Verteporfin

Photodynamic therapy (PDT) with verteporfin (Visudyne®), a photosensitising protoporphyrin derivative, is used in the management of subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD) or pathological myopia (PM).

PDT with verteporfin over 1 and 2 years reduces the decline in visual acuity in patients with classic-containing subfoveal CNV secondary to AMD. Verteporfin is generally well tolerated by most patients. Verteporfin is also effective in patients with CNV secondary to PM, although data in this indication are limited and further controlled studies are required. Although verteporfin has shown efficacy in patients with occult AMD-related subfoveal CNV lesions in early trials, data are currently limited on its first-line use in this indication; fully published data from the Verteporfin In Occult (VIO) trial are therefore awaited with interest. Verteporfin should be considered as a first-line treatment in patients with predominantly classic subfoveal CNV secondary to AMD, and in patients with smaller minimally classic subfoveal CNV lesions. It may also be considered an option for the treatment of patients with occult AMD-related subfoveal CNV in whom visual acuity decreases or predominantly classic features develop over time.

Verteporfin is a light-activated photosensitising drug administered in a liposomal formulation, which is preferentially taken up by cells such as neovascular endothelium that have increased expression of low-density-lipoprotein receptors. When activated with a 50 J/cm² light dose, verteporfin generates singlet oxygen and free radicals that cause endothelial damage and occlude smaller blood vessels. Light activation uses a 689nm wavelength, based on a 680–695nm verteporfin absorption peak that is close to the 700nm at which the best tissue penetration occurs.

The maximum plasma concentration of verteporfin occurs at the end of the intravenous infusion of the drug and the elimination half-life is ≈6 hours. The rapid uptake and clearance of verteporfin increases the likelihood of selective damage to neovascular cells, sparing retinal pigment epithelium and the retina. However, patent blood vessels may persist, necessitating repeated treatments in most patients, and angiogenesis may also occur after PDT. Verteporfin is mostly bound to plasma proteins. Only 10% is metabolised; 90% is excreted unchanged in faeces. Pharmacokinetics are not significantly affected by age or sex, and the potential for drug interactions is low.

PDT using verteporfin 6 mg/m² activated with a 50 J/cm² light dose (verteporfin therapy), 3-monthly as required, significantly reduced the loss of best-corrected visual acuity (BCVA) compared with placebo in patients with subfoveal CNV secondary to AMD over 12 months and/or 24 months. In several well designed trials of up to 24 months’ duration, a BCVA loss of <15 letters from baseline (primary efficacy outcome) in correctly enrolled patients occurred in 61% of verteporfin and 46% of placebo recipients with classic-containing CNV lesions over 1 year (primary endpoint) and 53% and 38% over 2 years; in 45% of verteporfin and 32% of placebo recipients with occult lesions over 2 years; and in 78% of verteporfin and 55% of placebo recipients with minimally classic lesions over 1 year (primary endpoint) and 60% and 38% over 2 years. Verteporfin recipients required more treatments (not statistically significant) in year 1 (mean 2.9–3.4) than in year 2 (0.8–2.2); corresponding numbers of annual treatments in placebo recipients were 3.0–3.7 and 1.4–2.8.

In an analysis of two of the trials, verteporfin was found to be more effective than placebo in almost all predominantly classic CNV lesions, but only in smaller minimally classic and occult lesions (sized ≤4 or ≤5 Macular Photocoagulation Study disc areas [MPS DA; 1 MPS DA = 2.54mm² on the retina]). In addition, recent preliminary results of a well designed trial in patients with occult CNV suggest that verteporfin did not significantly improve outcomes versus placebo. Results of a prospective noncomparative case series study have led to a recommendation of continued monitoring, instead of cessation of follow-up, for patients with occult AMD-related subfoveal CNV with no classic lesions. Of note, if visual acuity decreases or predominantly classic features develop in these patients, PDT with verteporfin can be considered as a treatment option.

In CNV secondary to PM, verteporfin was significantly better than placebo in reducing mild, moderate or severe loss of visual acuity after 1 year (primary endpoint), but not 2 years, in a well designed but relatively small study. CNV lesions were, however, significantly smaller in verteporfin recipients after 2 years.

Verteporfin was generally well tolerated in randomised trials. Common non-study-eye adverse events were injection-site reactions, infusion-related back pain, nausea, photosensitivity reactions, asthenia and hypercholesterolaemia, each affecting 1–10% of patients. Hypersensitivity reactions are uncommon but can be severe. Injection-site reactions, which occurred in 13.1% of verteporfin versus 5.6% of placebo recipients in two large trials, and infusion-related back pain, photosensitivity reactions, constipation and sleep disorders (each affecting 1.6–2.4% of verteporfin vs 0–0.3% of placebo recipients) were the only non-ocular events reported significantly more frequently with verteporfin.

Study-eye adverse events were also common, with ‘all visual disturbances’ significantly more frequent in verteporfin recipients in one trial (41.7% vs 22.8% with placebo) and numerically more common (22.1% and 15.5%) in another. An acute severe visual acuity decrease (BCVA loss of ≥20 letters within 7 days of verteporfin treatment) was the most serious event, affecting 15 verteporfin and 1 placebo recipients, in several large trials; the incidence was ≈5% in patients with good baseline visual acuity or occult lesions. Most patients subsequently recovered some visual acuity. About 13% of patients with post-verteporfin subfoveal haemorrhage also experienced an acute severe visual acuity decrease in a noncomparative study; haemorrhage was generally resorbed and some visual acuity recovered within 3 months.