Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

tion, as assessed by fundus photography or angiography or both, while no regression was seen in the three sham-treated patients or in the four fellow eyes. Three of the eight patients with regressed neovascularization experienced a recurrence between weeks 36 and 52 after pegaptanib therapy was discontinued (Fig. 19.3.2.5) [8].

19.3.2.2.2.3 Safety

Pegaptanib was well tolerated at all administered doses. Adverse events were transient and associated with the injection procedure, rather than with the study drug. One case of endophthalmitis occurred among 652 injections (0.15 % per injection); it was successfully treated and resolved without severe loss of vision [21].

Phase 2 trial, randomizing 172 patients with DME, to pegaptanib (0.3 mg, 1 mg, or 3 mg) or sham injection [21]

Pegaptanib treatment proved superior to sham for all prespecified endpoints, including measurements of VA, retinal thickness and need for further additional photocoagulation therapy for DME Mean change in VA in the 0.3 mg pegaptanib treatment group was +4.7 letters compared to –0.4 letters for sham

Eight of 13 pegaptanib-treated patients with revascularization in the study eye experienced its regression during the trial; regression of revascularization was not seen in any of three shamtreated patients or in the four fellow eyes [8] Pegaptanib was well tolerated, with only one case of endophthalmitis occurring among 652 injections (0.15 %)

19.3.2.3 Conclusions

The encouraging results of this trial support the strategy of targeting the underlying pathophysiology of DME and indicate that pegaptanib treatment offers significant clinical benefits. The possibility of treating DR safely by selective VEGF blockade, be the loss of vision caused by increased permeability or generation of neovascularization, validates the singular role VEGF plays in the clinical manifestations of diabetes within the eye. Pivotal phase 3 trials are justified to confirm the aforementioned observations and are currently under way.

Acknowledgements. The authors would like to acknowledge the editorial assistance of Lauren Swenarchuk, PhD.

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Core Messages

Vascular endothelial growth factor (VEGF) is a critical stimulus for diabetic macular edema (DME)

Ranibizumab is a humanized antigen-binding fragment (Fab) that inhibits all VEGF isoforms Phase II/III clinical trials for age-related macular degeneration (AMD) have demonstrated the safety and tolerability of ranibizumab

The READ-1 study is an open-label phase I study investigating the effect of intravitreal injections of ranibizumab in 20 patients with DME

The primary outcome of the READ-1 study was foveal thickness measured by optical coherence tomography at 7 months compared to baseline The READ-2 study, a phase II multicenter trial, is underway

19.3.3.1 Introduction

Diabetic retinopathy is the most prevalent cause of vision loss among working age adults, and diabetic macular edema (DME) is the most common cause of moderate vision loss in individuals with diabetes mellitus [9]. Although vision loss with DME is frequent, effective treatment with laser photocoagulation, metabolic control, intraocular steroids, and novel pharmacological therapy such as vascular endothelial growth (VEGF) factor blockers may help to decrease DME and may reverse vision loss associated with this disease. This chapter reviews the pathogenesis of DME, the rationale for the role of antiVEGF agents, and preliminary clinical studies on the use of ranibizumab (Lucentis, Genentech Inc., South San Francisco, CA) for DME.

19.3.3.2 Pathogenesis

Diabetic macular edema occurs from leakage of plasma into the central retina, resulting in thickening of the retina because of excess interstitial fluid. The excess interstitial fluid within the macula results in stretching and distortion of photoreceptors, which eventually leads to decreased vision. Histopathologic studies have demonstrated that microaneurysms are likely responsible for focal leakage that may be seen in eyes with DME. Microaneurysms are thought to form because of hyperglycemia-induced pericyte death, which weakens the walls of retinal vessels resulting in the formation of small aneurysms which

lose their barrier qualities and leak [12]. In addition to focal leakage caused by microaneurysms, eyes with DME may also demonstrate diffuse leakage from retinal capillaries that do not show visible structural changes such as microaneurysms. This pattern of diffuse leakage may be due to microscopic damage to retinal vessels that are not visible in images obtained during fluorescein angiography. It is possible that diffuse leakage results from the presence of excessive amounts of permeability factors.

