Advancing Treatments for Diabetic Macular Edema

Anti-inflammatory and antiangiogenic options may augment or replace laser.

Joseph M. Coney, MD • Jerome P. Schartman, MD • Lawrence J. Singerman, MD, FACS

Diabetes mellitus is a significant world health concern, and its prevalence is projected to increase. The aging of the population and increasing rates of obesity have caused more individuals to develop diabetes and face the threat of blindness. Globally, more than one billion adults are overweight, and at least 300 million are obese, including 34% of American adults. The rising incidence of obesity has contributed to a doubling of the prevalence of diabetes in the last decade. In 2007, the Centers for Disease Control and Prevention estimated the prevalence of diabetes in the United States to be nearly 24 million people, or 8% of the population, and diabetes is believed to be growing at a rapid rate.¹

By 2050, the number of Americans with diabetic retinopathy is projected to triple, from 5.5 million to 16 million, and those people with vision-threatening retinopathy will increase from 1.2 million to 3.4 million. Over time, all people with diabetes are at risk of developing some form of diabetic retinopathy. Diabetic retinopathy is the leading cause of blindness in the industrialized world in people between the ages of 25 and 74.² It is the most prominent and debilitating microvascular complication, responsible for 12,000 to 24,000 new cases of blindness each year in the United States.

Most commonly, the vision loss is associated with diabetic macular edema, an abnormal collection of extracellular fluid that affects the central vision as a result of the breakdown of the blood-retinal barrier. Macular edema affects approximately 29% of individuals with duration of diabetes of 20 years or longer.

Fundus photograph demonstrating photocoagulation of diabetic macular edema.

For nearly three decades, the standard of care and the only FDA-approved therapy for DME has been focal/grid laser photocoagulation.³ Although it has consistently shown efficacy in clinical trials, it is not without potential complications, and any visual improvement is often minimal.^4,5 The increasing incidence of sight-threatening diabetic eye disease and eyes with limited visual improvement following focal/grid laser treatment has challenged clinical researchers and the pharmaceutical industry to develop more efficacious alternatives for the treatment of DME.

INFLAMMATION AND ANGIOGENESIS

Emphasis has been placed on intravitreally injected anti-inflammatory or antiangiogenic agents. These include vascular endothelial growth factor (VEGF) inhibitors, such as pegaptanib sodium (Macugen, Eyetech, Inc.), ranibizumab (Lucentis, Genentech), bevacizumab (Avastin, Genentech) and VEGF Trap-Eye (Regeneron). Intravitreal delivery systems, which release corticosteroids such as fluocinolone acetonide (Iluvien, Alimera), dexamethasone (Ozurdex, Allergan), and triamcinolone acetonide (I-vation, SurModics), are also being added to the armamentarium against this disease.

Intravitreal Triamcinolone

Intravitreal triamcinolone acetonide (IVTA) has been widely reported in the literature as a treatment for diffuse, refractory DME. The rationale for using corticosteroids stems from the concept that DME results from a hypoxic stimulus regulated by VEGF-induced vessel permeability.^6-8 Corticosteroids have anti-VEGF and anti-inflammatory activity via nuclear translocation of the glucocorticoid receptor complex and activation of gene sets.⁹

Steroids have been used as an off-label therapy for nearly a decade, their use predicated on case studies and results in other retinal diseases. The Diabetic Retinopathy Clinical Research Network (DRCR.net) reported that long-duration steroid therapy does not appear to have benefit over focal/grid photocoagulation for patients with DME.¹⁰ They concluded that, over a two-year period, laser is more effective and has fewer side effects than 1 mg or 4 mg doses of preservative-free IVTA for patients with DME.

Their randomized clinical trial found that patients receiving IVTA showed statistically significant improvement in mean vision only at the four-month follow-up, but from month 12 through month 24, visual acuity was better in the laser-treated eyes. Similarly, reduction in median central subfield thickness was initially greater in eyes treated with 4 mg IVTA, but at month 24, central subfield thickness was less in laser-treated eyes. The side effects of triamcinolone included increased intraocular pressure in up to approximately one-third of eyes, cataract, endophthalmitis and pseudoendophthalmitis, which may be related to the particulate formulation of the drug.

These results suggest that laser is superior to IVTA for the treatment in DME. However, a subgroup analysis found some support and a possible option for the use of IVTA in patients whose visual acuity is very poor, although the sample size was too small to be statistically significant. With this in mind, new biodegradable and nonbiodegradable steroid delivery systems are being evaluated for long-term efficacy in chronic diseases such as DME.

