Current pharmacologic modalities for diabetic macular edema

INTRODUCTION

The proportion of individuals suffering from diabetes mellitus (DM) is expected to rise to 28.6 billion in 2045.^[1] The most common complication of DM that affects vision primarily, is diabetic macular edema (DME), where pharmacological agents are playing a great role in its treatment and management.

Hyperglycemia in DM could lead to the formation of advanced glycation end products that upregulates diacylglycerol levels, ultimately activates protein kinase C (PKC). PKC activation leads to upregulation of vascular endothelial growth factor (VEGF) (A mediator involved in angiogenesis both physiological and pathological) [Figure 1]. Other pathways that are involved in DME are-

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Figure 1:

Pathogenesis of diabetic macular edema. PKC: Protein kinase C, VEGF: Vascular endothelial growth factor DAG: Diacyl glycerol, NADPH: Nicotinamide adenine dinucleotide phosphate.

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1. Increase in glucose shunting through hexosamine pathway

2. Upregulation of Arynase

3. Activation of transforming growth factor (TGF), VEGF, Arginase, and inhibition of Micro RNAs (mi-RNA) Let-7a-5p. All these could lead to oxidative stress.

The first-line treatment had been laser photocoagulation that causes scarring which results in increasing retina oxygenation, reducing retinal hypoxia and occlusion of leaking microaneurysms. On the other hand, other treatment option widely used is by inhibiting VEGF that acts by reducing the vascular permeability. The rationale of our review is to discuss what is DME, its pathogenesis (various triggering factors), the role of inhibiting VEGF, and clinical trials that have been conducted on anti-VEGFs, biosimilars, and their role in DME, what other treatment options are available for treating DME and cost effectiveness of anti-VEGFs.

MATERIAL AND METHODS

A broad literature search was conducted for purpose of conducting a narrative review on DME. The literature has been searched through electronic database such as PubMed, Embase, and Scopus for identifying original articles, review articles. The key words such as DME and its pathogenesis, DME diagnosis, DME treatment and anti-VEGFs have been used. The narrative review focuses on the pathophysiology, tools available for diagnosing DME, current treatments, their drawbacks and advantages, the agents in trials, and laser modes available. The study is not registered with PROSPERO.

The current treatment options are as follows [Figure 2]:

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Figure 2:

How various anti-VEGF acts (Mechanism of action). Placental growth factor (PLGF) has been linked with angiogenesis and neovascularization. VEGF: Vascular endothelial growth factor.

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The VEGF exists in various forms, such as VEGF A-F and placental growth factors, as PIGF1 and PIGF2, also come in VEGF family. Any condition, leading to hypoxia, oxidative stress, release of Interleukin (IL)-6, IL-1 beta, and TGF-beta, are involved in VEGF-A over expression, which will result in neovascularization and vascular permeability. VEGF-B involved in inhibiting the oxidative stress and in inhibition of angiogenesis. VEGF-C and VEGF-D are involved in lymphatic system regulation.

Another pathway involved is Ang/Tie pathway (in inflammatory processes modulation).^[2] Angiopoietins ½ bind to Tie-1 receptor (Angiopoietin-2: Involved in vascular permeability, and intra retinal fluid accumulation).^[3] Therefore, the commonly used treatment modalities are based on inhibiting VEGF, angiopoietins, and PIGFs. Various anti-VEGFs are getting used for the treatment of DME such as ranibizumab, aflibercept, bevacizumab, faricimab, and brolucizumb [Figure 2].

Bevacizumab: A recombinant humanized monoclonal immunoglobulin G (IgG) antibody (149kDa), that is composed of IgG1 framework that causes inhibition of VEGF, which is responsible for angiogenesis and endothelial cell promotion. VEGF-A exists in many isoforms: VEGF 165 (most abundant in the eye), and the other forms are as follows: VEGF 145, VEGF 148, VEGF121, VEGF 183, VEGF 189, and VEGF 206. VEGF leads to the activation of endothelial cells, by binding to the vascular endothelial growth factor receptor (VEGFR-1) and VEGFR-2 (primarily responsible for angiogenesis), VEGFR-1 upregulated in angiogenesis during hypoxia. The drug has been approved initially for metastatic colorectal cancer and then for cervical/ovarian/fallopian tube cancers, glioblastoma, non-small cell lung cancer, and metastatic renal cell carcinoma.^[4]

The drug is being used off label for macular degeneration, being the most cost effective agent, in contrast to other anti-VEGFs, and has the potential to neutralise all VEGF isoforms. The drug is used as an intravitreal injection into the posterior segment of the eyes, the dose used is 1.25 mg in 0.05 mL in adult patients every month for a time period of 3 months. The drug’s half-life is 6.7 days, though it stays inside aqueous humor for 9.82 days.^[1,3,4] Avastin get distributed in heart, testis, bladder, kidneys and the majority remains in plasma.^[5]

