Curr Diab Rep (2014) 14:510 DOI 10.1007/s11892-014-0510-4
MICROVASCULAR COMPLICATIONS—RETINOPATHY (JK SUN, SECTION EDITOR)
Anti-VEGF Therapy for Diabetic Macular Edema Michael W. Stewart
# Springer Science+Business Media New York 2014
Abstract Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of diabetic macular edema (DME), the leading cause of vision loss among working-aged individuals. A decade of clinical trials demonstrated that drugs that bind soluble VEGF restore the integrity of the bloodretinal barrier, resolve macular edema, and improve vision in most patients with DME. Four drugs (pegaptanib, ranibizumab, bevacizumab, and aflibercept) effectively treat DME when administered by intravitreal injections. Only ranibizumab has received U.S. Food and Drug Administration (FDA) approval for DME, but bevacizumab is commonly used off-label, and an FDA application for aflibercept is pending. Effective treatment requires repeated injections, although recent data suggest that the treatment burden diminishes after 1 year. Intravitreal therapy is generally safe, although the incidence of systemic thromboembolic events varies among trials. Keywords Aflibercept . Bevacizumab . Diabetic macular edema . Pegaptanib . Ranibizumab . Vascular endothelial growth factor . VEGF
Introduction Diabetes mellitus is a leading cause of blindness in workingaged individuals of industrialized nations. Diabetes may be responsible for only 1 % of global blindness, but in some
This article is part of the Topical Collection on Microvascular Complications—Retinopathy M. W. Stewart (*) Department Of Ophthalmology, Mayo Clinic Florida, Jacksonville, FL 32224, USA e-mail:
[email protected] developed countries, its contribution reaches 5 % [1, 2]. This may be partially explained by the increasing prevalence of diabetes in the U.S. adult population between 1988 and 2005: from 5.1 % to 9.6 % [3, 4]. Since diabetes currently affects 382 million people worldwide [5], with this number expected to reach 592 million by 2035 [6], we will likely witness significant increases in the number of diabetic patients and those with diabetes-induced blindness. Diabetes causes both neuroretinal dysfunction and retinal vascular damage, known as diabetic retinopathy (DR). Current evidence suggests that the prevalence of DR in the U.S. is decreasing, probably due to improved control of risk factors, but the overall number of DR patients is increasing due to the growth of the diabetic population [7–9]. The prevalence rates of DR in many developing countries will probably increase as improved economic conditions lead to prolonged life spans and increased obesity rates [10, 11]. Severe loss of vision usually results from complications of proliferative diabetic retinopathy (PDR)—vitreous hemorrhage and traction retinal detachments—but diabetic macular edema (DME), defined as retinal thickening that approaches or involves the center of the macula, accounts for approximately three quarters of diabetic-related vision loss. It is estimated that DME is responsible for visual impairment in 3 % of the adult diabetic population of the U.K. [12]. DME development correlates with the duration and severity of disease and is exacerbated by conditions such as systemic arterial hypertension, hyperlipidemia, and smoking. Although intensive glucose control delays the onset of DME, it often is not preventative [13, 14]. The landmark Early Treatment of Diabetic Retinopathy Study (ETDRS) showed that macular laser photocoagulation reduces the 3-year risk of moderate vision loss due to DME by 50 % [15, 16]. Unfortunately, only 11 % and 16 % of the patients with initial visual acuities of 20/40 or worse improved by three lines at 1 and 3 years, respectively. Nonetheless, the
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ETDRS established macular laser photocoagulation as the standard of care for DME [16]. Intensive research during the 3 decades since the first ETDRS report has characterized the pivotal role of vascular endothelial growth factor (VEGF) in the development of several chorioretinal vascular diseases, including DME. Several VEGF-binding drugs effectively reduce DME (Fig. 1), improve visual acuity, and, as a result, have completely rewritten the paradigm for DME treatment. The balance of this article will discuss the role of VEGF in the formation of DME and the results of treatment with drugs that inhibit its effects.
