Review
Emerging drugs for diabetic macular edema
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
Stephen G Schwartz, Harry W Flynn Jr & Ingrid U Scott† †
Penn State College of Medicine, Penn State Hershey Eye Center, Ophthalmology and Public Health Sciences, Hershey, PA, USA
1.
Background
2.
Medical need
3.
Existing treatment
4.
Market review
5.
Current research goals
6.
Scientific rationale
7.
Competitive environment
8.
Potential development issues
9.
Conclusion
10.
Expert opinion
Introduction: Diabetic macular edema (DME) is the most common cause of visual impairment due to diabetic retinopathy. The treatment of DME has recently undergone a paradigm shift. Traditionally, photocoagulation was standard treatment, but pharmacologic therapies are becoming increasingly used for this purpose. All currently available drug therapies for DME are either anti-VEGF agents or corticosteroids. Areas covered: The pathogenesis of DME involves angiogenesis, inflammation and oxidative stress. The scientific rationale to treat DME through the pharmacologic blockade of VEGF and other pro-angiogenic factors is discussed. The fluocinolone insert is approved for the treatment of DME in several European countries, but not in the US at this time. Some medications that are already approved for other retinal diseases, most prominently aflibercept and the dexamethasone delivery system, have recently obtained approval for DME in the US. Other compounds are being studied in earlierphase clinical trials. Expert opinion: Pharmacologic treatment of DME will likely become increasingly used, especially for patients with edema involving the fovea. At this time, the two main classes of medication for treatment of DME are antiVEGF agents and corticosteroids. As we continue to collect clinical trials data, the precise role of individual agents, and the continuing role for photocoagulation, will become more clear. Keywords: aflibercept, bevacizumab, dexamethasone, diabetic macular edema, fluocinolone acetonide, randomized clinical trial, ranibizumab, triamcinolone acetonide, VEGF Expert Opin. Emerging Drugs (2014) 19(3):397-405
1.
Background
Diabetic macular edema (DME) is one of the major causes of visual loss among individuals with diabetes mellitus [1]. Duration of diabetes, as well as severity of hyperglycemia, hypertension and hyperlipidemia, have been reported as risk factors for DME [2]. All racial and ethnic groups are at risk for diabetic retinopathy and DME, but increased risk has been reported in patients of African, Latin American, South Asian and indigenous tribal ancestry [3]. The pathogenesis of DME remains poorly understood but involves angiogenesis, inflammation and oxidative stress [4]. Chronic hyperglycemia has been reported to cause leukocyte-mediated capillary endothelial damage [5] as well as activation of oxidative stress products such as advanced glycation end products and the protein kinase C pathway [6]. Inflammatory mediators that have been associated with DME include VEGF [7], placental growth factor (PlGF) [8], hepatocyte growth factor [9] and others.
10.1517/14728214.2014.938048 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted
397
S. G. Schwartz et al.
Table 1. Currently available medications for the treatment of diabetic macular edema.
injections and all medications are either anti-VEGF agents or corticosteroids (Table 1).
Class
Anti-VEGF agents Anti-VEGF agents work by antagonizing the activity of VEGF, which is important in the pathogenesis of DME and other ischemic retinal diseases [20]. Ranibizumab (Lucentis, Genentech, South San Francisco, CA, USA), an anti-VEGF agent delivered via repeated officebased intravitreal injection, was the first medication with US FDA approval for the treatment of DME (Figure 1) [21]. The labeled dosing is monthly. Bevacizumab (Avastin, Genentech, South San Francisco, CA, USA) is a systemic anti-VEGF agent with chemical similarities to ranibizumab. It has become used widely, through intravitreal injection, in the off-label treatment of DME and other retinal diseases because of its widespread availability and low cost. Intravitreal bevacizumab has been reported to have more favorable outcomes than photocoagulation in multiple RCTs [22,23]. Treatment generally is performed at approximately monthly intervals, similar to ranibizumab. Aflibercept (Eylea, Regeneron, Tarrytown, NY), previously known as VEGF Trap-Eye, is a recombinant fusion protein with activity against VEGF and PlGF, and is currently US FDA-approved for the treatment of neovascular AMD [24] and central retinal vein occlusion [25]. A Phase II RCT reported beneficial outcomes in the treatment of DME [26] and favorable Phase III data were reported by the manufacturer [27], but are not yet published in the peer-reviewed literature. The agent obtained US FDA approval for DME in July 2014. In addition, the manufactuer announced that the European Committee for Medicinal Products for Human Use recommended aflibercept for the treatment of DME.
Anti-VEGF
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
Corticosteroid
2.
Name
Notes
Ranibizumab (Lucentis) Aflibercept (Eylea) Bevacizumab (Avastin) Triamcinolone acetonide Fluocinolone insert (Iluvien) Dexamethasone delivery system (Ozurdex)
Approved in 2012 Approved in 2014 Off-label Off-label Only approved in Europe Approved in 2014
Medical need
The worldwide prevalence of diabetes is increasing, which will likely result in an increasing worldwide burden of DME [10]. Using a pooled analysis, it has been estimated that there are ~ 93 million people with diabetic retinopathy and 21 million with DME worldwide [11]. The 10-year incidence of DME has been reported as 11% in type 1 diabetics [12] and 14% in type 2 diabetics [13]. In England, an estimated 7.1% of diabetics have DME in one or both eyes [14]. It has been reported that, in the US, 16% of patients with DME have visual impairment defined as best-corrected visual acuity worse than 20/40 in the eye with DME, and that these patients appear to be underutilizing the US healthcare system [15]. In addition, all currently available therapies for DME have a percentage of nonresponders (patients who do not improve following treatment), and all currently available therapies are associated with risks of visual loss in a minority of treated patients.
3.1
Corticosteroids Corticosteroids are thought to be beneficial in the treatment of DME through multiple pathways, including a nonspecific antiinflammatory effect as well as by downregulation of VEGF [28,29]. Three synthetic corticosteroids have been studied as potential intravitreal treatments for DME: triamcinolone acetonide, dexamethasone and fluocinolone acetonide [30]. Triamcinolone acetonide has been used off-label to treat DME, but its use has declined as the use of anti-VEGF therapy has increased, at least in part due to cataract formation and intraocular pressure (IOP) elevation that are commonly associated with ophthalmic corticosteroids. A large RCT reported that, for most patients, triamcinolone acetonide was associated with generally poorer outcomes than was photocoagulation [31]. However, triamcinolone acetonide is effective in some patients unresponsive to other therapies [32]. Treatment generally is repeated at ~ 3-month intervals. A dexamethasone delivery system (Ozurdex, Allergan, Irvine, CA) is a bioerodable device that may be injected in an office setting and that is US FDA-approved for the 3.2
3.
Existing treatment
Intensive control of blood sugar, blood pressure and serum lipids may reduce complications of diabetic retinopathy, including DME, without any specific ophthalmologic treatment [16,17]. Focal/grid photocoagulation, which applies laser energy directly to leaking retinal microaneurysms and diffusely in areas of macular edema, was reported effective in a randomized clinical trial (RCT) and was standard therapy for decades [18]. Focal/grid photocoagulation typically does not improve visual acuity and may be associated with risks of foveal burn, macular ischemia, expansion of photocoagulation spots over time and secondary choroidal neovascularization. Although focal/grid photocoagulation is still employed, pharmacotherapies have been used increasingly over the past 10 years, especially in patients with DME involving the fovea [19]. At this time, all commonly used medications to treat DME are delivered by repeated office-based intravitreal 398
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
A.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
D.
B.
C.
E.
F.
G.
H.
