Take-home: Pharmacotherapy research for diabetic macular edema is looking at targets other than VEGF inhibition to develop treatments that can be used as standalone intervention or may be complementary to current options.
Omaha, NE—Pharmacotherapy with intravitreal injection of an anti-VEGF agent has been a major advance for the management of center-involving diabetic macular edema (DME), but clinicians are looking to the future as well because there are a number of novel compounds in the pipeline that are being investigated to treat this sight-threatening disease, said Quan Dong Nguyen, MD, MSc.
“We have been fortunate to have three outstanding anti-VEGF agents to use for management of DME. Nevertheless, these modalities also have their drawbacks and limitations,” said Dr. Nguyen, Chairman and Inaugural Director, McGaw Professor of Ophthalmology, Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE.
“Looking ahead, there are a number of pharmacologic agents in development addressing different targets. Hopefully, some of these will come to the clinic soon and allow us to improve the quality of vision for our patients with DME.”
Discussing the future of pharmacotherapy for DME, Dr. Nguyen focused on three molecules—the integrin peptide, ALG-10001 (Allegro Ophthalmics); a monoclonal antibody for insulin-like growth factor receptor 1(IGF-R1) (RV001; teprotumumab, River Vision Development); and a vascular adhesion protein-1 (VAP-1) inhibitor, ASP 8232 (Astellas Pharma).
Dr. Nguyen explained that integrins are receptors that mediate attachment between a cell and surrounding elements (i.e., cells or the extracellular matrix). In addition, integrins play a role in cell signaling, thereby regulating cellular shape, motility, and the cell cycle, and have been implicated in angiogenesis and vitreous liquefaction.
By blocking integrin receptors, the small peptide ALG-1001 has demonstrated activity for turning off the angiogenic cascade and for causing vitreolysis. In addition to this dual activity, prolonged duration of efficacy may be another attractive feature of ALG-1001 as clinical data indicate that its activity may persist for at least 90 days after injection.
Results of preclinical studies showed shown ALG-1001 was as effective as ranibizumab (Lucentis, Genentech) for reducing the area of choroidal neovascularization, and the combination of the two agents was found to have even greater benefit than either compound alone.
Results of a phase 1 clinical trial in patients with DME provided evidence of biological activity, showing reduction of central macular thickness, and ALG-1001 is now being evaluated as an intravitreal treatment for DME in a Phase 2 study (the DEL MAR study).
The story behind the development of teprotumumab begins 60 years ago when it was reported that patients with diminished pituitary function were resistant to the development of diabetic retinopathy ischemia. More recently, results from preclinical and clinical studies support a role of the IGF-1 receptor in diabetic retinopathy, Dr. Nguyen said.
“This research shows that intravitreal levels of IGF-1 and IGF-2 are increased two- to three-fold in the eyes of patients with proliferative diabetic retinopathy. In addition, evidence from a rodent model of diabetic retinopathy shows that systemic administration of a monoclonal antibody to the IGF-1 receptor reverses the expression of markers for diabetic retinopathy.”
Studies with teprotumumab show that it blocks activation of IGF-R1 by both IGF-1 and IGF-2.
“The inhibitory activity of teprotumumab seems to be highly selective for IGFR-1. It does not seem to recognize the insulin receptor, which is important for a medication intended for treatment of patients with diabetes,” Dr. Nguyen said.
Teprotumumab, which is administered by intravenous infusion, is currently being evaluated in an open-label, multicenter safety and pharmacodynamics study in patients with DME.
“Because of the systemic route of administration of this agent, patients are being carefully selected to be sure they have stable, controlled diabetes, as well as certain levels of IGF-1,” Dr. Nguyen said.
VAP-1 is expressed in retinal capillaries and acts as an amine oxidase and as an endothelial adhesion molecule for leukocytes. In discussing the scientific rationale for VAP-1 inhibition as a treatment for DME, Dr. Nguyen explained that VAP-1 activity in plasma as well as oxidative stress have been associated with the presence of macular edema in patients with diabetic retinopathy.
In a preclinical study performed in the streptozocin-induced diabetic rat model, treatment with ASP-8232 improved retinal hyperpermeability and inhibited plasma VAP-1 activity; combination treatment with an anti-VEGF antibody was associated with greater benefit than that achieved with either agent alone.
An ongoing phase II study, VAP-1 Inhibition In Diabetes (VIDI) is a controlled study being conducted at 15 centers across the United States. It is randomizing patients to ASP-8232 as standalone treatment or combined with ranibizumab 0.3 mg. The primary endpoint is reduction of central retinal thickness. The Ocular Imaging Research and Reading Center (OIRRC) serves as the reading center for the VIDI Study.