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Background
Age-related macular degeneration (AMD), characterized as a progressive degenerative disease of the macula, is the leading cause of blindness in developed countries afflicting approximately 15 million people in the United States.
There are two forms of AMD: neovascular and non-neovascular. The non-neovascular form of AMD is more common and leads to a slow deterioration of the macula with a gradual loss of vision over a period of years. The neovascular (wet) form of the disease is responsible for the majority of cases of severe vision loss and is due to proliferation of abnormal blood vessels behind the retina. These blood vessels leak blood and fluid into the retina, resulting in visual abnormalities. The development of these abnormal blood vessels is due in part to the activity of vascular endothelial growth factor (VEGF), which induces angiogenesis, and increases vascular permeability and inflammation, all of which are thought to contribute to the progression of the neovascular (wet) form of AMD.
Macugen (pegaptanib sodium injection) is an intravitreal injection developed for the treatment of neovascular (wet) AMD. Pegaptanib binds to VEGF and inhibits its binding to cellular receptors. Macugen’s anti-VEGF activity is expected to inhibit abnormal blood vessel proliferation and therefore decrease the vision loss associated with the proliferation of abnormal blood vessels.
Gragoudas, et al. (2004) reported the results of two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials (n = 1186) on the use of pegaptanib in the treatment of neovascular AMD. Intravitreous injection into one eye per patient of pegaptanib (at a dose of 0.3 mg, 1.0 mg, or 3.0 mg) or sham injections were administered every 6 weeks over a period of 48 weeks, for a total of nine treatments. The primary end point was the proportion of patients who had lost fewer than 15 letters of visual acuity at 54 weeks.
In the combined analysis of the primary end point, efficacy was demonstrated, without a dose-response relationship, for all three doses of pegaptanib (p < 0.001 for the comparison of 0.3 mg with sham injection; p < 0.001 for the comparison of 1.0 mg with sham injection; and P = 0.03 for the comparison of 3.0 mg with sham injection). Verteporfin photodynamic therapy (PDT) usage was permitted at the discretion of the investigators in patients with predominantly classic lesions. Concomitant use of PDT overall was low. More sham treated patients (25%) received PDT than Macugen 0.3 mg treated patients (20%). In the group given pegaptanib at 0.3 mg, 70% of patients lost fewer than 15 letters of visual acuity, as compared with 55 % among the controls (p < 0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22% in the sham-injection group to 10% in the group receiving 0.3 mg of pegaptanib (p < 0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33% vs. 23%; p = 0.003). As early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (p < 0.002). Dose levels above 0.3 mg did not demonstrate any additional benefit. 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. Among the adverse events that occurred, endophthalmitis (1.3% of patients), traumatic injury to the lens (0.7%), and retinal detachment (0.6%) were the most serious and required vigilance. These events were associated with a severe loss of visual acuity in 0.1% of patients. The authors concluded that pegaptanib appears to be an effective therapy for neovascular AMD; however, its long-term safety is not known.
Prescribing information available on the Eyetech Pharmaceuticals, Inc. and Pfizer, Inc. website reports that at the end of the first year (week 54), approximately 1050 patients were re-randomized to either continue the same treatment or to discontinue treatment through week 102. Macugen was shown to be less effective during the second year of the study than during the first year.
Macugen 0.3 mg should be administered once every six weeks by intravitreous injection into the eye to be treated. The safety and efficacy of Macugen therapy administered to both eyes concurrently have not been studied.
In a short-term phase II clinical trial, Cunningham, et al. (2005) assessed the safety and effectiveness of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). Subjects were individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections were administered at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. Main outcome measures include best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (p = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or = 10 letters (approximately 2 lines) (34% versus 10%, p = 0.003) and > or = 5 letters (18% versus 7%, p = 0.12). Mean central retinal thickness decreased by 68 micron with 0.3 mg, versus an increase of 4 micron with sham (p = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or = 100 micron (42% versus 16%, p = 0.02) and > or = 75 micron (49% versus 19%, p = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg versus sham, 25% versus 48%; p = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. Subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up. These investigators noted that confirmation of these preliminary results across a broad spectrum of patients with DME in sufficiently powered prospective clinical trials is being planned.