Figure 1. A 64 year-old man presented with complaints of bilateral visual loss. He was not previously known to be diabetic. Bestcorrected visual acuity was 20/100 in the right eye and 20/70 in the left eye. A. Fundus photography, right eye, demonstrating DME. B. Fundus photography, left eye, demonstrating DME. C. Optical coherence tomography, right eye, demonstrating macular edema. D. Optical coherence tomography, left eye, demonstrating macular edema. The patient was treated with bilateral ranibizumab at 1- to 2-month intervals for ~ 1 year. At the most recent follow-up, best-corrected visual acuity had improved to 20/40 in the right eye and 20/25 in the left eye. E. Fundus photography, right eye, demonstrating improved DME. F. Fundus photography, left eye, demonstrating improved DME. G. Optical coherence tomography, right eye, demonstrating improved macular edema. H. Optical coherence tomography, left eye, demonstrating improved macular edema. DME: Diabetic macular edema.
treatment of retinal vein occlusion [33] and noninfectious posterior segment uveitis [34]. In a Phase II RCT of patients with DME [35] and in an open-label trial of vitrectomized eyes with DME [36], the drug delivery system improved visual acuity, macular thickness and retinal vascular leakage. In both series, transiently increased IOP was reported in about 10 -- 15% of treated patients. In June 2014, the manufacturer announced that it had received FDA approval for the treatment of DME in pseudophakic patients or patients scheduled for cataract surgery. A fluocinolone acetonide insert (Iluvien, Alimera, Alpharetta, GA) is a nonbioerodable device that may be injected in an office setting and that elutes medication for 3 years [37]. In a Phase III RCT, the investigators reported that the fluocinolone insert was an effective treatment of DME but was associated with increased risks of cataract progression and IOP elevation [38]. The insert has achieved regulatory approval
in several European countries but not, at this time, in the US. Risks of intravitreal injections All intravitreal injections are associated with low risks of infectious endophthalmitis, which has generally been reported in the range of 0.03% per injection for antiVEGF agents and perhaps slightly higher for triamcinolone acetonide [39]. Infectious endophthalmitis, even if diagnosed promptly and treated appropriately, may lead to severe visual loss or loss of the eye. Intravitreal injections may also be associated with noninfectious intraocular inflammation, which may be difficult to distinguish from infectious endophthalmitis. In the early years of intravitreal injections, surgeons commonly employed pre- or postinjection topical antibiotics, but this practice has declined recently. Several studies have 3.3
Expert Opin. Emerging Drugs (2014) 19(3)
399
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
S. G. Schwartz et al.
reported that antibiotic use does not reduce rates of infectious endophthalmitis and may actually increase the risk. The reason for this possible increased risk is unknown but might be related to changes in antibiotic resistance patterns of conjunctival flora [40,41]. Triamcinolone acetonide and other corticosteroids have additional associated risks of cataract progression and IOP elevation, especially when administered by intravitreal injection [42]. Infrequently, IOP elevation may become severe or intractable, requiring additional medications or surgical interventions to control the pressure. Visually significant cataract may also require surgical intervention.
reduction of macular edema in patients with fovea-involving DME, especially in patients with moderate to severe visual loss [44]. In a Markov model, photocoagulation, intravitreal triamcinolone acetonide, intravitreal anti-VEGF therapy and combination therapies were compared. The authors reported that all treatments (except photocoagulation monotherapy) reduced costs, all treatments (except triamcinolone acetonide monotherapy) increased quality-adjusted life-years (QALYs) and the most effective treatment, as measured by discounted costs, gains in QALYs and incremental cost-effectiveness ratios, was anti-VEGF therapy with or without photocoagulation [45].
Preferred practice patterns The American Society of Retina Specialists (which also includes retina specialists in many other countries) conducts an annual ‘Preferences and Trends’ (PAT) survey of its members. In 2012, in response to the question “What is your initial treatment for [DME] not involving the foveal center?”, photocoagulation was selected by 75.9% of US and Canadian respondents, anti-VEGF therapy was selected by 16.3% of respondents, and the remainder selected observation or other therapies. International members responded similarly [43].
5.
3.4
4.
Market review
400
All currently available pharmacotherapies for DME are delivered by repeated office-based intravitreal injection. Injection must be performed by an ophthalmologist in a clinic setting, which is inconvenient for patients and family members, and potentially creates barriers to access for care. In addition, every injection is associated with small risks of endophthalmitis and other visionthreatening complications. Therefore, two major approaches to reduce the number of intravitreal injections are sustained-release medications and alternative drug delivery techniques. 6.
In the US, currently available choices for the treatment of DME include observation (including encouragement of tighter control of systemic factors, including blood pressure, blood sugar, serum lipids and body weight); focal/grid photocoagulation; the anti-VEGF agents ranibizumab and off-label bevacizumab; and off-label triamcinolone acetonide. In 2014, aflibercept and the dexamethasone delivery system were also approved for the treatment of DME. In several European countries, the fluocinolone insert (Iluvien) is now available but is generally used as a second- or third-line therapy. These therapies may be combined. Combination treatments may be beneficial for some patients, although at this time there is relatively little guidance available from the literature. For example, some patients appear to benefit from focal/grid photocoagulation to areas of DME outside the fovea combined with intravitreal pharmacotherapy for residual DME involving the fovea. Alternatively, some patients seem to respond more effectively to corticosteroids than to anti-VEGF agents, although corticosteroids may be associated with additional risks of cataract progression and IOP elevation. Therefore, a strategy that alternates anti-VEGF injections with corticosteroid injections may be reasonable for certain patients. Photocoagulation continues to be beneficial for many patients, especially for those whose DME does not involve the fovea. However, there is an increasing body of literature suggesting that anti-VEGF therapy provides generally more favorable improvements in visual acuity and
Current research goals
Scientific rationale
Sustained-release medications In theory, sustained-release drug delivery techniques might be preferable to repeated intravitreal injections if the duration of drug release exceeds the longest effective interval between injections and if the safety profile is favorable. This potential advantage is relatively greatest for patients requiring the most frequent (i.e., monthly) injections [46]. To date, there has been more progress in developing sustained-release corticosteroids than sustained-release antiVEGF agents. All currently available sustained-release intravitreal corticosteroids are delivered using bioerodable or nonbioerodable implants. In general, nonbioerodable implants offer more controlled release of medication and longer duration of action [47]. However, a nonbioerodable implant remains in the eye permanently unless removed surgically. 6.1
Alternative delivery techniques Frequent dosing may be more tolerable if intravitreal injections are avoided and if clinical outcomes are favorable. Unfortunately, at this time, no agent meets these criteria in the treatment of DME. Intravenous bevacizumab [48] and aflibercept [49] (a recombinant fusion protein with activity against VEGF and PlGF) were reported to have some efficacy in the treatment of neovascular age-related macular degeneration (AMD) in separate pilot studies, but systemic anti-VEGF agents are associated with risks of hypertension, proteinuria and thromboembolic events. 6.2
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
Table 2. Competitive environment of medications for the treatment of diabetic macular edema. Compound
Stage of development
Mechanism of action
Structure
Pegaptanib (Valeant) Ocriplasmin (ThromboGenics)
Discontinued Phase II
Anti-VEGF-165 Protease
Pegylated aptamer Recombinant plasmin
Danazol (Ampio) Dextromethorphan (NEI) Sirolimus (Santen)
Phase III Phase I/II Discontinued
Steroid Anti-NMDA Immunosuppressant
Derivative of ethisterone Morphinan Macrolide
AKB-9778 (Aerpio) PF-04634817 (Pfizer)
Phase II Phase II
Anti-VE-PTP Anti-CCR2/5
Modified sulfamic acid Synthetic small molecule
Indication
Neovascular AMD Symptomatic vitreomacular adhesion Endometriosis Cough Prophylaxis of organ rejection None None
AMD: Age-related macular degeneration; CCR: C-C chemokine receptor; NEI: National Eye Institute; PlGF: Placental growth factor; VE-PTP: Vascular endothelial protein tyrosine phosphatase.
Similarly, subconjunctival or peribulbar injections of various medications have not led to promising results. Sirolimus, or rapamycin, is a macrolide antifungal that has been studied as subconjunctival therapy for DME in early-stage trials [50,51], but the manufacturer (Santen, Osaka, Japan) has discontinued further efforts toward this indication. Peribulbar triamcinolone acetonide has demonstrated unsatisfactory efficacy in the treatment of DME [52,53]. 7.
