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Verteporfin

A Review of its Use in the Management of Subfoveal Choroidal Neovascularisation

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Summary

Abstract

Verteporfin (Visudyne®) therapy (photodynamic therapy with intravenous liposomal verteporfin) is the first treatment to effectively prevent the loss of visual acuity in patients with subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD), pathological myopia or presumed ocular histoplasmosis syndrome (POHS).

In adult patients with classic subfoveal CNV or occult with no classic subfoveal CNV secondary to AMD, or subfoveal CNV secondary to pathological myopia or POHS, verteporfin therapy slows or prevents loss of visual acuity. In well designed clinical trials, verteporfin therapy was superior to placebo in patients with subfoveal classic-containing CNV and occult with no classic CNV secondary to AMD at 12 and/or 24 months (Treatment of Age-related macular degeneration with Photodynamic therapy [TAP] Investigation and Verteporfin In Photodynamic therapy [VIP-AMD] trial) and in patients with pathological myopia at 12 months (Verteporfin In Photodynamic therapy [VIP-PM] trial). Limited data suggest that verteporfin therapy also prevents loss of visual acuity in patients with subfoveal CNV secondary to POHS.

Verteporfin therapy was generally well tolerated in clinical trials; most adverse events were mild to moderate in intensity and transient. The most frequently reported verteporfin therapy-related adverse events (incidence >2%) were visual disturbance, injection-site reactions, photosensitivity reactions and infusion-related back pain. Approximately 5% of patients with occult with no classic subfoveal CNV secondary to AMD reported severe vision decrease within 7 days of treatment in clinical trials; 3 months later, several patients had recovered some of this loss.

Conclusion: Photodynamic therapy with verteporfin, the first photosensitiser approved for the treatment of subfoveal CNV, is a well tolerated treatment that stabilises or slows visual acuity loss in adult patients with predominantly classic or occult with no classic subfoveal CNV secondary to AMD, and subfoveal CNV secondary to pathological myopia or POHS. Thus, verteporfin therapy provides a valuable option for the management of these patients for whom treatment options are few, and should be considered as a first-line therapy in these difficult-to-manage conditions.

Pharmacodynamic Properties

Verteporfin, a benzoporphyrin derivative monoacid ring A, is a highly hydrophobic, chlorin-like photosensitiser synthesised from protoporphyrin that is activated by low-intensity nonthermal laser light at a wavelength of 689nm. In its excited state, verteporfin is an efficient generator of singlet oxygen, which is believed to be primarily responsible for cell death after photodynamic therapy (PDT). Verteporfin is approximately four times more active in vitro than haematoporphyrin in absorbing light at wavelengths that best penetrate tissue (≈700nm). Although the exact mechanism of its action is not known, PDT is thought to involve cellular, vascular or immunological mechanisms, with the relative contribution of each depending on the photosensitiser, the tissue treated and treatment parameters.

Verteporfin is selectively taken up by cells with high levels of low-density lipoprotein receptors (including neovascular endothelium) as a result of its affinity for plasma lipoproteins.

Activated verteporfin had greater in vitro cytotoxicity against several human adherent and non-adherent cell lines than haematoporphyrin (10- to 70-fold) and against human PROb and REGb colon cancer cell lines than porfimer sodium (14-and 17-fold).

Verteporfin therapy (photodynamic therapy with liposomal verteporfin) selectively destroys areas of neovascularisation within the eye while sparing adjacent normal vasculature. Histopathological evidence from patients with subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD) or with malignant melanoma of the uvea showed that light-activated verteporfin appears to damage vascular endothelial cells.

In patients with subfoveal CNV secondary to AMD given single or 3-monthly treatments with intravenous (IV) verteporfin, the optimal dose (which was used in subsequent clinical trials) providing complete or partial occlusion of the lesion was verteporfin 6 mg/m2, activated 15 minutes after commencing the infusion using a 689nm laser light at an intensity of 600 mW/cm2 for 83 seconds delivering a light dose of 50 J/cm2. Complete occlusion of CNV was observed more frequently in patients with classic-containing subfoveal CNV than in those with occult with no classic subfoveal CNV. Dose-finding studies indicate that the maximum tolerated light dose is <150 J/cm2.

