Exploring future treatments of diabetic macular edema

The future of treatment for diabetic macular edema is likely to include a wider range of treatment options, improved efficacy, and the possibility of disease prevention.

Dr. Aiello

By Nancy Groves; Reviewed by Lloyd Paul Aiello, MD, PhD

Boston-Advances in the management of diabetic macular edema (DME) are likely to center on additional, more effective treatment options, streamlined delivery mechanisms, individualized therapy-and perhaps most importantly-greater emphasis on prevention, said Lloyd Paul Aiello, MD, PhD.

“I think that it is highly likely that in the future we will have expanded anti-VEGF (vascular endothelial growth factor) and steroid options and better known relative efficacy,” said Dr. Aiello, head of eye research at the Joslin Diabetes Center, Harvard Medical School, Boston. “I also think it is likely that less invasive and less burdensome therapeutic delivery mechanisms will become available. In the mid-term, new therapeutic options for eyes that have an incomplete anti-VEGF response may show efficacy, and at that time usher in a new era of individualized therapy.

“The ability to detect subclinical DME changes would allow better management of treatment initiation, cessation, and retreatment, as we move to the time when we prevent, rather than treat, diabetic macular edema,” he continued.

The past decade saw signifiant advances, but progress must continue, Dr. Aiello said.

Treatments

He noted that treatment is invasive with rare, but potentially severe complications, places an excessive and most likely unsustainable burden on the patient, the ophthalmologist, and the healthcare system, and is not completely effective for many patients.

Treatment approaches being investigated include topical, subcutaneous, and oral delivery methods.

Dr. Aiello said data may be released within a year or so on a phase II evaluation of topical NSAIDS in eyes with noncentral-involved DME being conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net Protocol R).

Investigators also have early human data on other agents for topical delivery, such as:

·      Dexamethasone-cyclodextrin microparticle eye drops

·      SAR 1118, a lymphocyte function-associated antigen-1 antagonist

·      Mecamylamine, a nonspecific nicotinic acetylcholine receptor blocker

·      Multi-targeted kinase (src) inhibitors

Some of these studies show enough promise to move forward, Dr. Aiello said.

Subcutaneous delivery strategies include:

·      Exenatide (glucagon-like peptide-1 agonist), which has one case report of complete regression of DME in type 2 diabetes

·      Lanreotide autogel, a synthetic somatostatin analogue

·      Vascular endothelial-protein tyrosine phosphatase inhibitor

Oral delivery methods being tested include:

·      PKC-beta inhibitors

·      Oral minocycline (microglial activation inhibitor)

·      Atorvastatin, a statin lipid-lowering agent

·      Vascular adhesion protein-1 inhibitor

·      Alpha V integrin antagonist

Approaches to reducing the treatment burden include implants and extended delivery devices.

“Another area that’s very exciting is nanoparticle formulations,” Dr. Aiello said. “These are underway in a variety of approaches and promise potentially better availability and longer duration of action.”

Analyzing further methods

Efficacy data across multiple anti-VEGF agents is also critically needed.

Ranibizumab is well documented, and more data is becoming available on avastin (Bevacizumab, Genentech) and aflibercept (Eylea, Regeneron), neither of which has FDA approval for DME.

“However, what is clearly missing is direct, head-to-head comparison studies to help us understand how to use these agents relative to each other,” Dr. Aiello said.

That gap is being addressed in DRCR.net Protocol T, a randomized clinical trial to compare the efficacy of intravitreal aflibercept (2.0 mg), bevacizumab (1.25 mg), and ranibizumab (0.3 mg) when given in eyes with center-involved DME and visual impairment.

Another challenge is improving the drug response rate.

Researchers suspect that VEGF-independent pathways contribute to the incomplete anti-VEGF response in up to half of treated patients. Several of these pathways are known, and many others may exist. Data from human vitreous samples show a broad gradient between high and low levels of VEGF as well as between levels of other components that may contribute to vascular leakage.

This finding has significant implications, Dr. Aiello said, since a high level of VEGF suggests that the eye would respond well to anti-VEGF treatment, while a low VEGF level means the eye might be relatively insensitive to a VEGF inhibitor, but potentially could be sensitive to other agents. Patients in the middle of the spectrum might require inhibition of multiple pathways to achieve a complete response.

“Relative contributions of VEGF and/or other pathways may mediate both clinical outcome as well as response to specific therapy,” Dr. Aiello said. “Individualized or sequential or multi-targeted treatment paradigms aimed at VEGF and other pathways may be required to optimize therapeutic response.”

What may seem like a more fanciful approach to treatment DME is prevention.

“This may not be so far in the future as we might think,” Dr. Aiello said. “Since anti-VEGF therapy improves nonproliferative diabetic retinopathy severity in all secondary analyses looked at to date, if we eventually treat in this way we may be preventing the onset of DME along with that treatment.”

Similarly, if an ongoing DRCR.net protocol shows that anti-VEGF therapy is effective at least transiently for proliferative diabetic retinopathy, this might concurrently treat or prevent onset of DME in these patients.

Improved retinal imaging could also enhance DME treatment. Noninvasive visualization at the cellular level, which is now coming close to reality, might detect DME changes before they become clinically relevant, allowing preventive treatment.

Lloyd Paul Aiello, MD, PhD

E: lpaiello@joslin.harvard.edu

P: 617-732-2520

Dr. Aiello is a consultant for Genentech, Genzyme, Kalvista, Vantia, Merck & Co., Thrombogenics. He also received grant support from Optos.

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