Ozurdex

One such apparatus is the Ozurdex biodegradable dexamethasone intravitreal implant, which is currently FDA-approved for the treatment of macular edema following venous occlusions and, most recently, for noninfectious uveitis. A clinical trial found that Ozurdex improved visual acuity for up to six months and macular thickness and fluorescein leakage for up to three months in eyes with persistent swelling due to a variety of eye conditions, including DME.¹¹

In a subset analysis of the eyes with DME, improvement in visual acuity of ≥10 lines at three months was seen in more eyes in the treatment groups (33% in the 700-µg group and 21% in the 350-µg group) than in the observation group (12.3%; P=.007 vs the 700-µg group). Treated eyes also had significantly greater improvements in central retinal thickness and fluorescein leakage (P=.03). At six months, the visual acuity improvement was seen in 30% of eyes in the 700-µg group, 19% in the 350-µg group, and 23% in the observation group (P≥.4, treated vs observed eyes).¹²

In a study of Ozurdex in vitrectomized eyes with DME, Ozurdex appeared to be effective, with effectiveness peaking at eight to 13 weeks after insertion. After 26 weeks, 21.4% of patients gained at least 10 letters of visual acuity, and 42.9% gained at least five letters. Central retinal thickness was reduced by 27% at week 13 and 9.6% at week 26.¹³

The adverse effects of Ozurdex include increased intraocular pressure, which peaks at day 60 and returns almost to baseline by day 180. The incidence was lower than that observed in trials with triamcinolone. The risk of glaucoma filtering surgery, cataract, and endophthalmitis appear to be smaller than expected based on the results of a phase 3 trial in patients with retinal venous occlusions and uveitis.

Iluvien

Another device that is being evaluated is the Iluvien nonbiodegradable intravitreal insert, which is designed to provide sustained-release fluocinolone acetonide (FA) therapy for 24 to 36 months. The Iluvien insert is only 3.5 mm in length and 0.37 mm in diameter and is delivered using a proprietary inserter with a 25-gauge needle, which allows for a self-sealing wound. By combining FA and a delivery device that provides for a unique long-term, low-dose delivery, the insert has the potential to improve vision while reducing common side effects of corticosteroids.

The two pivotal ongoing phase 3 clinical trials (collectively known as the FAME study) consist of two masked, multicenter trials with 956 randomized patients assigned to two doses of the FA insert (a higher dose with an initial release of approximately 0.45 µg per day or a lower dose with an initial release of approximately 0.23 µg per day) in the treatment of DME. Preliminary results showed a statistically significant difference in best-corrected visual acuity (BCVA) in treated patients vs control by three weeks, and this difference was maintained through month 24.¹⁴

At least 26% and 30% of patients receiving either dose had improvement in BCVA of 15 letters or more in the two trials. At 30 months, preliminary analysis of data combined from both trials showed a ≥15-letter BCVA improvement in 39.8% of patients (n=123) with the low-dose insert. Following release of results from the two phase 3 studies, a new drug application, including the 24-month low-dose data, was submitted to the FDA but was delayed recently after the FDA said the application for the drug could not be approved “in its present form” and requested analyses of safety and efficacy data through month 36 of the FAME study.¹⁵

In February 2011, Alimera announced that the 36-month results in the low-dose arm of the study showed that 28.4% and 29.0% of patients in the treatment groups, compared with 18.9% in the control group, had BCVA improvement of 15 or more letters from baseline.¹⁶ The consistency of results over time suggests that Iluvien may provide a long-term beneficial effect for patients with DME.

The adverse effect profile is better than that observed in the phase 3 trial of the surgically implanted fluocinolone device (Retisert). The lower risk of adverse effects is likely a result of the lower dose and the more posterior placement of the implant, more distant from the anterior chamber. An increase of IOP greater than 30 mm Hg was seen in 16.3% of the low-dose and 21.6% of the high-dose groups, compared with 2.7% in the control group. However, cataract rates were high, found in 80% and 87% of the low- and high-dose groups, compared with 43.6% of the control group at month 24.

I-vation

Another nonbiodegradable sustained-release steroid-delivery platform is the TA intrascleral implant (I-vation), which has a unique helical design that maximizes the surface area available for drug delivery.¹⁷ It is composed of a nonferrous metal alloy that is implanted through the pars plana with a 25-gauge needle stick less than 0.5 mm in diameter and is anchored against the sclera placed underneath the conjunctiva. This system offers a great deal of versatility and flexibility for formulation and pharmacokinetics that can utilize combinations of polymers and drug.

In a phase 1 study, 64% of patients receiving a slow-release implant (n=11, approximately 1-3 µg TA/day) and 72% of patients receiving a fast-release implant (n=14, approximately 3-5 µg TA/day) demonstrated improved visual acuity at 24 months. However, both groups experienced a rise in mean intraocular pressure, with an increase from 13.9 mm Hg at baseline to 16.6 mm Hg in the slow-release group and from 14.3 mm Hg to 15.9 mm Hg in the fast-release group.¹⁸

In 2008, Merck, which has been collaborating with SurModics on I-vation, suspended further funding of the device, citing recent trial results indicating that laser was superior to TA. “This decision was not based,” a press release read, “on any concerns about the safety or efficacy of I-vation TA, the I-vation platform or any of SurModics' other sustained drug delivery systems.” Since 2008, no further research has been conducted on I-vation.

