Introduction to diabetic retinopathy (DR) and diabetic macula edema pathogenesis
DR is the most common microvascular complication in patients with diabetes mellitus (DM), and remains the single greatest cause of blindness in working age adults around the world (1,2). DR results in vision loss through two main mechanisms: (I) an ischemic retinopathy that results in aberrant retinal neovascularization and fibrovascular proliferation causing vitreous hemorrhage, traction, and ischemia on the retina; and (II) macular edema resulting from breakdown of the blood retina barrier (1). The pathophysiology of DR remains incompletely understood, although several biochemical pathways linking chronic hyperglycemia to microvascular complications have been proposed. Some potential causes include: advanced glycated end-products, oxidative stress, polyol accumulation, and protein kinase C activation (3). Ultimately, hyperglycemia is primarily responsible for the complications of DM, including DR, although there are patients with poorly controlled DM who do not develop DR, and those with well-managed glucose levels without hypertension that will develop DR, suggesting there may be genetic or environmental factors that affect DR progression independent of glycemic control (4,5).
Clinically, DR manifests in microvascular changes in the retina including microaneurysms, exudative deposits, dot blot hemorrhages, venous beading, retinal neovascularization, and fibrovascular proliferation. DR is traditionally graded based on the classification from the Early Treatment of Diabetic Retinopathy Studies (ETDRS) and classified into non-proliferative and proliferative DR based on these microvascular changes in the retina. Current treatments for non-proliferative DR involve intensive glycemic control, while individuals with proliferative DR or high risk non-proliferative characteristics may require local treatments including laser treatment or intravitreal injections (6).
The treatment of DR and macular edema has gone through substantial changes over the years. The initial landmark studies in DR showed that panretinal photocoagulation (PRP) and focal laser can prevent vision loss in DR, and have now evolved to newer pharmacologic therapies such as intravitreal injection of steroids and anti-VEGF antibodies. This article will focus on a review of pharmacologic treatment for DR, with an emphasis on upcoming pharmacologic therapies in the pipeline for DR.
Multiple studies have demonstrated the importance of glycemic control in preventing progression of DR. Both the Diabetes Control and Complication Trial (DCCT) as well as the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive glucose control in both type 1 and type 2 diabetic patients reduced the risk of developing retinopathy and slowed progression of retinopathy (7,8).
In addition, systemic pharmacologic therapy for DR has also been investigated. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study examined the effect of the peroxisome proliferator-activated receptor α (PPAR-α) agonist fenofibrate on cardiovascular disease in type 2 DM. Compared to the placebo group, significantly fewer patients receiving fenofibrate required laser treatment for retinopathy (9). A sub-study of the 5-year trial revealed 4.9% of patients on placebo required first laser therapy compared to 3.4% on fenofibrate, and that 200 mg/d of fenofibrate reduced retinopathy progression for those with pre-existing disease (10). Expanding on these findings, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, compared to simvastatin alone, patients also receiving 160 mg/d of fenofibrate in combination had a 40% reduction in the odds of retinopathy progressing over 4 years (11). Based on these results, DR was added as an on-label indication for fenofibrate in Australia. Despite the results seen in FIELD and ACCORD, a 2015 meta-analysis of prospective, randomized controlled trials found that lipid lowering therapy did not significantly reduce the risk in worsening hard exudates or severity of DME (12). Fenofibrate can be associated with nausea and GI upset, and rarely myopathy, and serum creatine and transaminases need to be monitored while patients are on fenofibrate therapy, which may contribute to the lack of widespread adoption of fenofibrate for treatment of DR. Given these clinical trial results, further investigation is warranted.
Another oral therapy that has been investigated for DR is ruboxistaurin, a protein kinase C β inhibitor. Laboratory studies and early clinical studies demonstrated ruboxistaurin could prevent VEGF-induced retinal permeability and affect blood flow in patients with DR (13,14).
