Diabetic Macular Edema Therapy: The Role of Vascular Endothelial Growth Factor Inhibitors

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Lithuanian University of Health Sciences

Faculty of Medicine

Department of Ophthalmology

Final Master Thesis

Diabetic Macular Edema Therapy:

The Role of Vascular Endothelial Growth Factor

Inhibitors

Author:

Elisabeth Wolter

Supervisor:

Associate Professor Dr. Vilma Jūratė Balčiūnienė

Kaunas:

2020

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3. SUMMARY

Author’s name: Elisabeth Wolter

Research title: Diabetic Macular Edema Therapy: The Role of Vascular Endothelial Growth Factor

Inhibitors

Aim: To compare current studies regarding the outcomes and safety of intravitreal VEGF-inhibitor

treatment in diabetic macular edema.

Objectives: To identify characteristics of the three main VEGF-inhibitor drugs: Ranibizumab,

Aflibercept and Bevacizumab. To compare these three VEGF-inhibitors regarding their outcomes. To review safety and effectiveness of these intravitreal VEGF-inhibitors in the treatment of diabetic macular edema.

Methods: Data for this literature review was retrieved from PubMed and The Cochrane Library

databases. The search was conducted with Medical Subject Headings (MeSH) Keywords: “Macular edema/therapy”, “Diabetes mellitus”, “Vascular endothelial growth factor/antagonist” and terms “Diabetes mellitus” and “Macular edema” and “Vascular endothelial growth factor”, respectively. Further citations have been detected in bibliographies of those works. Selection dates – from January 2008 to December 2018. Primary selection criteria included scientific publications not older than 10 years, studies conducted with people and works presented in English language. Initially, 288 articles were found. From these, 42 have been reviewed after the elimination of the duplicates and applying selection criteria. After reviewing the full versions, 11 studies, collecting evidence about intravitreally applied AFL/BCZ/RBZ therapy efficacy and/or safety in DME therapy, and comparing AFL/BCZ/RBZ therapy outcomes to laser or sham injections, were included into a detailed analysis.

Results: Evidence suggests that anti-VEGF therapy is better than formerly used laser monotherapy

elucidated by substantial improvement in vision and anatomic outcomes in patients with DME with an overall good safety profile.

Conclusion: In clinical practice priority should be given to AFL therapy for treating DME patients with

a poor baseline vision of 20/50 ETDRS letters or worse, especially at the initial phase of the disease. Nonetheless, all three anti-VEGF agents achieved similarly good outcomes after 24 months since the beginning of their therapy. In case of considerably good starting vision, all anti-VEGF agents could be used, as no significant difference was found in their positive therapeutic effect. The intravitreal anti-VEGF application is considered to be safe, according to the recorded low incidence rate of side effects.

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4. ACKNOWLEDGEMENTS

I would like to thank my thesis supervisor Dr. Vilma Jūratė Balčiūnienė for her advice and help during the process of writing this work.

I dedicate this thesis to my family which supported and encouraged me consistently throughout my study years.

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5. CONFLICTS OF INTEREST

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6. PERMISSION ISSUED BY THE ETHICS COMMITTEE

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7. ABBREVIATIONS

AFL Aflibercept

AMD Age related macular degeneration BCVA Best corrected visual acuity BCZ Bevacizumab

CSME Clinically significant macular edema DM Diabetes mellitus

DME Diabetic macular edema DR Diabetic retinopathy FAG Fluorescein angiography

NPDR Non-proliferative diabetic retinopathy NVD New vessels on the optic disc

NVE New vessels elsewhere

PDR Proliferative diabetic retinopathy RBZ Ranibizumab

RPE Retinal pigment epithelium

SD-OCT spectral domain optical coherent tomography VEGF Vascular endothelial growth factor

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8. TERMINOLOGY

Intravitreal: “into the vitreous body of the eye”.

Metamorphopsia: A type of distorted vision in which a grid appears wavy and parts of the grid may

appear blank.

Sham injections: The injection of an agent that simulates another drug (a placebo) during clinical trials. Best corrected visual acuity: It evaluates a person’s ability to discriminate several symbols or letters

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9. INTRODUCTION

Diabetic macular edema (DME) is a vision threatening ocular complication of diabetes mellitus (DM). It is often preceded by diabetic retinopathy (DR) - a microvascular disease, which is number one cause of blindness in working aged people (including 25-65 years old) living in industrialized nations[1]. A great socio-economic problem is created considering the world wide rise in type 2 DM. Scientist have predicted that a total number of 592 million people will be suffering from this metabolic disease in 2035[2]. Several systemic factors are related to the prevalence and severity of DME. Those include: high blood glucose levels, increased systolic blood pressure, as well as serum lipids and a long duration of DM[3]. Between 2.7% and 11% of DR patients have DME and, although type 2 DM holds a greater risk to develop it earlier, within a disease duration of 25 years the prevalence of developing DME reaches 30% for type 1 and 2 DM[4]. DME may develop at any stage of DR and present as retinal thickening very close to or directly in the center of the eye’s macula. Further characteristics include hard exudate deposits and an amplified vascular permeability, thought to be related to the increased levels of vascular endothelial growth factor (VEGF) determined in DME patients’ vitreous[5]. When it appears at the fovea, it is defined as clinically significant[6]. Patients may experience different clinical manifestations, ranging from being asymptomatic to a diminished visual acuity (VA) or metamorphopsia and even up to permanent blindness, if left untreated. New technologies as spectral domain optical coherence tomography (SD-OCT) and fluorescent angiography (FAG) are the cornerstones of clinical assessment of DME. The foundation of treatment and prevention of DME progression lies in the strict control of chronic hyperglycemia, hypertension and hyperlipidemia. For some patients that alone may be sufficient to prevent the disease from occurring or to stop its progression. Others require specific ophthalmic treatment, such as intravitreal anti- vascular endothelial growth factor (anti-VEGF) drug injections, intravitreal corticosteroid treatment, laser photocoagulation and vitrectomy. In the mid-1980s laser photocoagulation applications were defined as the golden standard after the Early Treatment Diabetic Retinopathy Study (ETDRS)[7]. It has shown to diminish risks of moderate vision loss from clinically significant DME, though the application can cause retinal scarring further decreasing vision, particularly

in eyes with central involvement and does notimprove visual acuity sufficiently[8]. The potency of

anti-VEGF treatment vs. laser photocoagulation was evaluated in many studies. They found that anti-anti-VEGF agents injected intravitreally reduce central retinal thickness (CRT) and might improve vision in DME patients significantly in contrast to laser therapy. The purpose of this work was to portray the evolving role of anti-VEGF therapy in DME. It will give an overview on the effects of the three most commonly used intravitreal VEGF inhibitors alone and compared with each other. Furthermore, the effects of

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intravitreal drug monotherapy are being compared to combination treatments with laser. Also, the choice of specific drug use, regarding the outcome of the disease, associated risks and socioeconomic aspects are being analyzed.

