Treatment of DME Beyond Anti-VEGF

The results with anti-VEGF drugs are impressive, but new target molecules could revolutionize DME care.

DANIEL D. ESMAILI, MD • DAVID S. BOYER, MD

Diabetic retinopathy is a leading cause of visual morbidity worldwide and the most common cause of blindness in working age Americans.¹ Diabetic macular edema is the leading cause of visual impairment in DR and is estimated to affect 20% of individuals.²

The accepted standard of care for DME has historically included optimizing the management of systemic risk factors (glycemic, blood pressure, and serum lipid control) and focal laser photocoagulation. In recent years, anti-VEGF agents, including bevacizumab (Avastin, Genentech, South San Francisco, CA), ranibizumab (Lucentis, Genentech) and aflibercept (Eylea, Regeneron, Tarrytown, NY) have demonstrated superior clinical efficacy compared to focal laser, and they have established themselves as first-line treatments for DME.

Despite the success of anti-VEGF medications, retina specialists continue to struggle with patients who are partial or nonresponders. In phase 3 clinical trials using ranibizumab (RISE and RIDE), after two years of monthly treatment, macular edema (>250 µm on OCT) persisted in 23% of patients, and 40% of patients did not achieve a BCVA of ≥20/40.^3,4 Furthermore, the treatment burden of frequent injections in diabetic patients who often have multiple comorbidities can be problematic.

Recent years have seen increased attention paid toward developing novel treatment pathways for DME beyond anti-VEGF agents. This article will review currently available therapeutics, as well as provide a glimpse of potential treatments currently in the pharmaceutical pipeline.

INFLAMMATION

Mounting evidence has pointed to inflammation as a critical factor in the pathogenesis of DME.⁵ Several inflammatory cytokines, chemokines, and other mediators have been implicated in the pathogenesis of diabetic DR. Leukostasis, a major component of the inflammatory process, has also been hypothesized to play a central role in the breakdown of the blood-retina barrier.

Corticosteroids

Intravitreal corticosteroids have been effective in the treatment of DME, presumably through their ability to block the production of VEGF and other inflammatory mediators, while also inhibiting leukostasis and enhancing the blood-retina barrier.⁶

The Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol I established the efficacy of triamcinolone acetonide (Kenalog, Allergan, Irvine, CA) for DME and showed comparable efficacy to ranibizumab in pseudophakic eyes.

In 2014, the FDA approved Allergan’s dexamethasone implant (Ozurdex) for DME, which is a biodegradable, intravitreal implant that provides 0.7 mg of dexamethasone in sustained release.

Pooled data from the phase 3 randomized clinical trials showed that 22.2% of patients gained ≥15 letters in the 0.7-mg group with an average of four to five injections over a three-year period. The primary adverse effects include the development of cataracts that require cataract surgery in 59% of phakic eyes and elevated intraocular pressure, with two patients (0.3%) requiring trabeculectomy from the steroid implant.

Alimera Sciences’ (Alpharetta, GA) fluocinolone acetonide intravitreal implant (Iluvien) is designed for sustained release of fluocinolone. In the three-year phase 3 study (FAME study), 28.7% and 27.8% of patients gained ≥15 letters in the low- and high-dose treatment groups, respectively, compared to 18.9% in the sham group.

Cataracts requiring surgical intervention were seen in the majority of patients, and elevated IOP requiring incisional glaucoma surgery was seen in 4.8% and 8.1% of the low- and high-dose groups, respectively. Iluvien was recently approved in the United States for the treatment of DME in patients who have not experienced IOP elevation after a steroid challenge.

Other Inflammation-based Approaches

More selective approaches to augment the inflammatory cascade are also being investigated. Elevated chemokine levels in DR are hypothesized to play a central role in vascular inflammation by inducing leukocyte recruitment and activation.⁷

In animal studies, inhibition of CCL2, the most common chemokine that is significantly elevated in the vitreous, has been shown to provide a protective benefit to the blood-retinal barrier.⁸

Blockade of chemokine receptors is a potential strategy for DME. Currently, subcutaneous administration of a humanized anti-CCR2 monoclonal antibody (Pfizer, New York, NY) is being tested in a phase 2 clinical trial.

Plasma kalllikrein is an enzyme (a serine protease), chronic activation of which has been reported to increase the production of bradykinin and thus increase vascular inflammation and promote breakdown of the blood-retinal barrier.

KVD001 (KalVista Pharmaceuticals, Porton Down, United Kingdom) is a small-molecule kalllikrein inhibitor designed for intravitreal delivery. It recently entered phase 1 clinical trials for the treatment of DME.

The retinal microglia are the primary immune cells of the retina. They demonstrate increased activation and proliferation in diabetic retinas, and in animal models, they have been found to contribute to DR progression.

Minocycline is a second-generation tetracycline capable of inhibiting microglial activation. In an uncontrolled proof-of-concept study, Cukras et al demonstrated that oral administration of 100 mg of minocycline, given BID for six months, led to improved VA of 5.8 letters with associated reductions in macular edema and mean area of late leakage on fluorescein angiography.⁹

Danazol is an FDA-approved lipophilic steroid derivative of testosterone ethisterone that is currently being used for the treatment of endometriosis, among other conditions. It is currently being repurposed in a lower dose as Optina (Ampio Pharmaceuticals, Englewood, CO) for the treatment of DME. In low doses, danazol appears to enhance endothelial cell barrier function through its effects on filamentous actin, thereby reducing vascular leakage. A late-stage clinical trial has been completed, with results pending.

