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Core Messages

Vascular endothelial growth factor (VEGF), a potent inducer of angiogenesis and vascular permeability, has been strongly implicated in the etiology of ocular vascular diseases, including diabetic retinopathy (DR) and diabetic macular edema (DME)

Studies in animal models of diabetes have

shown that the VEGF164/165 isoform acts as an especially potent inflammatory cytokine in

mediating breakdown of the blood-retinal barrier (BRB)

Intravitreous injection of pegaptanib, an apta-

mer specific for VEGF165, has reversed BRB breakdown in diabetic rodents

In a phase 2 trial involving 172 subjects with DME, intravitreously injected pegaptanib produced clinical benefits, compared to sham injection, in all three principal outcomes: visual acuity, retinal thickness and need for photocoagulation

In this same trial, 8 of 13 patients showing retinal revascularization at study entry experienced regression or decreased fluorescein leakage in response to treatment with pegaptanib; such regression was not seen in three sham-injected eyes or in four untreated fellow eyes showing revascularization

These findings warrant confirmation in pivotal phase 3 trials

19.3.2.1 Background

19.3.2.1.1New Therapeutic Strategies: Targeting Vascular Endothelial Growth Factor

Vision loss associated with diabetes is caused both by retinal neovascularization and by damage to the retinal vasculature, leading to breakdown in the blood-retinal barrier (BRB) and/or ischemia. Diabetic macular edema (DME), a direct reflection of this vascular damage, causes a significant component of vision loss associated with diabetic retinopathy (DR), especially in patients suffering from type 2 diabetes [18]. Currently, laser photocoagulation is the standard of care in treating retinal complications of diabetes, and while it has contributed significantly to reducing the incidence of severe vision loss, it is basically a destructive intervention that does not address the underlying pathophysiology. Indeed, it is accompanied by frank destruction of neural tissue and can lead to perceptions of nyctalopia, visual field constriction, and dyschromatopsia. A progression in the severity of retinopathy after treatment is not uncommon [18]. There is thus a need for newer therapies with fewer side effects, especially approaches

that counter retinopathic change through targeting the underlying pathophysiology of DR, rather than relying on ex post facto ablation.

One major area of investigation is the use of angiogenesis inhibitors, with vascular endothelial growth factor (VEGF) a principal target for inhibition. Over the past 15 years, an extensive body of research has established that VEGF is a key regulator of both physiological and pathological angiogenesis, playing a variety of roles in promoting blood vessel growth and vascular permeability (see Callout 1). Alternative splicing of the human gene yields at least six biologically active isoforms, composed of 121, 145, 165, 183, 189, and 206 amino acids [25], with VEGF165, the most abundant isoform, being principally responsible for diabetesassociated ocular pathology [35, 39]. It is important to note, however, that the family of VEGF isoforms is much more than a promoter of angiogenesis as it acts in a wide variety of cellular processes (see Callout 2). Accordingly, strategies targeting VEGF in the clinical arena must pay particular heed to the potential for adverse events when inhibiting all isoforms of VEGF. In this regard, systemically administered VEGF inhibitors have been associated with an increased incidence of hypertension, proteinuria, bleeding and thromboembolic events [34, 37, 40, 41, 54, 70].

–Matrix metalloproteinases [33, 45]

–Plasminogen activator [62]

Callout 2 – Additional physiological processes involving VEGF

Bone growth [31, 66]

Wound healing [22, 58]

Female reproductive cycling [26, 66]

Vasorelaxation [49]

Glomerulogenesis [42]

Protection of hepatic cells [47]

Skeletal muscle regeneration [11]

Neural survival factor [57, 60, 70]

Trophic support of choriocapillaris [15, 52]

19.3.2.1.2 VEGF and Diabetic Retinopathy

The pathophysiology of DR is complex, with the products of several biochemical pathways being potential mediators in the relationship between hyperglycemia and retinal vascular damage. These include polyols, advanced glycation end products and reactive oxygen intermediates [18]. Anatomical correlates of the progression of DR include death of capillary pericytes, basement membrane thickening, and entrapment of leukocytes, leading to capillary blockages and local hypoxia [18, 55]. Upregulation of VEGF is likely to occur either directly, through stimulation by metabolites such as advanced glycation end products [44] and reactive oxygen intermediates [50], or indirectly, through the local hypoxia induced by capillary dropout. VEGF is synthesized by a wide range of retinal cell types [1, 5, 24] and this synthesis is significantly increased in hypoxic conditions [5, 15]. Clinical findings have confirmed that VEGF levels are elevated in both DR [2, 4, 16, 27, 51] and DME [17, 28 – 30].