The PKC-DR2 study group performed a large 685 patient multicenter randomized 3-year trial that demonstrated that oral ruboxistaurin could prevent vision loss and decreased macular edema in treated patients compared to controls (15). Interestingly, ruboxistaurin was not shown to affect progression of non-proliferative DR to DR, and first manifested its beneficial effect at 18 months, suggesting that long-term treatment with ruboxistaurin would be necessary. Clinical development of ruboxistaurin has been aborted, as the FDA required additional clinical trials prior to approval and the sponsor, Eli Lilly, decided to terminate the project.
Proliferative DR has been traditionally treated with PRP. This was based on the Diabetic Retinopathy Study (DRS), which demonstrated that photocoagulation significantly reduces visual loss from proliferative DR compared to no treatment (16). Although effective in preventing vision loss, PRP can leave patients with significant peripheral vision loss and decreases in night vision, prompting investigations if pharmacologic therapies may be useful for preventing progression for DR.
In the case of DME, for many years, focal laser photocoagulation had been the standard of care for DME. There are two methods of applying laser photocoagulation in the macula: focal laser photocoagulation, which is used for discrete fluorescein leaks identified by fluorescein angiography (FA), and grid laser photocoagulation, which is used for thickened areas of the retina and/or diffuse areas of fluorescein leakage (6). In the ETDRS study, compared to untreated DME patients, those treated with laser experienced a 50% reduction in moderate vision loss over time (17). While the mechanisms of action for focal photocoagulation are still not entirely understood, it can prevent further deterioration of vision if utilized sufficiently early, but does not typically restore lost vision (5). In both the ETDRS and subsequent studies, relatively few patients with vision loss saw any improvements in their best correct visual acuity (BCVA) (17). Thus although laser photocoagulation became the first truly successful treatment for DR and DME in the 1980’s, historically, it was not utilized until vascular lesions were severe enough to warrant laser ablation (18). Clinical trials have subsequently shown anti-VEGF drugs to be superior for first-line therapy compared to laser treatment, and while the use of VEGF inhibitors have slowed DR progression, focal and/or grid laser photocoagulation are still utilized in combination and for those who do not respond to anti-VEGF treatment (19).
In addition, newer focal laser treatments using subthreshold laser energy have been investigated to treat diabetic macular edema (DME). The premise of subthreshold photocoagulation is to use a laser with reduced duty cycle to selectively target the retinal pigment epithelium, while having minimal effect on the sensory retina and choroid (20). This treatment has not been demonstrated to cause visible damage to the retina. Preliminary studies suggest that subthreshold micropulse laser is as effective as ETDRS laser photocoagulation, with the benefit of increased retinal sensitivity (21). While promising, larger clinical studies still need to be performed to determine safety and efficacy in the context of other available treatment modalities.
Anti-VEGF pharmacologic treatments
The vascular pathology seen in DR and DME, notably neovascularization and breakdown of the blood-retinal barrier, led to the idea that VEGF may play a causative role in ophthalmologic neovascularization. In 2007 and 2009, the RISE and RIDE trials examined two intravitreal doses of the anti-VEGF antibody fragment ranibizumab (Genentech, South San Francisco, CA) in patients with DME. In RISE, 44.8% of patients receiving 0.3 mg and 39.2% of those receiving 0.5 mg gained ≥15 ETDRS letters from baseline after 24 months, compared to 18.1% of the patients receiving sham injections, whereas in RIDE, corresponding patient outcomes were respectively 33.6%, 45.7%, and 12.3% (17). A separate but simultaneous DME trial, RESTORE, examined ranibizumab with and without laser treatment, compared to laser photocoagulation alone. After 12 months, 65.2% of patients receiving ranibizumab and 63.6% receiving ranibizumab and laser gained ≥5 BCVA letters, compared to 33.6% receiving laser alone (22). A 2-year extension study with individualized dosing found that ranibizumab was well-tolerated and maintained BCVA improvement, with progressively decreasing injection frequency (23). Overall, these trials demonstrate the superiority of anti-VEGF treatment compared to focal laser for the treatment of DME.