Pharmacokinetic Properties

Mean area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) values increased proportionately in a mixed volunteer population of healthy individuals and patients with mild hepatic impairment, skin cancer or subfoveal CNV secondary to AMD who received verteporfin 3–20 mg/m2 over 1.5–45 minutes. There were no clinically important differences in the AUC or Cmax values in patients with mild hepatic impairment who received verteporfin compared with healthy volunteers.

The volume of distribution of verteporfin in healthy volunteers was 0.4–0.6 L/kg; 91% of a dose of liposomal verteporfin was bound to lipoproteins, with binding distributed relatively evenly between the high-density lipoprotein, low-density lipoprotein and very low-density lipoprotein fractions in vitro.

Verteporfin is metabolised minimally by liver and plasma esterases, with the majority of an IV dose eliminated unchanged in faeces; <0.01% is excreted via the kidney. Verteporfin has a biexponential elimination curve after IV infusion, with a terminal half-life (t½) of 5–6 hours. Cytochrome P450 isoenzymes do not appear to have a role in verteporfin metabolism. Clinically important differences in verteporfin t½ values were not observed in patients with mild hepatic impairment and dose adjustments are not required.

Age, race, and gender had no clinically important effects on the pharmacokinetic parameters of IV verteporfin.

Clinical Efficacy Secondary to AMD: Verteporfin therapy had a beneficial effect on the loss of visual acuity in patients with classic-containing subfoveal CNV secondary to AMD, according to data from the 2-year Treatment of Age-related macular degeneration with Photodynamic therapy (TAP) Investigation. Verteporfin therapy was superior to placebo in terms of loss of <15 letters (the primary efficacy outcome) and loss of contrast sensitivity letters at 12 and 24 months (all p < 0.001). The beneficial effect of verteporfin therapy was maintained at 60 months in patients with predominantly classic subfoveal CNV who had received verteporfin therapy in the TAP Investigation and participated in an extension study.

Subgroup analyses indicate that verteporfin therapy produced greater benefits in patients with predominantly classic subfoveal CNV than in those with minimally classic CNV. This was confirmed by 12-month relative risk reduction, absolute risk reduction and relative risk analyses.

Recurrence and progression of CNV and leakage from classic-containing subfoveal CNV were slowed by verteporfin therapy at 24 months compared with placebo (both p < 0.001). In addition, the need for 3-monthly treatments in both treatment groups decreased throughout the study period. These effects were maintained at 60 months in patients with predominantly classic subfoveal CNV who had received verteporfin therapy in the TAP Investigation and participated in an extension study.

Verteporfin therapy demonstrated a treatment benefit for patients with occult with no classic subfoveal CNV and presumed recent disease progression secondary to AMD after 24 months’ treatment, according to data from the AMD Verteporfin In Photodynamic therapy (VIP-AMD) trial. Verteporfin therapy was superior to placebo for loss of <15 letters at 24 months (p < 0.05), but not at the 12-month examination. Change in mean contrast sensitivity letter scores from baseline also favoured patients treated with verteporfin therapy at 24 months.

Leakage from, and the growth and progression of CNV appeared to be slowed with verteporfin therapy in patients with occult with no classic subfoveal CNV. At 24 months, absence of leakage from occult CNV was more common with verteporfin therapy than with placebo (p < 0.05), and verteporfin therapy recipients were more likely to have smaller lesions. Progression of occult CNV was observed in fewer verteporfin therapy than placebo recipients at 12 months (p = 0.004), but not at 24 months. The need for 3-monthly treatments in both study groups decreased during the study period.

Retrospective analyses of data from the TAP Investigation and the VIP-AMD trial showed that baseline lesion size (lesion size ≤4 Macular Photocoagulation Study disc areas) was an important predictor of treatment efficacy in patients with minimally classic or occult with no classic subfoveal CNV secondary to AMD.

