Researchers are finding out why some people don't respond to AMD medications

Researchers at Johns Hopkins University have identified a process in the eye that may explain why biologic drugs used to treat age-related macular degeneration (AMD) fail in some patients. Using this new knowledge, they developed a new drug that could counteract the disorders and increase the effectiveness of these treatments.

The researchers, led by Akrit Sodhi, MD, PhD, reported in Proceedings of the National Academy of Sciences new insights into the mechanism leading to increased expression of angiopoietin-like 4 (ANGPTL4) in patients who have failed anti-vascular endothelial growth factor (VEGF) drug therapy. Sodhi and his colleagues identified the protein in the watery fluid in front of the eye.

Despite the introduction of therapies targeting VEGF, fewer than half of all treated patients with wet AMD, the most common cause of severe vision loss in older Americans, benefit from significant improvement in vision, even with strict adherence to monthly intraocular injections of anti- Aging remedies. VEGF therapies, said Sodhi, an associate professor of ophthalmology at the Wilmer Eye Institute at the Johns Hopkins University School of Medicine in Baltimore Medscape Medical News. Most patients lose initial vision gains despite continued treatment, he added.

In a 2022 study, Sodhi's group identified ANGPTL4 as a potential trigger for nonresponse to anti-VEGF drugs approved for injection into the eye to stop retinal deterioration in neovascular or wet AMD, as well as in diabetic retina or to slow diseases and other retinal diseases.

What increases ANGPTL4 expression?

Now Sodhi and his research colleagues have identified the accumulation of a hypoxia-inducible factor 1-alpha (HIF-1-alpha) as a trigger for the expression of ANGPTL4. The group published previous results on HIF-1-alpha, but this study links it to ANGPTL4.

“Expression of a HIF-regulated vasoactive gene, ANGPTL4“works with VEGF to promote the development of choroidal neovascularization and predicts the poor response to anti-VEGF therapy in wet AMD eyes,” said Sodhi.

This study is notable because it clarifies the understanding of the role of HIF-1-alpha in the expression of ANGPTL4, says Joshua Dunaief, MD, PhD, professor of ophthalmology and associate director of research at the Scheie Eye Institute at the University of Pennsylvania in Philadelphia Medscape Medical News.

“It is known that HIF is a protein that is a kind of master regulator of the response to hypoxia,” Dunaief said. “This has been known for a long time. It is known to play a role in AMD, but the specific, exciting finding here is that it mediates this upregulation of ANGPTL4 following inhibition of VEGF.”

Possible treatment

The study found that inhibiting HIF-1-alpha and the downstream expression of ANGPTL4 could improve the effectiveness of anti-VEGF therapy.

The researchers also reported a potential treatment, 32-134D, that disrupted the increase in ANGPTL4 expression after anti-VEGF injections in mouse studies. The results suggest that combining 32-134D with existing anti-VEGF therapies could enhance the response of patients with wet AMD to anti-VEGF treatments, they wrote.

Sodhi said his group worked with 2019 Nobel Prize winner and fellow Johns Hopkins researcher Gregg Semenza, MD, PhD, who originally discovered HIF-1-alpha, to search for a HIF inhibitor alternative to acriflavine. Semenza is a co-author of the new study.

Sodhi's research team reported in 2023 that acriflavine had the potential to prevent the growth of new vessels in the retina, but also had a narrow therapeutic window and caused retinal toxicity. The new molecule appears more promising.

“32-134D is structurally unrelated to acriflavine, but is very effective in promoting the breakdown of HIF-1-alpha and HIF-2-alpha accumulation,” Sodhi said. “This in turn leads to a decrease in HIF-regulated gene expression, including VEGF And ANGPTL4and retinal neovascularization and vascular permeability in multiple models of retinal vascular disease.” Unlike acriflavine, he said, 32-134D “shows a remarkably broad therapeutic window.”

Hopkins researchers continue to study 32-134D in wet AMD and diabetic eye disease and other blinding diseases that do not respond to current treatments, first in larger animals and then, if these studies are successful, in humans, Sodhi said.

At least in mouse models, 32-143D has shown the ability to mediate the “see-saw” between VEGF and ANGPTL4 following anti-VEGF injections in patients who did not respond to therapy, Dunaief said.

“I would be cautiously optimistic,” said Dunaief. “The efficacy of this HIF-inhibiting drug was good; It was better than just blocking VEGF alone, and in fact the combination of blocking VEGF and blocking HIF proved to be the most effective therapy in the mouse model.”

HIF inhibition can be used alone or in combination with anti-VEGF drugs to treat eye diseases, he said.

“The reason I say I'm cautiously optimistic is because any new drug needs to be tested for safety, and blocking HIF could theoretically carry some risk of toxicity,” Dunaief said. “It is a transcription factor that not only regulates hundreds of genes VEGF And ANGPTL4and there may be some deleterious effects resulting from targeted treatment of HIF.”

Sodhi and Semenza are co-founders and shareholders of HIF Therapeutics, Inc. and inventors on a provisional patent application for 32-143D. Dunaief had no relevant information.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.