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Current Approaches to the Management of Diabetic Macular Edema
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Abstract
Three modalities have a role in the primary management of diabetic macular edema (DME): laser photocoagulation, intravitreal vascular endothelial growth factor (VEGF) inhibitors, and intravitreal corticosteroid implants. Intravitreal VEGF inhibitors are most commonly used for center-involved DME, but laser photocoagulation and intravitreal corticosteroids also have an important role in DME management. Until recently, the selection of a VEGF inhibitor for a patient was complicated by a lack of comparative data and a much lower cost for bevacizumab compared with other agents. Two-year results of the landmark head-to-head Protocol T trial will inform treatment selection for ophthalmologists and formulary decisions for managed care organizations. The study found that patients with better baseline visual acuity benefited from aflibercept, bevacizumab, or ranibizumab. However, aflibercept and ranibizumab were more effective than bevacizumab for patients with worse baseline visual acuity. A higher rate of nonfatal stroke and vascular death with ranibizumab in the Protocol T trial has raised concern in the community and needs to be investigated further. Emerging drugs for DME include VEGF inhibitors with less-frequent dosing intervals, and new agents that target other pathologic processes that contribute to vascular leakage and angiogenesis in DME.
Am J Manag Care. 2016;22:S292-S299
Diabetic retinopathy is the most common cause of vision loss in working-age Americans.1,2 The disease can take 2 forms: diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). An increase in intraocular vascular endothelial growth factor (VEGF) plays a key role in the development of both forms of the disease.3 After the role of VEGF in diabetic retinopathy
was elucidated in the early 1990s, 3 VEGF inhibitors have been used for DME: aflibercept, bevacizumab, and ranibizumab. Other therapeutic approaches to the initial management of DME include laser photocoagulation and intravitreal corticosteroid implants. The Diabetic Retinopathy Clinical Research Network (DRCR.net), with sponsorship from the National Institutes of Health, conducted a series of studies that established the role of these modalities in DME. Most recently, the DRCR.net completed a landmark head-to-head study of the 3 VEGF inhibitors called Protocol T.4,5 This article reviews the role of laser photocoagulation, intravitreal VEGF inhibitors, and intravitreal corticosteroid implants in the management of DME, and includes results from Protocol T.
Laser Photocoagulation
The efficacy of focal and grid laser photocoagulation in DME was initially established in the Early Treatment Diabetic Retinopathy Study (ETDRS). In the ETDRS, photocoagulation of icroaneurysms and other areas, within a thickened macula, reduced the risk of moderate vision loss by approximately 50%. In patients with visual impairment, 30% experienced an improvement in vision. However, photocoagulation failed to prevent vision loss in approximately 15% of patients, and only 3% of patients had an improvement in visual acuity.6 This study showed that although photocoagulation helps to prevent progression of DME, it has more limited benefit for restoring vision that is already lost. In DME, laser therapy causes a reaction in which melanin, within the retinal pigment epithelium and choroid, absorbs laser energy.7 Although the exact mechanism of action remains unclear, the resulting photocoagulation of the retinal layers closes leaking microaneurysms. It may also decrease edema via increased oxygenation, reduce metabolic load by decreasing the number of photoreceptors, and induce endothelial cell proliferation. The tissue destruction caused by photocoagulation may also downregulate angiogenesis and cytokines that cause macular edema.7,8 More recently, the DRCR.net Protocol I study compared ranibizumab with deferred or prompt laser, triamcinolone with prompt laser, and sham injections with prompt laser. Improvements in visual acuity were significantly greater with ranibizumab than with laser
