A Glimpse at Newand Emerging Treatments for DME
A Glimpse at New and Emerging Treatments for DME
The quest to preserve vision in diabetic eye disease is focusing on anti-VEGF drugs, implants and topical drops.
BY ASHISH SHARMA, MD, BARUCH D. KUPPERMANN, MD, PHD
Diabetic macular edema (DME) is a multifactorial disease. Excess, uncontrolled blood sugar damages the retinal microvasculature, causing fluid and lipids to leak into the retina. The relative hypoxia associated with this microvascular damage often triggers a vascular endothelial growth factor (VEGF) production cycle.
Primary prevention is the ideal treatment for DME, as the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated. However, prevention does not always work. Retinopathy and DME not only frequently occur despite good glycemic control, but they are often the initial presenting signs of diabetes.
Treatment is indicated once the physician observes clinically significant macular edema (CSME), as the Early Treatment Diabetic Retinopathy Study (ETDRS) trials defined it. The most common approaches in managing DME include focal or grid argon laser photocoagulation, pars plana vitrectomy with and without inner limiting membrane peeling, as well as intravitreal injections using triamcinolone acetonide or novel VEGF inhibitors. While focal and grid photocoagulation are the gold standard, the increasing availability of new agents raises the possibility of improving the standard of care for patients with diabetic maculopathy in the near future. Here, we review some new and emerging treatment approaches in the pipeline for DME.
Intravitreal Anti-VEGF Therapy
VEGF has been shown to be an important factor in the occurrence of vascular permeability in ocular diseases such as DME. In DME, microvascular damage leads to an increase in production of VEGF, which increases vascular permeability by a variety of mechanisms, including affecting endothelial tight junction proteins.1 The following anti-VEGF treatments have been shown to be effective in preventing or slowing the progression of vision loss in DME.
Anti-VEGF treatments for the treatment of DME are the focus of several clinical trials.
Drops utilizing small-molecule agents show promise for treating DME because they have appropriate polarity and can reach the posterior segment.
■ Ranibizumab (Lucentis). This is an antibody fragment that binds and blocks the effects of VEGF-A. Lucentis (Genentech, South San Francisco, Calif.) inhibits all isoforms of VEGF-A. The FDA recently approved Lucentis for treatment of DME. The following clinical trials have further evaluated its safety and efficacy in treating DME.
► READ-2 Study. The Ranibizumab for Edema of the Macula in Diabetes (READ-2) study randomized 126 eyes with DME to three groups: ranibizumab only (injection at baseline, months 1, 3 and 5); photocoagulation (at baseline and at 3 months if needed); and combined ranibizumab and photocoagulation (both at baseline, and ranibizumab only at three months if needed). The study was originally designed to last 24 months, but an amendment extended the trial follow-up to 36.
Six-month endpoint evaluation of the READ-2 data has been encouraging. On average, the vision of Lucentistreated patients improved to 20/63 at six months compared with essentially unchanged acuity scores of approximately 20/80 in both the laser and the combination treatment groups. In addition, in months six to 24, ranibizumab treatment as needed resulted in maintenance of BCVA benefits.2 Now the READ: Protocol 3 With High Dose trial — READ 3 — is underway.3
► RIDE and RISE Studies. These two phase 3 studies are investigating the efficacy and safety of intravitreal Lucentis injection. Patients have been randomized to receive monthly injections of 0.3 mg ranibizumab, 0.5 mg ranibizumab or sham. RIDE and RISE study results have shown that ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.4
► RESOLVE Study. The formal name of the study is Safety and Efficacy of Ranibizumab in Diabetic Macular Edema With Center Involvement — RESOLVE. This randomized, double-masked, multicenter, phase 2 study assessed the safety and efficacy of two concentrations of ranibizumab intravitreal injections compared with nontreatment for DME with center involvement.
