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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 2 forms of AMD: (i) neovascular and (ii) 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 2 concurrent, prospective, randomized, double-blind, multi-center, dose-ranging, controlled clinical trials (n = 1,186) on the use of pegaptanib in the treatment of neovascular AMD. Intravitreous injection into 1 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 9 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 3 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 % versus 23 %; p = 0.003). As early as 6 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 1,050 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 6 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. A total of 172 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 greater than or equal to 10 letters (approximately 2 lines) (34 % versus 10 %, p = 0.003) and greater than or equal to 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 greater than or equal to 100 micron (42 % versus 16 %, p = 0.02) and greater than or equal to 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.
A 2-year phase III study demonstrated that pegaptanib sodium improved vision in persons with diabetic macular edema (Pfizer, 2010). The study included 260 subjects who received 0.3 mg pegaptanib sodium or a sham procedure consisting of anesthesia and a simulated injection in the eye every 6 weeks for a total of 9 injections in year 1. In year 2, subjects received injections as often as every 6 weeks based on pre-specified criteria. Up to 3 focal or grid laser treatments per year were permitted beginning at week 18, at the investigator’s discretion. The primary outcome measure of the study was the proportion of subjects who, after 1 year, experienced an improvement in vision from baseline of 2 lines, or 10 letters, on the ETDRS eye chart. The investigators reported that 37 % of subjects treated with pegaptanib sodium gained 2 lines, or 10 letters, of vision on the ETDRS eye chart at 54 weeks, versus 20 % of subjects who received the sham procedure (p = 0.0047). On average, subjects treated with pegaptanib sodium gained 5.2 letters of vision at year 1 compared to 1.2 letters for subjects receiving sham (p < 0.05). At the end of year 2, subjects receiving pegaptanib sodium had gained on average 6.1 letters of vision compared to 1.3 letters for subjects in the sham arm of the study (p < 0.01). The investigators reported that adverse events were consistent with those observed in clinical trials of pegaptanib sodium in persons with neovascular age-related macular degeneration and similar to clinical experience with pegaptanib sodium.
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 5 patients completed the course of treatment and 1 year of follow-up. These 2 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 2 eyes. The authors 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 2 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 2 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. A total of 29 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.
The FDA-approved labeling of Lucentis recommends 0.5 mg of Lucentis administered by intravitreal injection once a month. Although less effective, treatment may be reduced to 1 injection every 3 months after the first 4 injections if monthly injections are not feasible. Compared to continued monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months. 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.
In June 2010, the FDA approved Lucentis (ranibizumab injection) for the treatment of macular edema following retinal vein occlusion (RVO). The FDA approval was based upon 2 randomized controlled clinical studies -- the BRAVO study, which assessed the safety and efficacy profile of ranibizumab in a total of 397 patients with macular edema following branch-RVO, and the CRUISE study, which assessed the safety and efficacy profile of ranibizumab in a total of 392 patients with macular edema following central-RVO. During the first 6-month period, participants in both trials received monthly injections of either 0.3 mg or 0.5 mg of ranibizumab (n = 527) or monthly sham injections (n = 262). The primary endpoint of both studies was mean change from baseline in best-corrected visual acuity (BCVA) at 6 months compared with patients receiving sham injections. In the BRAVO study, the percentage of patients in the ranibizumab 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month 6 was 61 % (compared with 29 % in the sham injection arm). In the CRUISE study, the percentage of patients in the ranibizumab 0.5 mg study arm who gained 15 or more letters in BCVA from baseline at month 6 was 48 % (compared with 17 % in the sham injection arm). At month 6, patients in BRAVO who received 0.5 mg of ranibizumab had a mean gain of 18.3 letters (compared to 7.3 letters in patients receiving sham injections). In the CRUISE study, at month 6, patients who received 0.5 mg of ranibizumab had a mean gain of 14.9 letters (compared to 0.8 letters for patients receiving sham injections).
Available evidence indicates that anti-VEGF therapy with either ranibizumab or bevacizumab plays an important role in the management of diabetic macular edema. An NIH-sponsored, multi-center, randomized clinical trial demonstrated that ranibizumab in combination with macular laser photocoagulation is superior to macular laser photocoagulation alone at 12 months of follow-up (Diabetic Retinopathy Clinical Research Network, 2010). The need for re-treatment was determined by retinal thickness as measured by optical coherence tomography (OCT) and visual acuity. The 1-year mean change in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9, p < 0.001) and ranibizumab + deferred laser group (+9, p < 0.001) but not in the triamcinolone + prompt laser group (+4, p = 0.31) compared with the sham + prompt laser group (+3). Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula.