Competitive environment
At this time, several medications are being studied for the treatment of DME (Table 2). These may be divided into drugs with regulatory approval for other ophthalmologic indications, drugs with regulatory approval for nonophthalmological indications and other agents. Drugs with regulatory approval for other ophthalmological indications
7.1
Pegaptanib (Macugen, Valeant, Bridgewater, NJ), a pegylated aptamer against the VEGF-165 isoform, is US FDA-approved for the treatment of neovascular AMD [54]. A Phase II/III RCT demonstrated favorable results in the treatment of DME [55]. However, at this time, the manufacturer is not pursuing FDA approval for DME. Ocriplasmin (Jetrea, ThromboGenics, Leuven, Belgium), a recombinant protease, has achieved US FDA approval for the treatment of symptomatic vitreomacular adhesion [56]. Vitreomacular adhesion may be associated with diabetic retinopathy, and it is reasonable to suspect that ocriplasmin may have a role in the treatment of DME [57]. At this time, the drug is being studied in a Phase II RCT for this purpose. Drugs with regulatory approval for nonophthalmological indications
7.2
Danazol, an androgen-like synthetic steroid, is US FDAapproved for the treatment of endometriosis and other
diseases [58]. Danazol has antiangiogenic properties and has, for example, been reported to decrease proliferation and tube length of human umbilical vein endothelial cells [59]. In a Phase IIA RCT, treatment with low-dose oral danazol (Optina, Ampio, Greenwood Village, CO) was associated with decreased retinal thickness and improved visual acuity in patients with DME [60]. The manufacturer is currently conducting a Phase III RCT. Dextromethorphan, an NMDA antagonist found in many antitussives, has been reported to have neuroprotective properties through inhibition of microglial activation [61]. The National Eye Institute has conducted a Phase I/II study of oral dextromethorphan in patients with DME, but results are not available at this time. Sirolimus, or rapamycin, is a macrolide antifungal with immunosuppressant properties that is indicated to prevent organ rejection after renal transplantation. Subconjunctival sirolimus was investigated as a treatment for DME [50,51], but further research for this indication has been discontinued. Other agents AKB-9778 is a novel agent that inhibits vascular endothelial protein tyrosine phosphatase, which subsequently inhibits endothelial Tie-2 receptor tyrosine kinase. In animal models, AKB-9778 has demonstrated antiangiogenic properties [62]. The manufacturer (Aerpio, Cincinnati, OH) is currently recruiting patients with DME for a Phase II RCT comparing subcutaneous AKB-9778 monotherapy, intravitreal ranibizumab monotherapy and combination therapy with the two agents. C-C chemokine receptor 2 (CCR2) is involved in macrophage attraction and angiogenesis. In a mouse model, CCR2-deficient animals exhibited reduced corneal neovascularization with reduced macrophage infiltration [63]. An oral chemokine CCR2/5 antagonist, called PF-04634817, is currently being tested by the manufacturer (Pfizer, New York, NY) in a Phase II RCT in comparison with intravitreal ranibizumab for patients with DME. 7.3
Expert Opin. Emerging Drugs (2014) 19(3)
401
S. G. Schwartz et al.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
8.
Potential development issues
At this time, the fluocinolone insert (Iluvien) has achieved marketing approval in several European countries but not in the US. Aflibercept has recently achieved markeint approval for the treatment of DME and it will likely compete with ranibizumab for physicians electing to use an approved anti-VEGF agent. In a Phase III RCT of neovascular AMD, aflibercept used monthly for 3 months, then every other month, was reported to be statistically noninferior to ranibizumab used monthly in maintaining visual acuity change from baseline [24]. This finding has led to the perception among some ophthalmologists that aflibercept has a longer duration of action than ranibizumab, although in clinical practice ranibizumab is often dosed at 2-month (or longer) intervals. Alternatively, a Phase III RCT of central retinal vein occlusion used aflibercept monthly (the same dosing as ranibizumab) [25]. The Phase III RCT that evaluated aflibercept for DME used both monthly and every-other-month treatment arms [27]. Aflibercept was approved with a schedule of five monthly doses, then every-other-month dosing, which may represent a perceived comparative advantage over ranibizumab for this indication. Furthermore, future therapies would likely have to demonstrate efficacy with every-other-month dosing schedules unless some other advantages were offered, such as improved efficacy, improved safety or a more tolerable delivery technique (such as systemic, topical or periocular as opposed to intravitreal). 9.
Conclusion
DME remains a major cause of visual loss worldwide. The treatment of DME is evolving from a surgical approach (photocoagulation) to a medical approach, and at this time several medications have achieved regulatory approval in the US for treatment of DME. Bevacizumab and triamcinolone acetonide are used in an off-label capacity. The fluocinolone insert (Iluvien) has achieved regulatory approval in Europe and the manufacturer has reapplied for approval in the US. Aflibercept and the dexamethasone delivery system (Ozurdex) recently achieved US FDA approval for the treatment of DME. Other agents are being studied in earlier-phase clinical trials at this time. 10.
Expert opinion
At this time, pharmacotherapy is replacing focal/grid photocoagulation in the treatment of DME involving the fovea. The authors continue to use focal/grid photocoagulation for certain patients with DME, such as those with DME not involving the fovea. First-line pharmacotherapy for foveainvolving DME is usually either ranibizumab or bevacizumab, depending on physician preference and the patient’s insurance 402
coverage. Ranibizumab has the advantage of FDA approval and, in the authors’ experience, is generally more effective in the treatment of DME than is bevacizumab. Alternatively, bevacizumab may be very effective for certain patients and is substantially less expensive. Triamcinolone acetonide is widely available and inexpensive, but is generally a second- or third-line agent because of associated risks of IOP elevation and cataract progression. Aflibercept and the dexamethasone delivery system have recently achieved US FDA approval for the pharmacologic treatment of DME and will likely become important options in the clinical management of these patients, although their precise roles remain undetermined at this time. In the authors’ opinion, if the fluocinolone insert (Iluvien) becomes available in the US, it will be used primarily in two circumstances: as a second- or third-line agent in patients unresponsive to other therapies, or in patients wishing to reduce the frequency of anti-VEGF reinjections. In summary, there are many currently available treatments that are effective for many patients with DME. However, there are several important unresolved issues that will likely become the focus of future research. First, some patients with DME will achieve anatomic improvement, but not visual improvement following any of these treatments, due to macular ischemia, permanent photoreceptor damage from longstanding macular edema and unknown causes. At this time, there are no available therapies for patients with these conditions, which do not appear to be responsive to photocoagulation, corticosteroids or VEGF antagonism. Second, most patients who do respond well to anti-VEGF injections will require repeated reinjections possibly over many years. Patients with DME may be substantially younger than patients with other retinal diseases (such as neovascular AMD), potentially requiring longer durations of therapy and more reinjections. This places substantial burdens on patients, family members and the healthcare system. Repeated intravitreal injections expose patients to cumulative risks of endophthalmitis and other vision-threatening complications. In addition, repeated injections of anti-VEGF agents create peaks and valleys of therapeutic effect, and it is reasonable to suspect that sustained medication release may be preferable to repeated bolus injections. The fluocinolone insert (Iluvien), which releases medication for up to 3 years in the vitreous cavity, may ameliorate this problem somewhat in patients eligible for the treatment, but at this time there is no long-acting anti-VEGF agent. A variety of approaches have been investigated for extended-release delivery of anti-VEGF agents to the macula [46]. Noninvasive techniques may include systemic or topical agents, iontophoresis, hydrogel contact lenses and gene transfer techniques. Bioerodable and nonbioerodable implants, similar in concept to the fluocinolone implant, might be beneficial. Colloidal carriers, including microparticles and
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
nanoparticles, are currently used in some approved medications, such as pegaptanib, which is synthesized with poly(ethylene-glycol), or PEG. Further clinical trials will hopefully provide additional information about emerging treatments for DME.
Declaration of interest
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
The work has been partially supported by NIH Center Core Grant P30EY014801 and RPB Unrestricted Award and Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
2.
3.
4.
5.
6.
7.
8.
Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology 2009;116:497-503 Rodriguez-Fontal M, Kerrison JB, Alfaro DV, Jablon EP. Metabolic control and diabetic retinopathy. Curr Diabetes Rev 2009;5:3-7 Sivaprasad S, Gupta B, Crosby-Nwaobi R, Evans J. Prevalence of diabetic retinopathy in various ethnic groups: a worldwide perspective. Surv Ophthalmol 2012;57:347-70 Ehrlich R, Harris A, Ciulla TA, et al. Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological process. Acta Ophthalmol (Copenh) 2010;88:279-91 Morigi M, Angioletti S, Imberti B, et al. Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J Clin Invest 1998;101:1905-15 Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615-25
9.
Cai W, Rook SL, Jiang ZY, et al. Mechanisms of hepatocyte growth factor-induced retinal endothelial cell migration and growth. Invest Ophthalmol Vis Sci 2000;41:1885-93
10.
Ding J, Wong TY. Current epidemiology of diabetic retinopathy and diabetic macular edema. Curr Diab Rep 2012;12:346-54
11.
Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556-64
12.
Romero-Aroca P, Baget-Bernaldiz M, Fernandez-Ballart J, et al. Ten-year incidence of diabetic retinopathy and macular edema: risk factors in a sample of people with type 1 diabetes. Diabetes Res Clin Pract 2011;94:126-32
13.
Klein R, Klein BEK, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XV: the long term incidence of macular edema. Ophthalmology 1995;102:7-16
14.
