Therapeutic in development to take on diabetic macular edema

(Image Credit: AdobeStock/littlewolf1989)

With 37 million people in the United States impacted by diabetes, and cases of diabetic macular edema (DME) on the rise, pipelines are primed for the development of new treatment options to combat the disease.

DME results from fluid buildup in the macula, the result of leaky blood vessel walls, causing symptoms like blurry vision and dark spots. Left untreated, the disease can progress to total vision loss, highlighting the need for a prompt diagnosis and early intervention.

David Boyer, MD, Adjunct Clinical Professor of Ophthalmology at the University of Southern California, Keck School of Medicine, participated in the first-in-human study of AG-73305 (Allgenesis), a novel bi-specific fc-fusion protein for the treatment of DME, with the initial focus on safety and efficacy.

Boyer pointed out that even in the age of anti-VEGFs, physicians have continued to see a large number of patients who are not able to reduce all the fluid in the eye. One reason, he explained, is that diabetic macular edema is a multifactorial disease.

“It’s not just VEGF-driven alone,” he said. “Anti-VEGFs was a wonderful addition to a clinician’s treatment option and saved many people’s vision since its introduction.”However, many ophthalmologists will acknowledge that they have patients who receive constant anti-VEGF treatment but do not respond well.

“So I think we're looking at improving that with this drug,” he explained. “We are also looking at extending the interval, as a lot of the patients with diabetic retinopathy are younger patients, they're still in the working age, and they have to take time off from work for treatment. So, this drug was designed to achieve two things: A different mode of action in addition to anti-VEGF to try to improve the overall diabetic macular edema, and to extend treatment intervals so that patients don't have to come in as frequently.”

In the clinical trial (NCT05301751), Boyer noted the goal was to evaluate the safety, tolerability, duration of effect, and the systemic pharmacokinetic (PK) and immunogenicity profile of ascending doses of AG-73305 administered by intravitreal (IVT) injection in patients diagnosed with DME. The researchers also set out to evaluate pharmacodynamic endpoints (e.g., best-corrected visual acuity, or BCVA, and central subfield thickness (CST) by spectral domain optical coherence tomography and OCT-angiography).

The trial looked at both naive as well as previously treated patients. It was designed to see, with a single injection, if there would be any impact on both BCVA as well as on the CST, and how long it would last with only one injection given.

AG-73305 is a bi-specific anti-VEGF and anti-integrin protein, and Boyer noted the dual mechanism of action has provided some interesting results.

“This treats both inflammation and is a strong anti-VEGF, very similar to aflibercept,” he said. “The anti-VEGF contribution was seen very early with immediate improvements. Very striking was the fact that this continued over a long period of time, and I think this is related to the anti-integrins, which takes a little longer to work, but works for a longer duration.”

This bifunctional mechanism of action of AG-73305 provides advantages for patients, explained Boyer. When conventional anti-VEGF monotherapies are used, it wears off, and the patient has to be retreated often. To address this, AG-73305’s anti-integrin domain blocks the interleukins, treats the inflammation and the abnormal items that contribute to the decrease in vision in patients diagnosed with diabetic macular edema, contributing to its prolonged effect.

“Using this combination, you certainly have a 2-prong approach to treating the mode of action that we see, because we know that inflammation plays a major role and anti-VEGF activity does not treat inflammation,” Boyer explained. “And then we also know that the integrins last longer.”

The paired modes of action results in a treatment that leads to an extended interval. During the trial, patients saw an immediate improvement as a result of the anti-VEGF activity, and the drug lasted longer. AG-73305 also could fit in well among the current treatment options.

“It can certainly be a primary treatment; it also can be something that is utilized for its longevity,” Boyer said. “After you initially dry them out, you would continue this treatment, but in much less frequent intervals.”

For patients who have received 2 or 3 injections of conventional anti-VEGFs and are not dry and haven’t seen any real improvements, Boyer said this could ultimately prove to be a viable option.

The next step is to continue along the clinical trial path, with the goal of one day providing a new treatment option for patients diagnosed with DME.

“The goal here is to improve the overall vision and decrease the intervals between treatments,” Boyer said. “So I think AG-73305 can be beneficial to all the ophthalmologists, that we would have a better hammer to be able to get rid of diabetic macular edema, and to the patients who would like not to have to come in to get a shot every 4, 8, or 10 weeks.”

Allgenesis officials told Ophthalmology Times they will continue seeking funding to continue the clinical trials. Once funding is secured to support its work, the company will produce, develop, and refine the product as it enters Phase 2b, which could start in 2025 or early 2026.