A second single-center, randomized clinical trial also demonstrated that intravitreal injection of bevacizumab every 6 weeks based on clinical response determined by OCT and visual acuity is superior to macular photocoagulation every 4 months (Michaelides et al, 2010). The authors reported the odds of gaining greater than or equal to 10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95 % confidence interval [CI]: 1.3 to 19.7; p = 0.019).
Ciulla and Rosenfeld (2009) stated that anti-VEGF treatments that arrest choroidal angiogenesis and reduce vascular permeability have revolutionized clinical practices for neovascular eye diseases. These researchers reviewed anti-VEGF therapies that are being evaluated in ocular diseases, other than neovascular AMD, in which neovascularization plays a critical role in pathogenesis. Early studies of the anti-VEGF agents, pegaptanib sodium, ranibizumab, bevacizumab, VEGF trap, and bevasiranib in the treatment of various neovascular diseases (e.g., diabetic macular edema, retinal vein occlusion, choroidal neovascularization) have shown promising results. The efficacy and safety of these agents, either alone or combined with standard treatments (e.g., laser photocoagulation), anti-inflammatory agents, or other non-VEGF-based anti-angiogenic therapies, was actively investigated. Non-VEGF-driven pathways and growth factors other than VEGF may play important roles in pathogenesis and are included in certain combination therapies with VEGF inhibitors. The authors concluded that the discovery of VEGF-A's role in the pathogenesis of neovascular ocular disease provided a strong rationale for the development of anti-VEGF-based therapies. There is now ample evidence that anti-VEGF therapies are viable treatment options for these diseases. Nevertheless, large, randomized controlled trials are still needed to confirm early safety and efficacy findings from small, open-label prospective studies.
Rodriguez-Fontal et al (2009) stated that ranibizumab is a Fab-Antibody with high affinity for VEGF, and is being designed to bind to all VEGF isoforms. This quality makes it a powerful drug for VEGF inhibition. Diseases of retinal and choroidal blood vessels are the most prevalent causes of moderate and severe vision loss in developed countries. Vascular endothelial growth factor plays a critical role in the pathogenesis of many of these diseases. Results of the pilot studies showed that intra-ocular injections of ranibizumab decrease the mean retinal thickness and improve the best corrected visual acuity in all the subjects. Proliferative diabetic retinopathy, currently treated with destructive laser photocoagulation, represents another potential target for anti-VEGF therapy. The early experience in animal models with proliferative retinopathy and neovascular glaucoma shows that posterior and anterior neovascularizations are very sensitive to anti-VEGF therapy. The outcome of 2 phase III clinical trials will increase the knowledge of the role of ranibizumab in the treatment of diabetic macular edema.
Neovascular glaucoma is a severe, blinding consequence of ocular ischemia. Rubeosis (neovascularization of the iris) develops followed by the onset of neovascular glaucoma once the angle structures are involved. The natural history of the disease is progressive, and may ultimately result in blindness. All cases of rubeosis and neovascular glaucoma require treatment of the underlying condition which caused the retinal ischemia, most often with panretinal photocoagulation (Sivak-Callcott et al, 2001). The onset of the beneficial effect of panretinal photocoagulation takes approximately 3 weeks after treatment to be evident. In patients with fulminant neovascular glaucoma where sight-threatening elevated intraocular pressure is present, treatment involves providing panretinal photocoagulation, or panretinal cryotherapy when the retina is not visible, followed by glaucoma filtration surgery, preferably waiting several weeks for the neovascularization to regress before the filter surgery (Allen et al, 1982). Florid neovascularization that is visible at presentation will slowly regress after panretinal photocoagulation, eventually positively influencing the outcome and reducing the complication rate of filtration surgery. However, during the several weeks waiting for an effect, the patient is at great risk for losing further vision due to glaucoma. For those eyes that have rubeosis with only minimal involvement of the anterior chamber angle withe neovascularization, intravitreal bevacizumab may be able to prevent further progression by hastening the regression of neovascularization. Case series have demonstrated that intravitreal bevacizumab will cause the intraocular pressure to drop rapidly. In order to preserve the effect, panretinal photocoagulation must still be performed, but the rapidity with which intravitreal bevacizumab acts in days may save substantial visual function. There is currently substantial published literature documenting the positive effect of bevacizumab-induced regression of anterior segment neovascularization and positive influences on the outcome of glaucoma surgery when it is necessary. This adjuvant use of intravitreal bevacizumab is not a repeated, long-term therapy to treat neovascular glaucoma; rather, it is used as a bridge to create a more favorable intraocular environment for further treatment of the neovascular glaucoma with other modalities like panretinal photocoagulation and filtration surgery. Concerns about intraocular pressure spikes and resulting secondary ischemia from intravitreal bevacizumab are outweighed by the need for prompt treatment of progressive ischemia from neovascular glaucoma.