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10. AIM AND OBJECTIVES

Aim:

To compare current studies regarding the outcomes and safety of intravitreal VEGF-inhibitor treatment in diabetic macular edema.

Objectives:

1.) To identify characteristics of the three main VEGF-inhibitor drugs: Ranibizumab, Aflibercept and Bevacizumab.

2.) To compare these three VEGF-inhibitors regarding their outcomes.

3.) To review safety and effectiveness of these intravitreal VEGF-inhibitors in the treatment of diabetic macular edema.

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11. LITERATURE REVIEW

11.1. Diabetic retinopathy:

Diabetic retinopathy (DR) progressively damages retinal blood vessels in both eyes of a person suffering from diabetes mellitus. The disease manifests with hemorrhages, microaneurysms, venous beading (venous dilation and narrowing), microvascular changes within the retina, hard exudates (debris of fat), cotton-wool spots (concentrations of axoplasmic deposits within neighboring ganglion cell axons, stimulated by the deprivation of retinal oxygen), and retinal neovascularization[9]. These findings determine the severity of DR. In non-proliferative diabetic retinopathy (NPDR), eyes have not yet induced neovascularization, but present other classical DR lesions. Proliferative diabetic retinopathy (PDR) manifests as an angiogenic reaction of the retina to profound ischemia. Retinal neovascularization can further be distinguished as being new vessels on the optic nerve head, called disc, (NVD) or new vessels elsewhere (NVE) in one-disc diameter distance or more from the optic nerve head. NVE commonly develop in between perfused and nonperfused regions of the retina[9].

11.2. DME development and classifications:

DME can be found in eyes at any stage of DR and can even run its independent course. Pathogenesis of DR begins with a decrease in the eye’s retinal oxygen tension, caused by prolonged hyperglycemia, manifesting itself as retinal capillary hyperpermeability and increased intravascular pressure[9]. The resulting up-regulation of vascular endothelial growth factor production is found to be a key mediator in the development of DME[5]. Angiogenesis is being promoted and a breakdown in the blood retinal barrier is caused by damage to the tight junctions between retinal endothelial cells[9]. It results in the capillary leakage and buildup of plasma proteins (such as albumin) exerting a high oncotic pressure and an inflammatory response in the neural interstitium of the retina[10]. All formerly mentioned, leading to interstitial edema causing subsequent dysfunction of the macula, resulting in blurring and distortion of central vision, which is reflected by a reduction in best-corrected visual acuity (BCVA). Therefore, targeted therapy is being directed at limiting the damaging effects of poor vascular integrity.

According to the Early Treatment Diabetic Retinopathy Study[7] macular edema is defined as “the retinal thickening or hard exudates at or within 1 disc diameter of the macula center”. Most commonly DME is classified into being clinically significant (CSME) or not clinically significant[7]. For the

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macular edema to be considered clinically significant, it has to meet at least one of the following criteria[7]: Thickening of the retina at or within 500µm of the center of the macula; hard exudates at or within 500µm of the center of the macula, if associated with thickening of adjacent retina (not counting residual hard exudates remaining after disappearance of retinal thickening); any zone(s) of retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of the center of the macula. The International Council of Ophthalmology (ICO) suggests the differentiation between three categories of DME severity, including no DME, noncentral-involved DME and central-involved DME, which are listed below in table 1. In their guidelines of diabetic eye care from January 2017, they state that this classification, based on dilated fundus examination, helps to assess the necessity of DME therapy and to choose adequate follow-up regimens. Figures 1-6 show a selection of DME cases, representing noncentral-involved DME (Fig.1-3) and central-involved DME (Fig.4-6).

A very detailed categorization was developed by Koleva-Georgieva. It relies on quantitative and qualitative data gathered during optical coherence tomography (OCT) investigation of the patients’ eyes. Under the consideration of the retina’s thickness, the retina’s morphology, the retina’s topography, the presence or absence of macular traction, as well as the foveal photoreceptor status. It allows the classification of DME into numerous types[11]. Other, more simplified classifications, which are likewise based on OCT findings, are primarily taking retinal morphology parameters into account. They mainly differentiate between four types: Type 1- sponge-like swelling; type 2- cystoid edema; type 3-

serous retinal detachment; type 4- posterior hyaloid traction (PHT)[12]. Based on fluorescein

angiography (FAG) results, DME may be classified into four categories[13] as follows: Focal leakage- a localized areas of leakage from microaneurysms or dilated capillaries; diffuse leakage- leakage, which involve the entire circumference of the fovea; diffuse cystoid leakage- mainly diffuse leakage, but with accumulation of dye within cystic areas of the macula during the late phase of an angiogram; and ischemic maculopathy.

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Table 1. International Classification of Diabetic Retinopathy and Diabetic Macular Edema

Diabetic Retinopathy Findings Observable on Dilated Ophthalmoscopy

No apparent DR No abnormalities Mild nonproliferative DR Microaneurysms only Moderate nonproliferative

DR

Microaneurysms and other signs (e.g., dot and blot hemorrhages, hard exudates, cotton wool spots), but less than severe nonproliferative DR

Severe nonproliferative DR Moderate nonproliferative DR with any of the following: • Intraretinal hemorrhages (≥20 in each quadrant); • Definite venous beading (in 2 quadrants);

• Intraretinal microvascular abnormalities (in 1 quadrant); • and no signs of proliferative retinopathy

Proliferative DR Severe nonproliferative DR and 1 or more of the following: • Neovascularization

• Vitreous/preretinal hemorrhage

Diabetic Macular Edema

Findings Observable on Dilated Ophthalmoscopy#

No DME No retinal thickening or hard exudates in the macula

Noncentral-involved DME Retinal thickening in the macula that does not involve the central subfield zone that is 1mm in diameter

Central-involved DME Retinal thickening in the macula that does involve the central subfield zone that is 1mm in diameter

# Hard exudates are a sign of current or previous macular edema. DME is defined as retinal thickening, and this requires a three-dimensional assessment that is best performed by a dilated examination using slit-lamp biomicroscopy and/or stereo fundus photography.

