Published Online, 18 July 2006, www.theannals.com, DOI 10.1345/aph.1G604.
The Annals of Pharmacotherapy: Vol. 40, No. 7, pp. 1322-1326. DOI 10.1345/aph.1G604
© 2006 Harvey Whitney Books Company.
NEW DRUG APPROVALS
Pegaptanib: A Novel Approach to Ocular Neovascularization
Julie A Chapman, PharmD CDE
Supervisor of Clinical Pharmacy Services, Pharmacy Practice Residency
Co-Director, Veterans Affairs Medical Center, West Palm Beach, FL
Cherylyn Beckey, PharmD
Assistant Professor of Pharmacy Practice, College of Pharmacy, Nova
Southeastern University, West Palm Beach
Reprints: Dr. Chapman, VA Medical Center, Pharmacy Service (119), 7305
N. Military Trail, West Palm Beach, FL 33410-6400, fax 561/422-7213,
Julie.chapman3{at}med.va.gov
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Abstract
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OBJECTIVE: To review pegaptanib, a novel aptamer for the treatment
of age-related macular degeneration (AMD).
DATA SOURCES: A literature search using MEDLINE (1980-January 2006)
and the Cochrane Database of Systematic Reviews (1978-January 2006) for
peer-reviewed, English-language publications was conducted. Abstracts from
recent meetings, including the Association for Research in Vision and
Ophthalmology and American Society of Retinal Specialists, were reviewed for
relevant abstracts and poster presentations.
STUDY SELECTION AND DATA EXTRACTION: Pharmacokinetic and
pharmacology data were extracted from animal and human studies, and
double-blind, randomized, controlled trials were included to describe the
efficacy and adverse effects of pegaptanib.
DATA SYNTHESIS: The efficacy of pegaptanib has been evaluated in 2
concurrent, prospective, randomized, double-blind trials. Patients with AMD
were randomly assigned to receive placebo or pegaptanib intravitreous
injection into 1 eye every 6 weeks for 48 weeks. The effectiveness of
pegaptanib was realized as early as week 6 and continued through week 54. At
week 54, 38% of patients receiving pegaptanib 0.3 mg were classified as
legally blind versus 56% of those receiving the sham injection.
CONCLUSIONS: Pegaptanib, a new inhibitor of ocular
neovascularization, provides patients with an alternative to photodynamic
therapy with verteporfin and offers a novel approach to future drug
developments for AMD. Pegaptanib offers the advantage of not requiring
photodynamic therapy in conjunction with drug delivery and may be a viable
option for institutions where this service is not easily accessible. Results
of clinical trials have shown that pegaptanib is effective in delaying
progression of AMD.
Key Words: age-related macular degeneration, ocular neovascularization, pegaptanib, vascular endothelial growth factor
Published Online, July 18, 2006. www.theannals.com, DOI 10.1345/aph.1G604
Age-related macular degeneration (AMD) is the leading cause of blindness in
the US.1
There are 2 subtypes of AMD: nonneovascular and neovascular. While
nonneovascular AMD is more common, neovascular AMD causes the most serious
vision loss and blindness. The primary characteristic of neovascular AMD is
choroidal neovascularization. In this process, the vessels that are located
beneath the choroid grow through and underneath the retinal pigment membrane
and Bruch's membrane, spreading beneath the retina. This process can cause
exudative or hemorrhagic retinal detachments that may develop into a fibrous
scar on the outer layers of the retina, diminishing visual
function.2
Treatment options for neovascular AMD include photocoagulation and
photodynamic therapy. However, because treatment with photocoagulation is
associated with damage to the retina, it is limited to areas of
neovascularization that do not involve the center of the macula. Photodynamic
therapy is a 2 step process that involves an intravenous infusion of a
photosensitive drug (verteporfin) and the use of an infrared laser that passes
through the retina. Clinical trials have shown that photodynamic therapy with
verteporfin can reduce severe visual loss by 30-50%, depending on the
characteristics of the
lesions.3 In
a subgroup analysis of verteporfin-treated patients, 59% of patients with
predominantly classic choroidal neovascularization lost fewer than 15 letters
of visual acuity at 24 months compared with 31% of those who received placebo.