Minassian DC, Owens DR, Reidy A. Prevalence of diabetic macular oedema and related health and social care resource use in England. Br J Ophthalmol 2012;96:346-9
15.
Bressler NM, Varma R, Doan QV, et al. Underuse of the health care system by persons with diabetes mellitus and diabetic macular edema in the United States. JAMA Ophthalmol 2014;132:168-73
Shams N, Ianchulev T. Role of vascular endothelial growth factor in ocular angiogenesis. Ophthalmol Clin North Am 2006;19:335-44 Miyamoto N, de Kozak Y, Jeanny JC, et al. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia 2007;50:461-70
Career Development Awards to the University of Miami. The Bascom Palmer Eye Institute has also received a grant from the Department of Defense (DOD Grant #W81xWH09-0675). SG Schwartz has been a consultant for Bausch & Lomb and Santen and has received speakers’ fees from ThromboGenics. HW Flynn Jr has been a consultant for Santen and received speakers’ fees from Vindico. IU Scott has been a consultant for Alcon, Genentech, Santen and ThromboGenics and has received speakers’ fees from Genentech.
16.
Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86
Expert Opin. Emerging Drugs (2014) 19(3)
17.
UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes: UKPDS 33. Lancet 1998;352:837-53
18.
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-806
19.
Javey G, Schwartz SG, Flynn HW Jr. Emerging pharmacotherapies for diabetic macular edema. Exp Diabetes Res 2012;2012:548732
20.
Caldwell RB, Bartoli M, Behzadian MA, et al. Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. Curr Drug Targets 2005;6:511-24
21.
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801 Phase III randomized clinical trial of ranibizumab for diabetic macular edema.
.
22.
Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 2007;114:1860-7
23.
Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study). 12-month data: report 2. Ophthalmology 2010;117:1078-86
24.
Schmidt-Erfuth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept for neovascular age-related
403
S. G. Schwartz et al.
for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129:545-53
macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014;121:193-201 Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology 2014;121:202-8
35.
26.
Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119:1658-65
36.
Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011;31:915-23
27.
Regeneron and Bayer report positive one-year results from two phase 3 trials of EYLEA (aflibercept) injection for the treatment of diabetic macular edema. Available from: http://investor.regeneron. com/releasedetail.cfm?releaseid=782911 [Last accessed 11 April 2014]
37.
Schwartz SG, Flynn HW Jr. Fluocinolone acetonide implantable device for diabetic retinopathy. Curr Pharm Biotechnol 2011;12:347-51
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
25.
28.
29.
Nauck M, Roth M, Tamm M, et al. Induction of vascular endothelial growth factor by platelet-activating growth factor and platelet-derived growth factor is downregulated by corticosteroids. Am J Respir Cell Mol Biol 1997;16:398-406 Ayalasomayajula SP, Ashton P, Kompella UB, et al. Fluocinolone inhibits VEGF expression via glucocorticoid receptor in human retinal pigment epithelial (ARPE-19) cells and TNF-alpha-induced angiogenesis in chick chorioallantoic membrane (CAM). J Ocul Pharmacol Ther 2009;25:97-103
30.
Edelman JL. Differentiating intraocular glucocorticoids. Ophthalmologica 2010;224(Suppl 1):225-30
31.
Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trail comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245-51
32.
33.
34.
404
38.
Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 2011;118:1580-7
45.
Pershing S, Enns EA, Matesic B, et al. Cost-effectiveness of diabetic macular edema. Ann Intern Med 2014;160:18-29
46.
Schwartz SG, Scott IU, Flynn HW Jr, Stewart MW. Drug delivery techniques for treating age-related macular degeneration. Expert Opin Drug Deliv 2014;11:61-8
47.
Kompella UB, Kadam RS, Lee VH. Recent advances in ophthalmic drug delivery. Ther Deliv 2010;1:435-56
48.
Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035-47
49.
Nguyen QD, Shah SM, Hafiz G, et al. A phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006;113:1522.e1-1522.e14
39.
Schwartz SG, Flynn HW Jr. Endophthalmitis associated with intravitreal anti-vascular endothelial growth factor injections. Curr Ophthalmol Rep 2014;2(1):1-5
40.
Milder E, Vander J, Shah C, Garg S. Changes in antibiotic resistance patterns of conjunctival flora due to repeated use of topical antibiotics after intravitreal injection. Ophthalmology 2012;119:1420-4
50.
Krishnadev N, Forooghian F, Cukras C, et al. Subconjunctival sirolimus in the treatment of diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2011;249:1627-33
41.
Yin VT, Weisbrod DJ, Eng KT, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol 2013;131:456-61
51.
42.
Schwartz SG, Flynn HW Jr, Scott IU. Intravitreal corticosteroids in the management of diabetic macular edema. Curr Ophthalmol Rep 2013;1(3): doi; 10.1007/s40135-013-0015-3
Dugel PU, Blumenkranz MS, Haller JA, et al. A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema. Ophthalmology 2012;119:124-31
52.
Bonini-Filho MA, Jorge R, Barbosa JC, et al. Intravitreal injection versus subTenon’s infusion of triamcinolone acetonide for refractory diabetic macular edema: a randomized clinical trial. Invest Ophthalmol Vis Sci 2005;46:3845-9
53.
Diabetic Retinopathy Clinical Research Network. Chew E, Trauber S, et al. Randomized trial of peribulbar triamcinolone acetonide with and without photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology 2007;114:1190-6
54.
Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for
43.
Schwartz SG, Flynn HW Jr, Beer P. Intravitreal triamcinolone acetonide use in diabetic macular edema: illustrative cases. Ophthalmic Surg Lasers Imaging 2010;1-6 Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453-60
Haller JA, Kuppermann BD, Blumenkranz MS, et al. Randomized controlled trial of an intravitreous drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 2010;128:289-96
.
diabetic macular edema. Am J Ophthalmol 2014;157:505-13 A recent review of clinical recommendations for management of diabetic macular edema.
44.
American Society of Retina Specialists. Preferences and Trends Survey. 2012. Available from: http://www.asrs. org/content/documents/ _2012asrspatsurveyresults.pdf [Last accessed 11 April 2014] Mitchell P, Wong TY; Diabetic Macular Edema Treatment Guideline Working Group. Management paradigms for
Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
cell function and angiogenesis. Fertil Steril 2007;88(4 Suppl):1065-70
age-related macular degeneration. N Engl J Med 2004;351:2805-16 55.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
56.
Sultan MB, Zhou D, Loftus J, et al. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011;118:1107-18 Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606-15
57.
de Smet MD, Castilla M. Ocriplasmin for diabetic retinopathy. Expert Opin Biol Ther 2013;13:1741-7
58.
Dmowski WP. Danazol: a synthetic steroid with diverse biologic effects. J Reprod Med 1990;35(Suppl):69-74
59.
Thomas GW, Rael LT, Shimonkevitz R, et al. Effects of danazol on endothelial
60.
Bar-Or D, Thomas G, Salottolo K, et al. Oral danazol for DME. Retina Today 2012;68-70
61.
Lisak RP, Nedelkoska L, Bejamins JA. Effects of dextromethorphan on glial cell function: proliferation, maturation, and protection from cytotoxic molecules. Glia 2014;62:751-62
62.
Goel S, Gupta N, Walcott BP, et al. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J Natl Cancer Inst 2013;105:1188-201
63.
Lu P, Li L, Liu G, et al. Opposite roles of CCR2 and CX3CR1 macrophages in alkali-induced corneal neovascularization. Cornea 2009;28:562-9
Affiliation Stephen G Schwartz1 MD MBA, Harry W Flynn Jr2 MD & Ingrid U Scott†3 MD MPH † Author for correspondence 1 Associate Professor of Clinical Ophthalmology, University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, 311 9th Street North, #100, Naples, FL 34102, USA 2 Professor of Ophthalmology, University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, 900 Northwest 17th Street, Miami, FL 33136, USA 3 Professor of Ophthalmology and Public Health Sciences, Penn State College of Medicine, Penn State Hershey Eye Center, 500 University Drive, HU19, Hershey, PA 17033, USA Tel: +1 717 531 8783; Fax: +1 717 531 5475; E-mail: [email protected]
Notice of correction Please note that corrections were made in Table 1, Table 2 and in the second paragraph of the Expert Opinion section after initial online publication of this article (21st August 2014).
Expert Opin. Emerging Drugs (2014) 19(3)
405
Emerging drugs for diabetic macular edema
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
Stephen G Schwartz, Harry W Flynn Jr & Ingrid U Scott† †
Penn State College of Medicine, Penn State Hershey Eye Center, Ophthalmology and Public Health Sciences, Hershey, PA, USA
1.