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Figure 1. Color fundus photography of noncentral-involved DME

Source: kindly provided by Dr. Vilma Jūratė Balčiūnienė, Lithuanian University of Health Sciences,

Department of Ophthalmology

Figure 2. OCT of noncentral-involved DME

Source: kindly provided by Dr. Vilma Jūratė Balčiūnienė, Lithuanian University of Health Sciences,

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Figure 3. OCT map showing DME without center involvement

Department of Ophthalmology

Figure 4. Color fundus photography of central-involved DME

Source: kindly provided by Dr. Vilma Jūratė Balčiūnienė, Lithuanian University of Health Sciences,

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Figure 5. OCT of central-involved DME

Department of Ophthalmology

Figure 6. OCT map of central-involved DME

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11.3 Evolution of DME therapy:

The vast majority of central vision loss in DM patients with DR is due to macular edema. At the present time, we have clear evidence that the chances of losing one’s vision to DME can be minimized with help of strict glycemic control[14], blood pressure optimization[15] and focal laser therapy[16]. During the mid-80’s of the past century, the Early Treatment Diabetic Retinopathy Study (ETDRS) implemented their guidelines for laser photocoagulation to microaneurysms and other regions in the thickened macula in DME therapy making it the standard treatment[16]. This Study did not only proof the potential of focal laser applications in reducing the risk of vision loss by 15 or more letters (designated a moderate visual acuity loss) for about 50% of patients within 36 months, but also in leading to a vision gain in 30% of individuals with reduced vision. Moreover, it revealed that roughly 15% experienced vision loss in spite of laser therapy[16]. The relatively low success rate of vision improvement through focal laser coagulation generated heightened interest to look for other therapy options. When it was discovered that inflammatory mechanisms participate in the development of DR, the effect of intravitreal injections of glucocorticoids was evaluated. It resulted in promising vision gains and significant macular edema reduction. A double blinded randomized clinical trial called “laser-Ranibizumab-Triamcinolone for DME” by Elman MJ et al. (n=691)[17] demonstrated that corticosteroids in combinations with laser therapy were superior to laser therapy alone after 6 month. But by the end of the 2nd_{year the study recorded that the combination therapy could not uphold its}

achievement in vision gain[18]. Furthermore, half or more of all patients treated with intravitreal steroids experienced an increase in intraocular pressure, holding an increased risk for glaucoma development[18]. And in almost all cases, patients, still in possession of their natural lenses, developed cataracts[18]. In conclusion, corticosteroids combined with laser therapy was not superior to simple laser therapy in DME[18]. Around 2007 more and more investigations started to analyze the effectiveness of intravitreal anti-VEGF injections after it became evident that vascular endothelial growth factor is greatly involved in the development of DME and retinal neovascularization. The observation made by Ajello et al.[5], which measured that intravitreal elevations of VEGF correlated with the disease severity of DME, promoted the investigation of anti-VEGF medication for intravitreal use. The first drug undergoing trials “Pegaptanib” showed rather limited efficacy. Soon Bevacizumab, an anti-VEGF medication known for intravenous anti-cancer therapy use, was started to be used “off-label”. Only later studies appeared observing its intravitreal use in DME and AMD. Other anti-VEGFs- Ranibizumab and Aflibercept were created and investigated for ophthalmic use. Nowadays, Bevacizumab off-label, Aflibercept and Ranibizumab are being used worldwide for DME therapy. Yet it is important not to forget what a multifactorial pathogenesis causes DME often requiring a multimodal management

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strategy involving combinations of laser, intravitreal anti-VEGF and corticosteroid therapy or even surgical approaches like vitrectomies tailored to each patient separately.

11.4. Primary outcome evaluation of DME therapy:

Initial evaluation of a patient suspected to suffer from DME involves an ophthalmologic examination, starting from BCVA evaluation (taking circadian changes into consideration), followed by an intraocular pressure measurement and a slit lamp examination. Later, more targeted examination methods including FAG for differentiation between leaking and nonleaking microaneurysms and widening of foveal avascular zone in the retina [19] as well as OCT or even optical coherence tomography- angiography (OCT-A) can be performed.

BCVA evaluates a person’s ability to discriminate several symbols or letters of known visual angle with well-adjusted visual aids[20]. This can then be measured according to the size of symbols or letters viewed. It is expressed as a fraction, using meters or feet as unit, representing the distance from the observer to the chart, relative to the norm. A visual acuity of 20/20 using feet as unit, is equivalent to 6/6 using meters and represent a normal vision. ETDRS and Snellen charts are commonly used to assess visual acuity (VA) and allow to evaluate the efficacy of DME therapy by constantly monitoring improvement or worsening of this parameter. ETDRS charts consist of a series of five letters being equally difficult to read on every row, having a standardized space between rows and letters, with a total of fourteen lines (that makes 70 letters)[20]. Nevertheless a maximum score of 100 can be achieved calculated as follows[21]: if at 4 meter distance 20 or more letters are being read correctly, VA is the number of correctly read letters plus 30. When less than 20 letters are identified correctly at 4 meters, VA is determined by the total number of letters read without mistakes at 4 meters, plus the number of letters identified at 1meter distance from the first six lines. An 85-letter score is equivalent to a 20/20 Snellen letter fraction. In conclusion, an improvement or worsening in VA under DME therapy can be described by a loss or gain in letters or lines. However, the importance of OCT in the process of monitoring DME evolvement, cannot be over-emphasized. Nowadays, morphological findings from OCT investigations apart from visual acuity evaluation as functional parameter, are recommended and necessary for evaluation of DME outcome and therapy decision making. Structural changes seen on OCT precede a decrease in vision. In DME structural damage of the retina has a higher predictive value than observing retinal thickness alone[22]. Still in many of the current studies investigating DME therapy, central retinal thickness (CRT) is the only OCT criterion utilized for evaluation of DME as in

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the RISE and RIDE[23] and DRCR.net protocol T[24] clinical trials. The authors of the 2017 released EURETINA guidelines for DME treatment[9] emphasize that OCT biomarkers are the key instruments to evaluate the individual retreatment necessity with anti-VEGF medication in patients following the pro re nata (PRN) regimen. This PRN strategy, consisting of monthly injections only in the case of active disease detection, has become the most commonly applied treatment regimen for anti-VEGF DME therapy in real life practice.