Rationale for Anti-VEGF Use Morphologic features associated with DR include accelerated apoptosis of vascular endothelial cells and pericytes, thickening of basement membranes, capillary occlusion, and the hallmark of DME—breakdown of the blood-retinal barrier (BRB). Compromised BRB integrity follows loss of junctional proteins, induction of transendothelial channels, increased vesicular transport, margination of white blood cells, and vasodilation-induced alteration of Starling’s equilibrium, all of which are associated with elevated VEGF concentrations [17–21]. Injection of exogenous VEGF into mice breaks down the BBB [22], and sustained VEGF release in monkey eyes causes macular edema [23]. In preclinical murine models, VEGF164 was capable of producing the typical findings of DR [24, 25]. VEGF synthesis is upregulated by tissue hypoxia [26, 27], proinflammatory mediators [28], and growth factors [29]. Aqueous VEGF concentrations in diabetic individuals are 5 times those of age-matched controls [30], are 3 times those in the plasma [31], and correlate with the severity of retinopathy. Increasing retinal oxygenation with the administration of exogenous oxygen improves DME [32].
Curr Diab Rep (2014) 14:510
received U.S. Food and Drug Administration (FDA) approval for several indications. Pegaptanib (Macugen®, Eyetech, New York) is a highaffinity (KD = 50 pM for VEGF165), 50-kDa, pegylated aptamer that attaches to the heparin binding site of VEGF-A isoforms with 165 or more amino acids [34]. It received FDA approval for the treatment of exudative AMD but, because of disappointing visual results, is only used sparingly. Ranibizumab (Lucentis®, Genentech, S. San Francisco, CA/ Roche, Basel, Switzerland) is a high-affinity (KD =46–192 pM for VEGF165) [35, 36], 48-kDa, recombinant, humanized, immunoglobulin G1 k isotope antibody fragment (Fab). It is approved for the treatment of exudative AMD, macular edema due to branch and central retinal vein occlusions, and DME. Bevacizumab (Avastin®, Genentech, S. San Francisco, CA/Roche, Basel, Switzerland) is a high-affinity (KD =58– 1,100 pM for VEGF165) [35, 37], 149-kDa, recombinant, humanized, full-length murine antibody that binds all isoforms of VEGF-A. It is approved for the treatment of colorectal carcinoma, renal cell carcinoma, nonsmall cell lung carcinoma, ovarian carcinoma, and glioblastoma, but its use for ocular diseases is off-label. Aflibercept (Eylea®, Regeneron, Tarrytown, NY) is a highaffinity (KD =0.45 pM for VEGF165) [35], 115-kDa, glycosylated, recombinant, fusion protein with native VEGFR ligandbinding sequences attached to the Fc segment of a human IgG1. Aflibercept binds all isoforms of VEGF-A, VEGF-B, and placental growth factor [38]. Aflibercept is approved for the treatment of exudative AMD and macular edema due to central retinal vein occlusions, and its systemic formulation, Zaltrap®, is approved for the treatment of colorectal carcinoma. An American Academy of Ophthalmology study group [39] concluded that five studies provide level I evidence supporting the use of ranibizumab for DME (RESTORE [40••], 2 Diabetic Retinopathy Clinical Research Network (DRCR.Net) Protocol I [41, 42••], RISE, and RIDE [43••]) and one for the use of pegaptanib [44]. Since then, the phase III VISTA and VIVID trials have provided level I evidence supporting the use of aflibercept [45].