Subjects were randomized to receive three monthly injections of either 0.3 or 0.5 mg ranibizumab or placebo. Treatment was then on an as needed basis. If edema persisted, the ranibizumab dose was doubled after one month. If needed, subjects received photocoagulation after three injections. The ranibizumab group showed statistically significant improvement in vision and macular thickness compared with the sham group.5
► RESTORE Study. This 12-month, double-masked, multicenter, phase 3 study involved 345 patients randomized to either ranibizumab and sham laser, ranibizumab and laser, or sham injections and laser. The study concluded that both ranibizumab monotherapy and combined ranibizumab-laser therapy provided superior visual acuity gain over standard laser treatment alone in patients with visual impairment due to DME.6
|Recently Approved Jetrea May Have Use in DME
The FDA last month approved Ocriplasmin (ThromboGenics NV, Leuven, Belgium) for symptomatic vitreomacular adhesion (VMA). With regards to diabetic eye disease, vitreous traction is one of the causes for persistent DME in some cases. The rationale is that inducing a posterior vitreous detachment (PVD) could be of help in these cases. Although instrumentation and techniques for vitreous surgery have greatly improved in recent years, the procedure can still cause complications such as retinal breaks, retinal detachment and retinal nerve fiber damage.29,30
Hence the desire for a biochemical agent that could cleave the vitreoretinal interface selectively without damaging the retina. Human microplasmin is a 29 kD protein containing one protease active site of plasmin. The Microplasmin Intravitreous Injection (MIVI) trial was a phase 2 trial that evaluated the safety and efficacy of intravitreal microplasmin in facilitating the creation of a total PVD in patients scheduled for PPV. The study showed that microplasmin injection at a dose of 125 μg favors induction of PVD better than placebo.31
■ Bevacizumab (Avastin). Avastin (Genentech) is the full antibody to VEGF-A from which ranibizumab is derived. This anti-VEGF molecule is FDA-approved for systemic treatment of metastatic colon cancer, but not for any ophthalmic indications. Its use in AMD, diabetic retinopathy and DME is currently off-label.
► National Eye Institute/Diabetic Retinopathy Clinical Research Network (DRCRnet) study. This important phase 2 study was published five years ago. The study aim was to provide preliminary data on the dose and dose-interval-related effects of intravitreally administered bevacizumab on retinal thickness and visual acuity in subjects with DME to aid in planning a phase 3 trial.7
The study randomly assigned 121 patients to one of five groups: focal photocoagulation at baseline; intravitreal injection of 1.25 mg bevacizumab at baseline and six weeks; intravitreal injection of 2.5 mg bevacizumab at baseline and six weeks; intravitreal injection of 1.25 mg bevacizumab at baseline and sham injection at six weeks; or intravitreal injection of 1.25 mg bevacizumab at baseline and six weeks with photocoagulation at three weeks.
The study measured central subfield thickness, based on optical coherence tomography (OCT), and BCVA at baseline and at 3, 6, 9, 12, 18 and 24 weeks. The results demonstrated that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial.
► Pan-American Collaborative Retina Study Group. This group performed an interventional retrospective multicenter study of patients with DME.8 The analysis reviewed clinical records of 115 consecutive patients (139 eyes) with DME at 11 centers in eight countries. Patients were treated with at least one intravitreal injection of 1.25 mg or 2.5 mg of bevacizumab. Primary intravitreal bevacizumab at doses of 1.25 to 2.5 mg seemed to provide stability or improvement in BCVA, OCT and FA in diffuse DME at 24 months. The results showed no difference between intravitreal bevacizumab at doses of 1.25 or 2.5 mg.
► Bevacizumab or Laser Therapy in the Management of DME (BOLT). This study has favored bevacizumab over laser photocoagulation at one year and, more recently, at two years.9
■ Pegaptanib (Macugen). Macugen (eyetech Inc., Cedar Knolls, N.J.) is an anti-VEGF aptamer, a small piece of RNA that self-folds into a shape that binds to and blocks the effects of VEGF165, an isoform of the VEGF family of molecules. The drug had been FDA-approved for treatment of wet AMD. A recent phase 2/3 randomized controlled trial reported that 0.3 mg pegaptanib therapy was associated with improved visual outcomes in patients with DME for up to two years.10 Subjects received pegaptanib or sham injections every six weeks in the first year of study, and were eligible to receive focal/grid photocoagulation beginning in the 18th week. After the first year, 49 of 133 subjects from the pegaptanib group and 25 of the 127 from the sham group experienced a VA improvement of at least 10 letters.