Anti-VEGF

In addition to steroids, drugs approved for wet age-related macular degeneration also appear to be effective in DME. Researchers are exploring antiangiogenic drugs to target VEGF, the overexpression of which is believed to play a role in numerous diseases, including DME and AMD.¹⁹

Ranibizumab and pegaptanib, drugs that inhibit VEGF-signaling and are FDA-approved to treat wet AMD, were highly effective in improving visual acuity in patients with DME in a series of randomized, controlled trials. A recent DRCR.net study examined the efficacy of ranibizumab in patients with DME involving the center of the macula.^20,21 The multicenter, double-masked clinical trial randomized a total of 854 eyes in 691 patients with visual acuity of 20/30 to 20/320 and with macular edema involving the fovea to receive treatment with one of the several regimens: prompt laser with sham intravitreal injections as a control (n=293); intravitreal ranibizumab (0.5 mg) plus laser treatment within three to 10 days after injection (n=187 eyes); ranibizumab injections (0.5 mg) plus laser treatment deferred by at least 24 weeks (n=188 eyes); and intravitreal injections with the corticosteroid triamcinolone (Triesence, Trivaris Intravitreal, 4 mg) plus prompt laser (n=186 eyes).

At the one-year follow up, intravitreal ranibizumab with deferred (24 weeks) or prompt focal/grid laser was superior to laser alone, with significantly more eyes gaining substantial vision and significantly fewer eyes losing substantial vision. Nearly 50% of eyes in each ranibizumab group gained at least 10 letters or more compared with the laser alone (28%) and with IVTA plus laser (33%).

Reduction in mean central subfield thickness in the IVTA/prompt laser group was similar to that in the ranibizumab groups and greater than that in the laser group. Two-year visual acuity outcomes were similar to one-year outcomes. In the subset of pseudophakic eyes, intravitreal triamcinolone with prompt focal/grid laser may be equally effective as ranibizumab at improving visual acuity and reducing retinal thickening but is associated with an increased risk of elevated IOP.

In contrast to ranibizumab, which inhibits all isoforms of VEGF-A, pegaptanib inhibits only VEGF-165, the predominate isoform in DME. A double-blind, phase 3 study compared pegaptanib with sham injection in a total of 260 patients with DME.^22,23 For the first year, either a sham or a pegaptanib 0.3 mg injection was given every six weeks for a total of nine injections. In the second year, injections were given on an as-needed basis, as frequently as every six weeks, based on the certain protocol criteria, including visual acuity, clinical examination, optical coherence tomography and the opinion of the investigator.

After 54 weeks, the study found that 37% of patients treated with pegaptanib gained two lines (10 ETDRS letters) at 54 weeks compared with 20% in the sham group (P =.0047). On average, patients treated with pegaptanib gained 5.2 letters of visual acuity at year 1 compared with 1.2 letters in the sham group (P < .05). At the end of year 2, patients receiving pegaptanib had gained an average of 6.1 letters in BCVA compared with 1.3 letters for patients in the sham arm (P < .01). An extended-release formulation of pegaptanib using microparticles technology is being evaluated to allow for a decrease in the dosing interval from six weeks to six months.^24,25

Bevacizumab is a full-length, humanized antibody related to ranibizumab, which is a fragment of the antibody. Like ranibizumab, it binds to all isoforms of VEGF. Bevacizumab is used extensively off-label in clinical practice to treat retinal diseases, but data from clinical trials are limited. In a retrospective, multicenter, interventional, comparative case series comparing two different doses of intravitreal bevacizumab (1.25 m or 2.5 mg) in 139 eyes with diffuse DME, BCVA, OCT and FA findings were stable or improved at 24 months. The difference in dose did not appear to be associated with a difference in outcomes.²⁶

Finally, a multicenter phase 2 study evaluating the efficacy and safety of VEGF Trap-Eye, a soluble VEGF-receptor fusion molecule that binds all forms of VEGF-A and placental growth factor, has reported positive results in patients with DME.²⁷ At 24 weeks, patients who received VEGF Trap-Eye 0.5 mg or 2 mg monthly (n=44 in both groups) had a mean increase of 8.6 and 11.4 letters in BCVA, respectively, while those receiving 2 mg as needed following three monthly injections had a 8.5-letter BCVA increase. All treatment arms showed an improvement compared with patients receiving laser (n=44, treatment average 1.7), who only had a mean 2.5-letter gain in BCVA.

CONCLUSION

That the emerging pharmaceutical industry is developing more efficacious treatments to treat DME is very exciting. New corticosteroid treatments promise to extend the duration of treatment effects by using dexamethasone or fluocinolone, both of which have an approximately five-fold increase in corticosteroid potency with a decreased risk of cataract and glaucoma in comparison with triamcinolone. Noncorticosteroid treatments have shown promising efficacy as well, with less risk of cataract and glaucoma but a greater burden of treatment, requiring more frequent injections. These promising new therapies will offer hope and options to patients suffering with DME. RP

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