The potential for topical delivery of corticosteroids to treat DME continues to be explored. Kala Pharmaceuticals (Waltham, MA) has developed a nanotechnology-based approach to improve posterior-segment penetration of topical medication.

Based on their mucous penetration particle (MPP) technology, topical loteprednol etabonate dosed, by MPP QID, is being studied in a phase 2 clinical trial for the treatment of DME.

INSULIN-LIKE GROWTH FACTOR I

It was first observed nearly 60 years ago that patients with diminished pituitary function showed resistance to DR. This resistance was felt to be due to reduced levels of growth hormone and its main effector molecule, insulin-like growth factor (IGF-1).

RV001 (River Vision, LLC, New York, NY) is a fully humanized monoclonal antibody that blocks IGF-1 receptor activation from both IGF-1 and IGF-2. In a phase 1 open-label study, RV001 is being administered by intravenous infusion to patients with DME.

INTRACELLULAR SIGNALING

Targeting the intracellular signaling cascade may provide a means for augmenting the effects of multiple growth factors via a common pathway. Squalamine is an antiangiogenic small molecule that counteracts multiple growth factors, including VEGF, platelet-derived growth factor, and basic fibroblast growth factor. A phase 2 clinical trial examining topically applied squalamine for DME is under way, conducted by Ohr Pharmaceuticals (New York, NY).

Tie2 (tyrosine kinase with immune globulin-like and EGF-like domains) is a receptor that is expressed on vascular endothelial cells and is felt to be a modulator of endothelial cell function and vascular stability.

AKB-9778 (Aerpio Therapeutics, Cincinnati, OH) is a small-molecule Tie2 activator that upregulates Tie2 signaling through the inhibition of tyrosine phosphatase beta (HPTPB). Phase 1 results of AKB-9778 showed good safety and tolerability, and a current phase 1/2, open-label, ascending dose study, using subcutaneous delivery of AKB-9778, is under way for the treatment of DME (Figure 1). Both Regeneron and Genentech are also studying the Ang/Tie2 pathways with intravitreal injections, with and without anti-VEGF drug therapy.

Figure 1. Phase 1 results for AKB-9778 showed good safety and tolerability.

iCo 007 (iCo Therapeutics, Vancouver, Canada) is a second-generation antisense molecule that inhibits C-raf expression and blocks MAP kinase signaling. This strategy has the potential to inhibit multiple growth factors that signal through C-raf. Although a phase 2, four-arm clinical trial showed some biologic activity of intravitreal iCo 007, future investigations have been halted.

EXTRACELLULAR MATRIX

Integrins are transmembrane receptors that facilitate cell-to-cell and cell-to-extracellular matrix (ECM) interactions. When triggered, integrins can facilitate signal transduction. Anti-integrin compounds have the potential to turn off angiogenesis at its source by inhibiting the production of VEGF and other mediators from endothelial cells.

ALG-1001 (Allegro Ophthalmic, LLC, San Juan Capistrano, CA) is an anti-integrin small peptide that is currently under investigation for the treatment of DME. In a phase 1 study, a mean improvement of approximately 10 letters in VA was maintained over 90 days (Figure 2); similarly, mean macular thickness on OCT decreased by 30% over the same time period (Figure 3, page 34).

Figure 2. A mean improvement of approximately 10 letters in VA was maintained over 90 days with ALG-1001.

Figure 3. With ALG-1001, mean macular thickness on OCT decreased by 30% over 90 days.

In addition to its proposed anti-angiogenic effects, ALG-1001 may also have a secondary benefit of inducing posterior vitreous detachment. It is concurrently being studied in a clinical trial for pharmacologic release of vitreomacular traction.

OXIDATIVE STRESS

Chronic oxidative stress has been proposed as a key etiologic factor in the development of retinal vascular leakage. Increased levels of reactive oxygen species, due either to an increased rate of production or a decreased rate of detoxification, can damage mitochondrial proteins to a sufficient extent that cytochrome c is released and apoptosis initiated.

MTP-131 (Stealth Peptides Inc., Newton, MA) is an agent designed to selectively bind and protect cardiolipin from peroxidation and thus reduce glucose- and peroxide-induced oxidative stress and improve the overall survival of endothelial cells. A phase 1/2 exploratory study of topical MTP-131 dosed QID is under way. Notably, MTP-131 is also being tested in renal and heart-related ischemia-reperfusion injury.

Vascular adhesion protein-1 (VAP-1) is an amine oxidase that also acts as an endothelial adhesion molecule for leukocytes. VAP-1 catalyzes the oxidative deamination of primary amines, producing toxic reactive oxygen species. Plasma levels of VAP-1 have been reported to be elevated in diabetic patients and implicated in DR.¹⁰

ASP8232 (Astellas Pharma, Northbrook, IL) is a VAP-1 inhibitor that was investigated in two phase 1 clinical studies, demonstrating safety and tolerability. VIDI is a phase 2 study of ASP8232 for DME.

CONCLUSION

DME is a complex disease with a multitude of potential therapeutics targets. Although anti-VEGF strategies have been exceptionally successful in recent years, the future holds tremendous promise for new and novel therapies that will further the goal of improving vision in patients with DME. RP

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