During the second study year, subjects received injections as often as every six weeks. At two years, 102 pegaptanib-treated subjects gained an average of 6.1 letters versus 1.3 letters for the sham group.
■ Aflibercept (Eylea). Formerly known in the literature as VEGF Trap-Eye, Eylea (Regeneron Pharmaceuticals Inc., Tarrytown, N.Y.), is a fully human, soluble VEGF receptor fusion protein that binds all forms of VEGF-A along with the related placental growth factor (PlGF). Aflibercept is a specific and highly potent blocker of these growth factors.
While aflibercept is FDA-approved for treatment of wet AMD, it is the subject of a Phase 2 clinical trial for treatment of DME. The DA VINCI study has shown favorable outcomes compared to laser photocoagulation in cases of DME, along with reduction of central retinal thickness.11 The investigators reported that the drug was well tolerated by the patients. Presently, a phase 3 randomized clinical trial is under way to investigate the efficacy of aflibercept for DME.12
|Ranibizumab with Laser Trial for DME
As a multifactorial disease, diabetes requires a comprehensive approach to address multiple pathophysiological mechanisms. Combination therapy can attack more than one pathophysiological factor responsible for DME simultaneously. Due to recent advancement in pharmacotherapeutics, a few trials have investigated the combination of gold-standard laser and newer drugs for treatment of DME.
A randomized phase 2 trial evaluating ranibizumab or triamcinolone plus laser demonstrated that ranibizumab with prompt or deferred focal/grid laser achieved superior visual acuity and OCT outcomes compared with focal/grid laser treatment alone.32
In the ranibizumab groups, approximately 50% of eyes had substantial improvement (10 or more letters) and 30% gained 15 or more letters. Intravitreal triamcinolone combined with focal/grid laser did not result in superior visual acuity outcomes compared with laser alone, but did appear to have a visual acuity benefit similar to ranibizumab in pseudophakic eyes.
Topical instillation of ophthalmic drops is the most common method used to administer drugs for ocular disease. However, topical therapy does not penetrate to the posterior segment readily, so drops have rarely been used for retinal diseases. The drugs listed here are small-molecule agents, have appropriate polarity, and are designed to reach to the posterior segment by transcorneal or transconjuctival/transscleral routes, or both.
■ Mecamylamine. This agent inhibits endothelial nicotinic acetylcholine (nACh) receptors and decreases angiogenesis and vascular permeability via this novel anti-VEGF pathway. A phase 2 study suggested that administration of topical mecamylamine (Comentis, South San Francisco, Calif.), a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with DME.
Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.13
■ Bromfenac (Bromday). This potent NSAID has prolonged pharmacokinetics, allowing twice-daily dosing. Bromfenac (Bausch + Lomb, Madison, N.J.) is FDA-approved for inflammation associated with cataract surgery. NSAIDS reduce vascular hyperpermeability associated with tissue inflammation by inhibiting prostaglandin synthesis, and increased inflammatory markers have been found in diabetic retinopathy in patients treated with NSAIDs.13
A nonrandomized, open-label, uncontrolled phase 1 pilot study was launched in 2007 to assess safety and biologic activity of topical bromfenac 0.09% in subjects with diffuse DME refractory to laser.14 However, the study has not been updated in five years.
■ Nepafenac (Nevanac). DRCRnet is currently recruiting a phase 2 RCT studying the use of topical nepafenac 0.1% (Alcon, Fort Worth, Texas) t.i.d. to treat nonclinically significant DME.15
Increasingly, corticosteroids have been employed to treat macular edema. Corticosteroids control DME by attacking pathophysiological factors such as inhibiting inflammatory mediators and VEGF, and improving vascular homeostasis. Steroids are the only drugs with which researchers have been successful in making sustained drug delivery devices for ophthalmic use.
