconsistent CNV closure.[11] Verteporfin PDT was also found to be effective in CNV due to pathologic myopia, leading to a phase 3 clinical trial and eventual approval for this indication.

Phase 3 clinical trials—Treatment of Age-Related Macular Degeneration Using Photodynamic Therapy (TAP) and Verteporfin in Photodynamic Therapy (VIP)—were carried out following the positive results of the phase 1/2 clinical studies. Twenty-two clinical centers in the United States and Europe enrolled 609 patients in the TAP study in 6 months—a testament to the lack of effective therapy at the time for these patients.

In the TAP study for patients with subfoveal CNV secondary to AMD with a classic angiographic component, 61% lost fewer than 3 lines of vision from baseline at 12 months of follow-up.[12] Few ocular or systemic adverse events were noted, but included transient vision disturbances and photosensitivity, vision decrease secondary to treatment, and infusion-related back pain. Follow-up at 24 months demonstrated that the beneficial outcomes of verteporfin were maintained.[13]

In the VIP study for patients with subfoveal CNV with occult but no classic angiographic components, no difference was found at 12 months of follow-up; however, treatment led to a decrease in the risk of moderate or severe vision loss at 24 months.[14] Meta-analysis of the VIP and TAP trials demonstrated correlation between vision benefit and smaller lesion size.[15] Subjects with CNV secondary to pathologic myopia studied in the VIP trial showed benefit from verteporfin PDT at 12-month and 24-month follow-up, confirming results from phase 1/2 studies.[16]

Verteporfin PDT (Visudyne) was first approved for use in Switzerland in December 1999, with approvals following in the United States (April 2000), the European Union (July 2000), and Japan (October 2003), making it the first pharmacological treatment for neovascular AMD. Patent protection of verteporfin PDT for CNV and other indications had been sought using the data from Dr. Miller and team.

Unfortunately, Mass. Eye and Ear had not completed license arrangements, leading to a decade-long legal battle in US federal court. Mass. Eye and Ear sued QLT, Inc and its partner, Novartis, who countersued, naming Drs. Miller and Gragoudas personally, and Massachusetts General Hospital joined the countersuit. This was an interesting and educational experience; Mass. Eye and Ear won the jury trial in 2006, and following unsuccessful appeals by QLT and Novartis, received a $126 million judgment in 2009, as well as an ongoing royalty of 3.01% of all sales worldwide as long as the drug is manufactured and sold.[17]

While verteporfin PDT was being developed, Dr. Miller’s research teams were working to determine the driver of pathologic angiogenesis—identifying vascular endothelial growth factor (VEGF) as the key driver. This led to the development of anti-VEGF agents, which have largely supplanted PDT in treating neovascular AMD. PDT is still useful for some patients, and work by Dr. Gregg Kokame and others has demonstrated the effectiveness of PDT for polypoidal choroidal vasculopathy (PCV),[18] a subtype of neovascular AMD, with clinical trials supporting these observations.[19-21]

Dr. Richard Spaide made the important observation that intraocular steroid at the time of PDT improves its efficacy and duration of effect.[22] Inflammation noted in PDT lesions suggests a biologic basis for improved results from PDT combined with adjunctive corticosteroids.[23] PDT also has been found effective in treating chronic central serous chorioretinopathy (CSR), specifically using a reduced, or half-fluence.[24, 25] Although there has been some confusion in the retina community, half-fluence is achieved by reducing time only, without a need to change laser power [Table 1].

PDT was the first pharmacologic treatment approved for neovascular AMD, and represented the beginning of a paradigm shift in retina care from a predominantly surgical specialty to one with a large medical component. It was exciting to be a part of this wave of change, and to see laboratory findings translated to successful clinical treatments.

Millions of patients around the world now receive intravitreal injections of medications for an array of retinal diseases, with greatly improved outcomes. The future of retina care is bright, with many exciting innovations underway, including gene-based and cell-based therapies, neuroprotection, and artificial intelligence (AI) approaches to diagnosis and management.

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References

1.     Macular Photocoagulation Study Group. Laserphotocoagulation of subfoveal neovascular lesion in age-related maculardegeneration: results of a randomized clinical trial. Arch Ophthalmol. 1991;109(9):1220-1231. doi:10.1001/archopht.1991.01080090044025

2.     Macular Photocoagulation Study Group. Laserphotocoagulation of subfoveal neovascular lesions of age-related maculardegeneration: updated findings from two clinical trials. Arch Ophthalmol. 1993;111(9):1200-1209. doi:10.1001/archopht.1993.01090090052019

3.     Nanda S, Hatchell D, Tiedeman J, Dutton J,Hatchell M, McAdoo T. A new method of vascular occlusion. Photochemicalinitiation of thrombosis. Arch Ophthalmol. 1987;105(8):1121-1124. doi:10.1001/archopht.1987.01060080123041

4.     Miller JW, Stinson WG, Gregory WA, El-Khoumy HA,Puliafito CA. Phthalocyanine photodynamic therapy of experimental irisneovascularization. Ophthalmology. 1991;98(11):1711-1719. doi:10.1016/s0161-6420(91)32079-7

5.     Kliman G, Puliafito C, Stern D, BorirakchanyavatS, Gregory W. Phthaloycyanine photodynamic therapy: new strategy for closure ofchoroidal neovascularization. Lasers Surg Med. 1994;15(1):2-10. doi:10.1002/lsm.1900150103

6.     Kliman G, Puliafito C, Grossman G, Gregory W.Retinal and choroidal vessel closure using phthalocyanine photodynamic therapy.Lasers Surg Med. 1994;15(1):11-18. doi:10.1002/lsm.1900150104