Background
2.
Medical need
3.
Existing treatment
4.
Market review
5.
Current research goals
6.
Scientific rationale
7.
Competitive environment
8.
Potential development issues
9.
Conclusion
10.
Expert opinion
Introduction: Diabetic macular edema (DME) is the most common cause of visual impairment due to diabetic retinopathy. The treatment of DME has recently undergone a paradigm shift. Traditionally, photocoagulation was standard treatment, but pharmacologic therapies are becoming increasingly used for this purpose. All currently available drug therapies for DME are either anti-VEGF agents or corticosteroids. Areas covered: The pathogenesis of DME involves angiogenesis, inflammation and oxidative stress. The scientific rationale to treat DME through the pharmacologic blockade of VEGF and other pro-angiogenic factors is discussed. The fluocinolone insert is approved for the treatment of DME in several European countries, but not in the US at this time. Some medications that are already approved for other retinal diseases, most prominently aflibercept and the dexamethasone delivery system, have recently obtained approval for DME in the US. Other compounds are being studied in earlierphase clinical trials. Expert opinion: Pharmacologic treatment of DME will likely become increasingly used, especially for patients with edema involving the fovea. At this time, the two main classes of medication for treatment of DME are antiVEGF agents and corticosteroids. As we continue to collect clinical trials data, the precise role of individual agents, and the continuing role for photocoagulation, will become more clear. Keywords: aflibercept, bevacizumab, dexamethasone, diabetic macular edema, fluocinolone acetonide, randomized clinical trial, ranibizumab, triamcinolone acetonide, VEGF Expert Opin. Emerging Drugs (2014) 19(3):397-405
1.
Background
Diabetic macular edema (DME) is one of the major causes of visual loss among individuals with diabetes mellitus [1]. Duration of diabetes, as well as severity of hyperglycemia, hypertension and hyperlipidemia, have been reported as risk factors for DME [2]. All racial and ethnic groups are at risk for diabetic retinopathy and DME, but increased risk has been reported in patients of African, Latin American, South Asian and indigenous tribal ancestry [3]. The pathogenesis of DME remains poorly understood but involves angiogenesis, inflammation and oxidative stress [4]. Chronic hyperglycemia has been reported to cause leukocyte-mediated capillary endothelial damage [5] as well as activation of oxidative stress products such as advanced glycation end products and the protein kinase C pathway [6]. Inflammatory mediators that have been associated with DME include VEGF [7], placental growth factor (PlGF) [8], hepatocyte growth factor [9] and others.
10.1517/14728214.2014.938048 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted
397
S. G. Schwartz et al.
Table 1. Currently available medications for the treatment of diabetic macular edema.
injections and all medications are either anti-VEGF agents or corticosteroids (Table 1).
Class
Anti-VEGF agents Anti-VEGF agents work by antagonizing the activity of VEGF, which is important in the pathogenesis of DME and other ischemic retinal diseases [20]. Ranibizumab (Lucentis, Genentech, South San Francisco, CA, USA), an anti-VEGF agent delivered via repeated officebased intravitreal injection, was the first medication with US FDA approval for the treatment of DME (Figure 1) [21]. The labeled dosing is monthly. Bevacizumab (Avastin, Genentech, South San Francisco, CA, USA) is a systemic anti-VEGF agent with chemical similarities to ranibizumab. It has become used widely, through intravitreal injection, in the off-label treatment of DME and other retinal diseases because of its widespread availability and low cost. Intravitreal bevacizumab has been reported to have more favorable outcomes than photocoagulation in multiple RCTs [22,23]. Treatment generally is performed at approximately monthly intervals, similar to ranibizumab. Aflibercept (Eylea, Regeneron, Tarrytown, NY), previously known as VEGF Trap-Eye, is a recombinant fusion protein with activity against VEGF and PlGF, and is currently US FDA-approved for the treatment of neovascular AMD [24] and central retinal vein occlusion [25]. A Phase II RCT reported beneficial outcomes in the treatment of DME [26] and favorable Phase III data were reported by the manufacturer [27], but are not yet published in the peer-reviewed literature. The agent obtained US FDA approval for DME in July 2014. In addition, the manufactuer announced that the European Committee for Medicinal Products for Human Use recommended aflibercept for the treatment of DME.
Anti-VEGF
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
Corticosteroid
2.
Name
Notes
Ranibizumab (Lucentis) Aflibercept (Eylea) Bevacizumab (Avastin) Triamcinolone acetonide Fluocinolone insert (Iluvien) Dexamethasone delivery system (Ozurdex)
Approved in 2012 Approved in 2014 Off-label Off-label Only approved in Europe Approved in 2014
Medical need
The worldwide prevalence of diabetes is increasing, which will likely result in an increasing worldwide burden of DME [10]. Using a pooled analysis, it has been estimated that there are ~ 93 million people with diabetic retinopathy and 21 million with DME worldwide [11]. The 10-year incidence of DME has been reported as 11% in type 1 diabetics [12] and 14% in type 2 diabetics [13]. In England, an estimated 7.1% of diabetics have DME in one or both eyes [14]. It has been reported that, in the US, 16% of patients with DME have visual impairment defined as best-corrected visual acuity worse than 20/40 in the eye with DME, and that these patients appear to be underutilizing the US healthcare system [15]. In addition, all currently available therapies for DME have a percentage of nonresponders (patients who do not improve following treatment), and all currently available therapies are associated with risks of visual loss in a minority of treated patients.
3.1
Corticosteroids Corticosteroids are thought to be beneficial in the treatment of DME through multiple pathways, including a nonspecific antiinflammatory effect as well as by downregulation of VEGF [28,29]. Three synthetic corticosteroids have been studied as potential intravitreal treatments for DME: triamcinolone acetonide, dexamethasone and fluocinolone acetonide [30]. Triamcinolone acetonide has been used off-label to treat DME, but its use has declined as the use of anti-VEGF therapy has increased, at least in part due to cataract formation and intraocular pressure (IOP) elevation that are commonly associated with ophthalmic corticosteroids. A large RCT reported that, for most patients, triamcinolone acetonide was associated with generally poorer outcomes than was photocoagulation [31]. However, triamcinolone acetonide is effective in some patients unresponsive to other therapies [32]. Treatment generally is repeated at ~ 3-month intervals. A dexamethasone delivery system (Ozurdex, Allergan, Irvine, CA) is a bioerodable device that may be injected in an office setting and that is US FDA-approved for the 3.2
3.
Existing treatment
Intensive control of blood sugar, blood pressure and serum lipids may reduce complications of diabetic retinopathy, including DME, without any specific ophthalmologic treatment [16,17]. Focal/grid photocoagulation, which applies laser energy directly to leaking retinal microaneurysms and diffusely in areas of macular edema, was reported effective in a randomized clinical trial (RCT) and was standard therapy for decades [18]. Focal/grid photocoagulation typically does not improve visual acuity and may be associated with risks of foveal burn, macular ischemia, expansion of photocoagulation spots over time and secondary choroidal neovascularization. Although focal/grid photocoagulation is still employed, pharmacotherapies have been used increasingly over the past 10 years, especially in patients with DME involving the fovea [19]. At this time, all commonly used medications to treat DME are delivered by repeated office-based intravitreal 398
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
A.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
D.
B.
C.
E.
F.
G.
H.