During the course of these trials with ranibizumab, many physicians were treating DME off-label with the anti-VEGF antibody bevacizumab (Genentech, South San Francisco, CA). A prospective phase-3 trial found that after a year, patients receiving 1.25 mg of intravitreal bevacizumab gained a median of 8 BCVA ETDRS letters, compared to those receiving modified EDTRS laser therapy who lost a median of 0.5 ETDRS letters (24).
A third anti-VEGF antibody has also been investigated for DR, Aflibercept (Regeneron, Tarrytown, NY), which was designed using domains of VEGF receptors 1 and 2 fused to the Fc domain of human immunoglobulin G1, and has a binding affinity 100 times greater than either bevacizumab or ranibizumab (25). Two phase 3 trials, VISTA and VIVID, found that after 52 weeks, patients receiving 2 mg intravitreal aflibercept every 4 weeks or every 8 weeks after 5 initial monthly doses had mean BCVA gains of 12.5 and 10.5 ETDRS letters respectively in the VISTA trial, whereas those in the VIVID trial had mean BCVA gains of 10.5 and 10.7 ETDRS letters respectively, compared to mean BCVA gains of 0.2 and 1.2 ETDRS letters respectively for VISTA and VIVID patients receiving laser photocoagulation (26).
In 2012, the DRCR.net conducted Protocol T, a 660 patient study across 89 clinical sites, and attempted to compare the safety and efficacy of these anti-VEGF drugs for treatment of DME. Treatment with aflibercept, ranibizumab, or bevacizumab all resulted in significant visual gains and there was no significant difference in visual acuity between these treatments. However, in pre-specified subgroup analysis of patients with vision of 20/50 or worse, visual gains were significantly greater with aflibercept compared to ranibizumab or bevacizumab (19). In the 2-year follow up, while there was no statistical difference between aflibercept and ranibizumab, there was still a difference between aflibercept and bevacizumab in the subgroup of patients with vision of 20/50 or worse. Additionally, it was noted that significantly fewer injections were required in the 2nd year for all anti-VEGF injections (10 injections first year vs. 5 second year). Overall, Protocol T demonstrated that all three drugs were effective in improving visual acuity in patients with DME, with a significant reduction in injection burden in year 2. For patients with vision of 20/50 or worse, aflibercept may provide superior visual gains in year one, but long-term benefits remain unclear.
While these studies demonstrated that anti-VEGF treatment is clinically superior to laser photocoagulation, the use of anti-VEGF in combination with laser treatment was not as well addressed. To this end, based on the visual improvements from ranibizumab seen in the RISE and RIDE trials, the Diabetic Retinopathy Clinical Research Network (DRCR.net) conducted a 5-year study on prompt versus deferred focal/grid laser treatment in DME patients receiving ranibizumab (27). They found no advantage to beginning laser treatment concurrently with ranibizumab compared to waiting 24 weeks to begin laser photocoagulation, and rather, 58% of patients receiving ranibizumab who deferred laser treatment saw an increase of at least 10 letters, compared to 46% who received ranibizumab with prompt laser photocoagulation. The authors of the study noted the possibility of prompt laser treatment potentially causing more damage to the retina than deferring laser photocoagulation, but patients who deferred laser treatment may require more injections over 5 years, and thus practical limitations such as access to care and cost of treatment can play a role in choosing an appropriate therapy.
