Mechanism of Action
Pegaptanib is a selective vascular endothelial growth factor (VEGF) antagonist.
VEGF is a secreted protein that selectively binds and activates its receptors
located primarily on the surface of vascular endothelial cells. VEGF induces
angiogenesis, and increases vascular permeability and inflammation, all of which
are thought to contribute to the progression of the neovascular (wet) form of
age-related macular degeneration (AMD), a leading cause of blindness. VEGF has
been implicated in blood retinal barrier breakdown and pathological ocular neovascularization.
Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts
a three-dimensional conformation that enables it to bind to extracellular VEGF.
Under in vitro testing conditions, pegaptanib binds to the major pathological
VEGF isoform, extracellular VEGF165, thereby inhibiting VEGF165
binding to its VEGF receptors. The inhibition of VEGF164, the rodent
counterpart of human VEGF165, was effective at suppressing pathological
In animals, pegaptanib is slowly absorbed into the systemic circulation from
the eye after intravitreous administration. The rate of absorption from the
eye is the rate limiting step in the disposition of pegaptanib in animals and
is likely to be the rate limiting step in humans.
In humans, a mean maximum plasma concentration of about 80 ng/mL occurs within
1 to 4 days after a 3 mg monocular dose (10 times the recommended dose). The
mean area under the plasma concentration-time curve (AUC) is about 25 μg·hr/mL
at this dose.
Pegaptanib is metabolized by nucleases and is generally not affected by the
cytochrome P450 system.
Two early clinical studies conducted in patients who received Macugen alone
and in combination with photodynamic therapy (PDT) revealed no apparent difference
in the plasma pharmacokinetics of pegaptanib.
Twenty-four hours after intravitreous administration of a radiolabeled dose
of pegaptanib to both eyes of rabbits, radioactivity was mainly distributed
in vitreous fluid, retina, and aqueous fluid. After intravitreous and intravenous
administrations of radiolabeled pegaptanib to rabbits, the highest concentrations
of radioactivity (excluding the eye for the intravitreous dose) were obtained
in the kidney. In rabbits, the component nucleotide, 2'fluorouridine is found
in plasma and urine after single radiolabeled pegaptanib intravenous and intravitreous
doses. In rabbits, pegaptanib is eliminated as parent drug and metabolites primarily
in the urine.
Based on preclinical data, pegaptanib is metabolized by endo- and exonucleases.
In humans, after a 3 mg monocular dose (10 times the recommended dose), the
average (± standard deviation) apparent plasma half-life of pegaptanib
is 10 (±4) days.
Plasma concentrations do not appear to be affected by age or gender, but have
not been studied in patients under the age of 50.
Macugen was studied in two controlled, double-masked, and identically designed
randomized studies in patients with neovascular AMD. Patients were randomized
to receive control (sham treatment) or 0.3 mg, 1 mg or 3 mg Macugen administered
as intravitreous injections every 6 weeks for 48 weeks. A total of approximately
1200 patients were enrolled with 892 patients receiving Macugen and 298 receiving
a sham injection. The median age of the patients was 77 years. Patients received
a mean 8.5 treatments out of a possible 9 total treatments across all treatment
arms. Patients were re-randomized between treatment and no treatment during
the second year. Patients who continued treatment in year 2 received a mean
of 16 treatments out of a possible total 17 overall.
The two trials enrolled patients with neovascular AMD characteristics including
classic, occult, and mixed lesions of up to 12 disc areas and baseline visual
acuity in the study eye between 20/40 and 20/320. The primary efficacy endpoint
was the proportion of patients losing less than 15 letters of visual acuity,
from baseline up to 54 week assessment.
Verteporfin PDT usage was permitted at the discretion of the investigators
in patients with predominantly classic lesions.
The groups treated with Macugen 0.3 mg exhibited a statistically significant
result in both trials for the primary efficacy endpoint at 1 year: Study EOP1003,
Macugen 73% vs. Sham 60%; Study EOP1004, Macugen 67% vs. Sham 53%. Concomitant
use of PDT overall was low. More sham treated patients (75/296) received PDT
than Macugen 0.3 mg treated patients (58/294).
On average, Macugen 0.3 mg treated patients and sham treated patients continued
to experience vision loss. However, the rate of vision decline in the Macugen
treated group was slower than the rate in the patients who received sham treatment.
See Figure 1.
Figure 1 : Mean Visual Acuity: Year 1
At the end of the first year (week 54), approximately 1050 of the original
1200 patients were re-randomized to either continue the same treatment or to
discontinue treatment through week 102. See Figure 2.
Macugen was less effective during the second year than during the first year.
The percentage of patients losing less than 15 letters from baseline to week
102 was: Study EOP1003, Macugen 38/67 (57%); Sham 30/54 (56%); Study EOP1004,
Macugen 40/66 (61%); Sham 18/53 (34%).
Figure 2 : Mean Visual Acuity: Year 2
Dose levels above 0.3 mg did not demonstrate any additional benefit. The safety
or efficacy of Macugen beyond 2 years has not been demonstrated.