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12. RESEARCH METHODOLOGY AND METHODS

This literature review was prepared searching the online databases PubMed and the Cochrane library. Additional material was retrieved by searching bibliographies of electronically identified relevant sources. The strategy for finding suitable publications included using the following Medical Subject Headings (MeSH): “diabetes mellitus”, “macular edema/therapy”, “vascular endothelial growth factor” and “vascular endothelial growth factor/antagonists”. Selection dates were chosen – from January 2008 to December 2018. Meta-analysis, clinical studies, systematic literature reviews and articles from scientific journals were accepted into the search. From the combined search on PubMed, the Cochrane Library 167 and 91 articles were obtained plus 30 extractions from bibliographies making a total of 288 collections. Publications were then checked for duplications, being written in the English language, and their full-text availability. Works that could not meet those inclusion criteria were excluded. Initially, relevant articles were selected based on their titles and abstracts. The further, more detailed evaluation of full texts of the remaining articles, regarding eligibility, eventually led to the collation of 11 studies. These studies were considered eligible in that they combine all of the following chosen requirements: Double blinded randomized clinical trials, conducted with people, analyzing center-involved DME, collecting evidence about intravitreally applied AFL/BCZ/RBZ therapy efficacy and/or safety in DME therapy, comparing AFL/BCZ/RBZ therapy outcomes to laser or sham injection results. Figure 7. illustrates the literature search. All of the studies selected for more detailed analysis used in this literature review (seen in tabl.2) are published in 2008 or later, except for the DRCR. net protocol H clinical trial[25] from 2007. Additional references were used, if they contained relevant information validating this work.

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13. RESULTS

The most commonly used anti-VEGF drugs in DME therapy include an antibody to VEGF (Bevacizumab), an antibody fragment to VEGF (Ranibizumab) and a so-called fusion protein (Aflibercept) that combines the Fc part of an immunoglobulin and a receptor for VEGF. A large number of clinical trials investigate anti-VEGF drugs regarding the reversal, stabilization and prevention of future vision loss. This work briefly presents major clinical trials for the 3 before mentioned, VEGF-targeting drugs in table 2.

Table 2. Comparison of DME therapy and outcome in 11 analyzed studies

Study Stu dy par tici pan ts (n) Goals Evaluation and Time point

Results Primary outcome: treatment group: mean value and ± standard deviation (if available) of ETDRS letter change from baseline

RESOLVE [26] 151 Efficacy and safety of RBZ compared to sham-injections for center-involved DME Efficacy measured in BCVA gain and CRT decrease seen on OCT plus safety after 1 year

RBZ improves BCVA and reduces retinal thickness significantly with good safety profile Sham:-1.4 ± 14.2 IVR 0.3-1mg 3q4:1+0.3 ±9.1 READ-2 [27] 126 Comparison of RBZ and laser or a combination of both in center-involved DME BCVA changes after 2 years

RBZ therapy was the superior therapy over 2 years, in combination with laser rest edema and injection frequency could be reduced Laser:+5.1 IVR 0.5mg 3q8:+7.7 IVR 0.5mg 3q8+Laser:+6.8 RESTORE/ RESTORE-Extension [28,29] 345/ 303 Manifesting superiority of RBZ +/- laser compared to laser therapy alone in center-involved DME BCVA changes after 1 year and safety profile/ BCVA changes after 3 years and safety profile RBZ alone or combined with laser therapy has shown to be better than laser monotherapy with good safety profile/ the effect lasts over 3years and number of necessary injections decrease in 3rd year Laser:+0.8±8.56 IVR 0.5mg 3q4:+6.1±6.43 IVR 0.5mg 3q4+Laser:+5.9±7.92 DRCR.net protocol I [17] 854 (eye s) Collect evidence of superiority of RBZ+laser therapy over BCVA changes and safety at 1 year

Combined laser and RBZ therapy was significantly more effective than laser with sham or

corticosteroid injections

Sham 3q4+Prompt Laser:+3±13 IVR 0.5mg 3q4+Prompt Laser:+9±11

IVR 0.5mg 3q4+Deferred Laser:+9±12

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with good safety profile. IV Triamcinolone+laser is superior to laser alone in pseudo phakic eyes, but increases risk of IOP elevation Triamcinolone+Prompt Laser:+4±13 RIDE [23,30] 382 Effectiveness and safety of RBZ compared to sham injections for center-involved DME Proportion of patients with BCVA gain of at least 15 letters at 2 years/3 years RBZ leads to a significant gain in BCVA and reduces retinal thickness while maintaining good safety profile. Risk for further BCVA loss decreases/effect persists to 3rd_year Sham q4:+2.3 IVR 0.3mg q4:+10.9 IVR 0.5mg q4:+12 RISE [23,30] 377 Sham q4:+2.6 IVR 0.3mg q4:+12.5 IVR 0.5mg q4:+11.9 BOLT [31] 80 Comparing BCZ and laser therapy for center-involved DME Difference between BCVA evaluated after 1 and 2 years Significant difference in vision and CRT emphasizes effectiveness of BCZ for DME without advanced macular

ischemia. Effect persists in 2nd_year Laser q12:-0.5±10.6 IVB 1.25mg q6:+8.6±9.1 DRCR.net protocol H [25] 121 Data collection on short-term safety and effect of intravitreal BCZ alone or in combination with focal laser for DME therapy CST thickness on OCT and change in BCVA from baseline measurement at 3, 6, 9, 12, 18, and 24 weeks