The drug has been found to cause adverse effects such as endophthalmitis, in a retrospective study, its occurence has been found 0.022% to 0.16%^[6] intraocular inflammation, rise in intra-ocular pressure (IOP) that needs no intervention, and normalises itself^[7], subconjunctival hemorrhage, and retinal detachment in the study conducted by Rehman et al.^[8,9] In the long-term extension study conducted by Oza et al., the most common adverse event reported were proteinuria and hypertension.^[10] Other complication such as wound healing and delay in surgery have been associated with Avastin, but occurrence is low at intravitreal doses used.^[8]

Macular edema is the most common cause of visual impairment in diabetic patients. The patho-physiology involved is complex that results in increasing vascular permeability, which will lead to fluid and plasma constituents leakage and has been the leading cause of retinal thickening. VEGF: Being the endothelial cell specific mitogen and an angiogenic inducer is proved to be the factor for increasing vascular permeability. In a study, the release of VEGF in the vitreous cavity could be the cause for the new vessels growth from retina and optic nerve and has been linked to be a response to ischemia.^[11] The patients have to undergo optical coherence tomography (OCT) for measuring central macular thickness (CMT) and for assessment of best-corrected visual acuity (BCVA). Macular edema is significant clinically, when thickening of retina and hard exudates are within 500 μm of the fovea center, in association with at-least one disc diameter of retinal thickening.^[12] Laser photocoagulation was used for the treatment of DME, but the adverse effects such as subretinal fibrosis, paracentral scotoma, secondary choroidal neovascularization, and expansion of laser scar have been seen.^[13] Dose of bevacizumab is used off label for this indication (Transconjunctival intravitreal injection is given into the posterior segment at an interval of 4–6 weeks at a dose 1.25 mg in 0.05 mL).^[14]

Role of Biosimilars In DME: The Biotechnological products, which can be comparable in terms of quality, non-clinical and clinical evaluation with the reference product, which is already approved is known as biosimilar.^[15,16] The main concern is the research and investment needed in their development. In 2004, US-Food and Drug Administration (US-FDA) has approved bevacizumab for the metastatic colorectal cancer treatment and, European medicines agency approved it in 2007. The expiration of Avastin’s patent with US and EMA has opened a new opportunity for the development of its biosimilars, such as Mvasi (Approved IN 2017 by US FDA and in 2018 by EMA) and Zirabev (Approved in 2019 by US FDA and EMA). B8, came with the brand name Aybintio, has been developed by Samsung Bioepis Co. Ltd. (Which is approved by EMA in 2020) and is the biosimilar of reference product Avastin.^[17] Biosimilar MYL-14020 has been well tolerated and safety profile has been similar to EU-reference Avastin and US-reference bevacizumab in male volunteers (healthy), in phase 1.^[18] The efficacy of BEVATAS (Bevacizumab) has been assessed in managing grade 1 retinopathy of prematurity (ROP) and Aggressive Posterior ROP (APROP), in a retrospective, single-center-based study. This has shown promising results in ROP Type 1, AND not in APROP.^[19] Another important term to be considered is Biobetter, considered to be an investigational new drug, the term was coined by Dr. Reddy’s labs CEO and it’s a biologic AGENT, which is far better in contrast to the original molecule, in many aspects, but the target of action is same. The main concern is the cost, which is 10 times more than producing a biosimilar.^[20] The approved biosimilars of ranibizumab are SB-11 (Byooviz, Ranibizumab-nuna), FYB-201 (Cimerli, Ranibizumab-eqrn). The approved biosimilars of aflibercept are Yesafili and Opuviz. Various biosimilars of aflibercept such as M710, CT-P42, SB-11, ABP-938, AVT06, ALT-L9, and SCD 411 are in trials.^[20]

Why BEVACIZUMAB is preferred? A systematic review and meta-analysis, which has included 17 randomized controlled trials, has reported superiority of intravitreal triamcinolone and the combination of triamcinolone and bevacizumab therapy in comparison to intravitreal bevacizumab alone.^[21] In a meta-analysis study by Abdul-Maboud et al.,^[21] the improvement which is seen in BCVA has been significant statistically, in the group receiving IVB at follow-up of 12,24 and 48 weeks. However, the CMT reduction was slight superior in IVB group at 4 weeks, in the combination of intravitreal triamcinolone+intravitreal bevacizumab (IVT + IVB) group in a duration of 12 weeks and in IVT monotherapy at 24 weeks. In addition, it has been found that visual acuity improvement is best associated with reduction in CMT from 480 μm.^[21] The bevacizumab is associated with statistically lowering IOP at 36 and 48 weeks follow-ups, in contrast to IVT and in combination IVB + IVT.^[21]