Intravitreal triamcinolone has been successfully used to treat chronic retinal inflammatory conditions and its crystalline formulation helps in drug delivery for long term, although crystals have been shown to be toxic in few in vitro studies.16 Clinical trials have shown the following corticosteroids have some potential in treating DME.
■ Nova63035 (Cortiject). This unique injectable emulsion allows for the sustained release of the pro-drug over six to nine months by using the proprietary Eyeject technology (Novagali Pharma, Genavenir, France). Enzymes in the retina and choroid, and absent in the vitreous, convert the pro-drug into the drug, making it safe and specific.
The company has confirmed that a phase 1, nonrandomized open-label, dose-escalation clinical trial is under way to assess the safety and tolerability of NOVA63035 in patients with DME secondary to diabetic retinopathy. However, the study is not recruiting participants and the estimated completion date was June 2011.17
■ Triamcinolone acetonide (TA). Intravitreal TA (IVTA) has been proposed as an alternative treatment for eyes with DME refractory to laser photocoagulation, and growing evidence suggests that it effectively reduces macular thickness and improves visual acuity in DME.
The phase 2 Intravitreal Triamcinolone Acetonide vs. Laser for DME trial, an NEI-sponsored study under the auspices of DRCRnet, compared the safety and efficacy of
TA with focal/grid photocoagulation. This study concluded
that over two years, focal/grid photocoagulation is more effective and has fewer side effects than 1-mg or 4-mg doses of preservative-free IVTA for most patients with DME with characteristics similar to the cohort in this trial. The study results also supported that clinical trials of DME should use focal/grid photocoagulation as the benchmark against which other treatments are measured.18 Recent three-year results are consistent with the two-year results.19
The Ozurdex applicator and a version of the implant used in phase 2 trials of patients with persistent macular edema.
Implantable Drug-Delivery Devices
Long-acting intravitreal drug-delivery implants can overcome many of the limitations of other therapeutic approaches, such as frequent intravitreal injections or systemic side effects. Implants may prove more useful in certain situations such as vitrectomized eyes in which intravitreal drug in solution washes out faster.20 Here is a look at the implants in varied stages of investigation.
■ Ozurdex. The Ozurdex (Allergan, Irvine, Calif.) implant is a sustained-delivery formulation of dexamethasone. This biodegradable implant has FDA approval for macular edema related to RVO and uveitis, and has been used off-label for DME. It has a polylactic glycolic acid polymer as the delivery vehicle, which undergoes hydrolysis with degradation to lactic acid and glycolic acid, two naturally occurring metabolic byproducts further broken down to water and carbon dioxide.
A phase 2 trial showed positive outcomes overall of two different dexamethasone dose implants (350 μg and 700 μg) in 315 patients with refractory, persistent macular edema due to various causes.21 At six months, 18.1% of patients in the 700-μg group had BCVA improved by 15 letters or more, compared to 14.6% of patients in the 350-μg group and 7.6% of patients in the observation group.
Results from a trial comparing Ozurdex plus laser with laser alone for treatment of DME have not yet been published, although they have been discussed at scientific conferences. This one-year trial has shown that patients with diffuse DME had better BCVA at 12 months when treated with Ozurdex plus laser versus laser alone.22 A published trial of the Ozurdex implant in post-vitrectomy eyes with persistent DME found the mean increase in best-corrected visual acuity from baseline (54.5 letters) was 6.0 letters at eight weeks and 3.0 letters 26 weeks.20
Comparative sizes of the Medidur implant for Iluvien and Retisert, along with the Vitrasert implant.
The study concluded that treatment with Ozurdex led to statistically and clinically significant improvements in both vision and vascular leakage from diabetic macular edema in difficult-to-treat vitrectomized eyes and had an acceptable safety profile.