Intravitreal bevacizumab is one form of treatment for rare causes of choroidal neovascularization such as degenerative myopia, idiopathic, angioid streaks, trauma, choroiditis and retinal dystrophies. Because these are rare conditions, it is not possible to perform definitive clinical trials. These diseases are characterized by a subretinal neovascular process which is similar to that seen in neovascular age-related macular degeneration. Therefore, there is strong biologic plausibility that intravitreal bevacizumab may be effective in these conditions. For these conditions, intravitreal bevacizumab would be indicated in persons with visual loss due to the presence of active choroidal neovascular as seen on fluorescein angiography or ocular coherence tomography.
In a pilot study, Lo Giudice et al (2009) evaluated the efficacy of single-session PDT combined with intra-vitreal bevacizumab (IVB) in the treatment of retinal angiomatous proliferation (RAP) in age-related macular degeneration. A total of 8 patients with RAP underwent indocyanine green angiography (ICGA)-guided single-session verteporfin PDT followed by IVB (1.25 mg) within a 0-day +/- 1-day interval. All patients were naïve to treatment. Best-corrected visual acuity, fluorescein angiography, ICGA, and OCT were performed at baseline and at each follow-up visit. All patients received 3 consecutive monthly IVB injections; thereafter, retreatment with bevacizumab was performed in the case of worsening BCVA or a deterioration of angiographic or OCT findings. All patients had 9 months of follow-up. Complete resolution of angiographical leakage was achieved in all eyes at 9 months. A significant improvement in the mean BCVA was observed at 1 month, 3 months, 6 months, and 9 months after combined treatment (p = 0.004). Visual acuity improved in 62.5 % and was stable in 37.5 % of cases. No patients had a decrease in BCVA of 3 or more lines during follow-up. Mean central macular thickness was significantly reduced in all patients (p < 0.0001) as controlled at 1-month, 3-month, 6-month, and 9-month intervals from initial treatment. The mean number of injections for the 9 months were 3.2 +/- 0.4. No ocular complications or systemic events developed. The authors concluded that sequenced combined treatment with single-session PDT and IVB injections may be useful in treating RAP, reducing or eliminating retinal edema, and improving or stabilizing visual acuity. They stated that further investigations are warranted to outline the appropriate treatment paradigm for combination therapy.
Mennel et al (2010) reported a case of retinal juxtapapillary capillary hemangioma causing consecutive leakage with macular involvement. The tumor was treated with a combination of anti-VEGF and PDT and was followed for 1 year. A 44-year-old woman with retinal juxtapapillary capillary hemangioma in the right eye experienced a decrease of visual acuity from 20/20 to 20/60 because of a severe leakage from the tumor involving the macula with lipid depositions. Two sessions of PDT (sparing the part of the hemangioma located within the optic disc) and 5 injections of bevacizumab were applied in a period of 5 months. Visual acuity, visual field testing, retinal thickness measurements, fundus photography and fluorescein angiography were performed to evaluate the treatment effect. One year after the last injection, visual acuity increased to 20/40. All lipid exudates at the posterior pole resolved. Retinal thickness decreased from 490 to 150 microm with the restoration of normal central macular architecture. Leakage in fluorescence angiography reduced significantly, but hyper-fluorescence of the tumor was still evident. Visual field testing and angiography did not show any treatment-related vaso-occlusive side-effects. The authors concluded that in this single case, the combination of anti-VEGF and PDT appeared to be an effective strategy for the treatment of retinal juxtapapillary capillary hemangioma without side-effects. The authors stated that further studies with a greater number of eyes and adequate follow-up are necessary to support these first clinical results.