However, in patients with minimally classic lesions, there was no
statistically significant difference in visual acuity in the verteporfin group
compared with the placebo
group.4
It has been shown that the level of vascular endothelial growth factor
(VEGF) is elevated in the vitreous of patients with ischemic retinal
diseases5;
therefore, recent research has been aimed toward agents that block or inhibit
VEGF. In December 2004, the Food and Drug Administration (FDA) approved
pegaptanib, the first inhibitor of VEGF on the market. This article provides
an overview of pegaptanib, a novel aptamer for AMD.
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Pharmacology
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Pegaptanib is an aptamer that exerts its action against VEGF. It is the
first drug to selectively inhibit
VEGF165.6
In patients with AMD, the blood supply to the retina is diminished and levels
of VEGF increase in the retina, vitreous, and aqueous
humor.7
Elevated levels of VEGF contribute to progression of ocular neovascularization
by increasing vascular permeability of the retina, stimulating endothelial
cell proliferation, and causing local
inflammation.7
Pegaptanib is a pegylated, modified oligonucleotide that utilizes its 3
dimensional structure to facilitate binding to extracellular
VEGF165. Pegaptanib binds with VEGF165 and
inhibits angiogenesis, decreasing permeability of the vascular bed and
decreasing inflammation. Since pegaptanib exerts its action selectively on
VEGF165, it is thought to not cause immunogenicity in
vitro.6
Systemically, VEGF is essential to normal cell development and growth. VEGF
contributes to wound healing, bone growth, endometrial and placental
development, and neuronal function in the brain and spinal
cord.8 In a
murine study, mice that had depressed VEGF levels were found to have a
phenotypically similar disease to the human degenerative disorder amyotrophic
lateral
sclerosis.9
There are also concerns that serious thromboembolic events may occur with
systemic VEGF suppression. In a study of patients with colon cancer who
received intravenous anti-VEGF monoclonal antibodies in combination with
fluorouracil, patients receiving this regimen had a 2 times higher risk of
serious thromboembolic events compared with those receiving standard
chemotherapy.10
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Pharmacokinetics
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Absorption appears to be the rate-limiting step in rabbits after an
intravitreal pegaptanib injection and is assumed to be similar in humans based
on clinical data obtained in Phase II
trials.11
The mean plasma half-life of pegaptanib in humans after a 3 mg intravitreal
dose (which is 10 times the FDA approved dosage) is 10 ± 4 days.
Maximal plasma concentrations of 80 ng/mL were reached 1-4 days after
injection, with mean AUC of 5 µg·h/mL with the 3 mg dose. Pegaptanib
has been studied in patients with mild-to-severe renal impairment, and no
dosing adjustments are required when administering the 0.3 mg dose. Pegaptanib
has not been studied in patients requiring hemodialysis, pregnant or nursing
women, pediatric patients, or patients with hepatic impairment.
Pegaptanib is metabolized by endo- and exonucleases and is eliminated
primarily in the urine. Plasma concentrations do not appear to be affected by
age or sex, although plasma concentrations were studied only in patients less
than 50 years of
age.6
Clinical trials to date have included approximately 1200 patients of both
sexes between the ages of 50 years and greater than 85
years.12
Drug interaction studies have not been conducted with
pegaptanib.6
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Clinical Trials
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The efficacy of pegaptanib has been evaluated in 2 concurrent, prospective,
randomized, double-blind
trials.12
The results of these trials subsequently led to the FDA approval of pegaptanib
for AMD. The trials had identical objectives and design and were conducted in
the US, Canada, Europe, Israel, Australia, and South America. Patients 50
years of age and older, with evidence of subfoveal sites of choroidal
neovascularization secondary to AMD, were included in the trials. Best
corrected visual acuity ranged from 20/40 to 20/320 in the study eye and
20/800 or better in the other eye. Patients with all subtypes of lesions,
defined by angiography, were enrolled.
Subjects were randomly assigned to receive a sham injection or pegaptanib
0.3, 1, or 3 mg intravitreous injection into 1 eye every 6 weeks for 48 weeks
for a total of 9 treatments. Procedures were specified to maintain masking.
