[35]. Like ranibizumab, pegaptanib was originally developed for the treatment of neovascular AMD and subsequently studied for DME. A phase II study with 172 patients evaluated the use of pegaptanib (0.3, 1, and 3 mg) for DME compared to sham injections [11]. Injections were given at baseline, week 6, 12, and then additional injections or laser treatments were given as needed during the next 18 weeks. The 0.3-mg pegaptanib group had the best vision results. 0.3 mg of pegaptanib led to a better mean visual acuity change of +4.7 letters as compared to the sham group with −0.4 letters (P = 0.04). Additionally, less patients within the 0.3-mg pegaptanib arm received laser as compared to sham treatment (25 vs. 48%, P = 0.04). These results contribute to the conclusion that VEGF plays a critical role in the pathogenesis of DME. The weaknesses of this study are that it did not directly compare pegaptanib to laser treatment alone and had a limited follow-up period.

BEVACIZUMAB FOR DME

Bevacizumab is another anti-VEGF medication that is being extensively studied for DME. Similar to ranibizumab and also produced by Genentech (South San Francisco, CA), bevacizumab is a humanized monoclonal antibody that inhibits all isoforms of VEGF-A. It is a whole antibody instead of only a Fab fragment (Fig. 17.2B). Bevacizumab is currently approved by the Food and Drug Administration (FDA) for metastatic colorectal cancer, breast cancer, and non-small cell lung cancer [36]. Although there have been no large-scale, randomized, ophthalmic clinical trials involving bevacizumab, many retina specialists are using this medication as an off-label treatment for neovascular AMD [37]. The primary motivation for the use of bevacizumab instead of ranibizumab is the significantly lower cost of bevacizumab. It is reasonable to consider that bevacizumab may also be used widely for DME if clinical trials demonstrate efficacy for ranibizumab.

The DRCR has completed a phase II clinical trial evaluating bevacizumab for DME [36]. One hundred and twenty-one patients were randomized to one of five groups:

(A) laser at baseline, (B) 1.25 mg of bevacizumab at baseline and 6 weeks, (C) 2.5 mg of bevacizumab at baseline and 6 weeks, (D) 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks, and (E) 1.25 mg of bevacizumab at baseline and 6 weeks with laser at 3 weeks. Both doses of bevacizumab caused reduction in central retinal thickness, and within the limits of the study, there was no clear difference between the two doses. The similar efficacy of these doses has also been found by others [38]. Defining a significant response as exceeding an 11% reduction in thickness compared to baseline, about half of the eyes treated with bevacizumab had a significant response of retinal thickness. While those eyes treated with bevacizumab had a greater reduction in thickness as compared to laser at 3 weeks, there was no significant difference seen with longer follow-up out to 12 weeks. The improvement in retinal thickness seemed to plateau or decrease between the 3- and 6-week visits, suggesting that subsequent injections should be sooner than 6 weeks. For visual acuity, groups B and C compared with laser, each had a significant difference of about 1-line greater improvement at 12 weeks. Within the short-term follow-up of the study, the combination treatment of bevacizumab and laser did not show any additional benefit compared to the other groups. While there was one

case of endophthalmitis, there were no complications that could clearly be attributed to the medication. Overall, the study showed the potential efficacy of bevacizumab and emphasized the need for a phase III trial to study both efficacy and safety.

A report by Kook et al. examined a population of 126 patients with chronic, diffuse DME followed for 6–12 months after treatment with bevacizumab [39]. In this study, “chronic” was defined as the presence of DME for more than 12 months. “Diffuse” edema was defined as thickening that included the fovea and extended to the arcades. All of the patients had received at least one previous treatment that included: focal laser (62%), vitrectomy with internal limiting membrane peeling (11%), and intravitreal triamcinolone (41%). Eleven percent had more than one focal laser treatment, and about 9% had more than one triamcinolone injection. Thirty-eight percent of the patients never had focal laser treatment because the clinician believed that the edema was too severe to respond to laser or that the source of leakage was too close to the fovea. None of the patients had received treatment within 6 months of the first bevacizumab injection. Additional bevacizumab injections were given as frequently as every 4 weeks if there was improvement from the prior injection or if there was significant recurrence of edema after injections were stopped. For the 59 (47%) patients that completed 12 months of follow-up, the mean number of injections was 2.7. While there was no significant improvement of visual acuity at 6 months, there was a significant improvement of +5.1 letters for the 47% of patients that completed 12 months of follow-up. Significant improvements of central retinal thickness compared to baseline (463 mm) were seen at both 6 months (374 mm) and 12 months (357 mm). While this study population was heterogeneous and lacked a control group, the results suggest that bevacizumab may still be beneficial in recalcitrant cases of DME. Importantly, the study raises the question of what subtypes of DME may be resistant to a certain therapy.