■ Retisert. This implant contains fluocinolone acetonide within a small reservoir containing only 0.59 mg of the drug. The implant delivers chronic sustained low levels of the drug (approximately 0.5 μg/day) into the vitreous cavity for up to three years. Retisert (Bausch + Lomb) demonstrated significant efficacy in patients with uveitis and was approved by the FDA for this indication.
A randomized, clinical trial compared the effects the Retisert with photocoagulation for DME. Although the study found no statistically significant differences in final visual acuity between the two groups, it did report resolution of DME in 57% of patients with the fluocinolone acetonide implant versus 20% of patients with photocoagulation at the end of one year, based on clinical examination and OCT.23 At three years, patients randomized to receive the fluocinolone acetonide implant had persistent treatment of macular edema, but 95% of phakic eyes developed significant cataract, and about one-third of eyes had IOP above 30 mm Hg.24
■ Iluvien. This is a similar but smaller fluocinolone acetonide-based implant that has two formulations: One that delivers 0.2 μg/day and the other 0.5 μg/day. The proprietary Medidur drug delivery technology, which Alimera Sciences (Alpharetta, Ga.) licensed from pSivida Corp. (Watertown, Mass.) for Iluvien, has two models; one is designed to last approximately three years, and the other lasts approximately 18 months. The FDA denied approval to Iluvien last year because of its side effects, although the implant is approved in some European countries.
Alimera conducted two 36-month, Phase 3 pivotal clinical trials, collectively known as FAME (Fluocinolone Acetonide for Macular Edema), involving 956 patients. At month 36, the percentages of subjects with demonstrated BCVA improvement of 15 letters or more from baseline were 28.4% and 29.0% for Trial A and Trial B, respectively.25 Statistical significance was seen in both trials as late as month 33, with Trial A at 28.4% and Trial B at 29.6%.
The trials noted IOP increases to 30 mm Hg or greater at any time during the study in 14.8% of patients by month 36, compared to 18.3% among the overall Iluvien-treated group. By month 36, 5.3% of these patients had undergone an incisional surgical procedure to reduce elevated IOP, compared to 4.8% in the full patient population. The incidence of cataracts among patients with a natural lens in their eye at the start of the study was 86% at month 36, with 85% undergoing a cataract operation, compared to 80% and 74.9%, respectively, in the full patient population.25
■ I-vation Implant. This sustained-release triamcinolone implant (SurModics Inc., Eden Prarie, Minn.) was suspended after the DRCRnet publication showing laser photocoagulation superior to IVTA in DME.26,27
The subconjunctival approach to drug delivery is safer and less invasive than intravitreal injection and also offers the potential advantage of localized, sustained-release drug delivery. Subconjunctival administration uses the large surface area of the sclera for drug penetration. However, subconjunctival delivery is associated with greater systemic exposure than intravitreal delivery, due to the presence of conjunctival and orbital blood vessels and tissue.
■ Sirolimus (Perceiva). Also known as rapamycin, sirolimus (MacuSight, Union City, Calif.) is FDA-approved for systemic use in renal transplantation. According to its developers, this drug acts by immunosuppressive, antiangiogenic, antimigratory, antiproliferative, antifibrotic and antipermeability mechanisms. This drug is 92% protein-bound with a half-life of 57 to 63 hours.
|Therapies That Got a Fleeting Look for Treating DME
Three other classes of drugs have been subjects of clinical trials for treatment of DME. They are:
► Tumor necrosis factor. TNF, cachexin or cachectin and formally known as TNF-α, is a cytokine involved in inflammation and is a member of a group of cytokines that stimulate the acute-phase reaction. Anti-TNF-α is thought to have the potential to reduce inflammation and improve DME. Two such agents have been the focus of clinical trials:
► Etanercept (Enbrel). Enbrel (Amgen Inc., Thousand Oaks, Calif.) is widely prescribed for rheumatoid arthritis and other similar conditions. A small pilot study in Greece in 2007 reported that intravitreal etanercept had shown some evidence of efficacy against refractory DME.33 However, no further evidence of its use for diabetic eye disease has been published.