BCZ can reduce DME in some eyes with a good safety profile, but the study was not designed to determine whether treatment is really beneficial DA VINCI [32] 221 Comparison of AFL in different dosages and injection frequencies to laser therapy in center-involved DME BCVA change after 24 and 52 weeks A significant gain in BCVA measured in the AFL arms at 24th_week

remained or improved even further until the 52nd

week Laser:+2.5(24th_)-1.3(52nd₎ IVA 0.5mg q4:+8.6(24th_)+11(52nd₎ IVA 2mg q4:+11.4(24th_)+13.1(52nd₎ IVA 2mg q8:+8.5(24th_)+9.7(52nd₎ IVA 2mg PRN:+10.3(24th_)+12(52nd₎ VIVID [33] 872 Comparison of AFL in 4 or 8 weeks treatment intervals (after 5 upload injections given 1 month apart) and laser therapy in center-involved DME Change in BCVA after 1 year A significant superiority of AFL therapy was present in both arms Laser:+1.2±10.6 IVA 2mg q4:+10.5±9.5 IVA 2mg q8:+10.7±9.3 VISTA [33] Laser:+0.2±12.5 IVA 2mg q4:+12.5±9.5 IVA 2mg q8:+10.7±8.2

q4: every 4 weeks, q8: every 8 weeks, q6: every 6 weeks, IVA: intravitreal aflibercept, IVB: intravitreal bevacizumab, IVR: intravitreal ranibizumab

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13.1. Ranibizumab therapy evidence:

The recombinant humanized Fab fragment of a monoclonal antibody, Ranibizumab (RBZ) is explicitly designed for intraocular use, binding and inactivating all isoforms of VEGF-A[9]. It was the first VEGF-therapy that has been approved by the U.S. Food and Drug Administration (FDA) for treatment of DME in 2012. As Adrian Au and Rishi P. Singh state in their work “A multimodal approach to DME”[34], four clinical trials have led to the FDA approval by reflecting RBZ’s potential in DME treatment. The randomized double blinded RESTORE study(n=345) published in 2011 by Mitchell P et al.[28] evaluates the effectiveness and safety of 0.5mg intravitreal RBZ, with or without laser therapy compared to laser therapy alone. After a starting dose of 3 monthly injections in 3 months, RBZ was continued to be given in the PRN mode depending on predefined criteria, demonstrating disease activity. Disease activity is signaled by BCVA decrease or OCT changes. If BCVA had not stabilized during the previous two consecutive injection visits, then monthly injections continued as described in the study’s protocol[28]. Laser was applied when needed, based on the ETDRS’s protocol [7] with a therapy interval of at least 3 month and starting applications 30 min prior to RBZ injections in the combined therapy group. Others received sham treatments. After 12 months, a mean BCVA increase by +6.1 letters in the RBZ monotherapy and +5.9 letters in the combined (drug and laser therapy) arm compared to a mere +0.8 letter increase in the laser monotherapy group showed a significant superiority of drug over laser monotherapy[28]. Also, the small difference between BCVA improvement in RBZ and RBZ plus laser therapy for DME patients points to the conclusion that no additional benefit is provided by combining intravitreal RBZ with laser therapy.

Another two clinical trials of intravitreal RBZ injections are the RISE and RIDE studies [23,30]. While only 8% of the RBZ patients received monthly injections in RESTORE study, RISE and RIDE treated patients with a fixed monthly intravitreal drug injection in two different dosages (0.3mg and 0.5mg) over 24 months. The results were compared to a sham injection treatment group. All patients were evaluated for the necessity of rescue laser treatments decided according to objective and subjective factors[23,30]. After two years, the mean BCVA under monthly 0.3mg RBZ injections improved by 10.9- 12.5 ETDRS letters while 0.5mg RBZ lead to an improvement of 11.9- 12 and sham injections to 2.3-2.6 letters in patients. RISE study also showed, that 44.8% of patients in the 0.3 mg RBZ arm and 39.2% of the ones receiving 0.5 mg RBZ improved by ≥15 letters (equivalent to 3 lines) compared to 18.1% of sham-treated patients. Similar proportions have been found in the RIDE groups with 33.6%, 45.7%, and 12.3%, respectively. A smaller number of RBZ-treated patients had significant (≥15 ETDRS letters) sight decrease in opposition to the sham-injection group. Based on the studies’ results, 0.3mg RBZ became the preferred dosing since it did not only accomplish a steady effect in treating DME, starting from 7 days after the injections, but also lowered the risk of possible systemic effects[23,30].

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The fourth study analyzed in this work, a multicentered randomized clinical trial, called protocol I (n=691) [17], performed by the Diabetic Retinopathy Clinical Research Network (DRCR.net) group, investigated RBZ efficacy plus safety in DME treatment and whether corticosteroids were helpful. One patient group received sham-injections with laser, another one 0.5mg RBZ with laser and the last one 4mg Triamcinolone together with laser. All patients were treated until their vision stabilized or a lack of further recovery presented. What the study showed after 12 months is, that RBZ used in combination with laser (prompt or deferred), was consequently more effective. This was demonstrated by a BCVA gain by +9 letters in the RBZ plus laser arm and only +3 letters with laser monotherapy. The average number of RBZ injections amounted to 8-9. Also, 30% of patients treated with RBZ reported a significant vision increase (≥15 ETDRS letters) in contrast to 15% amongst the laser monotherapy. From year 2 to year 3, following the beginning of this study, BCVA could be maintained with an average of only 1 to 2 injections of RBZ and even further reduced to 0 to1 injections throughout year 4 and 5[17,18,35]. Following the recognition of numerous clinical trials, RBZ monotherapy was established as a useful agent in treating DME.

Earlier studies like phase II clinical trials RESOLVE and READ-2 could as well demonstrate that RBZ reduces DME and sustainably improves visual acuity[26,27]. During the RESOLVE study (n=151)[26] 0.3mg and 0.5mg RBZ was given in 3 monthly doses for DME patients and continued or stopped according to protocol defined criteria , with a possibility of dose doubling. The results were compared to a sham-injection control group. At one year, over 60% of eyes treated with RBZ had ≥10 ETDRS letter gains in contrast to the sham group, were just 18% of eyes had similar results[26].