Soheilian et al. recently reported the results of a randomized trial comparing bevacizumab alone, bevacizumab with triamcinolone, and macular laser treatment for DME [40]. In this study, 150 eyes were randomized to one of these arms. The primary outcome was visual acuity at 24 weeks, but patients were followed out to 36 weeks. The bevacizumab dose was the commonly used amount of 1.25 mg, but it should be noted that the triamcinolone dose was only 2 mg. Instead of the more typical dose of 4 mg of triamcinolone, a 2-mg dose was chosen to minimize side effects. For all groups, retreatment was given every 12 weeks if the vision was not better than 20/40, and there was persistent clinically significant macular edema. Only one injection was given in 72% of the patients in the bevacizumab alone group. In this group, visual acuity improved significantly from baseline at all follow-up visits up; at 24 weeks, there was a change of −0.23 ± 0.22 logarithm of the minimum angle of resolution (log MAR). The bevacizumab with triamcinolone group and the laser alone group did not have a significant change in vision at 24 weeks compared to baseline. The percentage of patients with a >2 Snellen lines improvement at 36 weeks was 37, 25, and 14.8% of the bevacizumab alone, bevacizumab with triamcinolone, and laser alone groups, respectively. The central macular thickness decreased significantly in all groups only at the sixth week visit, and there was no significant difference among the groups. The authors suggested that bevacizumab alone may be a better primary treatment than laser, although they acknowledge that longer follow-up is needed to demonstrate a lasting benefit over laser. For this

Fig. 4. VEGF Trap-Eye is a fusion protein consisting of all human amino acid sequences. As shown here, the key domain (A) from VEGF receptors 1 and 2 have been fused (B) with the Fc portion of human IgG. This protein can penetrate the layers of the retina and binds with high affinity to all VEGF-A isoforms and placental growth factor more tightly than the native receptors (courtesy of Regeneron Pharmaceuticals, Inc.)

study, it is notable that only one injection was given to 72% of the bevacizumab alone group. This finding again raises the question as to what is the optimal dosing regimen of bevacizumab for DME.

VEGF TRAP-EYE FOR DME

VEGF Trap-Eye is another potential treatment on the horizon. It is a 115-kDa recombinant fusion protein designed such that the VEGF-binding domains of human VEGF receptors 1 and 2 are fused to the Fc domain of IgG1 [41] (Fig. 4A, B). In contrast to ranibizumab, VEGF Trap-Eye has a longer half-life and binds all VEGF-A isoforms as well as placental growth factor. VEGF Trap-Eye has a binding constant of approximately 0.5 pM Kd, and this is about 140 times that of ranibizumab [42, 43]. It is estimated that VEGF Trap-Eye has significant intravitreal activity for up to 10 weeks [42]. Thus, the medication has the potential to be given less frequently than ranibizumab, while perhaps being more efficacious.

Do et al. evaluated the safety of VEGF Trap-Eye in five patients with DME [44]. A single intravitreal injection of 4.0 mg of the medication was administered, and patients were followed for 6 weeks. There was no ocular toxicity or systemic adverse events related to the treatment. Although there were only five patients, there was a median improvement in visual acuity of nine letters at 1 month and three letters at 6 weeks. The gain in visual acuity was highest between weeks 1 and 4, and there was less of a gain after 6 weeks. When excess foveal thickness was examined, it was found that all five patients showed a reduction. The median excess foveal thickness was 69 mm at 1 month and 74 mm at 6 weeks. Similar to the visual acuity trend, the greatest effect on excess foveal thickness was seen between weeks 1 and 4. Two of the patients were able to have a reduction into the normal range that was sustained at 6 weeks. This small pilot study demonstrated the potential safety and efficacy of VEGF Trap-Eye for DME and suggested that further investigation is warranted. The phase II study of VEGF Trap-Eye in DME has finished recruitment; the trial investigates different doses and intervals of administration of VEGF Trap-Eye compared to laser photocoagulation. It is expected that detailed results of the 6 and 12 month outcomes will be available in late 2010 and early 2011.

OTHER CONSIDERATIONS IN THE MANAGEMENT OF DME

Treatment based on subtypes of DME is a consideration that may become more relevant in the future. Focal/grid laser is considered the gold standard for any type of DME. However, as exemplified in the above-mentioned study by Kook et al., some retina specialists think that laser treatment is less effective when there is extensive or diffuse edema [39]. A criticism of the DRCR study that compared laser with triamcinolone [22] is that the study does not compare subtypes of DME. There is potential to categorize DME more specifically based on the constellation of angiographic findings, clinical exam, duration, and OCT measurements. Perhaps there are cases of DME that are more responsive to one particular treatment over another. As these considerations move forward, it will be important to define what exactly the DME subtypes are such that effective comparisons can be made; currently, there are no established clinical trial definitions of DME subtypes. This is emphasized in a report by Browning et al. [45]. While there are many papers using the terms “focal” and “diffuse,” there are varying definitions for these terms. Browning et al. point out the need to arrive at a consensus on how to categorize DME subtypes. If DME is to be divided into subtypes, then the ability to grade the DME needs to be reproducible between clinicians and reading centers for clinical trials. Until such definitions are determined, one should be careful when interpreting conclusions about subtypes of DME and suggesting that certain therapeutic approaches may be more appropriate for certain types of DME.

In addition to subtypes based on angiography or clinical exam, future treatment of DME could also be stratified by biomarkers. What is it that causes one patient to have an astonishing improvement from ranibizumab while another patient’s response is only modest? One possibility is that biomarkers could indicate what level of response a patient may have to a treatment or whether a different treatment should be considered. There are numerous potential cytokines at play in DME. As discussed above, ICAM-1 is thought to have an important role in leukocyte-mediated vascular permeability [23]. A recent report