Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489, Greifswald, Germany
Pharmacotherapeutic group: Ophthalmologicals, Antineovascularisation agents
ATC code: S01LA01
Verteporfin, also referred to as benzoporphyrin derivative monoacids (BPD-MA) consists of a 1:1 mixture of the equally active regioisomers BPD-MAC and BPD-MAD. It is used as a light-activated medicinal product (photosensitiser).
By itself, the clinically recommended dose of verteporfin is not cytotoxic. It produces cytotoxic agents only when activated by light in the presence of oxygen. When energy absorbed by the porphyrin is transferred to oxygen, highly reactive short-lived singlet oxygen is generated. Singlet oxygen causes damage to biological structures within the diffusion range, leading to local vascular occlusion, cell damage and, under certain conditions, cell death.
The selectivity of PDT using verteporfin is based, in addition to the localised light exposure, on selective and rapid uptake and retention of verteporfin by rapidly proliferating cells including the endothelium of choroidal neovasculature.
Visudyne has been studied in two randomised, placebo-controlled, double-masked, multicentre studies (BPD OCR 002 A and B or Treatment of Age-related Macular Degeneration with Photodynamic Therapy [TAP]). A total of 609 patients were enrolled (402 Visudyne, 207 placebo).
The objective was to demonstrate the long-term efficacy and safety of photodynamic therapy with verteporfin in limiting the decrease in visual acuity in patients with subfoveal choroidal neovascularisation due to age-related macular degeneration.
The primary efficacy variable was responder rate, defined as the proportion of patients who lost less than 15 letters (equivalent to 3 lines) of visual acuity (measured with the ETDRS charts) at month 12 relative to baseline.
The following inclusion criteria were considered for the treatment: patients older than 50 years of age, presence of CNV secondary to AMD, presence of classic lesion components in the CNV (defined as a well-demarcated area of the fluorescence on angiography), CNV located subfoveally (involved the geometric centre of the foveal avascular zone), area of classic plus occult CNV ≥50% of the total lesion surface, greatest linear dimension of the entire lesion ≤9 Macular Photocoagulation Study (MPS) disc area, and a best-corrected visual acuity between 34 and 73 letters (i.e. approximately 20/40 and 20/200) in the treated eye. Presence of occult CNV lesions (fluorescence not well demarcated on the angiogram) was allowed.
Results indicate that, at 12 months, Visudyne was statistically superior to placebo in terms of the proportion of patients responding to the treatment. The studies showed a difference of 15% between treatment groups (61% for Visudyne-treated patients compared to 46% placebo-treated patients, p<0.001, ITT analysis). This 15% difference between treatment groups was confirmed at 24 months (53% Visudyne versus 38% placebo, p<0.001).
The subgroup of patients with predominantly classic CNV lesions (N=243; Visudyne 159, placebo 84) were more likely to exhibit a larger treatment benefit. After 12 months, these patients showed a difference of 28% between treatment groups (67% for Visudyne patients compared to 39% for placebo patients, p<0.001); the benefit was maintained at 24 months (59% versus 31%, p<0.001).
In patients followed from month 24 onwards and treated with uncontrolled, open-label Visudyne treatment as needed, long-term extension data suggest that month-24 vision outcomes may be sustained for up to 60 months.
In the TAP study in all lesion types, the average number of treatments per year were 3.5 in the first year after diagnosis and 2.4 in the second for the randomised placebo-controlled phase and 1.3 in the third year, 0.4 in the fourth and 0.1 in the fifth year for the open-label extension phase.
No additional safety concern was identified.
The benefit of the product in the AMD patient population who have occult subfoveal CNV with evidence of recent or ongoing disease progression has not been demonstrated consistently.
Two randomised, placebo-controlled, double-masked, multicentre, 24-month studies (BPD OCR 003 AMD, or Verteporfin in Photodynamic Therapy-AMD [VIP-AMD], and BPD OCR 013, or Visudyne in Occult Choroidal Neovascularisation [VIO]) were conducted in patients with AMD characterised by occult with no classic subfoveal CNV.