In a pilot study, Dahr et al (2007) examined the safety and effectiveness of pegaptanib for patients with juxtapapillary or large peripheral angiomas secondary to von Hippel-Lindau (VHL) disease. A total of 5 patients with severe ocular VHL lesions received intravitreal injections of pegaptanib (3 mg/100 microL), given every 6 weeks for minimum of 6 injections. The primary outcome of this study was a change of greater than or equal to 15 letters (3 lines) in best-corrected VA by 1 year. Secondary outcomes included changes in macular thickness, as determined by optical coherence tomography, and changes in fluorescein leakage. Two of five patients completed the course of treatment and 1 year of follow-up. These two patients had progressive decrease in retinal hard exudate and reduction in central retinal thickness measured by optical coherence tomography. One of these 2 patients had improvement in VA of 3 lines. No significant change in fluorescein leakage or tumor size was detected in either patient. Lesions in the other 3 patients continued to progress despite treatment, and these patients did not complete the entire treatment course. One patient developed a tractional retinal detachment. Additional serious adverse events included transient post-injection hypotony in two eyes. The authros concluded that intravitreal injections of pegaptanib may decrease retinal thickening minimally and reduce retinal hard exudates in some patients with advanced VHL angiomas. This finding may be related to a reduction in vasopermeability, because there was no apparent effect of treatment on the size of the primary retinal angiomas in this small pilot study.
On June 30, 2006, the United States Food and Drug Administration (FDA) approved Lucentis (ranibizumab injection, Genentech Inc., South San Francisco, CA) for the treatment of patients with neovascular AMD. Lucentis is designed to block new blood vessel growth and leakiness, and is the first treatment which, when given monthly, can maintain the vision of more than 90% of patients with this type of AMD. In contrast to pegaptanib (Macugen), ranibizumab is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF. Ranibizumab exhibits high affinity for human VEGF and exerts its neutralizing effects by inhibiting the VEGF-receptor interaction. Unlike the larger whole antibody, ranibizumab can penetrate the internal limiting membrane and reach the sub-retinal space following intravitreal injection (van Wijngaarden et al, 2005).
The FDA approval of Lucentis is based on data from two phase III clinical studies (MARINA and ANCHOR). In these studies, nearly all patients (about 95%) treated with Lucentis (0.5 mg) maintained (defined as the loss of less than 15 letters in VA) and up to 40% improved (defined as the gain of 15 letters or more in VA) vision at 1-year, as measured on the Early Treatment of Diabetic Retinopathy eye chart. On average, patients treated with Lucentis in the MARINA study experienced an improvement from baseline of 6.6 letters at 2-year compared to a loss of 14.9 letters in the sham group. In the ANCHOR study, patients treated with Lucentis, on average, experienced an 11.3 letter gain from baseline at 1-year compared to a loss of 9.5 letters in the Visudyne photodynamic therapy control group. Up to 40% of patients treated with Lucentis achieved vision of 20/40 or better.
In addition to data from the two phase III clinical trials, data from phase I/II studies were also included in the FDA review. In an open-label, 2-center, uncontrolled, randomized, phase I clinical trial, Rosenfeld and colleagues (2006) examined if multiple intravitreal doses of up to 2 mg of ranibizumab can be tolerated and are biologically active when injected using a dose-escalating strategy in eyes of patients with neovascular AMD. A total of 32 patients with primary or recurrent sub-foveal choroidal neovascularization secondary to AMD were enrolled. Baseline best-corrected VA in the study eye was from 20/40 to 20/640 (Snellen equivalent). Treatment regimens consisted of 5, 7, or 9 intravitreal injections of ranibizumab at 2- or 4-week intervals for 16 weeks, with escalating doses ranging from 0.3 to 2.0 mg. Patients were evaluated through day 140, 4 weeks after their last injection. Safety was assessed based on ocular and non-ocular adverse events, changes in VA, changes in intraocular pressure (IOP), slit-lamp ocular examination, changes in lesion characteristics based on fluorescein angiography and color fundus photography, and the presence of anti-ranibizumab antibodies. Twenty-nine patients received an injection at baseline, and 27 patients completed the study through day 140. Results were similar across the 3 treatment groups. All patients experienced ocular adverse events, most of which were mild. The most common ocular adverse events were iridocyclitis (83%), and injection-site reactions (72%). Inflammation did not increase with repeated injections, despite the increasing ranibizumab doses. Transient mild IOP elevations were common after ranibizumab injection. No serum anti-ranibizumab antibodies were detected. In general, median and mean VAs in the study eyes improved by day 140 in all 3 groups. Only 3 of the 27 patients lost significant vision. There was no significant lesion growth, and a decrease in area of leakage from choroidal neovascularization was detected through day 140. The authors concluded that multiple intravitreal injections of ranibizumab at escalating doses ranging from 0.3 to 2.0 mg were well-tolerated and biologically active in eyes with neovascular AMD through 20 weeks. Mild transient ocular inflammation was the most common post-injection adverse event.