Figure 1. A 64 year-old man presented with complaints of bilateral visual loss. He was not previously known to be diabetic. Bestcorrected visual acuity was 20/100 in the right eye and 20/70 in the left eye. A. Fundus photography, right eye, demonstrating DME. B. Fundus photography, left eye, demonstrating DME. C. Optical coherence tomography, right eye, demonstrating macular edema. D. Optical coherence tomography, left eye, demonstrating macular edema. The patient was treated with bilateral ranibizumab at 1- to 2-month intervals for ~ 1 year. At the most recent follow-up, best-corrected visual acuity had improved to 20/40 in the right eye and 20/25 in the left eye. E. Fundus photography, right eye, demonstrating improved DME. F. Fundus photography, left eye, demonstrating improved DME. G. Optical coherence tomography, right eye, demonstrating improved macular edema. H. Optical coherence tomography, left eye, demonstrating improved macular edema. DME: Diabetic macular edema.
treatment of retinal vein occlusion [33] and noninfectious posterior segment uveitis [34]. In a Phase II RCT of patients with DME [35] and in an open-label trial of vitrectomized eyes with DME [36], the drug delivery system improved visual acuity, macular thickness and retinal vascular leakage. In both series, transiently increased IOP was reported in about 10 -- 15% of treated patients. In June 2014, the manufacturer announced that it had received FDA approval for the treatment of DME in pseudophakic patients or patients scheduled for cataract surgery. A fluocinolone acetonide insert (Iluvien, Alimera, Alpharetta, GA) is a nonbioerodable device that may be injected in an office setting and that elutes medication for 3 years [37]. In a Phase III RCT, the investigators reported that the fluocinolone insert was an effective treatment of DME but was associated with increased risks of cataract progression and IOP elevation [38]. The insert has achieved regulatory approval
in several European countries but not, at this time, in the US. Risks of intravitreal injections All intravitreal injections are associated with low risks of infectious endophthalmitis, which has generally been reported in the range of 0.03% per injection for antiVEGF agents and perhaps slightly higher for triamcinolone acetonide [39]. Infectious endophthalmitis, even if diagnosed promptly and treated appropriately, may lead to severe visual loss or loss of the eye. Intravitreal injections may also be associated with noninfectious intraocular inflammation, which may be difficult to distinguish from infectious endophthalmitis. In the early years of intravitreal injections, surgeons commonly employed pre- or postinjection topical antibiotics, but this practice has declined recently. Several studies have 3.3
Expert Opin. Emerging Drugs (2014) 19(3)
399
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
S. G. Schwartz et al.
reported that antibiotic use does not reduce rates of infectious endophthalmitis and may actually increase the risk. The reason for this possible increased risk is unknown but might be related to changes in antibiotic resistance patterns of conjunctival flora [40,41]. Triamcinolone acetonide and other corticosteroids have additional associated risks of cataract progression and IOP elevation, especially when administered by intravitreal injection [42]. Infrequently, IOP elevation may become severe or intractable, requiring additional medications or surgical interventions to control the pressure. Visually significant cataract may also require surgical intervention.
reduction of macular edema in patients with fovea-involving DME, especially in patients with moderate to severe visual loss [44]. In a Markov model, photocoagulation, intravitreal triamcinolone acetonide, intravitreal anti-VEGF therapy and combination therapies were compared. The authors reported that all treatments (except photocoagulation monotherapy) reduced costs, all treatments (except triamcinolone acetonide monotherapy) increased quality-adjusted life-years (QALYs) and the most effective treatment, as measured by discounted costs, gains in QALYs and incremental cost-effectiveness ratios, was anti-VEGF therapy with or without photocoagulation [45].
Preferred practice patterns The American Society of Retina Specialists (which also includes retina specialists in many other countries) conducts an annual ‘Preferences and Trends’ (PAT) survey of its members. In 2012, in response to the question “What is your initial treatment for [DME] not involving the foveal center?”, photocoagulation was selected by 75.9% of US and Canadian respondents, anti-VEGF therapy was selected by 16.3% of respondents, and the remainder selected observation or other therapies. International members responded similarly [43].
5.
3.4
4.
Market review
400
All currently available pharmacotherapies for DME are delivered by repeated office-based intravitreal injection. Injection must be performed by an ophthalmologist in a clinic setting, which is inconvenient for patients and family members, and potentially creates barriers to access for care. In addition, every injection is associated with small risks of endophthalmitis and other visionthreatening complications. Therefore, two major approaches to reduce the number of intravitreal injections are sustained-release medications and alternative drug delivery techniques. 6.
In the US, currently available choices for the treatment of DME include observation (including encouragement of tighter control of systemic factors, including blood pressure, blood sugar, serum lipids and body weight); focal/grid photocoagulation; the anti-VEGF agents ranibizumab and off-label bevacizumab; and off-label triamcinolone acetonide. In 2014, aflibercept and the dexamethasone delivery system were also approved for the treatment of DME. In several European countries, the fluocinolone insert (Iluvien) is now available but is generally used as a second- or third-line therapy. These therapies may be combined. Combination treatments may be beneficial for some patients, although at this time there is relatively little guidance available from the literature. For example, some patients appear to benefit from focal/grid photocoagulation to areas of DME outside the fovea combined with intravitreal pharmacotherapy for residual DME involving the fovea. Alternatively, some patients seem to respond more effectively to corticosteroids than to anti-VEGF agents, although corticosteroids may be associated with additional risks of cataract progression and IOP elevation. Therefore, a strategy that alternates anti-VEGF injections with corticosteroid injections may be reasonable for certain patients. Photocoagulation continues to be beneficial for many patients, especially for those whose DME does not involve the fovea. However, there is an increasing body of literature suggesting that anti-VEGF therapy provides generally more favorable improvements in visual acuity and
Current research goals
Scientific rationale
Sustained-release medications In theory, sustained-release drug delivery techniques might be preferable to repeated intravitreal injections if the duration of drug release exceeds the longest effective interval between injections and if the safety profile is favorable. This potential advantage is relatively greatest for patients requiring the most frequent (i.e., monthly) injections [46]. To date, there has been more progress in developing sustained-release corticosteroids than sustained-release antiVEGF agents. All currently available sustained-release intravitreal corticosteroids are delivered using bioerodable or nonbioerodable implants. In general, nonbioerodable implants offer more controlled release of medication and longer duration of action [47]. However, a nonbioerodable implant remains in the eye permanently unless removed surgically. 6.1
Alternative delivery techniques Frequent dosing may be more tolerable if intravitreal injections are avoided and if clinical outcomes are favorable. Unfortunately, at this time, no agent meets these criteria in the treatment of DME. Intravenous bevacizumab [48] and aflibercept [49] (a recombinant fusion protein with activity against VEGF and PlGF) were reported to have some efficacy in the treatment of neovascular age-related macular degeneration (AMD) in separate pilot studies, but systemic anti-VEGF agents are associated with risks of hypertension, proteinuria and thromboembolic events. 6.2
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
Table 2. Competitive environment of medications for the treatment of diabetic macular edema. Compound
Stage of development
Mechanism of action
Structure
Pegaptanib (Valeant) Ocriplasmin (ThromboGenics)
Discontinued Phase II
Anti-VEGF-165 Protease
Pegylated aptamer Recombinant plasmin
Danazol (Ampio) Dextromethorphan (NEI) Sirolimus (Santen)
Phase III Phase I/II Discontinued
Steroid Anti-NMDA Immunosuppressant
Derivative of ethisterone Morphinan Macrolide
AKB-9778 (Aerpio) PF-04634817 (Pfizer)
Phase II Phase II
Anti-VE-PTP Anti-CCR2/5
Modified sulfamic acid Synthetic small molecule
Indication
Neovascular AMD Symptomatic vitreomacular adhesion Endometriosis Cough Prophylaxis of organ rejection None None
AMD: Age-related macular degeneration; CCR: C-C chemokine receptor; NEI: National Eye Institute; PlGF: Placental growth factor; VE-PTP: Vascular endothelial protein tyrosine phosphatase.
Similarly, subconjunctival or peribulbar injections of various medications have not led to promising results. Sirolimus, or rapamycin, is a macrolide antifungal that has been studied as subconjunctival therapy for DME in early-stage trials [50,51], but the manufacturer (Santen, Osaka, Japan) has discontinued further efforts toward this indication. Peribulbar triamcinolone acetonide has demonstrated unsatisfactory efficacy in the treatment of DME [52,53]. 7.