Other Anti-VEGFs [Table 1] such as Conbercept: A 143kDa fusion protein that acts as an antagonist to VEGF, that is being engineered and developed from human Complementary DNA (cDNA) sequence, has high potency and long half-life as it has an additional portion in the 4^th binding domain, which provides more stability for its binding complex to VEGF. The drug can bind to many isoforms of VEGF-1, VEGF-B, VEGF-C, and PIGF. The efficacy of IVR and IVC has been assessed and no statistical significance has been found in improving BCVA and in CRT reductions, in a trial by Huang et al., although number of injections in IVC group were 6.6 ± 0.9 injections/eye and in IVR group were 7.2 ± 1.0 injections/eye.^[22-25]

Table 1: Available vascular endothelial growth factor (VEGF)-antagonists for diabetic macular edema (DME) are:

Ranibizumab Recombinant Humanised Monoclonal Antibody Fragment (also known as Lucentis)	Aflibercept Recombinant Fusion Protein	Faricimab	Bevacizumab Recombinant Humanised Monoclonal Antibody
Fab (Fragment Antigen Binding) region of IgG against VEGF-A isoforms, derived by r-DNA.	115kDa, Fragment crystallizable (Fc) of human IgG1	It has dual antibody mechanism (Inhibitor of Anti-VEGF/anti-angiopoietin-2 (Ang-2) both)	A single chain 26kDa, Fv fragment which inhibits all forms of VEGF
Rapid and complete penetration into retina because of small molecular size 48kDa . Binds to all forms of VEGF-A, also to the VEGF110(biologically active molecule) Intravitreal half-life estimated to be 4.75 days.	Binds to all forms of VEGF 1 and VEGF 2 Has the potential to bind Placental growth factor-1 and Placental growth factor-2(PGF). The agent has half-life (intravitreal) of 7.1 days.	This 149kDa molecule has binding affinity to VEGF-A165 and VEGF-A121 is less in comparison to Aflibercept. It targets VEGF-A and Angipoietin-2 [Figure 2]. The agent was approved in 2022 by FDA for DME.	Time to achieve maximum concentration in retina has been 1-6hours.
Clinical efficacy has been demonstrated in phase 3 trials at a dose of 0.3mg and 0.5mg vial dosages that are given under local anaesthesia	Dose range given is 2mg to 4mg. Drug has been more effective in patients with poor baseline visual acuity.	Its Fc region is engineered so that it cannot bind to Fc gamma receptors and neonatal Fc receptors	Serious adverse effects such as intraocular inflammation and retinal vasculitis has been noted in trials. In HAWK and HARIER clinical trials, the Age related macular degeneration and rise in Intra-ocular inflammation (which was associated with decline in visual acuity).
In Phase 3 trials RISE and RIDE, the mean BCVA was gained at 24 months from baseline However the drug is not associated with decreasing VEGF as that of Bevacizumab and Aflibercept.	The means BCA showed improvement at 100 week with 2mg every 4 weeks, in VISTA trial and VIVID trials (Phase 3, multicentre, double blind).	In a 96 week treatment period, in YOSEMITE and RHINE studies, has shown drug not to be inferior than other anti-VEGF agents.	In KESTREL and KITE studies, the drug has shown improvement in BCVA and letter gaining but the adverse effects were serious.
Adverse events reported are: Rise in IOP, Dry eye, Endophthalmitis, Conjunctival Haemorrhage, risks of thromboembolism, stroke, myocardial infarction and vascular death have been associated.	Cataract, Conjunctival haemorrhage and eye pain were noted in	Well tolerated agent and has safety profile similar to Aflibercept.