READ-2 (n=126)[27] was a pioneering trial, started in 2009, where patients were randomized to received 0.5mg RBZ, laser, or both. Evidence of beneficial bioactivity of RBZ was provided with results of BCVA gains by +7.4 ETDRS letters in the RBZ groups compared to +0.5 letters in the laser monotherapy arm after the first 3 months. The study suggested, that combined drug and laser therapy could decrease the frequency of injections needed to control edema for at least 24 months[27]. Neither READ-2, nor any of the other studies found a significant difference in BCVA increase between RBZ monotherapy and RBZ plus laser therapy, meaning that the combination treatment is not superior and, hence, not recommended[36]. Grounded on the extensive evaluation of RBZ, this drug is considered highly efficacious with an overall acceptable safety profile for the intravitreal use in DME patients.

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13.2. Bevacizumab therapy evidence:

Bevacizumab (BCZ) is a full-length humanized monoclonal antibody that effectively binds and inhibits all known isoforms of VEGF[37]. Internationally this drug is used off-label for the treatment of DME as it has only been approved for systemic use in the treatment of several cancer forms[38,39] in Europe and the USA. One economic benefit is, that BCZ is produced in bigger vials which can be divided into multiple doses as they contain larger amounts of the drug. This lowers its cost immensely, compared to RBZ and Aflibercept (AFL). As BCZ is not officially approved for treating ocular disease, logically there is a great need for informative comparative data regarding safety and efficacy.

In 2007, the multicentered randomized phase II clinical trial, protocol H (n=121) by Scott IU et al. [25] provided the first data on short-term effects of intravitreal BCZ for DME therapy. They measured outcomes with central subfield changes (CST) from OCT and BCVA at baseline, after 3,6,9,12,18 and 24 weeks. The participants were divided into 5 different treatment groups. For all of them a CST decrease of >11% was considered the reliability limit and was observed at 3 weeks in 43% of BCZ treated eyes and 28% of laser alone treated eyes, following 50% and 37% at 6 weeks measured, respectively[25]. The study showed that combining laser with BCZ results in no apparent adverse outcome, though a concern of cerebrovascular and cardiovascular adverse events was high lightened by the authors Scott IU et al.[25]. The use of BCZ reduced DME in some eyes, yet the authors stated that the study was not created to prove whether treatment with BCZ is beneficial or not[25]. Positive findings, suggesting a better effect in DME outcome with BCZ therapy compared to laser were subsequently verified by the “Bevacizumab Or Laser Therapy” study (BOLT) (n=80)[31]. All patients were randomized into one out of two groups, either receiving laser therapy with retreatment at 16,32 and 48 weeks based on ETDRS guidelines or being treated with BCZ guided by OCT-based protocols (max. 9 injections in 12 months). After 12 months CST was decreased by -130±122μm in the BCZ group compared to -68±171μm in the laser group. Significant systemic adverse events had not been registered at any time[31]. After 2 years, a BCVA gain by +9 ETDRS letters in the BCZ arm demonstrated a significantly better outcome in contrast to the laser treatment arm with its +2.5 letters gain. Nowadays, BCZ is the most often used anti-VEGF drug for DME therapy, due to its affordability.

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13.3. Aflibercept therapy evidence:

Aflibercept (AFL) is a fusion protein made of two VEGF binding domains attached to the Fc domain of human Ig G1[40]. All isoforms of VEGF-A, VEGF-B as well as placental growth factor are bound by AFL[40]. It has a 100 times greater binding affinity to VEGF-A and a longer duration of action than BCZ or RBZ[41].

In the phase II, double blinded, multicenter trial called DA VINCI(n=221)[32], 4 different dosing schemes of AFL have been compared to laser coagulation therapy in patients with center-involving DME. Patients were randomly assigned to one of 5 different treatment groups. Either intravitreal AFL 0.5mg every 4 weeks (0.5q4), 2mg every 4 weeks (2q4), 2mg every 8 weeks after 3 initial monthly doses (2q8), 2mg as needed after 3 initial monthly doses (2PRN), or laser with sham injections[32]. The monthly treatment with 2mg intravitreal AFL injections resulted in the highest gain in visual acuity (+11 ETDRS letters) after 6 months observation. These early discoveries continued to manifest themselves over year one of the study. BCVA gains for 0.5q4, 2q4, 2q8, 2PRN and laser group were +11, +13, +10, +2.5 ETDRS letters, respectively. 24%-45% of patients treated with AFL gained at least 3 lines in vision and showed a central retinal thickness (CRT) reduction between 165 and 227μm measured on OCT. Most important findings of the DA VINCI study included the realization that 2PRN (with an average of 7 injections) and 2q8 arms (with an average of 7 injections) had similar gain in BCVA in comparison to the more frequent injection arms 0.5q4 (average of 12 injections) and 2q4 (average of 11 injections)[32]. These results promise a possibility of less frequent disease monitoring which could decrease the treatment burden connected with the high number of repeated VEGF-inhibitor injections.

Two parallel conducted, randomized, double-masked and multicentered clinical studies, named VIVID (in Europe) and VISTA (in the USA) (n=872) looked at the effects of AFL in two different dosing regimens versus laser treatment in DME patients[33]. The two patient groups, receiving intravitreal drugs, were treated with 2mg AFL every 4 weeks (2q4) and 2mg every 8 weeks (2q8) after 5 initial monthly doses. After one year the average BCVA increase in the 3 groups (2q4, 2q8 and laser) was +13, +11 and +0 ETDRS letters, respectively. Three or more lines were gained in 42%, 31% and 8% of the studied eyes in before mentioned arms. And the mean decrease of CRT was 186μm, 183μm and 73μm, respectively. The publication of Brown DM, et al. in 2015[42] reported about the sustained anatomical and functional benefits for DME patients under AFL injections compared to the laser control group at 100 weeks of the study. At that point, the AFL 2q4 arm presented a BCVA gain by +11.5 (in VIVID) and +11.4 (in VISTA) alongside a BCVA improvement by only +0.9 (in VIVID) and +0.7 (in VISTA) ETDRS letters in the laser arm[42].

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13.4. Comparing anti-VEGF therapies:

The safety and efficacy of anti-VEGF treatment in DME patients has been compared by several meta-analysis[43-45]. Having in mind, that most studies vary significantly in their inclusion criteria, laser rescue criteria, starting doses and treatment regimens, it is hard to compare their analyses.