photocoagulation.9 Over the last decade, other rigorous clinical trials have also established that intravitreal VEGF inhibitors are more effective than laser photocoagulation for center-involved DME.10,11 The American Academy of Ophthalmology considers laser photocoagulation the preferred treatment for non—center-involved DME, and it still has a role as an adjunct to VEGF inhibitors for center-involved DME.1 Long-term follow-up of the Protocol I study is helping to compare the benefits of prompt and deferred laser treatment in patients who received VEGF
inhibitors, including whether laser photocoagulation can help reduce the treatment burden with VEGF inhibitors.12 Potential adverse effects (AEs) of laser photocoagulation include a possible transient initial decrease in central vision, paracentral scotomas if laser burns are placed too close to the fovea, permanent central scotoma from inadvertent foveal burns, and expansion of a laser scar area.1 Innovative laser and imaging platforms address some of the shortcomings of laser photocoagulation. The Navilas navigated laser, which was approved for use in the United States in 2010, allows for greater precision and superimposes fluorescein angiography and the treatment plan on a live-tracked fundus image.8,13 With a higher microaneurysm hit rate than manual technique laser treatment, the Navilas laser is extremely accurate.13
VEGF Inhibitors
Sustained hyperglycemia triggers a cascade of pathophysiologic processes in the diabetic retina, including hypoxemia, and the release of pro-inflammatory cytokines and growth factors.14 This culminates in upregulation of VEGF, the key mediator that disrupts the blood-retinal barrier in DME.3,15 High levels of VEGF cause capillaries to leak, leading to macular edema. They also promote angiogenesis and the growth of weak new capillaries, the primary pathogenic process in PDR.14 The usual roles of VEGF are to promote angiogenesis and the growth of vascular endothelial cells, act as a survival factor for endothelial cells, and regulate vascular permeability. The VEGF family has 5 structurally related ligands: VEGF-A, -B, -C, -D, and placental growth factor (PlGF). VEGF-A has 4 isoforms that are identified by the number of amino acids they contain: VEGF121, VEGF165, VEGF189, and VEGF206. The most common isoform is VEGF165. VEGF-A and VEGF-B bind with 2 tyrosine kinase receptors on the cell surface of vascular endothelium: VEGFR-1 and VEGFR-2.16 Expression of VEGFR-2, a key mediator of endothelial cell mitogenesis, survival, and microvascular permeability, is increased in diabetic retinopathy.14 VEGF inhibitors reduce capillary leakage, prevent proliferation of weak new capillaries, and improve survival of retinal pericytes in patients with DME.17,18 The properties of VEGF inhibitors used for DME are compared in Table 1.5,14,19-22 Bevacizumab is a complete murine monoclonal humanized antibody that binds in a bivalent fashion to VEGF-A.21 Ranibizumab is an antibody fragment of bevacizumab that binds with enhanced affinity, but in a monovalent fashion, to VEGF-A.14 Aflibercept, a fusion protein composed of the extracellular binding domains of VEGFR-1 and VEGFR-2 attached to the fragment crystallizable region of human immunoglobulin G1,19 acts as a soluble decoy receptor that binds VEGF-A and PlGF. Compared with other VEFG inhibitors, the higher binding affinity of aflibercept and its PlGF inhibition may be responsible for a longer duration of action and a less frequent dosing interval.23 Because circulating VEGF protects blood vessel integrity, prolonged intravitreal administration of VEGF inhibitors theoretically has the potential to induce thromboembolic events.24 Systemic administration of bevacizumab and ziv-aflibercept, as antineoplastic agents, can increase the risk of bleeding and thromboembolic
events.21,25 All of the VEGF inhibitors are detected at low concentrations in the plasma after intravitreal administration, but bevacizumab has been reported to cause longer and greater suppression of plasma VEGF than ranibizumab.24,26,27 Considering that it has lower VEGF affinity, the implications of this are unclear.24 In 2012, ranibizumab was the first VEGF inhibitor to
receive FDA approval for DME, followed by aflibercept in 2014.19,22 Although intravenous bevacizumab received FDA approval for various malignancies in 2004, intra-vitreal administration is an off-label use that requires repackaging into small doses appropriate for intravitreal administration.5 Compounded intravitreal bevacizumab and triamcinolone have been associated with isolated