7.     Miller H, Miller B. Photodynamic therapy ofsubretinal neovascularization in the monkey eye. Arch Ophthalmol. 1993;111(6):855-860.doi:10.1001/archopht.1993.01090060145039

8.     MillerJW, Walsh AW, Kramer M, et al. Photodynamic therapy of experimental choroidalneovascularization using lipoprotein-delivered benzoporphyrin. ArchOphthalmol. 1995;113(6):810-818.doi:10.1001/archopht.1995.01100060136048

9.     KramerM, Miller JW, Michaud N, et al. Liposomal benzoporphyrin derivativeverteporfin photodynamic therapy: selective treatment of choroidalneovascularization in monkeys. Ophthalmology. 1996;103(3):427-438. doi:10.1016/s0161-6420(96)30675-1

10.  HusainD, Miller JW, Michaud N, Connolly E, Flotte TJ, Gragoudas ES. Intravenousinfusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimentalchoroidal neovascularization. Arch Ophthalmol. 1996;114(8):978-985. doi:10.1001/archopht.1996.01100140186012

11.  Miller J, Schmidt-Erfurth U, Sickenberg M, etal. Photodynamic therapy with verteporfin for choroidal neovascularizationcaused by age-related macular degeneration. Results of a single treatment in aPhase 1 and 2 study. Arch Ophthalmol. 1999;117(9):1161-1173. doi:10.1001/archopht.117.9.1161

12.  Treatment of Age-Related Macular Degeneration WithPhotodynamic Therapy (TAP) Study Group. Verteporfin (Visudyne™) therapy ofsubfoveal choroidal neovascularization in age-related macular degeneration.One-year results of two randomized clinical trials⎯TAPReport #1. Arch Ophthalmol. 1999;117(10):1329-1345. doi:10.1001/archopht.117.10.1329

13.  Treatment of Age-Related Macular Degeneration WithPhotodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfovealchoroidal neovascularization in age-related macular degeneration withverteporfin. Two-year vision results of two randomized clinical trials. TAPReport #2. Arch Ophthalmol. 2001;119(2):198-207.

14.  Verteporfin in Photodynamic Therapy StudyGroup. Verteporfin therapy of subfoveal choroidal neovascularization inage-related macular degeneration: two-year results of a randomized clinicaltrial including lesions with occult with no classic choroidalneovascularization—verteporfin in photodynamic therapy report 2. AmJ Ophthalmol. 2001;131(5):541-560. doi:10.1016/s0002-9394(01)00967-9

15.  Bressler NM, Arnold J, Benchaboune M, et al;Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP)Study Group. Verteporfin therapy of subfoveal choroidal neovascularization inpatients with age-related macular degeneration: additional informationregarding baseline lesion composition’s impact on vision outcomes—TAPreport No. 3. Arch Ophthalmol. 2002;120(11):1443-1454. doi:10.1001/archopht.120.11.1443

16.  Sickenberg M,Schmidt-Erfurth U, Miller JW, et al. A preliminary study of photodynamictherapy using verteporfin for choroidal neovascularization in pathologic myopia,ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. ArchOphthalmol. 2000;118(3):327-336. doi:10.1001/archopht.118.3.327

17.  Mass.Eye and Ear Infirmary v QLT Phototherapeutics, Inc,552, s. Cir, Editor. 2009, F3d 47, 57.

18.  Kokame GT, de Carlo TE, KanekoKN, Omizo J, Lian R. Anti-vascular endothelial growth factor resistance inexudative macular degeneration and polypoidal choroidal vasculopathy. Ophthalmol Retina. 2019;3(9):744-752. doi:10.1016/j.oret.2019.04.018

19.  KokameGT, Kim JE. Treatment for a subtype of exudative macular degeneration—anothermountain climbed. JAMA Ophthalmol.2020;138(9):942-944. doi:10.1001/jamaophthalmol.2020.2421

20.  LimTH, Lai TYY, Takahashi K, et al; EVEREST II Study Group. Comparison ofranibizumab with or without verteporfin photodynamic therapy for polypoidalchoroidal vasculopathy: the EVEREST II randomized clinical trial. JAMA Ophthalmol. 2020;138(9):935-942. doi:10.1001/jamaophthalmol.2020.2443

21.  KohA, Lai TY, Takahashi K, et al; EVEREST II Study Group. Efficacy and safety ofranibizumab with or without verteporfin photodynamic therapy for polypoidalchoroidal vasculopathy: a randomized clinical trial. JAMA Ophthalmol. 2017;135(11):1206-1213. doi:10.1001/jamaophthalmol.2017.4030

22.  Spaide RF, Sorenson J, Maranan L. Combinedphotodynamic therapy with verteporfin and intravitreal triamcinolone acetonidefor choroidal neovascularization. Ophthalmology. 2003;110(8):1517-1525. doi:10.1016/S0161-6420(03)00544-X

23.  She H, Nakazawa T, Matsubara A, et al. Photoreceptorprotection after photodynamic therapy using dexamethasone in a rat model ofchoroidal neovascularization. Invest Ophthalmol Vis Sci. 2008;49(11):5008-5014.doi:10.1167/iovs.07-1154

24.  ReibaldiM, Cardascia N, Longo A, et al. Standard-fluence versus low-fluence photodynamic therapy in chroniccentral serous chorioretinopathy: a nonrandomized clinical trial. Am J Ophthalmol. 2010;149(2):307-315. doi:10.1016/j.ajo.2009.08.026

25.  Bae SH, Heo J, Kim C, et al.Low-fluence photodynamic therapy versus ranibizumab for chronic central serous chorioretinopathy:one-year results of a randomized trial. Ophthalmology.2014;121(2):558-565. doi:10.1016/j.ophtha.2013.09.024

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