FDA: Food and drug administration, BCA: Best corrected acuity, IOP: Intraocular pressure, BCVA: Best corrected visual acuity

In DME, patient, refractory to ranibizumab, aflibercept, and faricimab, CONBERCEPT could be used to extend the treatment interval. In a study by Rush et al., the improvements in visual acuity and CMT were significant with faricimab, in contrast to patients, receiving aflibercept for persistent DME.^[26]

T-randomized clinical trial has been conducted by Diabetic Retinopathy Clinical Research (DRCR) Retina Network, which has shown the result, as the visual acuity improvement at 2 years was 12.8 letters in aflibercept group, 10.0 letters in Avastin group and in ranibizumab group was 12.3 letters. Avastin was less effective in 2 years, but the difference in improvement was almost same after 2 years. Although due to cost effectiveness, Avastin is preferred especially in developing countries like India.^[26,27]

In center involving DME: Anti-VEGF intravitreal injection is preferred at dose of 1.25 mg/0.05 mL of bevacizumab, 2 mg/0.05 mL of aflibercept, and ranibizumab 0.5 mg/0.05 mL. DRCR network protocol recommends intravitreal injection on a monthly basis for 4–6 months. If the decline is <10% in OCT and improvement is <1 line in visual acuity then, anti-VEGF is stopped, in such cases, steroids injection or some other anti-VEGF agent is considered.^[24-28]

Trials and Doses of Anti-VEGFs, have been summarised in Table 2.^[29-32] Various other treatment modalities for DME could be gene therapy, steroid implants, and laser photocoagulation have been used in DME, as elaborated below:

1. Another novel-VEGF, KSI-301 (Kodiak Sciences Inc.), Tarcocimab Tedromer (Antibody Biopolymer Conjugate), molecular weight 950 kDa. This agent acts by inhibiting the high levels of IL-6 that is involved in macular edema and by acting as anti-VEGF. The agent is found to have the longest half-life of 2.5 months in trials. The treatment-free interval has been found of around 6 months in DME patients in phase 1 b study. Inspite of various results in Phase 2b/3 trials, the drug has the potential to serve as a durable therapy in retinal disorders. The drug is undergoing various trials.^[33]

2. The need of inventing newer agents with long duration of action has found Abicipar (was engineered as MP-0112), which has a half-life of 6 days in comparison to aflibercept has only 4.7 days and ranibizumab has only 2.5 days. Although, the agent has shown a high risk of intraocular inflammation, and thus, it was used with a new modified manufacturing process (with the removal of intrinsic impurities in the product), which has been in phase 2, open-label MAPLE study (A multicentre clinical trial), at a dose of 2 mg, for age related macular degeneration (AMD). Although the risk of intraocular infections (IOI) with Abicipar is more in contrast to other approved anti-VEGFs.^[34]

3. Another agent in trial is ranibizumab, port delivery system (PDS), and has been approved for wet AMD. The biggest trial VOYAGER is started for assessing long term visual effects, efficacy as well as safety of PDS and Faricimab.^[35] This PDS system has been designed with the purpose of continuous delivery of drug intravitreal for a period of 6 months or more than that, thus, the burden of high injection rate with already available anti-VEGFs can be reduced.^[36]

4. Role of gene therapy: Gene therapy used is using adeno-associated virus mainly adeno associated virus (AAV)2 delivering SFLT (a protein)-1 (Vasoinhibins) through intravitreal route, that has been linked in inhibiting angiogenesis in mice models. AAV-5 vectors are also in trial through subretinal route.

   The molecules in trials are as follows: 4D-150 (R100 vector) in phase 2 SPECTRA trial and Rax-314 using AAV-8 vector in phase 2 ALTITUDE trial for diabetic retinopathy (DR) without DME. The delivery of gene therapy through subretinal route has drawbacks as retinal breaks, retinal detachments, cataract formation, and pars plana vitrectomy might be needed (this procedure is very costly for the patients). The drawbacks of delivering gene therapy through intravitreal route are development of neutralizing antibodies, transduction into outer retina, photoreceptors and retinal pigment epithelium [RPE]), viral vectors might cross into vitreous, internal limiting membrane, and inner retinal layer.^[37] There are various other treatment modalities for DME, other than anti-VEGF, that have been listed as.^[38-41]

5. Role of steroid implants Sustained release: Dexamethasone long acting intravitreal, biodegradable implant, at a dose of 0.7 mg is used in DME. Although the risk of raising IOP and cataract is more with it. Another implant is a long polymer tube of Fluocinolone acetonide (FAC), nonbiodegradable, containing 0.19 mg of FAC that releases 0.20 μg/day.^[42] Although regular IOP monitoring is needed with steroid implants. The 2^nd intravitreal injection of FA is not recommended during 12 months of first dose. The implant has shown positive results in terms of reducing DME recurrences and anatomical fluctuations, therapeutic burden. The implant is being regarded as a resolution in DME.^[43-45]

6. Intravitreal triamcinolone (IVTA)/Sub-Tenon triamcinolone acetonide (STTA) during cataract surgery: It has been effective, as after the cataract surgery, various cytokines such as IL-6,8,10, interferon-induced protein-10, VEGF, and monocyte chemotactic factor-1 have been found to rise in DME. In such cases, anti-VEGF has not shown any promising results, but STTA and IVTA combined with cataract surgery have resulted in maintaining the central retinal thickness reduction. IVTA once injected intravitreally can remain active for up to 3 months, which has shown promising results in Avastin resistant cases. In both IVTA/STTA, high local steroid concentrations are used, thus minimized systemic side effects.^[46]

7. The standard treatment option, for DME, has been the laser (Focal/Grid) Photocoagulation. Their frequency has decreased due to serious adverse effects such as central vision reduction, subretinal fibrosis, and neovascularization.

