PERSPECTIVES

“We need therapies fighting different hallmarks simultaneously”

Every person with diabetes is at risk of going blind. The two main causes are proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). From years of studying the progression of diabetic eye disease, Prof. Alan Stitt points to a need for better therapies compatible with the current standard of care.

PDR and DME are two manifestations of diabetic retinopathy (DR), and in many respects they stem from the same cause, explains Prof. Alan Stitt, Dean of Innovation & Impact and the McCauley Chair of Experimental Ophthalmology. “Diabetes causes damage to vascular cells in the retina. This progressive decline in vascular functions relates to depletion of blood vessels, causing a lack of nutrition and oxygen reaching the retina. This is known as ischemia, a kind of stroke, which can cause leakage and abnormal growth of blood vessels.”

Dysfunctional cells

In the first case the patient develops DME, in the second PDR, but both conditions can also occur at the same time. What’s more, blood vessels in the retina are surrounded by glial cells protecting neurons and immune cells. DR also damages them. “All those blood vessels and cells act together as one unit. If one becomes dysfunctional, the whole unit becomes suboptimal. Much research thus focuses on trying to understand what causes dysfunction of this so-called neurovascular unit which eventually leads to loss of blood vessels and retinal neurons,” says Prof. Stitt. “Stopping the early damage to the neurovascular unit could halt the progression of DR to PDR with or without DME.”

The professor believes inflammation is probably behind much of the pathology in DR in a very chronic and progressive manner. “It is not the same as having an acute infection. Inflammation in DR is much more low-key, but over time it becomes a key factor in vascular dysfunction. Novel therapies fighting this inflammation could therefore offer benefits to diabetes patients.”

Hand in hand with current therapies

The current standard of care for PDR and DME is repeated injections with anti-VEGF medicines.  “One result of a lack of oxygen in the retina is an upregulation of hypoxia mediated growth factor. This is an increase in the number of receptors in cells, making them more sensitive to a certain substance. The best known is vascular endothelial growth factor or VEGF,” explains Prof. Stitt. “It has been proven that if you block that growth factor using an antibody, you can effectively prevent the vascular leakage causing DME. Anti-VEGF therapy is very effective but quite intrusive for patients. They must undergo repeated injections or the retinal edema will return. Some patients respond very late, some in a delayed manner and some not at all. This argues in favor of novel therapies that can conform to this current standard of care and improve the outcome for patients.”

Oxurion is researching a PlGF antibody (anti-PlGF, THR-317) in a phase II clinical study for treating DME in persons with diabetes, in combination with anti-VEGF.  “This is a very promising clinical study. It positions very nicely alongside anti-VEGF medicines and potentially can also have anti-inflammatory aspects and protect the neurons in the retina. That would be a major benefit for patients. It might also work for non-responsive patients, or could mean that patients need fewer injections.”

Precision medicine

Prof. Stitt sees a major opportunity in enabling diabetic retinopathy to identify patients responding to anti-VEGF as opposed to non- or late responders. “Ophthalmology lags behind the cancer field in adopting a precision medicine approach. But research is ongoing, and if we could find a way to phenotype patients in a more detailed manner there may be an opportunity to treat non-responding patients with other medicines. For instance, anti-PlGF could potentially offer benefits for the non-responders.”

It is also hard to predict which patient will develop PDR and which will have DME. “There are hallmarks that indicate disease progression, but PDR and DME are often driven by the same ones. Some patients will progress quickly, others very slowly if at all. So therapies that can stop the progression at a very early stage, or novel treatments tackling several hallmarks simultaneously, would also be very advantageous.”

New pathways

Prof. Stitt says the search for therapies to treat DR or DME could also unlock opportunities for other eye diseases. “Diabetes is a pandemic, but another global challenge is definitely the ageing population. People worldwide are living longer so they suffer increasingly from age-related eye diseases like age-related macular degeneration (AMD). It is proven that, similar to PDR, abnormal angiogenesis drives one sub-type of AMD, known as the ‘wet’ form. The larger proportion of AMD patients have the so-called ‘dry’ form which is sometimes called geographic atrophy. In this form of AMD, retinal tissue slowly wastes away due to cell degeneration. The anti-inflammatory and neuroprotective aspects of anti-PlGF could potentially have some efficacy in geographic atrophy. All these aspects could be interesting targets to research.”

Strategic focus of Oxurion

“I believe Oxurion is well positioned to explore all these pathways and find innovative treatments for diseases affecting the back of the eye,” confirms Prof. Stitt. “The company has a strong strategic focus on the retina and long-standing core expertise in that area. It can screen drugs and look for their efficacy in its established preclinical programs. It also has good experience in clinical development, so it can efficiently move from preclinical evidence into early stage clinical trials. Its in-depth focus enables it to detect the added value and market position of new compounds,” concludes Prof. Stitt.

Prof. Alan Stitt
Prof. Alan Stitt

Dean of Innovation & Impact and the McCauley Chair of Experimental Ophthalmology