Nicholson and Schachat (2010) stated that diabetic retinopathy (DR) is a leading cause of vision loss in the working-age population worldwide. Many observational and pre-clinical studies have implicated VEGF in the pathogenesis of DR, and recent successes with anti-VEGF therapy for AMD have prompted research into the application of anti-VEGF drugs to DR. These researchers reviewed the early studies that suggested a potential role for anti-VEGF agents in the management of DR. The authors concluded that for DME, phase II trials of intra-vitreal pegaptanib and intra-vitreal ranibizumab have shown short-term benefit in visual acuity. Intra-vitreal bevacizumab also has been shown to have beneficial short-term effects on both VA and retinal thickness. For proliferative diabetic retinopathy (PDR), early studies suggest that intra-vitreal bevacizumab temporarily decreases leakage from diabetic neovascular lesions, but this treatment may be associated with tractional retinal detachment (TRD). Furthermore, several studies indicated that bevacizumab is likely to prove a helpful adjunct to diabetic pars plana vitrectomy (PPV) for TRD. Finally, 3 small series suggested a potential beneficial effect of a single dose of bevacizumab to prevent worsening of DME after cataract surgery. Use of anti-VEGF medications for any of these indications is off-label. These investigators stated that despite promising early reports on the safety of these medications, they eagerly await the results of large, controlled trials to substantiate the safety and efficacy of anti-VEGF drugs for DR.
Boscia (2010) noted that DR is a major cause of blindness in Europe and North America, and the incidence is expected to increase in parallel with the rising incidence of diabetes mellitus. Boscia reviewed the current state of knowledge of the epidemiology, clinical presentation and pathophysiology of DR and its principal associated complications, DME and neovascularization, and then proceeded to the primary focus of clinical management. A series of major randomized controlled trials conducted over the past few decades has confirmed that tight glycemic regulation is the most effective measure to reduce the risk of developing DR and to minimize the likelihood of its progression, and that control of blood pressure is also an important feature of preventive management. Laser-based therapies remain the cornerstone of treatment, with pan-retinal photocoagulation indicated for PDR and severe non-PDR and focal photocoagulation indicated for treatment of DME. For patients who do not benefit from these approaches, vitrectomy may provide therapeutic benefits. Medical therapies include 2 broad classes of agents: anti-inflammatory drugs and agents with molecular targets. The utility of oral anti-inflammatory drugs remains to be established, as dose-finding studies have yet to provide definitive conclusions. Intra-vitreal corticosteroids may be of value in specific circumstances, although adverse effects include cataract progression and elevated IOP. However, these complications appear to have been limited with new extended-release technologies. With respect to molecular targets, evidence has been adduced for the roles of VEGF, tumor necrosis factor (TNF)-alpha and protein kinase C (PKC)-beta2 in the pathogenesis of DR, and agents targeting these factors are under intense investigation. Preliminary efficacy of pegaptanib and ranibizumab in the treatment of DME is being confirmed in additional clinical trials with these agents and with the off-label use of bevacizumab, another monoclonal antibody related to ranibizumab. Moreover, other agents targeting VEGF, as well as drugs directed against TNF-alpha and PKC-beta2, are under study. Evaluation of the ultimate utility of these approaches will await the safety and effectiveness results of properly designed phase III trials.
In a review on diabetic retinopathy, Cheung and colleagues (2010) stated that although anti-VEGF therapy has promising clinical applications for management of DR, its long-term safety in patients with diabetes has not yet been established. Moreover, Elman and associates (2011) stated that further investigation is needed to ascertain the role of anti-VEGF drugs in the prevention or treatment of PDR.
Waisbourd et al (2011) summarized the latest developments in the treatment of DR with anti-VEGF drugs. These researchers reviewed recent studies that evaluated the role of the anti-VEGF agents bevacizumab, ranibizumab and pegaptanib in the treatment of DR. There was only 1 large randomized controlled trial that evaluated the role of ranibizumab in DME. Other prospective and retrospective studies provided important insight into the role of anti-VEGF drugs in DR, but most of them were not conducted in large scales. The growing evidence indicates that anti-VEGF drugs are beneficial in DR, especially in DME. The authors concluded that further studies are needed to fully evaluate the role of these agents, especially in PDR and in DR candidates for vitrectomy surgery.