A randomized clinical trial by Wells JA et al. from 2015 was dedicated to compare intravitreal BCZ, AFL and RBZ therapy for the treatment of center-involving DME with visual impairment between 20/32 and 20/320[46]. The study was called protocol T. It randomized all eyes into 3 groups. It has to be noted, that the included eyes were not allowed to have any previous anti-VEGF therapy within one year. The therapy used in this study consisted of a treatment at baseline and every following month until a vision of 20/20 or better together with a central subfield thickness (CST) less than the predetermined threshold (considering sex and type of OCT machine used for imaging) as well as no further recovery or worsening of BCVA at the last 2 injection visits (≥ 5 letters or ≥ 10% CST change) presented. After one year, the AFL arm, with 224 eyes studied, had a mean BCVA gain by +13 letters, as for the 218 eyes treated with BCZ a mean BCVA gain by +10 letters and for the 218 eyes receiving RBZ a mean BCVA gain by +11 letters were registered[46]. These results revealed no statistically significant difference between the three drugs. Only when those eyes with a 20/50 or worse baseline vision were considered, the difference in letter gain between the three drugs became statistically significant (+19 letters AFL, +12 letters BCZ, +14 letters RBZ). A baseline visus dependent therapy effect was found. Moreover, it has come to know, that AFL therapy results in a greater reduction in CST than BCZ or RBZ (169μm vs. 101μm vs. 147μm, respectively)[46]. Looking at the patients with a better baseline visual acuity (20/32-20/40), again not one drug therapy proved itself to be superior to another (+8 letters with AFL, +7.5 letters with BCZ, +8.3 with letters RBZ)[46]. Following the conduction of protocol T, a recommendation to implement AFL as first-line therapy for center-involved DME in patients with a baseline vision of 20/50 or worse was being published [47].

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13.5. Anti-VEGF therapy adverse effects: 13.5.1. Ocular events:

During the assessment of therapeutic effect of intraocular injected anti-VEGF drugs AFL, BCZ and RBZ, adverse events occurred at a similar rate compared to their respective control groups, receiving sham injections. These repeated observations during multiple trials, including studies testing anti-VEGF therapeutic effect for ocular diseases other than DME (i.e. age related macular degeneration[48,49]), propose that ocular complications are rather caused by the injection procedure than the drug itself. The ocular adverse events most often reported during clinical trials include intraocular pressure increase, subconjunctival hemorrhages and ophthalmic pain. An analysis of a trial by Bressler SB et al.[50] explored if multiple intravitreal RBZ injections hold an increased risk of causing elevated intraocular pressure. No eyes with previous open-angle glaucoma were evaluated. Altogether 582 eyes took part. Of those, 260 eyes were randomly grouped to receive sham injections together with laser therapy, the remaining 322 eyes (also randomly assigned) were treated with RBZ and laser therapy. Throughout the study, over a period of 3 years, 22 eyes in the RBZ arm and 6 eyes in the sham injection arm developed intraocular pressure elevation (≥22mmHg+ elevation of at least 6mmHg for 2 consecutive control visits from baseline)[50]. During the RISE and RIDE studies, after 2 years, only a single case with severe intraocular pressure increase was registered in the RBZ treated group[51]. Similar to previously mentioned studies, VIVID and VISTA trials also reported only one case of intraocular pressure elevation under intravitreal anti-VEGF injections as a serious adverse event within 100 weeks’ time[42]. In addition, several studies analyzed the risk for developing endophthalmitis in anti-VEGF treated eyes. This very concerning adverse event, which is an infection of the tissues inside the eyeball, presents a great threat to sight, for it often results in blindness. It has to be noted, that all studies are structured differently with diverging numbers of injections. Hence making the determination of an endophthalmitis incidence rate impossible. As for the RISE and RIDE studies 3 out of 250 patients developed endophthalmitis[23], furthermore 0 out of 42 patients were registered in the BOLT trial[31], one out of 45 patients in DA VINCI[32] and not one patient out of 287 developed endophthalmitis in the VIVID and VISTA studies[33]. The READ2 study did also not note a single case of endophthalmitis[27]. It appears that more endophthalmitis events were present in earlier trials, before the improvement of aseptic techniques and injection protocols. Meta-analysis by Lyall et al., 2012[52] and Moshfeghi et al., 2011[53] named Staphylococci and Streptococci the most common pathogens and calculated an approximate endophthalmitis risk of 0.025% during intravitreal anti-VEGF injections. Mc Cannel, 2011[54] recommends not to talk during the injection procedures, if staff is not wearing masks, as a prevention strategy, since the respiratory tract is the most probable origin of those before mentioned bacteria.

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13.5.2. Systemic events:

It is known that anti-VEGF agents, although administered intravitreally, may enter the systemic blood stream[55]. The systemic exposure measured in serum has shown to be larger for AFL and BCZ than RBZ[56]. Especially BCZ, which was originally designed for the systemic therapy of several cancer forms, has been created to be protected from fast proteolytic destruction so that it would remain in the serum for a long time[56]. Gordon and Cunningham, 2005[57] and Scappaticci et al.,2007[58] found an increase in the risk for thromboembolic events like myocardial infarction or stroke in studies evaluating the systemic application of anti-VEGF therapy. The importance of those findings for the clinical practice with intravitreal injections of AFL, BCZ and RBZ remains to be determined.