► Infliximab (Remicade). Remicade (Janssen Biotech Inc., Horsham, Pa.) is a genetically engineered antibody against a molecule in the body called TNF-α. It neutralizes the effects of TNF-α by binding to it. A small phase 1, nonrandomized, open-label, single-group assignment study started recruiting participants in 2008, but no further updates have been forthcoming.34
► Lipolytic agent. K Choline fenofibrate (SLV348), or fenofibrate (Abbott Laboratories, Abbott Park, Ill.), activates the peroxisome proliferator-activated receptor a (PPARa). This increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III. A one-year, phase 2, placebo-controlled, randomized study to evaluate the effect of fenofibrate on macular edema, as measured by OCT, in subjects with DME has been completed, but the results are not yet available.35
► Protein kinase-ß inhibitor. PKC inhibitor ameliorates the adverse effects of high glucose on microvasculature. Diabetes-induced activation of PKC-G appears to mediate increases in retinal vascular permeability and neovascularization in animal models and changes in retinal blood flow in diabetic patients. Only one such agent was the focus of a clinical trial: ruboxistaurin (Arxxant, Eli Lilly and Company, Indianapolis).
This agent limits the over-activation of-PKC β, a naturally occurring enzyme linked to the development of diabetic retinopathy. This would have been the first oral medication for the treatment of diabetic retinopathy, and the experimental drug was the focus of a number of published reports. The PKC-Diabetic Retinopathy Study (PKC-DRS) reported reduced incidence of moderate visual loss (doubling of the visual angle) with the use of ruboxistaurin.36
The PKC-DRS 2 reported reduced incidence of sustained moderate visual loss (for six months) with ruboxistaurin.37 The PKC-DME Study showed reduced progression of DME with ruboxistaurin.38 However, the FDA in 2007 demanded a new three-year clinical trial of the drug before it would consider approval, but Eli Lilly said it would not pursue the FDA’s ruling any further.39
For ocular applications, sirolimus is injected either subconjunctivally or intravitreally. It lasts up to three months when given subconjunctivally. Positive interim data from a phase 1 study in 50 patients with chronic, clinically significant DME demonstrated that sirolimus was safe and well-tolerated in all doses tested with two different routes of administration.28
Additionally, investigators noted improvements in visual acuity and foveal thickness reductions for up to 180 days following a single administration of sirolimus. This raised the possibility that sirolimus may be fundamentally changing the course of diabetic retinopathy through its impact on the rapamycin pathway rather than simply reversing macular edema in a more nonspecific way.28
Now a phase 2, randomized, double-masked, placebo-controlled, dose-ranging clinical study is under way to evaluate the safety and efficacy of sirolimus subconjunctival injections in patients with DME secondary to diabetic retinopathy. Estimated enrollment is 120 patients, and the primary end-point is the proportion of patients with BCVA improvement by ETDRS. The study has three experimental and one placebo arms; the experimental arm receiving two conjunctival injections of 220, 440 and 880 μg. Completion was estimated for March 2012, but no results have yet been disclosed.28
Since the results of landmark studies such as ETDRS, UKPDS and the Diabetic Retinopathy Study, retinal physicians have been managing diabetic retinopathy and its complications with a focus on metabolic control and laser photocoagulation. In spite of these best efforts, DME continues to cause visual loss in many patients.
DME management in the past few years has changed dramatically. At present anti-VEGF and steroids are the most commonly used treatment modalities along with variable combinations, and some of the most promising treatments are emerging. However, we hope that with these new emerging drug-delivery technologies and new drugs, the best is yet to come. OM
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||Ashish Sharma, MD, is consultant with the Retina Service at Lotus Eye Care Hospital and Institute, Coimbatoe, India. Baruch D. Kuppermann, MD, PhD, is professor of ophthalmology and biomedical engineering, chief of the retina service, and vice chair of clinical research at University of California, Irvine. Dr. Sharma reports no financial interests. Dr. Kuppermann reports financial interests in Genentech, Regeneron, Bausch + Lomb and Allergan. Dr. Sharma can be reached via e-mail at firstname.lastname@example.org.
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