The VIO study included patients with occult with no classic subfoveal CNV with a visual acuity score of 73-34 letters (20/40-20/200), and patients with lesions >4 MPS disc areas were to have baseline visual acuity <65 letters (<20/50). 364 patients (244 verteporfin, 120 placebo) were enrolled in this study. The primary efficacy parameter was the same as in TAP (see above), with an additional endpoint of month 24 defined. Another efficacy parameter was also defined: the proportion of patients who lost less than 30 letters (equivalent to 6 lines) of visual acuity at months 12 and 24 relative to baseline. The study did not show statistically significant results on the primary efficacy parameter at month 12 (15-letter responder rate 62.7% versus 55.0%, p=0.150; 30-letter responder rate 84.0% versus 83.3%, p=0.868) or at month 24 (15-letter responder rate 53.3% versus 47.5%, p=0.300; 30- letter responder rate 77.5% versus 75.0%, p=0.602). A higher percentage of patients who received Visudyne, compared with those who received placebo, experienced adverse events (88.1% versus 81.7%), associated adverse events (23.0% versus 7.5%), events leading to discontinuation (11.9% versus 3.3%) and events leading to death (n=10 [4.1%] versus n=1 [0.8%]). No death was considered to be related to treatment.
The VIP-AMD included patients with occult with no classic subfoveal CNV with a visual acuity score of >50 letters (20/100). This study also included patients with classic containing CNV with a visual acuity score >70 letters (20/40). 339 patients (225 verteporfin, 114 placebo) were enrolled in this study. The efficacy parameter was the same as in TAP and VIO (see above). At month 12, the study did not show statistically significant results on the primary efficacy parameter (responder rate 49.3% versus 45.6%, p=0.517). At month 24, a statistically significant difference of 12.9% in favour of Visudyne compared to placebo was observed (46.2% versus 33.3%, p=0.023). A group of patients who had occult with no classic lesions (n=258) showed a statistically significant difference of 13.7% in favour of Visudyne compared to placebo (45.2% versus 31.5%, p=0.032). A higher percentage of patients who received Visudyne, compared with those who received placebo, experienced adverse events (89.3% versus 82.5%), associated adverse events (42.7% versus 18.4%) and events leading to discontinuation (6.2% versus 0.9%). A lower percentage of Visudyne patients had events leading to death (n=4 [1.8%] versus n=3 [2.6%]); no death was considered to be related to treatment.
One multicentre, double-masked, placebo-controlled, randomised study (BPD OCR 003 PM [VIP-PM]) was conducted in patients with subfoveal choroidal neovascularisation caused by pathological myopia. A total of 120 patients (81 Visudyne, 39 placebo) were enrolled in the study. The posology and retreatments were the same as in the AMD studies.
At month 12, there was a benefit of Visudyne for the primary efficacy endpoint (percentage of patients who lost less than 3 lines of visual acuity) – 86% for Visudyne versus 67% for placebo, p=0.011. The percentage of patients who lost less than 1.5 lines was 72% for Visudyne and 44% for placebo (p=0.003).
At month 24, 79% Visudyne patients versus 72% placebo patients had lost less than 3 lines of visual acuity (p=0.38). The percentage of patients who lost less than 1.5 lines was 64% for Visudyne and 49% for placebo (p=0.106). This indicates that clinical benefit may diminish over time.
In patients followed from month 24 onwards and treated with uncontrolled, open-label Visudyne treatment as needed, long-term extension data suggest that month-24 vision outcomes may be sustained for up to 60 months.
In the VIP-PM study in pathological myopia, the average number of treatments per year were 3.5 in the first year after diagnosis and 1.8 in the second for the randomised placebo-controlled phase and 0.4 in the third year, 0.2 in the fourth and 0.1 in the fifth year for the open-label extension phase.
No additional safety concern was identified.
The two regioisomers of verteporfin exhibit similar pharmacokinetic properties of distribution and elimination and thus both isomers are considered verteporfin as a whole from the pharmacokinetic perspective.