One of the latest studies comparing BCZ, AFL and RBZ therapy for DME treatment[46], reported a higher occurrence rate of cardiovascular events in patients receiving RBZ (17%) sized up against AFL (9%) and BCZ (9%). Nevertheless, experts proposed this result only to have been an exception as these observations did not match other findings of the multiple previously conducted clinical studies analyzing cardiovascular adverse reactions between the anti-VEGF drugs used in different retinal pathologies[47]. Amongst the longest period of data collection on safety reports for intravitreal anti-VEGF treatment in DME patients are the RISE and RIDE trials. Using the Antiplatelet Triallists’ Collaboration classification 7%, 10% and 11% of participants receiving sham injections, 0.5mg or 0.3mg RBZ injections, respectively, experienced arterial thromboembolic events within 3 years[23]. Throughout this time, 3%(sham), 6%(0.5mg RBZ) and 4%(0.3mg RBZ) of the patients died from progressive DM complications. Additionally, serious cerebrovascular events have been registered in 2% + 3.6% of 0.3mg and 0.5mg RBZ schemes. Considering that more than half of DME patients suffer disease involvement of both eyes and therefore require simultaneous bilateral therapy, it is recommended to use a 0.3mg RBZ regimen to minimize potentially related complications while still achieving effective disease suppression[23]. In contrast to the aforementioned findings, during the protocol I, Elman MJ et al. recorded a greater number of Antiplatelet Trialists’ Collaboration classified systemic events in the sham injection arm than amongst the participants treated with RBZ[17]. Until this point, the importance of

presently known observations on intravitreal AFL, BCZ and RBZ injectionsfor clinical practice remains

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14. DISCUSSION OF CURRENT CONTROVERSIES

Internationally it has been noted that there exists a disparity between the results from randomized controlled studies analyzing the efficacy of anti-VEGF drugs in DME and real-world outcomes[59-61]. The less satisfying visual prognosis under real-life conditions are believed to be related to several factors. Ophthalmologists select between various treatment regimens and follow up intervals for anti-VEGF therapy, taking into the consideration not only medical, but also social aspects of their patients. This stands in a clear contrast to the uniform, predetermined regimens in clinical studies [62]. Furthermore, participants of clinical studies are selected beforehand for their compliance regarding consistent adherence to their visits which are being scheduled for them. Expenses arising from the individual journey to medical-care centers and other costs involved are usually covered by the organization performing the trial. Whereas, in daily life, patients often lack financial means and time due to work and or the necessity to manage other comorbidities[62]. In many cases this leads to a reduced number of intravitreal injections throughout the therapy, demonstrably correlating with inferior BCVA gains[59,61]. Previously outlined relations are also reflected in several examples of real-life clinical practice data presented in Browning et. al.’s publication: “Diabetic macular edema: Evidence based management”[63]. A Danish study, which analyzed intravitreal RBZ for DME, recorded a mean of 5 injections with average BCVA change by +5 ETDRS letters at 1 year[64]. In addition, a German study of anti-VEGF drug injections in DME observed a mean gain by +3 letters at 1 year with an average of 6 injections[65]. In contrast, patients treated with RBZ in the RISE and RIDE trials received 12 injections in their first year[51] and during the DRCR.net protocol T the mean number of AFL, RBZ or BCZ injections was 9-10[46]. Another point to discuss is the great burden, also correlating with the high number of subsequent treatment and monitoring visits in anti-VEGF therapy of DME and the inevitable absence from work for patients and their caregivers at times. It causes the healthcare systems to carry an increasing financial load on their shoulders. Browning et al. [63] for example, underline in their article “Diabetic macular edema: Evidence based management”, that diabetic patients with DME consume on average 1.3 times more resources of the USA’s national healthcare program “Medicare” compared to diabetic patients without retinal complications[66]. A therapeutic regimen that helps to reach the top of the line of every patients’ visual potential while simultaneously limiting previously mentioned burdens would be ideal. To eventually reach such ambitious aims, multiple studies are investigating different regimen approaches. The single blinded, randomized, clinical study RETAIN[67] compared a treat-and-extend, to a PRN regimen using RBZ in DME patients. They concluded, that none of these two treatment possibilities, allowing greater intervals between single visits for DME patients, are inferior to one

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another. It should be pointed out that RETAIN did not have a monthly treated control arm which is often considered “standard” regimen in many DME trials[67]. Further studies need to be conducted to answer current controversies and to provide optimal therapy options.

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15. CONCLUSION

The frequent ophthalmic manifestation of DM- DME- is capable of causing significant loss of sight. With the implementation of anti-VEGF therapy, amongst other modern strategies, evolved a phenomenal alternative to the formerly rather crudely managed complication of DM. Intravitreally injected RBZ, BCZ and AFL have shown noteworthy enhancements in anatomic outcomes and visual acuity for DME patients. Anti-VEGF agents compare clearly favorably with traditional laser coagulation monotherapy. Between the three most commonly used intraocular anti-VEGF remedies, AFL has resulted in a greater visual improvement for DME patients with bad initial vision (20/50 ETDRS or less) within the first 12 months of therapy. Looking at the treatment effect in patients with better baseline vision, all three agents have proved to be coequal regarding their results. And while observing RBZ and BCZ in their effects on eyes with lesser initial vision, the previously manifested advantage of AFL

therapy did not persist after the 2nd_{year. This accentuates the need for further studies comparing AFL,}

RBZ and BCZ in their long-term outcomes. Regarding safety, serious complications were equally rare in association with all three intraocularly injected anti-VEGF agents. Only ophthalmic pain was noted to be a frequently accompanying side effect. Prospectively nascent anti-VEGF treatments are expected to facilitate greater therapy intervals and thereby limit the current burden to patients and healthcare systems. Lastly, despite the presently encouraging results of novel therapies for DME, it cannot be stressed enough, that controlling systemic comorbidities related to DM, significantly contribute to the prevention and good outcome of DME treatment and should therefore be of primary importance.

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Diabetic Macular Edema Therapy: The Role of Vascular Endothelial Growth Factor Inhibitors

Lithuanian University of Health Sciences

Faculty of Medicine

Department of Ophthalmology

Final Master Thesis

Diabetic Macular Edema Therapy:

The Role of Vascular Endothelial Growth Factor

Inhibitors

Author:

Elisabeth Wolter

Supervisor:

Associate Professor Dr. Vilma Jūratė Balčiūnienė

Kaunas:

2020

TABLE OF CONTENTS

3. SUMMARY

4. ACKNOWLEDGEMENTS

5. CONFLICTS OF INTEREST

6. PERMISSION ISSUED BY THE ETHICS COMMITTEE

7. ABBREVIATIONS

8. TERMINOLOGY

9. INTRODUCTION

10. AIM AND OBJECTIVES

11. LITERATURE REVIEW

12. RESEARCH METHODOLOGY AND METHODS

13. RESULTS

14. DISCUSSION OF CURRENT CONTROVERSIES

15. CONCLUSION

16. REFERENCES