It is now well established that increases in ocular concentrations of VEGF are closely linked both to the aberrant growth of new vessels and to increased exudation and tissue edema. This edema further exacerbates the vision loss associated with DR (see Callout 3) and other ocular neovascularizing syndromes such as age-related macular degeneration (AMD)

[2 – 4, 6, 9, 32, 43, 46, 51, 53, 59, 67, 72 – 75]. The neovascularization and edema signal two of VEGF’s salient properties: (1) as a central promoter of angiogenesis [25] and (2) as the most potent known enhancer of vascular permeability [68]. The increase in permeability reflects several VEGF-mediated processes, including induction of fenestrations in the endothelium [64], dissolution of tight junctions [10], and of promotion adherence to the retinal vasculature by leukocytes which then act to damage the endothelium [38, 39].

Callout 3 – Key findings linking VEGF to the pathophysiology of DR

VEGF levels are elevated in eyes of patients suffering from DR [2, 4, 16, 51] and DME [17, 28 – 30]

Experimental elevation of VEGF in normal primate eyes induces many changes typical of DR, including formation of microaneurysms and exudation following BRB breakdown [73, 74]

Studies with rodent models of diabetes have revealed that DR is associated with increases in retinal VEGF levels (Fig. 19.3.2.1), which underlie a local inflammation and consequent vascular damage and leakage [35, 39, 63]

One VEGF isoform (VEGF165 in humans, VEGF164 in rodents) is especially important in mediating this inflammation [35, 39, 77]

Elevation of retinal levels of VEGF164 occur in parallel with BRB breakdown in diabetic rodents [63] Intravitreous injection of VEGF164 induces BRB breakdown in normal animals more potently than VEGF120 [35]

Fig. 19.3.2.1. Retinal vascular endothelial growth factor mRNA levels are increased in early diabetes. (Adapted from [63])

Pegaptanib is a nuclease-resistant, pegylated 28-nu- cleotide RNA aptamer (Fig. 19.3.2.2) that binds to the

VEGF164/165 isoform at high affinity (200 pM) while showing little activity toward the VEGF120/121 isoform [56] (see Callout 4). Pegaptanib inhibits VEGF164/165 from binding to its cellular receptors, preventing the

initiation of downstream signaling events. From the perspective of DR and DME, two of the most important cellular processes which are inhibited are VEGF’s actions in promoting angiogenesis and in enhancing vascular permeability. In experiments with cultured endothelial cells, pegaptanib inhibited the induction of mitogenesis by VEGF165, but not by VEGF121, consistent with pegaptanib’s specificity for VEGF165 [14]. In addition, in the Miles assay for vascular permeability, the VEGF-induced increase in vascular leakage was inhibited by 83 % when VEGF was pre-incubated with pegaptanib [65]. In subsequent studies, using a rodent model of retinopathy of prematurity, intravitreous injection of pegaptanib was shown to inhibit pathological revascularization, but not the physiological vascularization of the retina [36], suggesting that pegaptanib treatment might be relatively harmless to the normal retinal vasculature. Further evidence of pegaptanib’s sparing of physiological tissues came from studies of retinal ischemia in which VEGF120 was shown to be sufficient to exert a neuroprotective effect [51]. Most importantly for DR, in experiments with diabetic rodents, intravitreous injection of pegaptanib was shown to cause restoration of the BRB (Fig. 19.3.2.3 [35]).

Pegaptanib includes a 40-kDa polyethylene glycol moiety at the 5’ terminal [65], a change that prolongs intravitreal half-life [23]. Pivotal phase 3 trials [32] have already demonstrated that intravitreously ad-

-

-

-

III 19

-

-

- 40kDaPEG-5' 3'-3'-dT-5'

Fig. 19.3.2.2. Pegaptanib – secondary structure. PEG polyethylene glycol (With permission from [56])

ministered pegaptanib is effective in treating neovascular AMD and is associated with a low risk of adverse events such as endophthalmitis, traumatic lens injury or retinal detachment; where these occurred they were related to the injection procedure rather than to the study drug itself. The success of the trials led to pegaptanib’s approval for neovascular AMD by regulatory authorities in the United States, Canada and Brazil, and its recommendation for market authorization by the Committee for Human Medicinal Products of the European Union.

Taken together with the data implicating VEGF165 in the pathophysiology of DR/DME, and the positive safety record of pegaptanib in clinical trials [71], these findings led to a phase 2 trial to examine pegaptanib’s utility as a treatment for DME.

BRB breakdown (% of non-diabetes)

a

BRB breakdown (% of non-diabetes)

b

P <0.01

700

600

500

400

300

200

0

Untreated PEG Aptamer

Callout 4 – Pegaptanib

The study was a randomized, sham-controlled, double-masked, dose-finding phase 2 trial which enrolled 172 patients 18 years and older with type I or type II diabetes, visual acuity (VA) between 20/50 and 20/320 and clinically significant DME affecting the center of the macula (see Callout 5). Only patients judged not likely to need photocoagulation therapy for 16 weeks were enrolled. Principal exclusion criteria included photocoagulation or other retinal treatments within the previous 6 months, abnormalities preventing VA or photographic measurements, severe cardiac disease, clinically significant peripheral vascular disease, uncontrolled hypertension, and glycosylated hemoglobin levels

13 % [21].