outbreaks of endophthalmitis, but this appears to be rare.28,29 In the largest retrospective cohort study, which evaluated over 500,000 VEGF-inhibitor intravitreal injections, there was no difference in the endophthalmitis rate for aflibercept (0.035%), bevacizumab (0.039%), or ranibizumab (0.035%).30 The cost of intravitreal bevacizumab is substantially lower than that of the other agents.5 Although the earliest studies in DME were conducted with bevacizumab, it has not been evaluated in a phase 3 FDA registration trial like ranibizumab and aflibercept.31
Ranibizumab
Ranibizumab was evaluated in DME in 2 identical phase 3 clinical trials called RIDE and RISE. Patients with a best-corrected visual acuity (BCVA) of 20/40 to 20/320 and a central subfield thickness (CST) of at least 275 μm on optical coherence tomography (OCT) were randomized (1 eye per subject) to receive monthly intravitreal injections of ranibizumab 0.3 mg, ranibizumab 0.5 mg, or a sham for 24 months. The primary outcome of the studies was the percentage of patients achieving a gain of at least 15 letters at 24 months (ie, 3 lines on the eye chart). The percentage of patients achieving this outcome compared with the percent receiving sham injections in RIDE was 24.3% higher with ranibizumab 0.3 mg (95% CI: 13.8-34.8; P <.0001), and 20.9% higher with ranibizumab 0.5 mg (95% CI: 10.7-31.1; P <.001). In RISE, this represented a difference from sham injections of 20.8% (95% CI: 11.4-30.2; P <.0001) for ranibizumab 0.3 mg and 33.3%
(95% CI: 23.8-42.8: P <.0001) for ranibizumab 0.5 mg. In RISE, mean BCVA gains from baseline were 12.5 and 11.9 letters for ranibizumab 0.3 mg and 0.5 mg, respectively, compared with 2.6 letters for sham injections (P <.0001). Respective letters gained were 12.0, 10.9, and 2.3 letters in RIDE (P <.0001). In RISE, the incidence of vision loss (≥15 letters) was 2.4% with ranibizumab 0.3 mg and 0.5 mg, compared with 10.2% with sham injections (P = .0086 for ranibizumab 0.3 mg vs sham; P = .0126 for ranibizumab 0.5 mg vs sham). Respective vision loss in RIDE was 1.6%,
3.9%, and 9% (P = .0119 for ranibizumab 0.3 mg vs sham; P = .1384 for ranibizumab 0.5 mg vs sham).32 Fewer patients who received ranibizumab required laser procedures, with the mean number of procedures in 24 months ranging from 0.3 to 0.8 in the 2 dosage groups of ranibizumab in RISE and RIDE compared with 1.8 and 1.6 procedures for sham injections in the respective trials (P <.0001 for all comparisons).32 In terms of anatomic improvement, the pooled mean change in central foveal thickness (CFT) at month 24 was −255.2 μm for ranibizumab 0.3 mg, −262.0 μm for ranibizumab 0.5 mg, and −129.5 μm for sham injections.33 Improvements in visual acuity and reductions in retinal thickness occurred rapidly with ranibizumab. Fewer patients given ranibizumab developed PDR or required panretinal photocoagulation.32 After 24 months, patients who received sham injections were allowed to cross over to ranibizumab 0.5 mg. Patients initially randomized to ranibizumab 0.3 mg or 0.5 mg continued to receive their respective medications. At month 36, patients who received ranibizumab from the start of the trial maintained the improvements in BCVA and CFT observed at month 24. Patients who received delayed treatment did not gain as much visual acuity improvement as those originally randomized to ranibizumab.
At 36 months, the percentage of patients in RIDE achieving a gain of at least 15 letters was 19.2% in the sham/0.5 mg ranibizumab group, 36.8% in the ranibizumab 0.3 mg group (P = .0026 vs sham/0.5 mg ranibizumab), and 40.2% in the ranibizumab 0.5 mg group (P = .0001 vs sham/0.5 mg ranibizumab). Respective increases in RISE were 22.0%, 51.2% (P <.0001 vs sham/0.5 mg ranibizumab), and 41.6% (P = .0005 vs sham/0.5 mg ranibizumab).33 During the first 24 months of the RIDE and RISE studies, the most common serious ocular AE was vitreous hemorrhage, which occurred in 7 sham-treated eyes and 2 ranibizumab-treated eyes. Injection-related AEs were uncommon, with 4 cases of endophthalmitis, 3 cases of traumatic cataracts, and 1 rhegmatogenous retinal detachment occurring with 10,584 injections. Ranibizumab and sham injections had similar rates of cataracts, intraocular inflammation, and glaucoma.32 Systemic AEs, possibly related to VEGF inhibition, were assessed according to Antiplatelet Trialists’ Collaboration (APTC) criteria. At 24 months, the overall incidence of these events was 4.9% to 5.5% for sham-injection groups (5.2% for pooled data) compared with 2.4% to 8.8% for ranibizumab groups.32,33 At 36 months, the overall incidence of APTC events was 7.2% for sham/0.5 mg