Anti-VEGF for proliferative DR
During the RISE and RIDE Trials, it was seen that not only did DME improve, but also progression of DR was inhibited in patients receiving ranibizumab (28). This led to the DRCR.net Protocol S, which demonstrated that ranibizumab was non-inferior to pan-retinal photocoagulation in preventing vision loss from DR (29). These data resulted in the FDA approval of ranibizumab for treatment of all types of DR. In 2017 a phase 2b trial on aflibercept, the CLARITY study, found aflibercept to be non-inferior to PRP for proliferative DR and resulted in improved outcome at 1-year (30). There is currently an on-going Phase 3 trial (PANORAMA) investigating whether aflibercept can prevent progression of DR.
While anti-VEGF neutralizing antibodies have been the primary treatment for DME, it is well recognized that the causes of DME are multi-factorial, and there is a significant inflammatory component to disease. Steroids have long been used to treat DME given their effects on multiple inflammatory pathways. They have been shown to inhibit VEGF, as well as inhibit leukocyte recruitment and stabilize the blood retina barrier (31).
Intravitreal triamcinolone acetonide (IVTA) was the first steroid used to treat DME, and has been shown to be effective in multiple studies (32). The DRCR Protocol I demonstrated that IVTA plus laser had similar efficacy as ranibizumab plus laser at 2 years (33,34). IVTA is available in multiple formulations, including preservative-free, all of which are used off-label for DME. Treatments with triamcinolone formulations generally last 2–4 months, however they have significant side effects including progression of cataracts, and glaucoma (35).
Additional formulations and sustained release steroids have subsequently been developed to reduce frequency of injections. Ozurdex (Allergan, Irvine, CA, USA) is a sustained release biodegradable dexamethasone implant with a proposed duration of 3–6 months. In the MEAD trial, 22% of patients with a 0.7 mg dexamethasone intravitreal implant injected every 6 months, and 18% of those with a 0.35 mg implant had at least a 15 letter gain compared to 12% in the sham group (36). 0.7 mg Ozurdex was subsequently FDA approved for the treatment of DME, and a subgroup study from patients treated in the MEAD trial found that Ozurdex improved BCVA and CRT in patients previously treated with anti-VEGF therapy (37). While there were high rates of cataract formation, only 3 patients in the MEAD trial required incisional glaucoma surgery. However, Ozurdex was injected at most every six months in the trial which is less than the q3 month dosing commonly used in practice.
Iluvien (Alimera, Alpharetta, GA) is a sustained release formulation of fluocinolone acetonide (FA) designed to last 3 years. Iluvien was demonstrated to be effective for DME in the FAME trials, two phase III clinical trials investigating a low dose (0.19 g) or high dose (0.50 mg) FA implant (38). While almost all patients developed cataracts, only 5% in the low dose group and 8% in the high dose group required incisional glaucoma surgery (39). Hence although Iluvien carries the potentially serious risk of increasing IOP, the 0.19 mg dose has been FDA approved for treatment of DME. Additionally, in post hoc analysis of patients in the FAME study, it was found that patients on the FA implant also had decreased progression of DR compared to controls, suggesting that long term steroid use can also prevent progression of DR (38).
Retisert (Bausch and Lomb, Rochester, NY, USA), a surgically inserted sustained release FA implant, has also been studied for DME. A prospective clinical trial found Retisert produced significant improvements in visual acuity compared to grid laser (40). However, nearly all of the patients (91%) required cataract surgery, and 34% of patients required incisional glaucoma surgery. Given this side effect profile, Retisert is not FDA approved for DME, and in conjunction with its very high cost is uncommonly used to treat DME (41).