Cmax after a 10-minute infusion of 6 and 12 mg/m² body surface area in the target population is approximately 1.5 and 3.5 μg/ml, respectively. The volume of distribution of around 0.60 l/kg at steady state and clearance of around 101 ml/h/kg has been reported following a 10-minute infusion in dose range of 3-14 mg/m². A maximum 2-fold inter-individual variation in plasma concentrations at Cmax (immediately after end of the infusion) and at the time of light administration was found for each Visudyne dose administered.
In whole human blood, 90% of verteporfin is associated with plasma and 10% associated with blood cells, of which very little was membrane associated. In human plasma, 90% of verteporfin is associated with plasma lipoprotein fractions and approximately 6% are associated with albumin.
The ester group of verteporfin is hydrolysed via plasma and hepatic esterases, leading to the formation of benzoporphyrin derivative diacid (BPD-DA). BPD-DA is also a photosensitiser but its systemic exposure is low (5-10% of the verteporfin exposure, suggesting that most of the active substance is eliminated unchanged). In vitro studies did not show any significant involvement of oxidative metabolism by cytochrome P450 enzymes.
Plasma elimination half-life mean values ranged from approximately 5–6 hours for verteporfin.
Combined excretion of verteporfin and BPD-DA in human urine was less than 1%, suggesting biliary excretion.
The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m².
Although mean plasma Cmax and AUC values in elderly patients who received verteporfin are higher than those in young volunteers or patients, these differences are not considered to be clinically significant.
In a study of patients with mild hepatic impairment (defined as having two abnormal hepatic function tests at enrolment), AUC and Cmax were not significantly different from the control group. Half-life, however, was significantly increased by approximately 20%.
No studies on the pharmacokinetics of verteporfin in patients with renal impairment are reported. The renal excretion of verteporfin and its metabolite is minimal (<1% of the verteporfin dose) and thus, clinically significant changes in verteporfin exposure in patients with renal impairment are unlikely.
The pharmacokinetics of verteporfin have been reported to be similar in healthy Caucasian and Japanese men after a dose of 6 mg/m² by a 10-minute infusion.
At the intended dose, pharmacokinetic parameters are not significantly affected by gender.
The acute and light-dependent toxicity of verteporfin was characterised by dose dependent localised deep-tissue damage as a consequence of the pharmacological effect of PDT with verteporfin. Toxicity observed following multiple doses of verteporfin without light was associated mainly with effects on the haematopoietic system. The extent and severity of these effects were consistent among all studies and were dependent on drug dose and dosing duration.
Levels of ocular toxicity in healthy rabbits and monkeys, particularly on the retina/choroid, correlated with medicinal product dose, light dose, and time of light treatment. A retinal toxicity study in healthy dogs with intravenous verteporfin and ambient light on the eye showed no treatment-related ocular toxicity.
In pregnant rats, intravenous verteporfin doses of 10 mg/kg/day (approximately 40-fold human exposure at 6 mg/m² based on AUCinf in female rats) were associated with an increased incidence of anophthalmia/microphthalmia and doses of 25 mg/kg/day (approximately 125-fold the human exposure at 6 mg/m² based on AUCinf in female rats) were associated with an increased incidence of wavy ribs and anophthalmia/microphthalmia. There were no teratogenic effects observed in rabbits at doses up to 10 mg/kg/day (approximately 20-fold human exposure at 6 mg/m² based on body surface area).
No effect on male or female fertility has been observed in rats following intravenous verteporfin doses of up to 10 mg/kg/day (approximately 60 and 40-fold human exposure at 6 mg/m² based on AUCinf in male and female rats, respectively).
No studies have been conducted to evaluate the carcinogenic potential of verteporfin.
Verteporfin was not genotoxic in the absence or presence of light in the usual battery of genotoxic tests. However, photodynamic therapy (PDT) induces the formation of reactive oxygen species and has been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNA degradation, and DNA-protein cross links which may result in chromosomal aberrations, sister chromatid exchanges (SCE) and mutations. It is not known how the potential for DNA damage with PDT agents translates into human risk.
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