ranibizumab, 10.8% for ranibizumab 0.3 mg, and 10.4% for ranibizumab 0.5 mg. Compared with the 0.3 mg dose, ranibizumab 0.5 mg had higher rates of all-cause mortality (6.4% vs 4.4%) and stroke (4.8% vs 2.0%). Although some data in RIDE and RISE suggested minimally better efficacy for the 0.5 mg dose, pooled data found the 2 doses were equivalent. Ranibizumab was approved by the FDA for DME at a dose of 0.3 mg once monthly, presumably because the 0.5 mg dose was associated with a higher risk of systemic AEs and death.33
Aflibercept
Aflibercept was evaluated in DME in 2 identical phase 3 clinical trials lasting 148 weeks called VIVID and VISTA. Patients with a BCVA of 20/40 to 20/320 and a 1-mm CST were randomized (1 eye per subject) to receive either intravitreal injections of aflibercept 2 mg every month (2 mg q4 weeks), aflibercept 2 mg every month for 5 months and then every 2 months (2 mg q8 weeks), or laser photocoagulation. The primary outcome was the change from baseline in ETDRS letter scores at 1 year. In VISTA, mean BCVA gains from baseline were 2.5 and 10.7 letters for the 2 mg q4 and 2 mg q8 regimens of aflibercept compared with 0.2 letters for laser therapy (P <.0001). Respective letter increases were 10.5, 10.7, and 1.2 letters in VIVID (P <.0001). The respective percentage of patients’ eyes gaining at least 15 letters was 41.6%, 31.1%, and 7.8% in VISTA (P <.0001), and 32.4%, 33.3%, and 9.1% in VIVID (P <.0001). The incidence of vision loss (≥15 letters) with laser therapy was 9.1% in VISTA and 10.6% in VIVID, compared with less than 1% in any of the aflibercept groups. At 1 year, mean reductions in central retinal thickness (CRT) with aflibercept 2 mg q4, 2 mg q8, and laser therapy were −185.9, −183.1, and −73.3 μm (P <.0001) in VISTA, and −195.0, −192.4, and −66.2 μm (P <.0001) in VIVID, respectively.34 At 100 weeks, patients receiving either dosage regimen of aflibercept maintained significant improvements in visual outcomes compared with those receiving laser therapy. In VISTA, mean BCVA gains from baseline were 11.5 and 11.1 letters for the 2 mg q4 and 2 mg q8 regimens of aflibercept, respectively, compared with 0.9 letters for laser therapy (P <.0001). Respective mean letter increases
were 11.4, 9.4, and 0.7 letters in VIVID (P <.0001). The respective percentages of patients’ eyes gaining at least 15 letters were 38.3%, 33.1%, and 13.0% in VISTA (P <.0001), and 38.2%, 31.1%, and 12.1% in VIVID (P ≤.0001 for 2 mg q4 vs laser; P = .001 for 2 mg q8 vs laser). In VISTA, the incidence of vision loss (≥15 letters) was 3.2% and 0.7% for the 2 mg q4 and 2 mg q8 regimens of aflibercept, respectively, compared with 9.7% for laser therapy (P = .022 for 2 mg q4 vs laser; P = .0004 for 2 mg q8 vs laser). Respective vision loss in VIVID was 2.2%, 1.5%, and 12.9% (P = .0008 for 2 mg q4 vs laser; P = .0002 for 2 mg q8 vs laser). At 100 weeks, mean reductions in CRT with aflibercept 2 mg q4, 2 mg q8, and laser therapy were −191.4, −191.1, and −83.9
μm (P <.0001) in VISTA, and −211.8, −195.8, and −85.7 μm (P <.0001) in VIVID, respectively.11 At 1 year, the treatment groups had a similar incidence of ocular and systemic AEs.34 In addition, the incidence of APTC systemic AEs was similar across treatment groups. At 100 weeks, the incidence of serious ocular AEs was 3.8% for aflibercept 2 mg q8, 4.2% for aflibercept 2 mg q4, and 5.9% for laser therapy.11 Cataracts were the most frequent serious ocular AE, with an incidence of 1.0%, 2.4%, and 0.3%, respectively. The respective incidence of any APTC-defined arterial thrombotic event was 5.6%, 7.2%, and 4.2%. Considering that the 2 regimens had comparable efficacy, aflibercept was approved by the FDA at a dose of 2 mg every month for 5 months, followed
by 2 mg every other month.11,19
DRCR.net Protocol T Study
The landmark Protocol T study was a head-to-head comparison of aflibercept, bevacizumab, and ranibizumab in patients with DME. This single-blind, multicenter trial randomized 660 patients (1 eye each) with centerinvolved DME and a BCVA letter score of 78 to 24 to receive 2 years of treatment with aflibercept 2 mg, bevacizumab 1.25 mg, or ranibizumab 0.3 mg every 4 weeks.