Clinical Trials Pegaptanib Overview Understanding VEGF’s pivotal role in the pathogenesis of DME, exudative AMD, and edema due to retinal vein occlusions led to the development of several drugs that interfere with its signaling actions. The first evidence linking VEGF blockade to improved DME in humans came from an orally administered, nonspecific protein kinase C inhibitor [33]. Subsequent anti-VEGF development focused on drugs that bind soluble VEGF, thereby preventing activation of its transmembrane cognate receptors. Several recombinant strategies were pursued, resulting in four VEGF-binding drugs that
The phase II Macugen Diabetic Retinopathy Study compared three doses of pegaptanib (0.3, 1, and 3 mg) given q6wk×3 then pro re nata (PRN) versus sham injections. Pegaptanibtreated eyes were more likely to gain two lines of vision (34 % vs. 10 %; p=.003) and achieved better thinning of the macula (−64 vs. 4 μm; p=.02), with a reduced need for focal/scatter photocoagulation [46]. A phase II/III trial evaluated the safety and efficacy of intravitreal pegaptanib sodium 0.3 mg every 6 weeks for 1 year versus sham injections. Patients were eligible to receive focal/ grid photocoagulation for persistent edema beginning at week
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Fig. 1 This figure documents the 1-year clinical course of an eye with diabetic macular edema treated monthly with intravitreal ranibizumab. The sequential OCTs from top to bottom show progressive decreases in macular edema
18. During year 2, subjects received injections as often as every 6 weeks according to prespecified criteria. Forty-nine of the 133 (36.8 %) subjects from the pegaptanib group and 25 of the 127 (19.7 %) in the sham group met the primary endpoint: VA improvement of at least 10 letters at week 54 (p=.0047). At week 102, pegaptanib-treated subjects gained an average of +6.1 letters, as compared with +1.3 letters for patients in the sham group (p15 letters and 8 (80 %) gained >1 letter. Average VA in the low-dose group improved by +12 letters, as compared with +7.8 letters in the high-dose group. The mean decreases in macular thickness were −45 μm (0.3 mg) and −197 μm (0.5 mg) [48]. These encouraging results spawned further research along three largely independent lines: READ, RISE, and RIDE; RESOLVE and RESTORE; and DRCR.net Protocol I. Each produced level I evidence that supports the use of ranibizumab for the treatment of DME. Since each track used different treatment regimens, particularly with regard to the frequency of ranibizumab injections and the use of macular laser photocoagulation for persistent edema, the morphologic and visual acuity results differ, as do the resultant conclusions regarding the optimal treatment strategy.
Pilot Studies READ, RISE, and RIDE In the first of two pilot studies, 10 eyes (9 that were previously treated with laser or corticosteroids) received ranibizumab at baseline, 1, 2, 4, and 6 months. At month 7, there were
The READ-2 trial randomized 126 patients to ranibizumab (baseline and months 1, 3, and 5), laser (baseline and month 3
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PRN), or ranibizumab combined with laser. Average improvements in VA at 6 months were greater in group 1 (+7.24 letters) than in group 2 (−0.43 letters), whereas group 3 (+ 3.8 letters) was not significantly different from either. Threeline improvements were experienced by 22 %, 0 %, and 8 % of subjects, and excess thickness was reduced by 50 %, 33 %, and 45 %. Thirty-six of 42 patients receiving laser had persistent edema at 6 months [49]. Beginning at 6 months, all group 1 and 2 patients were eligible to receive ranibizumab every 2 months if retreatment criteria were met, whereas group 3 patients were eligible for treatment every 3 months. Mean numbers of injections from months 6 to 24 were 5.3 (ranibizumab group), 4.4 (laser group), and 2.9 (ranibizumab+laser group). At 24 months, the mean improvements in VA were +7.7, +5.5, and +6.8 letters, the percentages of patients with visual acuities of 20/ 40 or better were 45 %, 44 %, and 35 %; the percentages of patients who gained three lines of vision were 24 %, 18 %, and 26 %; and the mean macular thicknesses were 340, 286, and 258 μm. Sixty-eight percent of group 1 patients had persistent macular edema, suggesting that injections every 2 months constituted undertreatment. Of patients with dry maculas, none in group 1 had poor vision, yet 19 % and 22 % of group 2 and 3 patients, respectively, had poor vision, suggesting that laser may compromise visual recovery [50]. Monitoring and treatment frequencies were increased during year 3, when all patients returned monthly and received ranibizumab if central subfield thickness (CST) was >250 μm. Average VA in the ranibizumab group improved from +7.3 letters (month 24) to +10.2 letters (month 36), and CST decreased from 352 to 282 μm. The mean number of ranibizumab injections was greater in the ranibizumab than in the laser group (5.4 vs. 2.3, p=.008) but was not significantly different from the ranibizumab+laser group (3.3, p=.11) [51]. The parallel, methodologically identical, phase III RISE and RIDE trials randomized patients to sham injections or monthly ranibizumab (0.3 or 0.5 mg) for 24 months. Rescue laser was available for all patients beginning at month 3. At 24 months in RISE, 18.1 % of the sham group gained >15 letters, as compared with 44.8 % of the 0.3-mg ranibizumab group (p20/40 VA were 55 %, 44.9 %, and 23.6 %. Mean improvements in macular thickness were −118, −128, and −61 μm (p250 μm, and 20 %–24 % were >300 μm [42, 55, 56]. Bevacizumab The DRCR.Net performed a 12-week trial in which 121 eyes were randomized to receive laser, bevacizumab 1.25 mg at 0 and 6 weeks, bevacizumab 2.5 mg at 0 and 6 weeks, bevacizumab 1.25 mg at baseline with a sham injection at week 6, and bevacizumab 1.25 mg at baseline and 6 weeks with laser at 3 weeks. Sixty-nine percent of enrolled eyes were refractory to previous treatment (laser and/or triamcinolone). The mean VA improvement in the two bevacizumab groups was one line greater than in the laser group. As compared with the laser group, CST improvements in the bevacizumab groups were significant at 3 weeks (p=.009 and 270 μm) or laser every 4 months as needed. Most patients received the maximum number of injections (nine) and lasers (three). More patients receiving bevacizumab, rather than laser, gained >15 (11.9 % vs. 5.3 %) and >10 (31 % vs. 7.9 %) letters, and fewer lost >15 (2.4 % vs. 26.3 %) and >30 (0 % vs. 5.3 %) letters. Median gains in vision were +8 (bevacizumab) and −0.5 (laser) letters (p=.0002). As compared with those receiving laser, patients receiving bevacizumab were 5.1 times as likely to gain 10 letters. Bevacizumab led to greater mean improvements in macular thickness (507 to 378 μm) than did laser (481 to 413 μm) [58]. By completion of the second year, mean VA improvements were +8.6 (bevacizumab) and +0.5 (laser) letters (p=.005); more bevacizumab-treated patients gained at least +15 letters (32 % vs. 4 %), and fewer lost −15 letters (0 % vs. 14 %; p=.03). The median number of injections was 13, and the median number of laser treatments was 4 [59•]. In a 2-year prospective trial, 150 patients were randomized to receive bevacizumab every 3 months as needed, bevacizumab plus intravitreal triamcinolone, or laser. The bevacizumab group achieved better VA at 6 months, but at 2 years, there were no significant differences in VA and CMT among the groups [60, 61]. The Pan-American Collaborative Retina Study Group treated patients with 1.25 or 2.5 mg bevacizumab as needed for 2 years. Nearly 52 % of eyes improved by +10 letters, CRT
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improved from 446 to 279 μm, and patients received an average of 5.8 bevacizumab injections [62]. Aflibercept In a pilot study, 5 subjects received single injections of aflibercept 4 mg and were followed for 6 weeks. At 4 weeks, the median excess macular thickness decreased from 108 to 59 μm, and the BCVA improved by +9 letters; at 6 weeks, four of five eyes had improved excessive thickness (median improved from 108 to 74 μm; two were normal), and the BCVA improved by an average of +3 letters [63]. In the phase II DA VINCI trial, 221 patients with centerinvolving macular edema were randomized to one of five treatment groups: aflibercept 0.5 mg q4wk, 2 mg q4wk, 2 mg q4wk×3 followed by q8wk, 2 mg q4wk×3 followed by PRN, and laser. Laser was not offered to patients receiving aflibercept until 6 months. The average improvements in VA at 52 weeks were +11.0, +13.1, +9.7, +12.0, and −1.3 letters; the proportions of eyes with gains of >15 letters were 40.9 %, 45.5 %, 23.8 %, 42.2 %, and 11.4 %; and the average macular thinning was −165.4, −227.4, −187.8, −180.3, and −58.4 μm. Patients receiving 2 mg PRN received an average of 7.4 injections, as compared with 7.2 for the 2-mg q8wk group. The laser group received an average of 2.5 procedures, as compared with 0.5–0.8 for the aflibercept groups. Improvements in DR scores were seen in 31 %–64 % of aflibercept patients, but only 12 % of laser patients, and worsening occurred in 0 %, as compared with 14 %–24 %. Ocular adverse events were consistent with those seen in other trials with anti-VEGF drugs [64•]. The recently completed phase III VIVID and VISTA trials were similarly designed to evaluate the efficacy and safety of aflibercept for DME. Patients were randomized to monthly aflibercept 2 mg, 2 mg q8wk (after 5 monthly loading injections), or laser. The improvements in VA at 52 weeks in VIVID were +10.5, +10.7, and +1.2 letters (p