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AGE-RELATED MACULAR DEGENERATION

CASE 54-13

QUESTION 1: E.A., a 77-year-old woman, informs you she read information from the Internet and she thinks

her symptoms of blurred vision and the need for a bright light to read are consistent with age-related macular

degeneration. She asks which of the available medicines would be best for her.

Age-related macular degeneration is the leading cause of blindness in Americans

of European descent who are 55 years of age and older.

170 There are two forms of

macular degeneration, wet and dry. The dry form, affecting about 85% of patients,

develops as a result of the breakdown of light-sensitive cells in the macula.

171 The

most common symptom associated with dry macular degeneration is blurred vision.

In this situation, details (e.g., faces, words in a book) are seen less clearly. Wet

macular degeneration occurs in 15% of patients and is the more serious form,

responsible for the most cases of vision loss. One of the first symptoms of wet

macular degeneration is the appearance of straight lines as wavy. Wet macular

degeneration is associated with abnormal growth of blood vessels behind the retina,

known as choroidal neovascularization. Vascular endothelial growth factor (VEGF)

is associated with the pathogenesis of choroidal

p. 1168

p. 1169

neovascularization. VEGF may stimulate neovascularization by influencing

endothelial cell proliferation, vascular permeability, and ocular inflammation.

172 The

correlation between VEGF and wet age-related macular degeneration has led to

interest in VEGF inhibitors (pegaptanib, bevacizumab, ranibizumab) as treatment

agents.

PEGAPTANIB

Pegaptanib inhibits angiogenesis, decreases permeability of the vascular bed, and

decreases inflammation. The efficacy of pegaptanib has been evaluated in two

concurrent, prospective, randomized, double-blind trials involving 1,208 patients. A

total of 1,190 patients received at least one study treatment, with four subjects being

excluded from the efficacy analysis owing to insufficient assessment of visual acuity

at baseline. A combined analysis of 1,186 patients at week 54 showed a statistically

significant reduction in vision loss associated with pegaptanib, realized as early as

week 6 and continued through week 54.

173 The FDA-approved dose of pegaptanib

(0.3 mg intravenously every 6 weeks) is no less effective than 1- or 3-mg doses, and

the most serious injection-related adverse events were endophthalmitis (12 patients),

traumatic injury to the lens (five patients), and retinal detachment (six patients).

173

Patients should be monitored for elevations in IOP after injection; increases in IOP

have been seen within 30 minutes of injection and should be monitored within 2 to 7

days after the injection.

BEVACIZUMAB

Bevacizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody

approved for intravenous use for first- or second-line treatment of metastatic

colorectal cancer. This product has been used off-label via the intravenous and

intravitreal routes for the treatment of neovascular ocular disorders in more than

3,500 patients.

172

Intravenous bevacizumab 5 mg/kg was administered every 2 weeks

for two or three infusions in 18 patients for whom 12- and 24-week results on

subfoveal choroidal neovascularization were published separately. Therapy was

associated with improved visual acuity. No serious ocular or systemic adverse

effects were noted, although a statistically significant increase in blood pressure was

noted at week 3. Nineteen published, uncontrolled case series studies have evaluated

the use of intravitreal bevacizumab for the treatment of wet macular degeneration as

well as other conditions associated with neovascularization. The most common

intravitreal dose was 1.25 mg, usually administered every 4 to 6 weeks. Doses could

be repeated if signs of progression occurred. The longest period of study for

intravitreal use was 1 year. The majority of patients in these open-label trials were

followed up for 3 months. Mean visual acuity improved, and no serious ocular

effects were noted.

RANIBIZUMAB

Ranibizumab is a Fab fragment of bevacizumab approved in June 2006 for the

intravitreal treatment of wet macular degeneration. Ranibizumab is approximately

one-third the size of bevacizumab. Its size may facilitate retinal penetration after

intravitreal injection. Ranibizumab has a shorter-systemic half-life and higher VEGF

binding affinity than bevacizumab, but bevacizumab has two binding sites per

molecule versus one for ranibizumab. The clinical relevance of these

pharmacokinetic and pharmacodynamic differences is not known.

172 The

recommended dosage of ranibizumab is 0.5 mg via the intravitreal route administered

every 4 weeks. This treatment has been associated with maintenance or improvement

of vision for 12 to 24 months.

173 The primary ocular side effects associated with

ranibizumab administration include conjunctival hemorrhage, eye pain, and increased

IOP.

Bevacizumab is significantly less expensive than ranibizumab. Similar efficacy

associated with lower cost may lead to increased use for neovascular age-related

macular degeneration. The National Eye Institute has initiated the Comparisons of

Age-Related Macular Degeneration Treatments Trials, a multicenter, randomized

clinical trial of ranibizumab and bevacizumab in the treatment of neovascular agerelated macular degeneration.

174

AFLIBERCEPT

In September 2012, aflibercept became the second VEGF inhibitor approved for

treatment of macular edema secondary to choroidal vein retinal occlusion (CRVO).

Preliminary results from the ongoing COPERNICUS and GALILEO trials proved the

efficacy of this medication in treating macular edema secondary to CRVO. Of the

combined 358 patients studied in COPERNICUS and GALILEO, 56% and 60%,

respectively, of the patients receiving aflibercept 2 mg monthly achieved at least a

15-letter improvement in best-corrected visual acuity (BCVA) from baseline over 6

months compared with just 12% and 22% in the control group (p < 0.01 for both).

Additionally, in COPERNICUS and GALILEO, patients achieved a 21.3- and 14.7-

letter improvement, respectively, in BCVA compared with placebo ( p < 0.01 for

both).

175

While efficacy and safety appear similar to other anti-VEGF treatments, the higher

potency, binding affinity, and duration of action make aflibercept an appealing new

option.

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