Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals, Antineovascularisation agents, ATC code: S01LA01 
Mechanism of action

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.

Clinical efficacy and safety

Age-related macular degeneration with predominantly classic subfoveal lesions 
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.


VIS API-NOT OCT18 CL V8                             7                             Ref: EU SmPC July 2018 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 relation to TAP extension:
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.

Age-related macular degeneration with occult with no classic lesions
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 
VIS API-NOT OCT18 CL V8                            8                            Ref: EU SmPC July 2018 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.

Pathological myopia

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 re-treatments 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 relation to VIP-PM extension:
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 was 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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
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.

Distribution

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.

Biotransformation

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 
VIS API-NOT OCT18 CL V8                            9                            Ref: EU SmPC July 2018 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.

Elimination

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.

Linearity/non-linearity

The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2.

Special populations

Elderly (65 years of age or above)
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.

Hepatic impairment
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%.

Renal impairment
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.

Ethnic groups/races
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.

Effects of gender
At the intended dose, pharmacokinetic parameters are not significantly affected by gender.