Researchers Identify Why Some Don’t Respond to Drugs for AMD

Researchers at Johns Hopkins University have identified a process in the eye that may explain why biologic drugs for treating age-related macular degeneration (AMD) fail in some patients. Using that new knowledge, they developed a new drug that may counteract the interference and boost the effectiveness of those treatments.

The researchers, led by Akrit Sodhi, MD, PhD, reported in the Proceedings of the National Academy of Sciences new findings about the mechanism that leads to increased expression of angiopoietin-like 4 (ANGPTL4) in patients who failed therapy with drugs targeting vascular endothelial growth factor (VEGF). Sodhi and his colleagues identified the protein in aqueous fluid in the front of the eye.

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

In a 2022 study, Sodhi’s group identified ANGPTL4 as a potential culprit in nonresponse to anti-VEGF drugs, which are approved for injections into the eye to halt or slow deterioration of the retina in neovascular, or wet, AMD, as well as diabetic retinal disease and other retinal illnesses.

What Increases ANGPTL4 Expression

Now, Sodhi and his fellow researchers 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 findings on HIF-1-alpha, but this study makes the connection with ANGPTL4.

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

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

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

Potential Treatment

Inhibiting HIF-1-alpha and the downstream expression of ANGPTL4, the study found, could enhance the effectiveness of anti-VEGF therapy.

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

Sodhi said his group collaborated with 2019 Nobel Prize recipient and fellow Johns Hopkins researcher Gregg Semenza, MD, PhD, who initially discovered HIF-1-alpha, to look for an HIF inhibitor alternative to acriflavine. Semenza is a coauthor on the new study.

Sodhi’s research team reported in 2023 that acriflavine showed 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 very effectively promotes degradation of HIF-1-alpha and HIF-2-alpha accumulation,” Sodhi said. “In turn, this results in a decrease in HIF-regulated gene expression, including VEGF and ANGPTL4, and retinal neovascularization and vascular permeability in multiple models of retinal vascular disease.” Unlike acriflavine, he said, 32-134D demonstrated “a remarkably wide therapeutic window.”

Hopkins researchers are further investigating 32-134D in wet AMD and diabetic eye disease, as well as other blinding diseases that do not respond to current treatments, first in larger animals and then, if those studies pan out, in humans, Sodhi said.

At least in mouse models, 32-143D has demonstrated an ability to mediate the “seesaw” between VEGF and ANGPTL4 after anti-VEGF injections in patients who do not respond to therapy, Dunaief said.

“I’d be cautiously optimistic about it,” Dunaief said. “The effectiveness of this HIF inhibitory drug was good; it was better than just blocking VEGF alone, and actually the combination of blocking VEGF and blocking HIF was shown to be the most effective therapy in the mouse model.”

HIF inhibition has the potential to be used alone and in combination with anti-VEGF drugs to treat eye disease, he said.

“The reason I say I’m cautiously optimistic is because any new drug has to be tested for safety, and theoretically blocking HIF could have some toxicity risk,” Dunaief said. “It’s a transcription factor that regulates hundreds of genes, not just VEGF and ANGPTL4, and there may be some deleterious effects that result from targeting HIF.”

Sodhi and Semenza are cofounders and equity holders in HIF Therapeutics, Inc., and inventors on a provisional patent application for 32-143D. Dunaief had no relevant disclosures.

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