Competitive environment
At this time, several medications are being studied for the treatment of DME (Table 2). These may be divided into drugs with regulatory approval for other ophthalmologic indications, drugs with regulatory approval for nonophthalmological indications and other agents. Drugs with regulatory approval for other ophthalmological indications
7.1
Pegaptanib (Macugen, Valeant, Bridgewater, NJ), a pegylated aptamer against the VEGF-165 isoform, is US FDA-approved for the treatment of neovascular AMD [54]. A Phase II/III RCT demonstrated favorable results in the treatment of DME [55]. However, at this time, the manufacturer is not pursuing FDA approval for DME. Ocriplasmin (Jetrea, ThromboGenics, Leuven, Belgium), a recombinant protease, has achieved US FDA approval for the treatment of symptomatic vitreomacular adhesion [56]. Vitreomacular adhesion may be associated with diabetic retinopathy, and it is reasonable to suspect that ocriplasmin may have a role in the treatment of DME [57]. At this time, the drug is being studied in a Phase II RCT for this purpose. Drugs with regulatory approval for nonophthalmological indications
7.2
Danazol, an androgen-like synthetic steroid, is US FDAapproved for the treatment of endometriosis and other
diseases [58]. Danazol has antiangiogenic properties and has, for example, been reported to decrease proliferation and tube length of human umbilical vein endothelial cells [59]. In a Phase IIA RCT, treatment with low-dose oral danazol (Optina, Ampio, Greenwood Village, CO) was associated with decreased retinal thickness and improved visual acuity in patients with DME [60]. The manufacturer is currently conducting a Phase III RCT. Dextromethorphan, an NMDA antagonist found in many antitussives, has been reported to have neuroprotective properties through inhibition of microglial activation [61]. The National Eye Institute has conducted a Phase I/II study of oral dextromethorphan in patients with DME, but results are not available at this time. Sirolimus, or rapamycin, is a macrolide antifungal with immunosuppressant properties that is indicated to prevent organ rejection after renal transplantation. Subconjunctival sirolimus was investigated as a treatment for DME [50,51], but further research for this indication has been discontinued. Other agents AKB-9778 is a novel agent that inhibits vascular endothelial protein tyrosine phosphatase, which subsequently inhibits endothelial Tie-2 receptor tyrosine kinase. In animal models, AKB-9778 has demonstrated antiangiogenic properties [62]. The manufacturer (Aerpio, Cincinnati, OH) is currently recruiting patients with DME for a Phase II RCT comparing subcutaneous AKB-9778 monotherapy, intravitreal ranibizumab monotherapy and combination therapy with the two agents. C-C chemokine receptor 2 (CCR2) is involved in macrophage attraction and angiogenesis. In a mouse model, CCR2-deficient animals exhibited reduced corneal neovascularization with reduced macrophage infiltration [63]. An oral chemokine CCR2/5 antagonist, called PF-04634817, is currently being tested by the manufacturer (Pfizer, New York, NY) in a Phase II RCT in comparison with intravitreal ranibizumab for patients with DME. 7.3
Expert Opin. Emerging Drugs (2014) 19(3)
401
S. G. Schwartz et al.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
8.
Potential development issues
At this time, the fluocinolone insert (Iluvien) has achieved marketing approval in several European countries but not in the US. Aflibercept has recently achieved markeint approval for the treatment of DME and it will likely compete with ranibizumab for physicians electing to use an approved anti-VEGF agent. In a Phase III RCT of neovascular AMD, aflibercept used monthly for 3 months, then every other month, was reported to be statistically noninferior to ranibizumab used monthly in maintaining visual acuity change from baseline [24]. This finding has led to the perception among some ophthalmologists that aflibercept has a longer duration of action than ranibizumab, although in clinical practice ranibizumab is often dosed at 2-month (or longer) intervals. Alternatively, a Phase III RCT of central retinal vein occlusion used aflibercept monthly (the same dosing as ranibizumab) [25]. The Phase III RCT that evaluated aflibercept for DME used both monthly and every-other-month treatment arms [27]. Aflibercept was approved with a schedule of five monthly doses, then every-other-month dosing, which may represent a perceived comparative advantage over ranibizumab for this indication. Furthermore, future therapies would likely have to demonstrate efficacy with every-other-month dosing schedules unless some other advantages were offered, such as improved efficacy, improved safety or a more tolerable delivery technique (such as systemic, topical or periocular as opposed to intravitreal). 9.
Conclusion
DME remains a major cause of visual loss worldwide. The treatment of DME is evolving from a surgical approach (photocoagulation) to a medical approach, and at this time several medications have achieved regulatory approval in the US for treatment of DME. Bevacizumab and triamcinolone acetonide are used in an off-label capacity. The fluocinolone insert (Iluvien) has achieved regulatory approval in Europe and the manufacturer has reapplied for approval in the US. Aflibercept and the dexamethasone delivery system (Ozurdex) recently achieved US FDA approval for the treatment of DME. Other agents are being studied in earlier-phase clinical trials at this time. 10.
Expert opinion
At this time, pharmacotherapy is replacing focal/grid photocoagulation in the treatment of DME involving the fovea. The authors continue to use focal/grid photocoagulation for certain patients with DME, such as those with DME not involving the fovea. First-line pharmacotherapy for foveainvolving DME is usually either ranibizumab or bevacizumab, depending on physician preference and the patient’s insurance 402
coverage. Ranibizumab has the advantage of FDA approval and, in the authors’ experience, is generally more effective in the treatment of DME than is bevacizumab. Alternatively, bevacizumab may be very effective for certain patients and is substantially less expensive. Triamcinolone acetonide is widely available and inexpensive, but is generally a second- or third-line agent because of associated risks of IOP elevation and cataract progression. Aflibercept and the dexamethasone delivery system have recently achieved US FDA approval for the pharmacologic treatment of DME and will likely become important options in the clinical management of these patients, although their precise roles remain undetermined at this time. In the authors’ opinion, if the fluocinolone insert (Iluvien) becomes available in the US, it will be used primarily in two circumstances: as a second- or third-line agent in patients unresponsive to other therapies, or in patients wishing to reduce the frequency of anti-VEGF reinjections. In summary, there are many currently available treatments that are effective for many patients with DME. However, there are several important unresolved issues that will likely become the focus of future research. First, some patients with DME will achieve anatomic improvement, but not visual improvement following any of these treatments, due to macular ischemia, permanent photoreceptor damage from longstanding macular edema and unknown causes. At this time, there are no available therapies for patients with these conditions, which do not appear to be responsive to photocoagulation, corticosteroids or VEGF antagonism. Second, most patients who do respond well to anti-VEGF injections will require repeated reinjections possibly over many years. Patients with DME may be substantially younger than patients with other retinal diseases (such as neovascular AMD), potentially requiring longer durations of therapy and more reinjections. This places substantial burdens on patients, family members and the healthcare system. Repeated intravitreal injections expose patients to cumulative risks of endophthalmitis and other vision-threatening complications. In addition, repeated injections of anti-VEGF agents create peaks and valleys of therapeutic effect, and it is reasonable to suspect that sustained medication release may be preferable to repeated bolus injections. The fluocinolone insert (Iluvien), which releases medication for up to 3 years in the vitreous cavity, may ameliorate this problem somewhat in patients eligible for the treatment, but at this time there is no long-acting anti-VEGF agent. A variety of approaches have been investigated for extended-release delivery of anti-VEGF agents to the macula [46]. Noninvasive techniques may include systemic or topical agents, iontophoresis, hydrogel contact lenses and gene transfer techniques. Bioerodable and nonbioerodable implants, similar in concept to the fluocinolone implant, might be beneficial. Colloidal carriers, including microparticles and
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
nanoparticles, are currently used in some approved medications, such as pegaptanib, which is synthesized with poly(ethylene-glycol), or PEG. Further clinical trials will hopefully provide additional information about emerging treatments for DME.
Declaration of interest
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
The work has been partially supported by NIH Center Core Grant P30EY014801 and RPB Unrestricted Award and Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
2.
3.
4.
5.
6.
7.
8.
Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology 2009;116:497-503 Rodriguez-Fontal M, Kerrison JB, Alfaro DV, Jablon EP. Metabolic control and diabetic retinopathy. Curr Diabetes Rev 2009;5:3-7 Sivaprasad S, Gupta B, Crosby-Nwaobi R, Evans J. Prevalence of diabetic retinopathy in various ethnic groups: a worldwide perspective. Surv Ophthalmol 2012;57:347-70 Ehrlich R, Harris A, Ciulla TA, et al. Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological process. Acta Ophthalmol (Copenh) 2010;88:279-91 Morigi M, Angioletti S, Imberti B, et al. Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J Clin Invest 1998;101:1905-15 Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005;54:1615-25
9.
Cai W, Rook SL, Jiang ZY, et al. Mechanisms of hepatocyte growth factor-induced retinal endothelial cell migration and growth. Invest Ophthalmol Vis Sci 2000;41:1885-93
10.
Ding J, Wong TY. Current epidemiology of diabetic retinopathy and diabetic macular edema. Curr Diab Rep 2012;12:346-54
11.
Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556-64
12.
Romero-Aroca P, Baget-Bernaldiz M, Fernandez-Ballart J, et al. Ten-year incidence of diabetic retinopathy and macular edema: risk factors in a sample of people with type 1 diabetes. Diabetes Res Clin Pract 2011;94:126-32
13.
Klein R, Klein BEK, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XV: the long term incidence of macular edema. Ophthalmology 1995;102:7-16
14.
Minassian DC, Owens DR, Reidy A. Prevalence of diabetic macular oedema and related health and social care resource use in England. Br J Ophthalmol 2012;96:346-9
15.