In a multi-center, controlled, open-label, phase I/II clinical study, Heier and associates (2006) evaluated the safety of repeated intravitreal injections of ranibizumab in treating neovascular AMD, and assessed changes in VA and AMD lesion characteristics. A total of 64 patients with sub-foveal predominantly or minimally classic AMD-related choroidal neovascularization were enrolled. In part 1, patients were randomized to monthly intravitreal ranibizumab for 3 months (4 injections of 0.3 mg or 1 injection of 0.3 mg followed by 3 injections of 0.5 mg; n = 53) or usual care (UC; n = 11). In part 2, patients could continue their regimen for 3 additional months or cross over to the alternative treatment. Main outcome measures were adverse events, IOP, VA, and lesion characteristics assessed by fluorescein angiography and fundus photography. Of the 64 randomized subjects, 62 completed the 6-month study. Twenty of 25 subjects (80%) randomized to 0.3 mg, and 22 of 28 subjects (79%) randomized to 0.5-mg ranibizumab in part 1 continued on that treatment in part 2; 9 of 11 (82%) subjects randomized to UC in part 1 crossed over to ranibizumab treatment in part 2. The most common side effects with ranibizumab were reversible inflammation and minor injection-site hemorrhages. Serious side effects were iridocyclitis, endophthalmitis, and central retinal vein occlusion (1 subject each). Post-injection, IOP increased transiently in 22.6 % of ranibizumab-treated eyes in parts 1 and 2. After 4 ranibizumab injections (day 98), mean (+/- standard deviation) VA increased 9.4 +/- 13.3 and 9.1 +/- 17.2 letters in the 0.3- and 0.5-mg groups, respectively, but decreased 5.1 +/- 9.6 letters with UC. In part 2 (day 210), VA increased from baseline 12.8 +/- 14.7 and 15.0 +/- 14.2 letters in subjects continuing on 0.3 and 0.5 mg, respectively. Visual acuity improved from baseline greater than or equal to 15 letters in 26 % (day 98) and 45 % (day 210) of subjects initially randomized to and continuing on ranibizumab, respectively, and areas of leakage and sub-retinal fluid decreased. No UC subject had a greater than or equal to 15-letter improvement at day 98. These investigators concluded that repeated intravitreal injections of ranibizumab had a good safety profile and were associated with improved VA and decreased leakage from choroidal neovascularization in subjects with neovascular AMD.
In clinical trials, the most common side effects among patients treated with Lucentis (reported in at least 6% more patients than in the control groups in at least one study) included conjunctival hemorrhage, eye pain, vitreous floaters, increased IOP and intraocular inflammation. Although there was a low rate (less than 4%) of arterial thromboembolic events observed in the Lucentis clinical studies that was not statistically different between the Lucentis and control groups, there is a theoretical risk of arterial thromboembolic events following intravitreal use of inhibitors of VEGF. Serious side effects related to the injection procedure occurred in less than 0.1% of intravitreal injections, including endophthalmitis (severe inflammation of the interior of the eye), retinal tear, retinal detachment, and traumatic cataract. Lucentis is contraindicated in patients with hypersensitivity and ocular or periocular infections.
Although the FDA-approved labeling of Lucentis recommends monthly injections, Genentech said the average patient will receive only 5 to 7 injections in their 1st year because of the risk of eye pain, inflammation, and increased IOP.
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