Ishikawa et al (2009) evaluated the safety and effectiveness of IVB as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy (PDR). A total of 8 eyes of 6 patients (33 to 64 years old, all male subjects) with severe PDR were investigated. An intra-vitreal injection of 1.25 mg bevacizumab was carried out 3 to 30 days before planned vitrectomy. All cases showed minimum bleeding during surgical dissection of fibro-vascular membrane. Two cases receiving bevacizumab 7 days before the surgery showed strong fibrosis and adhesion of fibro-vascular membrane, resulted in some surgical complications. The cases having IVB for shorter time did not show extensive fibrosis. The authors concluded that pre-treatment of bevacizumab is likely effective in the vitrectomy for severe PDR. The appropriate timing of vitrectomy after bevacizumab injection should be further evaluated.
In a prospective, comparative case series, El-Sabagh and colleagues (2011) evaluated the effects of intervals between pre-operative IVB and surgery on the components of removed diabetic fibro-vascular proliferative membranes. A total of 52 eyes of 49 patients with active diabetic fibro-vascular proliferation with complications necessitating vitrectomy were included in this study. Participant eyes that had IVB were divided into 8 groups in which vitreo-retinal surgery was performed at days 1, 3, 5, 7, 10, 15, 20, and 30 post-injection. A group of eyes with the same diagnosis and surgical intervention without IVB injection was used for comparison. In all eyes, proliferative membrane specimens obtained during vitrectomy were sent for histopathologic examination using hematoxylin-eosin stain, immunohistochemistry (CD34 and smooth muscle actin), and Masson's trichrome stain. Main outcome measure was comparative analysis of different components of the fibro-vascular proliferation (CD34, smooth muscle actin, and collagen) among the study groups. Pan-endothelial marker CD34 expression levels starting from day 5 post-injection were significantly less than in the control group (p < 0.001), with minimum expression (1+) in all specimens removed at or after day 30 post-injection. Positive staining for smooth muscle actin was barely detected in the control eyes at day 1, and consistently intense at day 15 and beyond (p < 0.001). The expression level of trichrome staining was significantly high at day 10, compared with control eyes (p < 0.001), and continued to increase at subsequent surgical time points. The author concluded that a pro-fibrotic switch was observed in diabetic fibro-vascular proliferation after IVB, and these findings suggest that at approximately 10 days post-IVB the vascular component of proliferation is markedly reduced, whereas the contractile components (smooth muscle actin and collagen) are not yet abundant. Moreover, the authors noted that their histologic findings are in agreement with many published clinical findings and might be predictive of an optimal time interval for the pre-operative use of adjunctive IVB, which makes surgery more successful with less intra-operative bleeding and complications; thus resulting in better visual outcomes. However, such favorable outcomes need validation from large-scale clinical studies.
In a comparative, retrospective case series, Fong et al (2010) compared VA outcomes after bevacizumab or ranibizumab treatment for AMD. These researchers followed 452 patients in a retrospective study of exudative AMD treated with anti-VEGF drugs; 324 patients were treated with bevacizumab and 128 patients with ranibizumab. All treatment-naive patients who received either bevacizumab or ranibizumab were followed for 1 year. Baseline characteristics and VA were recorded using standard descriptive statistics. Main outcome measure was VA. At 12 months, the distribution of VA improved in both groups with 22.9 % of bevacizumab and 25.0 % of ranibizumab attaining greate than or equal to 20/40. Improvement in vision was observed in 27.3 % of the bevacizumab group and 20.2 % of the ranibizumab group. The mean number of injections at 12 months was 4.4 for bevacizumab and 6.2 for ranibizumab. There were 8 (2 %) deaths in the bevacizumab group and 4 (3 %) in the ranibizumab group. Two patients developed endophthalmitis in the bevacizumab group and the ranibizumab group. The bevacizumab group had slightly worse acuity at baseline, but both groups showed improvement and stability of vision over time. The authors concluded that both treatments seem to be effective in stabilizing VA loss. There was no difference in VA outcome between the 2 treatment groups. Because the study is a non-randomized comparison, selection bias could mask a true treatment difference. Results from the Comparison of the Age-related Macular Degeneration Treatment Trials (CATT) will provide more definitive information about the comparative effectiveness of these drugs.