Bressler NM, Varma R, Doan QV, et al. Underuse of the health care system by persons with diabetes mellitus and diabetic macular edema in the United States. JAMA Ophthalmol 2014;132:168-73
Shams N, Ianchulev T. Role of vascular endothelial growth factor in ocular angiogenesis. Ophthalmol Clin North Am 2006;19:335-44 Miyamoto N, de Kozak Y, Jeanny JC, et al. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia 2007;50:461-70
Career Development Awards to the University of Miami. The Bascom Palmer Eye Institute has also received a grant from the Department of Defense (DOD Grant #W81xWH09-0675). SG Schwartz has been a consultant for Bausch & Lomb and Santen and has received speakers’ fees from ThromboGenics. HW Flynn Jr has been a consultant for Santen and received speakers’ fees from Vindico. IU Scott has been a consultant for Alcon, Genentech, Santen and ThromboGenics and has received speakers’ fees from Genentech.
16.
Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86
Expert Opin. Emerging Drugs (2014) 19(3)
17.
UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes: UKPDS 33. Lancet 1998;352:837-53
18.
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-806
19.
Javey G, Schwartz SG, Flynn HW Jr. Emerging pharmacotherapies for diabetic macular edema. Exp Diabetes Res 2012;2012:548732
20.
Caldwell RB, Bartoli M, Behzadian MA, et al. Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. Curr Drug Targets 2005;6:511-24
21.
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801 Phase III randomized clinical trial of ranibizumab for diabetic macular edema.
.
22.
Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 2007;114:1860-7
23.
Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study). 12-month data: report 2. Ophthalmology 2010;117:1078-86
24.
Schmidt-Erfuth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept for neovascular age-related
403
S. G. Schwartz et al.
for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129:545-53
macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014;121:193-201 Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology 2014;121:202-8
35.
26.
Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119:1658-65
36.
Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011;31:915-23
27.
Regeneron and Bayer report positive one-year results from two phase 3 trials of EYLEA (aflibercept) injection for the treatment of diabetic macular edema. Available from: http://investor.regeneron. com/releasedetail.cfm?releaseid=782911 [Last accessed 11 April 2014]
37.
Schwartz SG, Flynn HW Jr. Fluocinolone acetonide implantable device for diabetic retinopathy. Curr Pharm Biotechnol 2011;12:347-51
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
25.
28.
29.
Nauck M, Roth M, Tamm M, et al. Induction of vascular endothelial growth factor by platelet-activating growth factor and platelet-derived growth factor is downregulated by corticosteroids. Am J Respir Cell Mol Biol 1997;16:398-406 Ayalasomayajula SP, Ashton P, Kompella UB, et al. Fluocinolone inhibits VEGF expression via glucocorticoid receptor in human retinal pigment epithelial (ARPE-19) cells and TNF-alpha-induced angiogenesis in chick chorioallantoic membrane (CAM). J Ocul Pharmacol Ther 2009;25:97-103
30.
Edelman JL. Differentiating intraocular glucocorticoids. Ophthalmologica 2010;224(Suppl 1):225-30
31.
Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trail comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245-51
32.
33.
34.
404
38.
Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 2011;118:1580-7
45.
Pershing S, Enns EA, Matesic B, et al. Cost-effectiveness of diabetic macular edema. Ann Intern Med 2014;160:18-29
46.
Schwartz SG, Scott IU, Flynn HW Jr, Stewart MW. Drug delivery techniques for treating age-related macular degeneration. Expert Opin Drug Deliv 2014;11:61-8
47.
Kompella UB, Kadam RS, Lee VH. Recent advances in ophthalmic drug delivery. Ther Deliv 2010;1:435-56
48.
Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035-47
49.
Nguyen QD, Shah SM, Hafiz G, et al. A phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006;113:1522.e1-1522.e14
39.
Schwartz SG, Flynn HW Jr. Endophthalmitis associated with intravitreal anti-vascular endothelial growth factor injections. Curr Ophthalmol Rep 2014;2(1):1-5
40.
Milder E, Vander J, Shah C, Garg S. Changes in antibiotic resistance patterns of conjunctival flora due to repeated use of topical antibiotics after intravitreal injection. Ophthalmology 2012;119:1420-4
50.
Krishnadev N, Forooghian F, Cukras C, et al. Subconjunctival sirolimus in the treatment of diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2011;249:1627-33
41.
Yin VT, Weisbrod DJ, Eng KT, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol 2013;131:456-61
51.
42.
Schwartz SG, Flynn HW Jr, Scott IU. Intravitreal corticosteroids in the management of diabetic macular edema. Curr Ophthalmol Rep 2013;1(3): doi; 10.1007/s40135-013-0015-3
Dugel PU, Blumenkranz MS, Haller JA, et al. A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema. Ophthalmology 2012;119:124-31
52.
Bonini-Filho MA, Jorge R, Barbosa JC, et al. Intravitreal injection versus subTenon’s infusion of triamcinolone acetonide for refractory diabetic macular edema: a randomized clinical trial. Invest Ophthalmol Vis Sci 2005;46:3845-9
53.
Diabetic Retinopathy Clinical Research Network. Chew E, Trauber S, et al. Randomized trial of peribulbar triamcinolone acetonide with and without photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology 2007;114:1190-6
54.
Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for
43.
Schwartz SG, Flynn HW Jr, Beer P. Intravitreal triamcinolone acetonide use in diabetic macular edema: illustrative cases. Ophthalmic Surg Lasers Imaging 2010;1-6 Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453-60
Haller JA, Kuppermann BD, Blumenkranz MS, et al. Randomized controlled trial of an intravitreous drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 2010;128:289-96
.
diabetic macular edema. Am J Ophthalmol 2014;157:505-13 A recent review of clinical recommendations for management of diabetic macular edema.
44.
American Society of Retina Specialists. Preferences and Trends Survey. 2012. Available from: http://www.asrs. org/content/documents/ _2012asrspatsurveyresults.pdf [Last accessed 11 April 2014] Mitchell P, Wong TY; Diabetic Macular Edema Treatment Guideline Working Group. Management paradigms for
Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant
Expert Opin. Emerging Drugs (2014) 19(3)
Emerging drugs for diabetic macular edema
cell function and angiogenesis. Fertil Steril 2007;88(4 Suppl):1065-70
age-related macular degeneration. N Engl J Med 2004;351:2805-16 55.
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Newcastle on 10/07/14 For personal use only.
56.
Sultan MB, Zhou D, Loftus J, et al. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011;118:1107-18 Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606-15
57.
de Smet MD, Castilla M. Ocriplasmin for diabetic retinopathy. Expert Opin Biol Ther 2013;13:1741-7
58.
Dmowski WP. Danazol: a synthetic steroid with diverse biologic effects. J Reprod Med 1990;35(Suppl):69-74
59.
Thomas GW, Rael LT, Shimonkevitz R, et al. Effects of danazol on endothelial
60.
Bar-Or D, Thomas G, Salottolo K, et al. Oral danazol for DME. Retina Today 2012;68-70
61.
Lisak RP, Nedelkoska L, Bejamins JA. Effects of dextromethorphan on glial cell function: proliferation, maturation, and protection from cytotoxic molecules. Glia 2014;62:751-62
62.
Goel S, Gupta N, Walcott BP, et al. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J Natl Cancer Inst 2013;105:1188-201
63.
Lu P, Li L, Liu G, et al. Opposite roles of CCR2 and CX3CR1 macrophages in alkali-induced corneal neovascularization. Cornea 2009;28:562-9
Affiliation Stephen G Schwartz1 MD MBA, Harry W Flynn Jr2 MD & Ingrid U Scott†3 MD MPH † Author for correspondence 1 Associate Professor of Clinical Ophthalmology, University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, 311 9th Street North, #100, Naples, FL 34102, USA 2 Professor of Ophthalmology, University of Miami Miller School of Medicine, Bascom Palmer Eye Institute, 900 Northwest 17th Street, Miami, FL 33136, USA 3 Professor of Ophthalmology and Public Health Sciences, Penn State College of Medicine, Penn State Hershey Eye Center, 500 University Drive, HU19, Hershey, PA 17033, USA Tel: +1 717 531 8783; Fax: +1 717 531 5475; E-mail: [email protected]
Notice of correction Please note that corrections were made in Table 1, Table 2 and in the second paragraph of the Expert Opinion section after initial online publication of this article (21st August 2014).
Expert Opin. Emerging Drugs (2014) 19(3)
405