Starting at the 6-month visit, persistent DME that was not improving was treated with a focal and/or grid laser. Following the publication of 1-year trial results, treatment groups were unblinded. At that time, patients could be switched to an anti-VEFG agent not used in the study. The primary end point of the study was the mean change from baseline in visual acuity at 1 year.4,5 At 1 year, in the entire study cohort, the increase in mean visual acuity letter score was 13.3 with aflibercept, 11.2 with ranibizumab, and 9.7 with bevacizumab (P = .03 for aflibercept vs ranibizumab; P <.001 for aflibercept vs bevacizumab). For patients with better visual acuity scores at baseline (78 to 69; roughly equivalent to 20/32 to 20/40 vision), there was no significant difference in primary outcome for the 3 drugs (mean improvement of 8.0 with aflibercept, 7.5 with bevacizumab, 8.3 with ranibizumab; P >.50). For patients with poor vision at baseline (initial letter score <69; equivalent to approximately 20/50 or worse), aflibercept was associated with significantly greater improvement than bevacizumab (18.8 vs 11.8; P <.001) and ranibizumab (18.9 vs 14.2;
P = .003). For the entire cohort, the decrease in OCT CST was −210 μm with aflibercept, −176 μm with ranibizumab, and −135 μm with bevacizumab (P <.001 for aflibercept vs bevacizumab and ranibizumab vs bevacizumab).5 Over the 2-year treatment period, there was an insignificant difference in the median number of injections for the 3 drugs. In the second year of the study, patients
required approximately half the number of injections that they required in the first year. The proportion of patients receiving at least 1 laser treatment was 41% with aflibercept, 64% with bevacizumab, and 52% with ranibizumab (P <.001 aflibercept vs bevacizumab; P = .04 aflibercept vs ranibizumab; P = .01 bevacizumab vs ranibizumab). Similar to 1-year results, improvements
in visual acuity varied according to baseline visual acuity. In patients with better baseline visual acuity, respective mean increases of 7.8, 6.8, and 8.6 letters were not significantly different. In patients with worse baseline visual acuity, the mean improvement was 18.3, 13.3, and 16.1 letters (P = .02 aflibercept vs bevacizumab). Similar to results at 1 year, bevacizumab was less effective at reducing retinal thickness. At 2 years, the mean change in OCT CST in the entire cohort was −171 μm with aflibercept, −149 μm with ranibizumab, and −126 μm with bevacizumab (P <.001 aflibercept vs bevacizumab; P = .001 ranibizumab vs bevacizumab).4 After 2 years, the incidence of APTC-defined events was 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (P = .047 for aflibercept vs ranibizumab). This result was driven by more nonfatal strokes and vascular deaths with ranibizumab.4 It has raised concern and warrants further investigation, as a dose-response increase in rate of death was also observed in the RISE and RIDE ranibizumab FDA registration trials.32 Overall, after 2 years, all VEGF inhibitors had a low incidence of ocular AEs, including endophthalmitis, inflammation, vitreous hemorrhage, retinal tear or detachment, or increased intraocular pressure.4 In summary, the DRCR.net Protocol T study found little difference in efficacy among the 3 VEGF inhibitors for patients with mild visual acuity loss. For patients with worse baseline visual acuity, aflibercept was more effective than bevacizumab and ranibizumab after 1 year of treatment. After 2 years, aflibercept was still more effective than bevacizumab for improving visual acuity, but it was no longer more effective than ranibizumab.4,5 Aflibercept was shown to achieve vision gains more rapidly and dry the retina more quickly compared with the other 2 agents. A special communication from the American Society of Retina Specialists (ASRS), based on the 1-year results of the DRCR.net Protocol T study, endorsed continued use of bevacizumab in patients with good initial visual acuity (20/32 to 20/40) when adequately packaged bevacizumab is available. The ASRS also recommended that ophthalmologists have access to all 3 agents to provide individualized therapy.35
Intravitreal Corticosteroids
Recognition that DME has an inflammatory component led to the evaluation of intravitreal corticosteroids for DME. Corticosteroids reduce edema, at least in part, by reducing VEGF expression.36 Two intravitreal corticosteroid implants have received FDA approval for the management of DME: dexamethasone and fluocinolone acetonide. They differ according to dosage, biodegradability,
and duration of action (Table 237-39). Intravitreal corticosteroids that have been used off label for DME include another fluocinolone formulation (Retisert) and triamcinolone acetonide suspension.9,40 Intravitreal triamcinolone was evaluated for DME in a series of DRCR.net-conducted studies. In a phase 3 clinical trial (Protocol B) conducted over 2 years with an additional year of follow-up, improvements in visual acuity and retinal thickness were greater with laser therapy than intravitreal off-label triamcinolone.41,42 A second 2-year trial (Protocol I) confirmed that intravitreal offlabel triamcinolone was inferior to ranibizumab plus laser therapy or laser therapy alone in phakic eyes.9,43 However, for eyes that were pseudophakic at baseline, triamcinolone plus prompt laser therapy produced visual acuity improvements comparable to ranibizumab and better than laser therapy alone. In these studies, off-label triamcinolone increased intraocular pressure (IOP) and the need for cataract surgery.9,41-43 Results from 2 phase 3, randomized, double-blind, multicenter clinical trials utilizing intravitreal dexamethasone (MEAD study) and fluocinolone acetonide (FAME study) have been published. In both studies, which included approximately 1000 patients each, intravitreal dexamethasone and fluocinolone acetonide improved