In a multi-center, single-blind, non-inferiority trial, Martin and colleagues/the CATT Research Group (2011) randomly assigned 1,208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in VA at 1 year, with a non-inferiority limit of 5 letters on the eye chart. Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, p = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (p > 0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1 % versus 19.0 %; risk ratio, 1.29; 95 % confidence interval [CI]: 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. The authors concluded that at 1 year, bevacizumab and ranibizumab had equivalent effects on VA when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study.
In an editorial that accompanied the afore-mentioned study, Rosenfeld (2011) stated that "The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD ... The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab".
Schmucker and associates (2011) performed a systematic review to compare adverse effects (AE) and the reporting of harm in randomized controlled trials (RCTs) and non-RCTs evaluating intravitreal ranibizumab and bevacizumab in AMD. Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. Studies which compared bevacizumab or ranibizumab as monotherapy with any other control group were included. Case series were included if they met pre-defined quality standards. The results of phase III trials evaluating ranibizumab showed that the rates of serious ocular AE were low (less than or equal to 2.1 %) but indicated major safety concerns (RR 3.13, 95 % CI: 1.10 to 8.92). A possible signal with regard to thrombo-embolic events (RR 1.35, 95 % CI: 0.66 to 2.77) and a significant increase in non-ocular hemorrhage (RR 1.62, 95 % CI: 1.03 to 2.55) were also noted. In contrast to ranibizumab trials, the RCTs evaluating bevacizumab were of limited value. The main shortcomings are small sample sizes and an apparent lack of rigorous monitoring for AE. A critical assessment of the large number of published case series evaluating bevacizumab also showed that no reliable conclusions on safety can be drawn using this study design. Therefore, any perception that intravitreal bevacizumab injections are not associated with major ocular or systemic AE are not supported by reliable data. The authors concluded that bevacizumab studies showed too many methodological limitations to rule out any major safety concerns. Higher evidence from ranibizumab trials suggested signals for an increased ocular and systemic vascular and hemorrhagic risk that warrants further investigation.
Aflibercept, also known as VEGF Trap-Eye, is a highly potent blocker of VEGF and placental growth factor. It is a fully human fusion protein consisting of portions of VEGF receptors 1 and 2, which binds all forms of VEGF-A, along with the related placental growth factor, which the drug blocks.
In a multi-center, randomized, double-masked study, Heier et al (2011) evaluated anatomic outcomes and vision, injection frequency, and safety during the as-needed (PRN) treatment phase of a study evaluating a 12-week fixed dosing period followed by PRN dosing to week 52 with VEGF Trap-Eye for neovascular (wet) AMD. A total of 159 patients with subfoveal choroidal neovascularization (CNV) secondary to wet AMD were included in this study. Patients were randomly assigned to 1 of 5 intra-vitreal VEGF Trap-Eye treatment groups: 0.5 mg or 2 mg every 4 weeks or 0.5, 2, or 4 mg every 12 weeks during the fixed-dosing period (weeks 1 to 12). From weeks 16 to 52, patients were evaluated monthly and were retreated PRN with their assigned dose (0.5, 2, or 4 mg). Main outcome measures included change in central retinal/lesion thickness (CR/LT), change in total lesion and CNV size, mean change in BCVA, proportion of patients with 15-letter loss or gain, time to first PRN injection, re-injection frequency, and safety at week 52. The decrease in CR/LT at week 12 versus baseline remained significant at weeks 12 to 52 (-130 μm from baseline at week 52) and CNV size regressed from baseline by 2.21 mm(2) at 48 weeks. After achieving a significant improvement in BCVA during the 12-week, fixed-dosing phase for all groups combined, PRN dosing for 40 weeks maintained improvements in BCVA to 52 weeks (5.3-letter gain; p < 0.0001). The most robust improvements and consistent maintenance of VA generally occurred in patients initially dosed with 2 mg every 4 weeks for 12 weeks, demonstrating a gain of 9 letters at 52 weeks. Overall, a mean of 2 injections was administered after the 12-week fixed-dosing phase, and the mean time to first re-injection was 129 days; 19 % of patients received no injections and 45 % received 1 or 2 injections. Treatment with VEGF Trap-Eye was generally safe and well-tolerated, with few ocular or systemic AEs. The authors concluded that PRN dosing with VEGF Trap-Eye at weeks 16 to 52 maintained the significant anatomic and vision improvements established during the 12-week fixed-dosing phase with a low frequency of re-injections. Repeated dosing with VEGF Trap-Eye was well-tolerated over 52 weeks of treatment.