Traditional standard photodynamic therapy with verteporfin was permitted in
patients with predominantly classic lesions (population ranging from 24% to
27%) at the discretion of the ophthalmologist, who was also masked to
treatment. The primary endpoint was the proportion of patients who lost fewer
than 15 letters of visual acuity between baseline and week
54.12
A total of 1208 patients were randomly assigned to treatment in the 2
studies. Of the patients randomized, 1190 received at least one study
treatment. Four subjects were excluded from efficacy analysis due to
insufficient assessment of visual acuity at baseline. Baseline demographic and
ocular characteristics were similar among treatment groups. A combined
analysis of 1186 patients was performed at week 54. The primary endpoint was
observed in 70% (n = 294) of the patients receiving 0.3 mg, 71% (n = 300) of
those receiving 1 mg, 65% (n = 296) of the patients receiving 3 mg, and 55% (n
= 296) of the subjects receiving a sham
injection.12
Results of the intent-to-treat analysis of patients who were evaluated both
at baseline and 54 weeks were similar. The results of both trials were
statistically significant (Figure
1). The effectiveness of pegaptanib was realized as early as week
6 and continued through week 54. The FDA-approved dose of pegaptanib is 0.3 mg
intravitreous injection every 6 weeks. There was no evidence in this efficacy
analysis that 1 or 3 mg is more effective than 0.3 mg. The percentage of
patients who received photodynamic therapy during the trial was similar among
the 4 treatment groups; approximately 78% of subjects never received
photodynamic therapy during the trial. In addition, variation in subtypes of
the lesion, size of the lesion, and baseline visual acuity did not preclude a
treatment
benefit.12
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Figure 1. Efficacy results based on primary endpoint of percentage of patients who
lost <15 letters of visual acuity after treatment with sham injection or
pegaptanib 0.3, 1, or 3 mg after 54 weeks and percentage of patients who lost
<15 letters of visual acuity after treatment with pegaptanib 0.3 mg or sham
injection after 102
weeks.12,13
* p < 0.001, ** p < 0.04, *** p <
0.05
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Secondary endpoints included maintenance or gain of 0 or more, 5 or more,
10 or more, and 15 or more letters; loss of 30 or more letters; and visual
acuity 20/200 or better in the study eye (legal blindness). The results for
the secondary endpoints were consistent with those for the primary end-point.
Patients in the sham injection group were twice as likely to have severe
vision loss as were patients receiving pegaptanib 0.3 mg (22% vs 10%; p <
0.001). At week 54, 38% of the patients receiving pegaptanib 0.3 mg were
classified as legally blind versus 56% of those receiving the sham injection
(p < 0.001). In addition, there was a slowing in the growth of the total
area of the lesion, the size of the choroidal neovascularization, and the
severity of leakage in the groups receiving pegaptanib compared with the sham
injection. Given the broad entry criteria for these studies, several post hoc
analyses of certain subgroups have been performed. Pegaptanib was effective in
all angiographic subtypes of lesions including predominantly classic,
minimally classic, and occult, as well as various lesion
sizes.12
To assess long-term therapy with pegaptanib, patients originally assigned
to pegaptanib were randomized at week 54 in a 1:1 ratio to either receive
pegaptanib for an additional 48 weeks or discontinue
therapy.13
Participants who received pegaptanib 0.3 mg for a second year showed a mean
loss of 9.4 letters compared with a loss of 17 letters in patients receiving
sham injection (p < 0.05). Therefore, it appears a second year of therapy
with pegaptanib resulted in additional treatment benefit in the absence of
additional occurrence of adverse effects.
The VISION clinical trial group also performed an exploratory analysis of
subjects with early disease who received pegaptanib 0.3 mg or sham injection
to assess the benefit of pegaptanib in the treatment of early subfoveal
choroidal neovascularization secondary to
AMD.14
Subjects were divided into 2 groups based on clinical characteristics and
definitions of early disease. Responder rates for pegaptanib were 76% and 80%
in treatment groups 1 and 2 versus 50% and 57% in the usual care groups 1 and
2 (p = 0.03 and 0.05), respectively. This analysis may provide further insight
as to when it is the most appropriate time to initiate treatment with
pegaptanib. In addition to its use for AMD, pegaptanib has been studied for
treatment of diabetic macular edema. Recently published Phase II trials have
shown that patients with evidence of diabetic macular edema receiving
pegaptanib had better outcomes based on visual acuity than those receiving
sham
injections.15
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Limitations
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Although pegaptanib appears to be safe and effective for up to 2 years of
therapy, long-term data are needed to thoroughly assess safety and efficacy
beyond this time. Furthermore, the results of pegaptanib therapy with respect
to lesion size and choroidal neovascularization may have been confounded by
changes in permeability that accompanied
treatment.12
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Dosage Recommendations
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Pegaptanib is administered every 6 weeks via an intravitreous injection.