Secondary to Pathological Myopia: Verteporfin therapy was more effective than placebo at preventing loss of visual acuity in patients with subfoveal CNV secondary to pathological myopia at 12 months, according to data from the VIP Trial in patients with pathological myopia (VIP-PM trial). At this timepoint, more verteporfin therapy than placebo recipients lost <8 letters (primary endpoint; p < 0.01) and the overall distribution of changes in contrast sensitivity favoured verteporfin therapy (p = 0.02 vs placebo). The beneficial outcome of verteporfin therapy in patients in the VIP-PM trial was maintained for a further 12 months; however, differences in primary and secondary outcomes compared with placebo were no longer statistically significant.

Leakage from CNV and disease progression occurred in similar percentages of verteporfin therapy and placebo recipients at 12 and 24 months. The need for 3-monthly treatments in both treatment groups decreased during the study.

Secondary to Presumed Ocular Histoplasmosis Syndrome (POHS): Verteporfin therapy stabilised or improved vision in patients with subfoveal CNV secondary to POHS, according to results of the Verteporfin in Ocular Histoplasmosis (VOH) study. Improvements in median visual acuity and contrast sensitivity from baseline observed at 12 months were maintained at 24 months. Lesion progression or leakage outside the baseline area of CNV was observed in 50% or fewer patients (n = 25) at the 12-month examination.

Pharmacoeconomic Analyses

Limited pharmacoeconomic data from retrospective UK, Canadian and Australian studies (based on data from the TAP Investigation, the TAP Extension study and the VIP-AMD trial) suggest that verteporfin therapy is a cost effective treatment in selected patients with classic-containing subfoveal CNV secondary to AMD.

A UK analysis that was based on costs for treatment and social care for people with poor vision suggested that verteporfin therapy was cost effective relative to placebo in the long term (5 years; currency year not given) in patients with predominantly classic subfoveal CNV, provided baseline visual acuity was good (20/40).

In the Australian studies, the estimated incremental cost/vision-year gained with verteporfin therapy from a societal perspective compared with no treatment was considerably lower than the generally accepted Australian threshold of incremental cost effectiveness (currency year not given).

The Canadian analysis (which was conducted from the perspective of a for-profit third-party insurer) showed that verteporfin therapy in patients with good visual acuity (20/40) was modestly cost effective at 2 years and approached cost effectiveness at 11 years (currency year 2000). In patients with poor visual acuity (20/200), verteporfin was not cost effective at 2 years, but achieved modest cost effectiveness at 11 years.

Tolerability

Verteporfin therapy was generally well tolerated in patients with subfoveal CNV secondary to AMD, pathological myopia or POHS. Adverse events were generally transient and mild to moderate in intensity and were not considered to be serious or life-threatening, nor were any treatment-related deaths reported. Few patients (1.7% of verteporfin recipients with AMD in the TAP Investigation and and 4.8% of those in the VIP-AMD trial, and one verteporfin recipient with pathological myopia in the VIP-PM trial) withdrew from the trials because of a verteporfin therapy-related adverse event.

In the TAP Investigation (classic-containing subfoveal CNV secondary to AMD), similar percentages of treatment-related adverse events were reported by verteporfin therapy or placebo recipients at 24 months (48% vs 34%). The most common clinically relevant adverse events in recipients of verteporfin therapy or placebo were visual disturbance (22.1% vs 15.5% of patients) and injection-site reactions (15.9% vs 5.8%). Less frequently reported adverse events (≤4%) included infusion-related back pain, allergic reactions, vitreous haemorrhage and retinal capillary non-perfusion. In verteporfin therapy recipients, photosensitivity reactions thought to be caused by verteporfin therapy occurred in a minority of patients (3.5%); these were generally a transient, mild-to-moderate sunburn within 24 hours of drug administration. Verteporfin therapy was well tolerated for up to 60 months in patients with subfoveal CNV secondary to AMD who were assigned to verteporfin therapy in the TAP Investigation and who participated in the TAP Extension study.

The type and incidence of adverse event reported in the VIP Trial in patients with occult with no classic subfoveal CNV secondary to AMD (VIP-AMD) or subfoveal CNV secondary to pathological myopia (VIP-PM) were generally similar to those seen in patients with classic-containing subfoveal CNV secondary to AMD.