19.3.3.3Vascular Endothelial Growth Factor

Retinal hypoxia has been implicated in the pathogenesis of DME [13]. Hypoxia causes increased expression of VEGF, a potent inducer of vascular permeability that has been shown to cause leakage from retinal vessels [4, 16].

The VEGF family, which includes VEGF-A, VEGF- B, VEGF-C, VEGF-D, and placental growth factor, plays an important role in angiogenesis and vascular permeability [11, 15, 19]. Studies have demonstrated that VEGF-A is a primary activator of angiogenesis and vascular permeability, whereas other VEGF family members play a lesser role in angiogenesis. Nine VEGF-A isoforms are produced through alternate splicing of the mRNA of the human VEGF-A gene:

VEGF121, VEGF145, VEGF148, VEGF162, VEGF165, VEGF165b, VEGF183, VEGF189, and VEGF206 [20]. Among the nine isoforms, VEGF165 is the most abun-

dantly expressed VEGF-A isoform, and it plays a crit-

ical role in angiogenesis. However, other isoforms,

such as VEGF121, VEGF183, and VEGF189, are also commonly expressed in various tissues [8].

Animal studies have demonstrated that VEGF-A plays a vital role in the pathogenesis of ocular diseases in which neovascularization and increased vascular permeability occur, such as proliferative diabetic retinopathies, macular edema, and neovascular age-related macular degeneration (AMD) [1, 5, 6]. Overexpression of VEGF-A has been reported to cause ocular neovascularization and macular edema in monkeys [10]. In addition, elevated levels of VEGF-A have been identified in the vitreous of patients with diabetic retinopathy [2], and higher VEGF-A levels are found in the vitreous and aqueous humor of patients with diabetic macular edema [5, 6]. Evidence from animal and clinical studies has clearly demonstrated a pathologic role for overexpression of VEGF; therefore anti-VEGF therapies are likely to have an important role in the treatment of DME and proliferative diabetic retinopathy.

19.3.3.4 Ranibizumab

19.3.3.4.1 Biology

Ranibizumab is an FDA-approved humanized anti- gen-binding fragment (Fab) designed to bind and inhibit all VEGF-A isoforms and their biologically active degradation products. The vitreous half-life of ranibizumab after intravitreal administration in monkeys is 3 days with very low systemic exposure following intravitreal administration in both humans and monkeys [7, 17].

19.3.3.4.2Clinical Experience in Age-Related Macular Degeneration

Phase I/II/III clinical trials in patients with choroidal neovascularization (CNV) secondary to AMD have shown intravitreal injection of ranibizumab to be safe and well tolerated. In addition, two pivotal phase III clinical trials [Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD (MARINA) Trial and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) Trial] demonstrated the efficacy of ranibizumab in patients with neovascular AMD; these studies were the first to show visual improvement, not just a stabilization of visual acuity, in individuals with neovascular AMD.

The MARINA Trial was a randomized, doublemasked, sham-controlled clinical trial of patients with minimally classic or occult with no classic CNV secondary to AMD who were treated with monthly

intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections for 24 months. In the MARINA trial, approximately 90 – 92 % of ranibizumab-treated patients lost fewer than 15 letters of VA compared with 53 % of sham-injected patients after 24 months [16]. In addition, at 24 months of follow-up, approximately 33 % of ranibizumab-treated patients experi-

enced visual improvement of 15 or more letters com- III 19 pared with 4 % of the sham-injected patients.