On November 18, 2011, the FDA approved aflibercept ophthalmic solution (Eylea, Regeneron Pharmaceuticals Inc.) for the treatment of neovascular (wet) AMD. The FDA's approval of Eylea was based on positive results from the 2 phase III VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) trials. Both found the drug non-inferior to ranibizumab, which is currently the most potent FDA-approved treatment option for wet AMD. In VIEW 1 (n = 1,217), conducted in the United States, and VIEW 2 (n = 1,240), conducted in Europe, all regimens of the drug, including 2 mg dosed every 2 months (after 3 loading doses), successfully met the primary endpoint of statistical non-inferiority compared with ranibizumab. The proportions of patients who maintained or improved vision over the course of 52 weeks in VIEW 1 were 96 %, 95 %, and 95 % of patients receiving aflibercept 0.5 mg monthly, 2.0 mg monthly, and 2.0 mg every 2 months, respectively. This compared with 94 % of patients receiving the standard 0.5-mg monthly dose of ranibizumab. For the secondary endpoint, visual acuity, the new drug was better. Patients receiving 2 mg monthly had a greater mean improvement in visual acuity at week 52, with a gain of 10.9 letters compared with 8.1 letters with ranibizumab (p < 0.01). All other dose groups were not significantly different from ranibizumab with respect to this secondary endpoint. In VIEW 2, vision was maintained in 96 % of all aflibercept dose groups and in 94 % of the ranibizumab group. All doses were statistically non-inferior to ranibizumab, and no differences were noted between the drugs in visual acuity gain.
The most commonly reported AEs in patients receiving aflibercept included eye pain, conjunctival hemorrhage, vitreous floaters, cataract, and an increase in eye pressure. Aflibercept should not be used in those who have an active eye infection or active ocular inflammation. It has not been studied in pregnant women, so the treatment should be used only in pregnant women if the potential benefits of the treatment outweigh any potential risks. Age-related macular degeneration does not occur in children and aflibercept has not been studied in children. The recommended dose is 2 mg every 4 weeks (monthly) for the first 12 weeks, followed by 2 mg every 8 weeks (2 months).
In September of 2012 the FDA approved aflibercept injection (Eylea) for use in macular edema following central retinal vein occlusion (CRVO). Boyer et al (2012) conducted a multi-center, randomized, prospective, controlled trial to assess the efficacy and safety of intravitreal VEGF Trap-Eye in eyes with macular edema secondary to CRV. A total of 189 eyes with macular edema secondary to CRVO were included in this study. Eyes were randomized 3:2 to receive VEGF Trap-Eye 2 mg or sham injection monthly for 6 months. At week 24, 56.1 % of VEGF Trap-Eye treated eyes gained 15 letters or more from baseline versus 12.3 % of sham-treated eyes (p < 0.001). The VEGF Trap-Eye treated eyes gained a mean of 17.3 letters versus sham-treated eyes, which lost 4.0 letters (p < 0.001). Central retinal thickness decreased by 457.2 µm in eyes treated with VEGF Trap-Eye versus 144.8 µm in sham-treated eyes (p < 0.001), and progression to any neovascularization occurred in 0 and 5 (6.8 %) of eyes treated with VEGF Trap-Eye and sham-treated eyes, respectively (p = 0.006). Serious ocular AEs were reported by 3.5 % of VEGF Trap-Eye patients and 13.5 % of sham patients while incidences of non-ocular serious AEs generally were well-balanced between both groups. Conjunctival hemorrhage, reduced VA, and eye pain were the most common AEs. The investigators concluded that at 24 weeks, monthly intra-vitreal injection of VEGF Trap-Eye 2 mg in eyes with macular edema resulting from CRVO improved VA and CRT, eliminated progression resulting from neovascularization, and was associated with a low rate of ocular AEs related to treatment.
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