Patients were randomized to four treatment arms (0.3 mg, 1 mg or 3 mg pegaptanib or sham injection), with stratification by study site, size of the thickened retina area (2.5 disk areas versus > 2.5 disk areas), and baseline VA (letter score 58 versus < 58). Injections were given at baseline and every 6 weeks thereafter for a minimum of three and a maximum of six injections. Final assessments were made at week 36, or 6 weeks after the last injection. Refraction, VA assessment, an ophthalmologic examination, optical coherence tomography (OCT), and color fundus photography were conducted at baseline and at each visit, while fluorescein angiography was carried out at baseline and 6 weeks after the last injection. Overall, 169 patients received at least one injection, and more than 90 % of patients in each treatment group completed the study. Prespecified efficacy criteria included VA, retinal thickness as measured by OCT, and the need for rescue photocoagulation therapy. In addi-

tion, patients found to show diabetic neovascularization at baseline were evaluated for the impact of pegaptanib treatment upon its advance or regression [21].

19.3.2.2.2 Results

19.3.2.2.2.1Principal Endpoints – Visual Acuity, Retinal Thickness, Retinal Volume, and Need for Photocoagulation

Pegaptanib treatment was superior to sham injection according to all prespecified endpoints. Mean change in VA in the 0.3 mg pegaptanib-treated group was +4.7 letters compared to –0.4 letters for sham (P = 0.04; Table 19.3.2.1). Pegaptanib treatment also resulted in more patients gaining 0, 5, 10, and

15 letters of VA (Fig. 19.3.2.4). Mean change in center point retinal thickness was –68 μm in the 0.3 mg pegaptanib arm compared to +3.7 μm in the sham group (P = 0.02), and pegaptanib treatment resulted in significantly more patients experiencing decreases in thickness of 75 and 100 μm (Table 19.3.2.2). As well, macular volume decreased 58 mm3 in the 0.3 mg pegaptanib arm but increased 12 mm3 with sham (P = 0.009) [data on file: (OSI) Eyetech, Inc. and Pfizer Inc. 2005]. OCT center point thickness at baseline and change in thickness from baseline to week 36 had a modest correlation with VA at baseline or change in VA from baseline to week 36 (R2= 0.18). Lastly, in the 0.3 mg pegaptanib arm, only 25 % of patients required further treatment with photocoagulation, compared to 48 % in the sham group (P = 0.042; Table 19.3.2.3) [21].

Fig. 19.3.2.4. Percentage of patients treated with pegaptanib sodium maintaining or gaining visual acuity from baseline to week 36 (intention-to-treat population, N = 172). *P < 0.05,

†P < 0.01. (With permission from [21])

Table 19.3.2.1. Changes from baseline to week 36 in visual acuity (intention-to-treat population, N = 172a) (ANCOVA model). (With permission from [21])

Table 19.3.2.2. Changes from baseline to week 36 in retinal thickness of the center point of the central subfield (inten- tion-to-treat population,

N = 172a). (With permission from [21])

ANCOVA analysis of covariance

a For missing baseline data, day 0 data were used for the analysis. For missing data at subsequent time points, the last observation was carried forward. Missing relevant data for one patient each in the 1 mg and sham groups

bANCOVA model adjusted for baseline retinal thickening area and baseline vision (P values of pairwise comparisons unadjusted for multiplicity)

CI confidence interval

aFor missing baseline data, day 0 data were used for the analysis. For missing data at week 36, the last observation was carried forward. Missing relevant data for one patient in the 0.3 mg,

five patients in the 1 mg, six patients in the 3 mg, and five patients in the sham groups

bAnalysis of covariance model adjusted for baseline retinal thickening area, baseline vision, and baseline retinal thickness. P value for difference in least square means between each dose group and sham

cCochran-Mantel-Haenszel test adjusted for baseline retinal thickening area and baseline vision. P value for difference in odds ratios between each dose group and sham

Table 19.3.2.3. Patients receiving focal/grid laser at week 12 or later in study eye (intention-to-treat population, N = 172a). (With permission from [21])

19.3.2.2.2.2Retinal Revascularization – Retrospective Analysis

Fundus photographs and fluorescein angiograms were analyzed for changes between baseline, week 36 and week 52. Nineteen patients in all were found to have retinal revascularization in the study eye, 16 of whom were available for full analysis. Four of the 16 patients also had neovascularization in the fellow eye. Thirteen patients had received pegaptanib while the other three received sham injections. At 36 weeks, 8 of the 13 patients in the pegaptanib groups (61 %) showed regression of neovasculariza-