Emerging pharmacotherapies for DR and DME
Numerous new therapies for DR and DME are under active investigation. In Tables 1 and 2, we list selected studies that we found on clinicaltrials.gov in December 2017 using the search terms “diabetic retinopathy” and “diabetic macular edema.” This produced 439 and 397 studies, respectively. In order to limit the discussion to novel therapies, we excluded those studies using established, conventional pharmacologic agents already in routine clinical use, specifically anti-VEGF agents (e.g., bevacizumab, ranibizumab and aflibercept) and corticosteroids (e.g., fluocinolone and dexamethasone). We also excluded all studies involving non-pharmacologic interventions, such as lasers and surgery, as well as all studies that were terminated, withdrawn, or suspended. This resulted in 43 and 45 studies, respectively, with an overlap of twelve studies between the two search terms (Tables 1 and 2). Many of the remaining clinical trials can be separated into one of several groups, including non-angiogenic targets, novel angiogenic factors, as well as new anti-VEGF agents. Given the relative paucity of published, peer-reviewed reports regarding many of the studies, we will focus the discussion to studies that appear to be active and may ultimately lead to broader commercial availability, as determined by press releases, recent presentations at conferences, or other publicly available information.
Integrin receptor antagonists
Novel therapeutic targets include anti-integrin therapy as exemplified by the peptide LUMINATE (ALG-1001, Allegro Therapeutics, San Juan Capistrano, CA, USA), which inhibits retinal neovascularization via interfering with integrin receptors essential for development of aberrant blood vessel growth (42). ALG-1001 is delivered by intravitreal injection, and has shown promising results with monthly administration either as a monotherapy or in combination with bevacizumab (43). As shown in Table 2, a phase II study is underway to determine the optimal therapeutic dose.
The angiopoietin-2 (Ang2)/Tie2 tyrosine kinase pathway represents an attractive therapeutic target in DR and DME, given the data supporting a role for these proteins in contributing to the control of vascular permeability (44). AKB-9778 (Aerpio Therapeutics, Blue Ash, OH), is a small molecule inhibitor of VE-PTP, a critical negative regulator of Ang2/Tie2. It has the novelty of being a patient self-administered subcutaneous injection (similar to insulin) that has shown efficacy in promoting responsiveness to anti-VEGF therapy (ranibizumab) in DME or as a monotherapy (Time-2; Tables 1 and 2). REGN910-3 (nesvacumab) is a monoclonal antibody targeting Ang2 that was investigated conjointly by Regeneron and Bayer AG (Leverkusen, GER) in combination with aflibercept; per the latest press release in November 2017, it will not be pursued in a Phase III study. RG7716 is an agent by Hoffmann-La Roche AG (Basel, SUI) that is a bi-specific monoclonal antibody targeting VEGF and Ang-2. A phase II study has been completed with top line results showing statistically significant improvements of visual acuity at 6 months in patients with DR and DME treated with RG7716 versus ranibizumab (45). A phase III study is currently being discussed with the FDA.
Plasma kallikrein inhibitor
The kallikrein-kinin system represents a therapeutic target in DME independent of VEGF due to its effect on promoting vascular permeability (46).
KVD001 is an intravitreal administered plasma kallikrein inhibitor produced by Kalvista Pharmaceuticals (Cambridge, MA, USA) that completed a Phase I study in 2015 with promising results. Per the company website, a Phase II trial was announced in January of 2018 in collaboration with Merck (Kenilworth, NJ, USA), and oral plasma kallikrein antagonists are under development (47).
Abicipar pegol is a DARPin (designed ankyrin repeat protein), a novel agent developed by Molecular Partners AG (Zurich-Schlieren, SUI) and investigated with Allergan that targets VEGF. DARPins are small, stable, high potency proteins and this particular molecule offers the advantage of longer duration of action and has yielded encouraging results in a phase II study completed in 2016; per the company website, it was equally efficacious as Lucentis in treating DME while being administered every 8 weeks (48). The timing of a Phase III trial remains unannounced at this time. They also describe a combination anti-VEGF/PDGF DARPin under development.
Treatments for DME and DR have undergone an evolution from initial laser based treatments to a variety of pharmacotherapies. While anti-VEGF agents and steroids remain the mainstay of pharmacotherapy for DR, many promising therapies are currently in the clinical pipeline.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Spencer DB, Protopsaltis NJ, Chao DL. New pharmacotherapies for diabetic retinopathy. Ann Eye Sci 2018;3:43.