The ANCHOR Trial was a randomized, doublemasked, sham-controlled clinical trial of patients with predominantly classic CNV secondary to AMD treated with intravitreal ranibizumab (0.3 or 0.5 mg) and sham photodynamic therapy (PDT) or sham injection and PDT (monthly administration for ranibizumab and every 3 months for PDT) for 24 months. After 12 months of follow-up, 94 % and 96 % of ranibizumabtreated patients (0.3 and 0.5 mg, respectively) lost fewer than 15 letters of VA compared with 64 % of PDTtreated patients [3]. In addition, 36 % and 40 % of rani- bizumab-treated patients experienced visual improvement of 15 or more letters (0.3 and 0.5 mg, respectively) compared with 6 % of PDT-treated patients.

19.3.3.5Ranibizumab in Diabetic Macular Edema

Nguyen and colleagues conducted an open-label study (Ranibizumab for Edema of the mAcula in Diabetes: A Phase I Study – the READ-1 Study) to investigate the effect of intravitreal injections of ranibizumab in 20 patients with DME [14]. Intraocular injections of 0.5 mg of ranibizumab were administered at study entry and at 1, 2, 4, and 6 months after entry. The injection regimen was selected to assess the effect of 3 monthly injections and then determine the impact of increasing the time interval between injections to 2 months for the last two injections. The primary outcome measure was foveal thickness measured by optical coherence tomography (OCT) at 7 months compared to baseline. Secondary outcome measures were macular volume measured by OCT and visual acuity measured by the protocol of the Early Treatment Diabetic Retinopathy Study (ETDRS) [21] at 7 months compared to baseline.

Among the first ten subjects (five men and five women) enrolled, pertinent baseline characteristics included: eight eyes that had received at least two sessions of focal/grid laser photocoagulation not less than 5 months prior to study entry (range 5 – 120 months), three eyes that had received intraocular steroids not less than 10 months prior to entry (range 10 – 20 months), and a mean foveal thickness of 503 ± 115 μm (range 326 – 729 μm) at baseline, indicating the presence of severe, chronic DME that was poorly responsive to standard therapies.

19.3.3.5.1Effect on Foveal Thickness and Macular Volume

OCT scans from two subjects whose DME showed response to ranibizumab are shown in Fig. 19.3.3.1. Compared to baseline, mean foveal thickness was reduced by 246 μm at the primary endpoint of the

19 III study (7 months after the first ranibizumab injection), representing an elimination of 85 % of the excess foveal thickness that had been present at baseline. OCT scans from two subjects are shown in Fig. 19.3.3.2. In addition, mean macular volume was reduced from 9.22 mm3 at baseline to 7.47 mm3 at 7 months, a reduction of 1.75 mm3 which was statistically significant (P = 0.009). This reduction constituted 77 % of the excess macular volume that was present at baseline.

19.3.3.5.2 Effect on Visual Acuity

Throughout each study time point, mean and median visual acuities were better than those at baseline. At the primary endpoint (7 months after the initial ranibizumab injection), mean and median visual acuity improved by 12.3 and 11 letters, which represents an improvement of a little more than 2 lines (Fig. 19.3.3.3).

In this study cohort, there was a strong correlation (R2 value of 0.78) between visual acuity and foveal thickness as measured by OCT (Fig. 19.3.3.4). However, the rate of change of these two outcome measures was different, and rapid changes in foveal thickness were associated with more gradual improvements in visual acuity. Further studies are

Fig. 19.3.3.1. Horizontal cross sectional optical coherence tomography (OCT) scans at all time points for patients 3 and 9 to illustrate two patterns of response over time. Seven days after the first intraocular injection of 0.5 mg of ranibizumab (D7), patient 3 showed a marked improvement in the appearance of the OCT scan with elimination of several large cysts and return of a normal foveal contour. At month 1 (M1), 1 month after the first injection, and M2 and M3, 1 month after the second and third injections, respectively, the scans for patient 3 were worse than the scan at D7, suggesting loss of effect of ranibizumab or transient effects that are lost by 1 month after injection. An OCT scan done 7 days after the third injection (M3+7 days) substantiates the latter of these two possibilities. At M4,