The recommended dose is 0.3 mg per
injection.6
The safety and efficacy of pegaptanib use beyond 2 years have not been
evaluated.12
Pegaptanib is contraindicated in patients with ocular or periocular
infections. Aseptic technique should be strictly adhered to during
administration since endophthalmitis was the most serious injection-related
adverse effect associated with pegaptanib administration in clinical
trials.12
Aseptic technique should include the use of sterile gloves, sterile drape, and
sterile eyelid speculum. Anesthesia and an ophthalmic broad-spectrum
antibiotic should be administered to the treated eye to reduce the risk for
infection.6
Pegaptanib is supplied in a single-use 1 mL glass syringe that contains 0.3
mg of the drug deliverable in a 90 µL volume. Each syringe is fitted with a
27 gauge needle and rubber plunger—all contained in a foil pouch.
Pegaptanib should be stored in the refrigerator at 2-8 °C until time of
use. The solution should be inspected visually before administration for
particulate matter and to ensure integrity of the
product.6
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Adverse Effects
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The most serious injection-related adverse events in 890 patients treated
with pegaptanib were endophthalmitis in 12 patients, traumatic injury to the
lens in 5 patients, and retinal detachment in 6 patients. The most common
ocular adverse effects in pegaptanib-treated patients compared with placebo
are listed in Table
1.12
The incidence of per-injection serious ocular adverse events in that
study12 was
similar to that demonstrated in a review of more than 15 000 intravitreous
injections.16
Two-thirds of the patients with endopthalmitis demonstrated positive cultures
and were infected most commonly with Staphylococcus epidermiditis and
treated with intravitreous
antibiotics.12
Patients should be monitored for elevations in intraocular pressure (IOP)
following injection. Increases in IOP have been seen within 30 minutes of
injection of pegaptanib and should be monitored after injection and within 2-7
days following
injection.6
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Cost
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The current average wholesale price (AWP) price of pegaptanib is between
$995.00 and $1243.75 depending on the pharmacy distributor used by the
institution. This compares with an AWP price of $1350.00 for verteporfin.
Verteporfin is dosed every 3 months compared with every 6 weeks for pegaptanib
and requires the use of concomitant photodynamic therapy as well as infusion
clinic services. The average yearly cost of pegaptanib administered every 6
weeks would be $7960-9950 per patient treated 8 times during a year compared
with $5400 for verteporfin per patient treated 4 times in a year. However,
drug costs alone cannot be the only consideration for these medications since
they differ significantly and administration of verteporfin requires
additional non-pharmacy costs.
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Future Developments
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A VEGF receptor, analog sFlt-1; a receptor-immunoglobulin fusion protein;
and a humanized anti-VEGF monoclonal antibody fragment called ranibizumab are
currently being evaluated in Phase III
studies.8
Ranibizumab is currently in Phase III trials, and a Biologics License
Application (BLA) was submitted to the FDA in December 2005. Ranibizumab was
awarded a priority review designation, and action will be expected from the
FDA in mid-2006.
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Summary
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Preliminary clinical trials have demonstrated that, to date, pegaptanib
appears to be the most effective therapy available for AMD. It provides
patients with an alternative to photodynamic therapy and verteporfin and
offers a novel approach to future drug developments for AMD. Additional
long-term efficacy and safety data are needed to firmly establish its place in
therapy; however, pegaptanib now provides hope for delaying progression of a
disease that has a dynamic impact on both the healthcare system and patients'
quality of life.
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Footnotes
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We thank Nick Beckey PharmD BCPS and Peng Chen MD for their assistance with
reviewing the final draft of the manuscript.
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References
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- Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth
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