BCVA compared with sham injections, with a relatively few number of injections needed compared with anti-VEGF agents. Some patients receiving either corticosteroid developed cataracts requiring surgery and increased IOP.44,45 These intraocular AEs were found to be manageable in the vast majority of patients; therefore, their use in the management of DME is expanding. The role of corticosteroids in combination with VEGF inhibitors is currently being investigated in clinical trials.46
Emerging Therapies for DME
The treatment burden of intravitreal injections is driving the search for strategies that lengthen the treatment interval. One approach is drug delivery implants that release currently available VEGF inhibitors over a longer period of time.47,48 Another approach is to design molecules with improved binding capacity, such as RTH258, an antibody fragment with a molecular weight of only 25 kDa that may have a longer duration of action than ranibizumab.49 Conbercept, a VEGF inhibitor with a 7-day half-life, also has the potential to provide a longer dosing interval.47 It is a fusion protein of the extracellular binding domains of VEGFR-1 and VEGFR-2 similar to aflibercept, but inclusion of the fourth binding domain of VEGFR-2 may enhance VEGF binding. In China, where it is already approved for macular degeneration, a phase 3 trial in DME is under way.47,50 A number of investigational agents target unique pathologic processes that contribute to vascular leakage and angiogenesis in DME. A few agents that have advanced to phase 2 clinical trials are described here. ALG-1001 (Luminate) is an integrin antagonist that reduces vascular leakage and inhibits angiogenesis.48,51 A single intravitreal dose may improve visual acuity for up to 3 months.48 A phase 2 trial is comparing ALG-1001 to bevacizumab.52 In DME, high levels of angiopoietin-2 inhibit TIE-2 (also known as TEK receptor tyrosine kinase) signaling, a process that normally stabilizes blood vessels and maintains vascular integrity. Vascular endothelial-protein tyrosine phosphatase (VE-PTP) is a negative regulator at the TIE-2 receptor. By competitively inhibiting VE-PTP, AKB-9778, a competitive inhibitor of VE-PTP, restores TIE-2 signaling and blocks the pathologic effects of angiopoietin-2.53 Because AKB-9778 is given by subcutaneous injection, it has the potential to be self-administered.54 A phase 2 trial evaluated AKB-9778 alone or in combination with ranibizumab. 55 DMI-5207 (Optina) is a very low dose of oral danazol (15-45 mg twice daily) that reduces endothelial leakage by enhancing endothelial cell barrier function.56,57
Conclusion
The Protocol T trial established that patients with better baseline visual acuity can benefit from aflibercept, bevacizumab, or ranibizumab. Aflibercept and ranibin zumab are more effective than bevacizumab for patients with worse baseline visual acuity. A higher rate of nonfatal stroke and vascular death was observed with ranibizumabin the Protocol T trial. The results of Protocol
T support an individualized approach to the selection of a VEGF inhibitor. Because DME has a multifactorial etiology, combination approaches with laser therapy, anti-VEGF agents, and corticosteroids may be sensible and are gaining popularity. Healthcare professionals are hopeful that drugs in development for DME will reduce the treatment burden of frequent injections.
Author affiliation: University of Chicago, Chicago, IL.
Funding source: This activity is supported by an educational grant from Genentech.
Author disclosure: Dr Hariprasad reports serving as a consultant or being on speakers bureaus for Alcon, Alimera Sciences, Allergan, Bayer, Biomedical, Clearside, Janssen, Ocular Therapeutix, OD-OS, Optos, Regeneron, and Spark.
Authorship information: Concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
Address correspondence to: retina@uchicago.edu.
REFERENCES
1. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred practice panel guidelines. Diabetic retinopathy. American Academy of Ophthalmology website. http://www.aao.
org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2016. Published 2016. Accessed May 26, 2016.
2. American Diabetes Association. 9. Microvascular complications and foot care. Diabetes Care. 2016;(39 suppl 1):S72-S80. doi: 10.2337/dc16-S012.
3. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-
1487. doi: 10.1056/nejm199412013312203.
4. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359. doi: 10.1016/j.ophtha.2016.02.022.
5. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203. doi: 10.1056/NEJMoa1414264.
6. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol.
1985;103(12):1796-1806.
7. Blumenkranz MS. The evolution of laser therapy in ophthalmology: a perspective on the interactions between photons, patients, physicians, and physicists: the LXX Edward Jackson
Memorial Lecture. Am J Ophthalmol. 2014;158(1):12-25.e1. doi: 10.1016/j.ajo.2014.03.013.