Fewer verteporfin therapy than placebo recipients experienced an increase in subretinal or intraretinal haemorrhage from baseline throughout the TAP Investigation or the VIP-AMD trial. A small number of verteporfin therapy recipients with occult with no classic subfoveal CNV secondary to AMD (10 of 225 patients in the VIP-AMD trial) experienced an acute severe vision decrease within 7 days of treatment, which partially resolved in some patients.

Dosage and Administration

Verteporfin therapy, a two-step process requiring administration of the drug and its activation by nonthermal red light, is recommended in more than 70 countries, including the US and the EU, for the treatment of eligible adult patients with predominantly classic (and in more than 30 countries, including the EU, in those with occult with no classic lesions) subfoveal CNV secondary to AMD or subfoveal CNV secondary to pathological myopia; it is also recommended in the US for the treatment of subfoveal CNV secondary to POHS. The recommended dose of IV verteporfin is 6 mg/m2 administered over 10 minutes. Fifteen minutes after commencing the verteporfin infusion, a light dose of 50 J/cm2 at an intensity of 600 mW/cm2 is delivered over 83 seconds, using nonthermal 689nm wavelength laser light. Patients should be re-evaluated every 3 months for signs of leakage from CNV and treated as required. In patients who have eligible lesions in both eyes, concurrent treatment should be considered.

In the US, caution is required in patients with moderate or severe hepatic impairment or biliary obstruction, as efficacy and tolerability have not been evaluated in these patients; in the EU, verteporfin therapy is contraindicated in patients with severe hepatic impairment. Dose reduction is not required in the elderly, or in patients with mild hepatic impairment or with renal impairment. Patients should avoid exposure to sunlight or bright indoor light for 48 hours (EU and other countries, including Canada and Australia) or 5 days (US). Verteporfin is contraindicated in patients with porphyria and is not recommended for use in patients under the age of 18 years, in pregnant women, or in breastfeeding women (in the EU only). Verteporfin therapy should not be administered to an anaesthetised patient, as efficacy and tolerability have not been established in these patients.

Although no clinical studies have been conducted, verteporfin may potentially interact with several drugs including other photosensitising agents, drugs that quench oxygen species or scavenge free radicals, and those that decrease clotting or cause vasoconstriction or platelet aggregation.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Susan J. Keam, Lesley J. Scott & Monique P. Curran

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  1. Susan J. Keam
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  2. Lesley J. Scott
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  3. Monique P. Curran
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Correspondence to Susan J. Keam.

Additional information

Various sections of the manuscript reviewed by: P. Kaiser, The Cleveland Clinic Foundation, Cole Eye Institute, Cleveland, Ohio, USA; M. Potter, University of British Columbia, Department of Ophthalmology, Vancouver, British Columbia, Canada; S. Sharma, Queen’s University, Department of Ophthalmology, Kingston, Ontario, Canada; M. Stur, University of Vienna Medical School, Allegemeines Krankenhaus, Department of Ophthalmology, Vienna, Austria; S. Wolf, Klinik und Poliklinik für Augenheilkunde, Leipzig, Germany.

Data Selection

Sources: Medical literature published in any language since 1980 on drug-name, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘verteporfin’ or ‘BPD MA’. EMBASE search terms were ‘verteporfin’ or ‘BPD MA’. AdisBase search terms were ‘verteporfin’ or ‘BPD MA’. Searches were last updated 3 October 2003.

Selection: Studies in patients with subfoveal choroidal neovascularisation secondary to age-related macular degeneration, presumed ocular histoplasmosis or pathologic myopia who received verteporfin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Verteporfin, photodynamic therapy, choroidal neovascularisation, age-related macular degeneration, presumed ocular histoplasmosis syndrome, pathologic myopia, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Keam, S.J., Scott, L.J. & Curran, M.P. Verteporfin. Drugs 63, 2521–2554 (2003). https://doi.org/10.2165/00003495-200363220-00016

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