2 months after the third injection, the scan showed substantial deterioration, but at M5, 1 month after the fourth injection, there was improvement. This was followed by deterioration at M6, 2 months after the fourth injection, but then at M7, the primary endpoint and 1 month after the fifth injection, there was improvement to the point that the scan looked more like the two previous scans that had been done 7 days after an injection than like those that had been done 1 month after an injection. Like patient 3, patient 9 also showed substantial improvement at D7 compared to baseline with resolution of several large cysts. However, unlike patient 3, patient 9 showed continued improvement and then stability at subsequent time points regardless of the time after injection that the scan was done. This suggests that the beneficial effects of ranibizumab were more sustained in patient 9 than in patient 3. (Reprinted from [15] with permission)

Fig. 19.3.3.2. The mean excess foveal thickness at each study visit. Each bar represents the mean value for excess foveal thickness for all patients at the designated study visit (data for eight of ten patients at

month 9). The arrows show when intraocular injections of 0.5 mg of ranibizumab were administered. The bars at baseline and the primary endpoint, month 7, are shaded. Compared to baseline, foveal thickness was reduced by 246 μm at the primary endpoint of the study, constituting elimination of 85 % of the excess foveal thickness that had been present at baseline. (Reprinted from [15] with permission)

Fig. 19.3.3.3. Mean and median change in visual acuity from baseline at each study visit. The shaded line shows the mean change in visual acuity measured in number of letters read on an ETDRS visual acuity chart and the unshaded line shows the median change in visual acuity. The arrows show times of intraocular injection of

0.5 mg of ranibizumab. At the primary endpoint, 7 months, there was an improvement of 12.3 letters in mean visual acuity and 11 letters in median visual acuity. (Reprinted from [15] with permission)

Fig. 19.3.3.4. Scatter plot of reduction in foveal thickness versus gain in visual acuity at the primary endpoint compared to baseline for all patients. The reduction in foveal thickness in micrometers on the y-axis is plotted against the improvement in visual acuity measured by numbers of letters read on an ETDRS visual acuity chart. There is a strong correlation with an R2 value of 0.78. (Reprinted from [15] with permission)

19.3.3 Ranibizumab for the Treatment of Diabetic Macular Edema 389

III 19

underway to investigate the correlation between visual acuity and retinal thickness as measured by OCT.

19.3.3.5.3 Safety

Intraocular injections of ranibizumab were tolerated 19 III well with no ocular inflammation or adverse events.

There were no systemic adverse events, thromboembolic events, cerebral vascular accidents, or myocardial infarctions. Capillary nonperfusion was measured by image analysis at baseline and month 6 fluorescein angiograms with the investigator masked with respect to time point. The mean area of nonperfusion was 0.19812 disk areas at baseline and 0.19525 at 6 months. Therefore, no significant change in capillary nonperfusion was seen throughout the study.

19.3.3.6 Summary

Treatment of DME is complex and involves both systemic and ocular therapies. Although focal laser photocoagulation is considered the gold standard for the treatment of macular edema, novel therapies directed at decreasing vascular permeability at the molecular level with anti-VEGF agents have shown beneficial effects in early clinical trials. The READ-1 Study has demonstrated safety, tolerability, and bioactivity of intravitreal ranibizumab in subjects with DME. A large, multicenter, phase II trial, the READ-2 Study, is underway: (a) to obtain data on the bioactivity and dose interval effects of intravitreal ranibizumab alone, as well as in combination with laser photocoagulation, on retinal thickness and visual acuity in subjects with DME; and (b) to obtain additional safety and bioactivity data to aid in the design of a phase III clinical trial to evaluate ranibizumab as a therapeutic option for patients with DME. Novel anti-VEGF agents such as ranibizumab may provide additional therapeutic options to the armamentarium of treatments for DME.

The authors have no proprietary interests in any aspect of this report.

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