8. Yun SH, Adelman RA. Recent developments in laser treatment of diabetic retinopathy. Middle East Afr J Ophthalmol. 2015;22(2):157-163. doi: 10.4103/0974-9233.150633.
9. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology.
2010;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031.
10. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular
edema. Ophthalmology. 2011;118(4):615-625. doi: 10.1016/j. ophtha.2011.01.031.
11. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122(10):2044-
2052. doi: 10.1016/j.ophtha.2015.06.017.
12. Elman MJ, Ayala A, Bressler NM, et al; Diabetic Retinopathy Clinical Research Network. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment:
5-year randomized trial results. Ophthalmology. 2015;122(2):375-381. doi: 10.1016/j.ophtha.2014.08.047.
13. Kozak I, Oster SF, Cortes MA, et al. Clinical evaluation and treatment accuracy in diabetic macular edema using navigated laser photocoagulator NAVILAS. Ophthalmology.
2011;118(6):1119-1124. doi: 10.1016/j.ophtha.2010.10.007.
14. Simo R, Sundstrom JM, Antonetti DA. Ocular anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care. 2014;37(4):893-899. doi:
10.2337/dc13-2002.
15. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology.
2003;110(9):1690-1696. doi: 10.1016/s0161-6420(03)00568-2.
16. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581-611. doi: 10.1210/er.2003-0027.
17. Jampol LM, Bressler NM, Glassman AR. Revolution to a new standard treatment of diabetic macular edema. JAMA. 2014;311(22):2269-2270. doi: 10.1001/jama.2014.2536.
18. Giurdanella G, Anfuso CD, Olivieri M, et al. Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A
pathway. Biochem Pharmacol. 2015;96(3):278-287. doi: 10.1016/j. bcp.2015.05.017.
19. Eylea (aflibercept) [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals: 2016.
20. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab.
Angiogenesis. 2012;15(2):171-185. doi: 10.1007/s10456-011-9249-6.
21. Avastin (bevacizumab) [package insert]. South San Francisco, CA: Genentech Inc; 2015.
22. Lucentis (ranibizumab injection) [package insert]. South San Francisco, CA: Genentech Inc; 2015.
23. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92(5):667-668. doi: 10.1136/bjo.2007.134874.
24. Semeraro F, Morescalchi F, Duse S, Gambicorti E, Cancarini A, Costagliola C. Pharmacokinetic and pharmacodynamic properties of anti-VEGF drugs after intravitreal injection. Curr Drug
Metab. 2015;16(7):572-584.
25. Zaltrap (ziv-aflibercept) [package insert]. Bridgewater, NJ: sanofi-aventis US, LLC; 2016.
26. Carneiro AM, Costa R, Falcao MS, et al. Vascular endothelial growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab
or ranibizumab. Acta Ophthalmol. 2012;90(1):e25-30. doi: 10.1111/j.1755-3768.2011.02240.x.
27. Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach GF. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and
pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema. Br J Ophthalmol. 2013;97(4):454-459. doi: 10.1136/bjophthalmol-2012-302451.
28. Staes C, Jacobs J, Mayer J, Allen J. Description of outbreaks of health-care-associated infections related to compounding pharmacies, 2000-12. Am J Health Syst Pharm. 2013;70(15):1301-
1312. doi: 10.2146/ajhp130049.
29. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol. 2015;133(10):1159-1164. doi: 10.1001/jamaophthalmol.
2015.2556.
30. Rayess N, Rahimy E, Storey P, et al. Postinjection endophthalmitis rates and characteristics following intravitreal bevacizumab, ranibizumab and aflibercept. Am J Ophthalmol. 2016;165:88-93. doi: 10.1016/j.ajo.2016.02.028.
31. Scott IU, Edwards AR, Beck RW, et al; Diabetic Retinopathy Clincial Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema.
Ophthalmology. 2007;114(10):1860-1867. doi: 10.1016/j.ophtha. 2007.05.062.
32. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE.
Ophthalmology. 2012;119(4):789-801. doi: 10.1016/j.ophtha. 2011.12.039.
33. Brown DM, Nguyen QD, Marcus DM, et al; RISE and RIDE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III
trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022. doi: 10.1016/j.ophtha.2013.02.034.
34. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254. doi: 10.1016/j.ophtha.2014.05.006.
35. Heier JS, Bressler NM, Avery RL, et al; American Society of Retina Specialists Anti-VEGF for Diabetic Macular Edema Comparative Effectiveness Panel. Comparison of aflibercept,
bevacizumab, and ranibizumab for treatment of diabetic macular edema: extrapolation of data to clinical practice. JAMA Ophthalmol. 2016;134(1):95-99. doi: 10.1001/jamaophthalmol.