8. Sodium glucose transporter-2 inhibitors have been shown to decrease the incidence of DME. This transporter has been found in bovine retinal pericytes and the drugs tofogliflozin and dapagliflozin have shown promising results.

9. Another agent which bispecific antibody to VEGF-A and angiopoietin-2, faricimab (Intravitreal injection) has been shown non inferior to aflibercept and ranibizumab in terms of showing improvement in visual acuity and CMT. Angiopoietin/tyrosine kinase regulates the vascular stability desensitize vessels to VEGF-A and angiogenesis. In various trials, Faricimab has shown long time stay in vitreous, as long as >4 months.^[47,48] The summary of all Anti-VEGF has been elaborated in Table 2.

Novel Anti-VEGF, Tarcocimab Tedromer was in trials, but has been discontinued.

ML-1701 P(Momenta Pharmaceuticals And Mylan) In Phase 3 trials for DME.

OPT-302(Sozinibercept, Opthea) in phase 3 trials for AMD. Tyrosine Kinase Inhibitors, Kallikrein Kinin Inhibitors and Senolytic Therapy are in trials.^[49]

Cost effectiveness analysis: In a series of randomized clinical trials, various monoclonal antibodies against VEGFs have been accepted and cost effectiveness was analyzed by the increment of the cost of treatment/Letter gain (in terms of BCVA improvement). The cost one subject has to pay in the ranibizumab and laser group was 20.951 times more than the Avastin + Laser group.^[50] In another study, 4-year cost of Avastin was found to be 2.5 times more cheaper in United States Dollar (USD) in comparison to aflibercept and ranibizumab.^[51] Cost-effective analysis has shown that even if considering treatment for longer duration, considering the adverse effects or gain in BCVA, Avastin is more cost effective than other anti-VEGFs.^[51] In a study by Pilones and Zabala, Incremental Cost-Effective Ratio (ICER) and Quality adjusted life years (QALY) were assessed. The ICER was assessed by total cost of laser-total cost of anti-VEGF treatment. QALY was assessed by QALY with laser-QALY with anti-VEGF. The most cost effective was intravitreal bevacizumab, though QALY was higher in ranibizumab. Total cost over 5 years was 1,58,101.69 with 6 weekly Avastin, bimonthly injection of ranibizumab was 817,867.94, and bimonthly aflibercept was 1,238,951.81.^[52] The biosimilars will be more cost effective though more studies need to be conducted.^[52,53] Intravitreal anti-VEGF injections are a better therapy than laser therapy, although it costs more than 100,000 dollars on annual basis. The cost effectiveness could be done by comparison of Medicare allowable of reference drug payments and wholesome acquisition cost of biosimilars.^[54,55]

Different laser modes used in DME:

1. Selective retina therapy: To target retinal pigment epithelium, laser treatment is given in form of pulse laser + short pulses. R:GEN (only commercially available SRT,that offers reall time titration of laser energy delivery to RPE) laser and spectralis centaurus are used. In SRT, the integrity of the adjacent structures is prevented.^[56,57]

2. Focal laser photocoagulation getting used in combination with anti-VEGF agents

3. Anti-VEGF in combination with focal laser/subthreshold laser/navigated laser/targeted retinal photocoagulation. Subthreshold laser, with stimulation of RPE for 3 ns, the adjacent structures are not stimulated.^[56]

4. Semiautomated multispot laser: Pattern scanning laser commonly used.

5. Pars plana vitrectomy.^[49]

CONCLUSION

DME is the complication of DR. The pathophysiology has been elaborated in this review article. The strategies of treatment are many anti-VEGF and laser modes to target RPE. However, the laser has declined as various agents targeting VEGF and cytokines have been developed. Most commonly used treatment strategies are intravitreal steroid implants as they have better compliance and anti-VEGF agents specifically bevacizumab, in developing countries, as it is the most cost effective. Other modalities such as laser in combination with anti-VEGF agents, switching from one anti-VEGF to another if patient does not respond, intravitreal triamcinolone along with laser have been adopted. Nowadays, artificial intelligence tools and algorithms have been developed for early screening and diagnosing DME.