2015.4110.
36. Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle
cells. Eur J Pharmacol. 1998;341(2-3):309-315.
37. Ozurdex (dexamethasone intravitreal implant) [package insert]. Irvine, CA: Allergan, Inc; 2014.
38. Iluvien (fluocinolone acetonide) [package insert]. Alpharetta, GA: Alimera Sciences Inc; 2014.
39. Dugel PU, Bandello F, Loewenstein A. Dexamethasone intravitreal implant in the treatment of diabetic macular edema. Clin Ophthalmol. 2015;9:1321-1335. doi: 10.2147/opth.s79948.
40. 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(8):1580-1587. doi: 10.1016/j.ophtha.2011.02.048.
41. Diabetic Retinopathy Clincal Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9):1447-1449, 1449.e1-10. doi: 10.1016/j. ophtha.2008.06.015.
42. Beck RW, Edwards AR, Aiello LP, et al; Diabetic Retinopathy Clinical Research Network (DRCR.net). Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and
intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245-251. doi: 10.1001/archophthalmol. 2008.610.
44. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic
macular edema. Ophthalmology. 2012;119(10):2125-2132. doi: 10.1016/j.ophtha.2012.04.030.
45. Boyer DS, Yoon YH, Belfort R, Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular
edema. Ophthalmology. 2014;121(10):1904-1914. doi: 10.1016/j. ophtha.2014.04.024.
46. Maturi RK, Bleau L, Saunders J, Mubasher M, Stewart MW. A 12-month, single-masked, randomized controlled study of eyes with persistent diabetic macular edema after multiple anti-VEGF
injections to assess the efficacy of the dexamethasone-delayed delivery system as an adjunct to bevacizumab compared with continued bevacizumab monotherapy. Retina. 2015;35(8):1604-
1614. doi: 10.1097/iae.0000000000000533.
47. Lally DR, Shah CP, Heier JS. Vascular endothelial growth factor and diabetic macular edema. Surv Ophthalmol. 2016. pii: S0039-6257(15)30035-7. doi: 10.1016/j.survophthal.2016.03.010.
48. Kaiser PK. The DME pipeline. Retina Today website. retinatoday. com/2015/04/the-dme-pipeline. Accessed April 13, 2016.
49. Holz FG, Dugel PU, Weissgerber G, et al. Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular agerelated macular degeneration: a randomized controlled study.
Ophthalmology. 2016;123(5):1080-1089. doi: 10.1016/j.ophtha. 2015.12.030.
50. Safety and efficacy study of conbercept in diabetic macular edema (DME) (Sailing). ClinicalTrials.gov website. clinicaltrials. gov/ct2/show/NCT02194634. Updated January 5, 2016. Accessed
April 10, 2016.
51. Das A, McGuire PG, Rangasamy S. Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology. 2015;122(7):1375-1394. doi: 10.1016/j.ophtha.2015.03.024.
52. A phase 2 randomized, controlled, double-masked, multicenter clinical trial designed to evaluate the safety and exploratory efficacy of luminate (ALG-1001) as compared to avastin and focal
laser photocoagulation in the treatment of diabetic macular edema. ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02348918. Updated January 23, 2015. Accessed April 13, 2016.
53. Shen J, Frye M, Lee BL, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014;124(10):4564-4576. doi: 10.1172/jci74527.
54. Campochiaro PA, Sophie R, Tolentino M, et al. Treatment of diabetic macular edema with an inhibitor of vascular endothelialprotein tyrosine phosphatase that activates Tie2. Ophthalmology.
2015;122(3):545-554. doi: 10.1016/j.ophtha.2014.09.023.
55. The TIME-2 study: A phase 2 study of AKB-9778, a novel Tie-2 activator, in patients with diabetic macular edema (TIME-2). ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/
NCT02050828. Updated August 24, 2015. Accessed April 13, 2016.
56. Thomas GW, Rael LT, Bar-Or R, et al. Biphasic effect of danazol on human vascular endothelial cell permeability and -actin cytoskeleton dynamics. Biochem Biophys Res Commun.
2012;421(4):707-712. doi: 10.1016/j.bbrc.2012.04.066.
57. Efficacy and safety study to evaluate two doses of oral DMI-5207 in adult subjects with diabetic macular edema. ClinicalTrials. gov website. clinicaltrials.gov/ct2/show/NCT02002403. Updated
December 5, 2013. Accessed April 13, 2016.
43. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-614. doi: 10.1016/j.ophtha.2010.12.033.
